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Please list the 4 genes involved in Sanfilippo syndrome, also known as mucopolysaccharidosis III (MPS-III). | Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of the four enzymes involved in the catabolism of glycosaminoglycan heparan sulfate. The genes are SGSH, NAGLU, HGSNAT or GNS. | Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a progressive
disorder in which patients are characterized by severe central nervous system
degeneration together with mild somatic disease. MPS III results from a
deficiency in one of the four enzymes involved in the heparan sulfate
degradation, with sulfamidase (SGSH), α-N-acetylglucosaminidase (NAGLU),
acetyl-coenzyme A: α-glucosaminide N-acetyltransferase (HGSNAT), and
N-acetylglucosamine-6-sulfatase (GNS) being deficient respectively in MPS IIIA,
MPS IIIB, MPS IIIC and MPS IIID. Mutation screening using PCR
reaction/sequencing analysis on genomic DNA fragments was performed in seven
Tunisian index cases with MPS IIIA, three with MPS IIIB and two with MPS IIIC.
QMPSF (Quantitative Multiplex PCR of Short fluorescent Fragments) analysis was
developed for the detection of genomic deletions and duplications in the SGSH
gene. These approaches allowed the identification of 11 mutations, 8 of them
were novel including a mutation involving the start codon (p.Met1?), one small
duplication (p.Leu11AlafsX22), one small deletion (p.Val361SerfsX52) and a large
deletion of exon 1 to exon 5 in the SGSH gene, one missense mutation
(p.Pro604Leu) and one nonsense mutation (p.Tyr558X) in the NAGLU gene and,
finally, one missense mutation (p.Trp627Cys) and one nonsense mutation
(p.Trp403X) in the HGSNAT gene. |
What is CardioClassifier? | CardioClassifier (http://www.cardioclassifier.org) is a semiautomated decision support tool for clinical genome interpretation. CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data. | PURPOSE: Internationally adopted variant interpretation guidelines from the
American College of Medical Genetics and Genomics (ACMG) are generic and require
disease-specific refinement. Here we developed CardioClassifier (
http://www.cardioclassifier.org ), a semiautomated decision-support tool for
inherited cardiac conditions (ICCs).
METHODS: CardioClassifier integrates data retrieved from multiple sources with
user-input case-specific information, through an interactive interface, to
support variant interpretation. Combining disease- and gene-specific knowledge
with variant observations in large cohorts of cases and controls, we refined 14
computational ACMG criteria and created three ICC-specific rules.
RESULTS: We benchmarked CardioClassifier on 57 expertly curated variants and
show full retrieval of all computational data, concordantly activating 87.3% of
rules. A generic annotation tool identified fewer than half as many clinically
actionable variants (64/219 vs. 156/219, Fisher's P = 1.1 × 10-18), with
important false positives, illustrating the critical importance of disease and
gene-specific annotations. CardioClassifier identified putatively
disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with
leading ICC laboratories. Through addition of manually curated data, variants
found in over 40% of cardiomyopathy cases are fully annotated, without requiring
additional user-input data.
CONCLUSION: CardioClassifier is an ICC-specific decision-support tool that
integrates expertly curated computational annotations with case-specific data to
generate fast, reproducible, and interactive variant pathogenicity reports,
according to best practice guidelines. |
List clinical disorders or diseases where uc.189 is involved? | Univariate and multivariate Cox regression analysis demonstrated that over-expression of uc.189 predicted poor prognosis in Cervical squamous cell carcinomas (CSCC) and Endometrial adenocarcinomas (EAC). Thus, several findings suggested uc.189 might be an evaluating prognosis marker of gynecological tumors. In addition, high expression of uc.189 might reflect poor prognosis of Esophageal squamous cell carcinoma (ESCC) and indicate a potential diagnostic target in ESCC patients. Uc.189 might be considered as a novel molecule involved in ESCC progression, which provides a potential prognostic biomarker and therapeutic target. | |
Is verubecestat effective for Alzheimer’s Disease? | No. Verubecestat is not effective for treatment of Alzheimer’s Disease. | The amyloid hypothesis has long been the central dogma in drug discovery for
Alzheimer's disease (AD), leading to many small-molecule and biological drug
candidates. One major target has been the β-site
amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma
companies expending great resources in the search for BACE-1 inhibitors. The
lack of efficacy of verubecestat in mild-to-moderate AD raises important
questions about the timing of intervention with BACE-1 inhibitors, and
anti-amyloid therapies in general, in AD treatment. It also suggests new
possibilities for discovering BACE-1-targeted compounds with more complex
mechanisms of actions and improved efficacy. Herein, we review the major
advances in BACE-1 drug discovery, from single-target small molecule inhibitors
to multitarget compounds. We discuss these compounds as innovative tools for
better understanding the complexity of AD and for identifying efficacious drug
candidates to treat this devastating disease. Verubecestat is an inhibitor of β-site amyloid precursor protein cleaving enzyme
1 (BACE1) being evaluated in clinical trials for the treatment of Alzheimer's
disease. Synthetic route development involves diastereoselective transformations
with a need for etiomeric excess (ee) determination of each intermediate and
final active pharmaceutical ingredient (API). The analytical technical package
of validated methods relies on etioselective SFC and RPLC separations using
multiple 3 and 5 μm coated polysaccharide-based chiral stationary phases (CSPs)
and mobile phases combinations. Evaluation of recently developed chiral columns
revealed a single chiral selector (Teicoplanin) bonded to 2.7 μm core-shell
particles using H3PO4 in H2O/ACN and triethylammonium acetate: methanol based
eluents at different isocratic compositions allowed good enatioseparation of all
verubecestat intermediates. EE determination of verubecestat is easily performed
on NicoShell, another macrocyclic glycopeptide chiral selector bonded to 2.7 μm
superficially porous particles. This approach enables fast and reliable
etiopurity analysis of the entire verubecestat synthetic route using only two
chiral columns and mobile phases on a conventional HPLC system, simplifying
technical package preparation, method validation and transfer to manufacturing
facilities. |
What is the role of metalloproteinase-17 (ADAM17) in NK cells? | The metalloproteinase-17 (ADAM17) is involved in CD16A cleavage and acts as a regulatory checkpoint in NK cells | TNF-alpha and its receptors TNFRI and TNFRII are cleaved from the surface of
leukocytes by a proteolytic process referred to as ectodomain shedding. The role
of a disintegrin and metalloproteinase 17 (ADAM17) in this process by the major
professional phagocytes neutrophils and macrophages, the primary producers of
TNF-alpha during inflammation induction, is based entirely on indirect evidence,
and other sheddases have been implicated as well. As Adam17 gene-targeting in
mice is lethal, we assessed the protease's relative contribution to TNF-alpha,
TNFRI, and TNFRII shedding using radiation chimeric mice with leukocytes lacking
functional ADAM17. We report ablated, soluble TNF-alpha, TNFRI, and TNFRII
production by neutrophils and macrophages stimulated with various microbial
antigens and greatly reduced TNF-alpha levels in vivo following inflammation
induction. This is the first simultaneous analysis of TNF-alpha, TNFRI, and
TNFRII shedding by neutrophils and macrophages and the first direct evidence
that ADAM17 is a primary and nonredundant sheddase. ADAM17 (a disintegrin and metalloproteinase 17, also referred to as TNFα
converting enzyme or TACE) is a cell-surface metalloproteinase that regulates
signaling via the epidermal growth factor receptor (EGFR) and has important
roles in diseases such as cancer and rheumatoid arthritis. ADAM17 can be
activated by stimulation of several tyrosine kinase receptors, raising questions
about whether oncogenic tyrosine kinases could also enhance EGFR signaling and
activation of extracellular signal-regulated kinase (ERK) via stimulation of
ADAM17. The main goal of this study was to evaluate the role of Src in
activating ADAM17. We provide evidence that a constitutively active transforming
form of Src, the E378G mutant, as well as v-Src enhance ADAM17-mediated shedding
of the EGFR ligand TGFα. Moreover, we demonstrate that constitutive shedding of
TGFα can be reduced by inhibition of Src in several cell lines, including COS7,
MCF7 (the human breast cancer cell line), PAE (a pig aortic endothelial cell
line) and HaCaT (the human keratinocyte cell line) cells. Src(E378G)-stimulated
shedding of TGFα is abolished in Adam17(-/-) cells, but can be rescued by
wild-type (wt) ADAM17 and a mutant ADAM17 lacking its cytoplasmic domain. These
findings demonstrate that ADAM17 is the principal TGFα sheddase that is
activated by Src in a manner that does not require the cytoplasmic domain of
ADAM17. Finally, we show that stimulation of ADAM17 by Src(E378G) leads to
enhanced paracrine signaling via release of EGFR ligands into the culture
supernatant. These results raise the possibility that activation of ADAM17 by
oncogenic forms of Src can aid in promoting tumorigenesis by enhancing signaling
via the EGFR and ERK in an autocrine and paracrine manner. Enhanced autocrine
signaling could further activate tumor cells expressing oncogenic mutants of
Src, whereas paracrine signaling could stimulate EGFR and ERK signaling in
surrounding non-transformed cells such as stromal cells, thereby contributing to
crosstalk between tumor cells and stromal cells. A disintegrin and metalloproteinase-17 (ADAM17) is a member of the
metalloproteinase superfamily and involved in the cleavage of ectodomain of many
transmembrane proteins. ADAM17 is overexpressed in a variety of human tumors,
which is associated with tumor development and progression. In the present
study, we sought to investigate the expression and function of ADAM17 in
hypoxia-treated hepatocellular carcinoma (HCC) cells. Western blot analysis was
used to measure the expression of ADAM17 in HCC cell lines (Hep3B and HepG2
cells). Annexin V/PI double staining was performed to analyze the effects of
ADAM17 on hypoxia-mediated cisplatin resistance. ADAM17 expression was
upregulated by hypoxia treatment in HCC cells at both mRNA and protein levels.
Overexpression of ADAM17 reduced cisplatin-induced apoptosis in HCC cells,
accompanies by less cleavage of caspase-3 and poly (ADP-ribose) polymerase
(PARP). Forced expression of ADAM17 enhanced the phosphorylation of epidermal
growth factor receptor (EGFR) and Akt without affecting the expression of total
EGFR and Akt. Pretreatment with EGFR inhibitor AG1478 or phosphatidylinositol
3-kinase (PI3K) inhibitor LY294002 rescued ADAM17-mediated cisplatin resistance
of HCC cells. ADAM17 silencing attenuated hypoxia-induced cisplatin resistance
and enhanced the accumulation of cleaved caspase-3 and PARP. Western blot
analysis showed that overexpression of hypoxia-inducible factor-1α (HIF-1α), a
transcription factor, upregulated the expression of ADAM17 and HIF-1α silencing
downregulated the expression of ADAM17 in hypoxia-treated HCC cells, indicating
the regulation of ADAM17 by HIF-1α. Taken together, our results indicated that
ADAM17 is upregulated by hypoxia and contributes to hypoxia-induced cisplatin
resistance via EGFR/PI3K/Akt pathway. Natural killer (NK) cells recognize targets stressed by maligt transformation
or infection and can be long-lived. They become educated by interacting with
major histocompatibility antigen (MHC) class I molecules to gain function to
kill targets and produce cytokines. In the clinic, haploidentical NK cells can
be adoptively transferred to treat cancer. Persistence and in vivo expansion of
NK cells depends on lymphodepleting chemotherapy to make space and induce
release of endogenous IL-15. In vivo expansion is also enhanced by cytokine
administration but IL-2 has the down side of stimulating CD25hi regulatory T
cells (Tregs). Other limitations to NK-cell therapy include poor in vivo
survival and lack of specificity. Bispecific or trispecific killer engagers that
target CD16 on NK cells to enhance recognition of tumor antigens, and
desintegrin and metalloproteinase 17 (ADAM17) inhibition that prevents CD16
shedding after NK-cell activation should promote enhanced killing of cancer with
specificity. These are exciting times; more than 35 years after NK cells were
initially described, we are exploiting their capacity for clinical therapy. Epithelial regeneration is a key process for the recovery from ulcerative
colitis (UC). Here we demonstrate that a disintegrin and metalloproteinase-17
(ADAM17), a main sheddase for tumor necrosis factor (TNF)-α, is essential for
defensive epithelial properties against UC by promoting epithelial cell growth
and goblet cell differentiation in mouse and human. Mice with systemic deletion
of Adam17 developed severe dextran sulfate sodium-induced colitis when compared
to mice with myeloid cell Adam17 deletion or control littermates. ADAM17 was
predomitly expressed by regenerating epithelia in control mice, and its loss
or inhibition attenuated epidermal growth factor receptor (EGFR) activation,
epithelial proliferation, mucus production and barrier functions. Conversely,
ectopic EGFR stimulation promoted epithelial regeneration thereby partially
rescuing the severe colitis caused by ADAM17 deficiency. In UC patients,
epithelial ADAM17 expression positively correlated with both cell proliferation
and goblet cell number. These findings suggest that maintaining ADAM17-EGFR
epithelial signaling is necessary for the recovery from UC and would be
beneficial to therapeutic strategies targeting ADAM17-mediated TNF-α shedding. |
What is the triad of Melkersson-Rosenthal syndrome? | Melkersson-Rosenthal syndrome is an uncommon granulomatous disease characterized by the triad of relapsing facial paralysis, orofacial edema and fissured tongue. | Melkersson-Rosenthal syndrome is a rare condition, classically associated with a
triad of facial and/or lip edema, fissured tongue, and relapsing facial palsy.
This article offers a review of the literature and presents two cases of
Melkersson-Rosenthal syndrome associated with elevated serum levels of
angiotensin converting enzyme in two patients of Thai descent. The Melkersson-Rosenthal syndrome (MRS) is a rare condition characterized by the
triad of familial relapsing peripheral facial palsy, facial edema, and lingua
plicata. Within a well-documented family aggregate of MRS, an index case
simultaneously demonstrated all the elements of the triad, as well as gingival
changes similar to those of cheilitis granulomatosa. When the incomplete or
oligosymptomatic forms are considered, the MRS may be more common than
previously thought. The Melkersson-Rosenthal syndrome is a rare disorder of unknown etiology
characterized by a triad of recurrent orofacial swelling, relapsing facial
paralysis, and fissured tongue. Exacerbations and recurrences are common. The
orofacial swelling is characterized by fissured, reddish-brown, swollen,
nonpruritic lips or firm edema of the face. The facial palsy is
indistinguishable from Bell's palsy. The fissured tongue is seen in one third to
one half of patients and, although the least common manifestation, its presence
assists in diagnosis. The classic triad is not seen frequently in its complete
form; therefore, diagnosis is difficult. This is particularly true because
monosymptomatic and oligosymptomatic variants are seen more commonly. Cheilitis
granulomatosa of Miescher is an example of a monosymptomatic variant of the
Melkersson-Rosenthal syndrome. The histologic findings of noncaseating,
sarcoidal granulomas support the diagnosis. These granulomas are not invariably
present, and their absence does not exclude the diagnosis of the
Melkersson-Rosenthal syndrome. Thus, the Melkersson-Rosenthal syndrome is a
disease with elements of orofacial granulomatosis. Orofacial granulomatosis is a
clinicopathologic entity describing oral lesions with noncaseating granulomas.
The spectrum of this entity includes patients with oral Crohn's disease,
patients with oral lesions who will develop typical bowel symptoms of Crohn's
disease in the ensuing months to years, patients with tooth-associated
infections, patients with sarcoidosis, and patients with food or contact
allergies. The value of the clinicopathologic construct of orofacial
granulomatosis is to provoke the careful search for provocative causes for the
reactive symptom complex of the Melkersson-Rosenthal syndrome. Melkersson-Rosenthal syndrome is a rare disorder consisting of the triad of
persistent or recurrent orofacial edema, relapsing facial paralysis and fissured
tongue. It is far more uncommon to find the complete triad since it generally
presents in oligosymptomatic forms. We present three cases of the
Melkersson-Rosenthal syndrome with the classic triad of symptoms and discuss the
etiology and the clinical and electromyography findings of this syndrome. Melkersson-Rosenthal syndrome (MRS) is characterized by the triad of recurrent
facial palsy, lingua plicata, and facial edema. Herein, we report a case of MRS
associated with Ehlers-Danlos syndrome due to rare presentation. To the best of
our knowledge only one case of MRS associated with Ehlers-Danlos syndrome has
been reported in the literature until now. A triad of facial palsy, facial edema, and furrowed tongue characterizes
Melkersson-Rosenthal syndrome, a rare, noncaseating granulomatous disease of
unknown cause. Although most reported cases of Melkersson-Rosenthal syndrome
involve swelling of the perioral area, the authors present a case of
Melkersson-Rosenthal syndrome involving the periocular area. Because of its
rarity, the syndrome is usually ignored and misdiagnosed; however, the syndrome
should not only be considered in the classic perioral presentation but also in
the rare periocular form, which may be confused with orbital tumors and orbital
pseudotumors. Biopsies should be performed routinely in all patients who present
with eyelid edema of unknown etiology. The physician and surgeon who see
patients with head and neck pathology should be familiar with
Melkersson-Rosenthal syndrome, and with the possibility of its presentation in
the orbit and periocular region. Melkersson-Rosenthal syndrome is an uncommon disorder of uncertain aetiology
characterized by orofacial oedema, facial nerve palsy and lingua plicata. The
triad is seldom seen in its complete form, and oligo-symptomatic or
mono-symptomatic forms are more common. An unusual case of Melkersson-Rosenthal
syndrome involving the left upper eyelid is presented. The pathology, clinical
features and management of this disorder are discussed. The Melkersson-Rosenthal syndrome consists of triad of symptoms: recurrent
oedema of lips, recurrent facial nerve paralysis and lingua plicata. Treatment
is usually symptomatic and required cooperation of different specialists as:
dermatologists, neurologists, dentists, laryngologists, surgeons. A rare case of
Melkersson-Rosenthal syndrome in 49-year-old man was observed in the Clinic of
Dermatology Silesian Medical Academy in Katowice. Melkersson-Rosenthal syndrome is an uncommon disorder characterized by a triad
of facial nerve palsy, orofacial edema, and fissured tongue. A 42-year-old woman
with Melkersson-Rosenthal syndrome presented with painless, nonpitting,
bilateral asymmetric upper eyelid edema. The left eyelid was a bit larger than
the right eyelid. CT and MRI demonstrated periorbital soft tissue thickening
compatible with the microscopic findings of infiltration of lymphocytes, edema,
and cystic dilatation of lymphatic vessels. After treatment by systemic
doxycycline and corticosteroid, she showed some improvement of the eyelid edema.
Isolated bilateral eyelids swelling may be observed in Melkersson-Rosenthal
syndrome. In the case of unexplained nonpitting eyelid edema, biopsy should be
performed. We present a rare case of bilateral crocodile tears syndrome (CTS) in the course
of Melkersson-Rosenthal syndrome. Melkersson-Rosenthal syndrome is characterised
by a triad of recurrent orofacial swelling, relapsing facial paralysis, and
fissured tongue. The classic triad is infrequent and oligosymptomatic variants
are seen more frequently. CTS is a rare complication of facial nerve paralysis
characterised by inappropriate lacrimation on the side of the palsy in response
to salivary stimuli. It results from aberrant reinnervation of the lacrimal
gland by salivary parasympathetic fibres. The therapeutic approach for an acute
bout of Melkersson-Rosenthal syndrome consists mainly of steroid administration.
CTS management is composed of anticholinergic drugs and surgical procedures.
Botulin toxin injection into the lacrimal gland is the most modern therapeutic
option. In the case presented CTS developed in a 50-year-old man after 5
incidents of facial palsy due to Melkersson-Rosenthal syndrome. The case
deserves attention due to the rarity of the observed symptoms and signs. Melkersson-Rosenthal syndrome (MRS) is a rare neuromucocutaneous syndrome marked
by the triad of recurrent nonpitting orofacial edema, fissured dorsal tongue
(lingua plicata), and lower motoneuron facial paralysis. Large case series
including treatment are limited. A retrospective records review was performed
for the diagnoses Melkersson-Rosenthal syndrome, granulomatous cheilitis, and
orofacial granulomatosis, confirmed by noncaseating granulomas on biopsy, at the
Mayo Clinic in Rochester, Minnesota (1979-2009). There were 72 patients [51
women (71 %), mean age at presentation 39 years (range 8-79)] identified with
facial edema with noncaseating granulomas on skin biopsy. Lingua plicata
occurred in 34 cases (47 %, 95 % confidence interval 35.3-59.3 %). Unilateral or
partial facial nerve palsy occurred in 14 cases (19.4, 95 % confidence interval
11.4-30.8 %). Comorbidities among those with facial edema included periodontal
disease (n = 10, 14 %), history of allergic disease (n = 10, 14 %), Crohn's
Disease (n = 6, 8 %), migraine headaches (n = 5, 7 %), and systemic lupus
erythematosus (n = 2, 3 %). There were no patients who had low C1q or C4 levels
among those who were tested. Overall, the full triad canonical of
Melkersson-Rosenthal syndrome was observed in nine patients (seven female,
median age at symptomatic presentation 35 years (range 10-74 years), 13 %, (95 %
confidence interval 6.2-22.9 %) with a median time from first symptoms to
diagnosis of 4 years (range 1-35). The medication treatments attempted in the
nine patients with the full triad of symptoms included non-steroidal
anti-inflammatory drugs, oral and intra-lesional steroids, metronidazole,
dapsone, acyclovir, methotrexate, and thalidomide with no consistent treatment
responses. The Melkersson-Rosenthal syndrome may present over the course of most
of the lifespan and may require several years of observation to be diagnosed.
Neurologists who observe a combination of facial edema and facial palsy in a
patient should consider the diagnosis of MRS and proceed to a diagnostic skin
biopsy and a trial of steroid treatment for their patient. Melkersson-Rosenthal syndrome (MRS) is a rare granulomatous inflammatory disease
characterised by the triad of orofacial oedema, facial nerve palsy and furrowed
tongue. We describe the case of a 29-year-old patient suffering from an
oligosymptomatic form of the disease with orofacial oedema, cobblestone pattern
on the buccal mucosa and swelling of the tongue, accompanied by intermittent
fatigue, influenza-like symptoms, intermittent tinnitus and acute hearing loss.
An increase of several autoimmune-associated antibodies was also detected.
Treatment with prednisolone, azathioprine or methotrexate failed to adequately
control all symptoms in the long term. In the absence of a specific and
well-established therapy for MRS, treatment with adalimumab was administered.
Under adalimumab, total remission of all symptoms was achieved, indicating that
tumour necrosis factor-α blockers are a promising therapeutic option for
patients with Melkersson-Rosenthal syndrome. PURPOSE OF REVIEW: We aim to illustrate the potential viability of MCTD as an
underlying aetiology of Melkersson-Rosenthal syndrome. The case is probably the
first description available in the literature of the Melkersson-Rosenthal as an
early manifestation of mixed connective tissue disease.
RECENT FINDINGS: The Melkersson-Rosenthal syndrome consists of a triad of
recurrent lip and/or face swelling, fissured tongue, and intermittent facial
palsy. Mixed connective tissue disease is a multisystemic disorder with
overlapping features of systemic lupus erythematosus, scleroderma, and
polymyositis, and is differentiated from them by a high titer of antibodies to
ribonucleoprotein. The paper presents a case report of Melkersson-Rosenthal
syndrome with an onset in childhood that derived from vasculitis that turned out
to be an early manifestation of mixed connective tissue disease. We used MRI to
evaluate patient's brain structure and Immunoblot Ena Profil 1 test to test
serum autoantibodies level. The patient has a typical for Melkersson-Rosenthal
syndrome triad of symptoms: bilateral facial nerve palsy, lingua plicata and
facial oedema. Both TC and MRI of the head show no changes as well as laboratory
tests except Anti-SS-A (Anti-Ro) and Anti-RNP autoantibody serum level that was
highly positive. Neurological involvement of the MCTD usually includes,
according to the frequency of the occurrence, trigeminal neuralgia, headaches,
sensorineural hearing, cerebral haemorrhage, transverse myelitis, cauda equina
syndrome, retinal vasculitis, progressive multifocal encephalopathy, and
demyelinating neuropathy. For clinical practice it is important to remember that
Melkersson-Rosenthal syndrome can also be the neurological manifestation of
MCTD, especially when accompanied by other systemic symptoms. Melkersson-Rosenthal syndrome (MRS) is an uncommon granulomatous disease
characterized by the triad of relapsing facial paralysis, orofacial swelling,
and fissured tongue. Genital swelling in MRS is rarely reported. We presented
the first case of complete MRS with genital swelling in a child. Biopsy
examinations of both the child's lower lip and penis showed noncaseating
granuloma and intralymphatic granuloma infiltration. No symptoms or signs of
other systemic disease (Crohn's disease or sarcoidosis) were observed after 2
years of follow-up. Genetic screening for CARD15/NOD2 in this patient showed
negative, which further confirmed the diagnosis of MRS. Eleven other cases of
suspected complete or incomplete MRS with genitalia involved were reviewed. Our
case emphasizes the specific clinical feature of MRS with genitalia involved,
which was genetically different from Crohn's disease and could be an independent
entity. Lymphatic obstruction is responsible for localized edema in MRS. Melkersson Rosenthal Syndrome is a rare neuro-mucocutaneous disorder
characterized by the classic triad of facial swelling, recurrent facial nerve
palsy and fissured tongue. The clinical course is usually progressive, and
etiology is unknown. The authors describe oligosymptomatic Melkersson Rosenthal
Syndrome in a young girl presenting sequentially with recurrent, metachronous
facial nerve palsy and hemifacial swelling in early childhood followed by
fissuring in the tongue in late-childhood. Histopathological examination from
the affected labial area showed non-granulomatous inflammation. Bilateral facial
nerve conduction and blink reflex studies showed asymmetrical affection of both
facial nerves with mixed features of axonal and demyelinating involvement. The
patient remained steroid-refractory, and subsequent attacks remitted with
partial recovery. The combination of facial edema and facial palsy in a child
should alert the physicians to the diagnosis of Melkersson Rosenthal Syndrome. A
diagnostic mucosal biopsy, evaluation for systemic and oro-facial granulomatous
disorders, and short course of corticosteroid treatment are recommended. Melkersson-Rosenthal syndrome (MRS) is a rare syndrome of facial nerve palsy,
facial edema, and lingua plicata that can be difficult to treat. We observed a
patient with MRS of 4 years' duration that was unsuccessfully treated with
multiple therapies. After a variety of diagnoses were considered at outside
institutions, including Bell palsy, we diagnosed the patient with MRS based on
clinical presentation of the classic triad. Treatment with adalimumab, a tumor
necrosis factor α (TNF-α) antibody, showed improvement and relapse-free
progress. Further research is needed regarding the role of TNF-α inhibitors in
managing this rare condition. BACKGROUND AND OBJECTIVE: Melkersson Rosenthal syndrome (MRS) is a rare disorder
of unknown etiology and comprises the triad: orofacial edema, recurrent facial
paralysis and lingua plicata. In the current literature confusing heterogeneity
exists, mixing together the historically grown terms cheilitis granulomatosa or
granulomatous cheilitis, Melkersson Rosenthal syndrome and the umbrella term
Orofacial Granulomatosis (OFG).
METHODS: We provide a systematic review comprising all three disease entities of
orofacial granulomatosis using the computerized database "Pubmed Medline"
entering the keywords "orofacial granulomatosis" (141 references),
"Melkersson-Rosenthal syndrome" (207 references), "granulomatous cheilitis" or
"cheilitis granulomatosa" (102 references) back to 1956. Full-text journals and
case studies were included, and data synthesis was performed individually.
RESULTS: Etiology remains unclear for all three disease entities. Etiological
relatedness to chronic inflammatory bowel disease is under discussion and
effectiveness was found for different treatments, e.g. local triamcinolone
injections, antibiotics, surgical interventions, TNF alpha blockers or exclusive
enteral nutrition. No randomized controlled trial concerning the therapy of
orofacial granulomatosis was found. As a consequence, the therapeutic conclusion
is drawn mainly from small case series, thus limiting the evidence of
therapeutic interventions.
CONCLUSION: OFG with the sub-entities MRS and cheilitis granulomatosa is an
etiological obscure disease process with various possible therapeutic
interventions potentially alleviating the disease course but to broaden
treatment knowledge further study in randomized controlled trials is needed. Author information:
(1)Manchester Centre for Genomic Medicine, Evolution and Genomic Sciences,
University of Manchester, Manchester, UK.
(2)Manchester Centre for Genomic Medicine, Evolution and Genomic Sciences,
University of Manchester, Manchester, UK; Manchester Centre for Genomic
Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust,
Manchester, UK.
(3)Department of Ophthalmology, Inverclyde Royal Hospital, Greenock, PA16 0XN,
UK.
(4)Department of Otolaryngology, Inverclyde Royal Hospital, Greenock, PA16 0XN,
UK.
(5)Manchester Centre for Genomic Medicine, Evolution and Genomic Sciences,
University of Manchester, Manchester, UK; Manchester Centre for Genomic
Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust,
Manchester, UK. Electronic address: [email protected]. |
Is galcanezumab effective for treatment of migraine? | Yes. Galcanezumab is a humanized monoclonal antibody binding calcitonin gene-related peptide that is used for migraine prevention. | Conflict of interest statement: Conflict of Interest Disclosures: Drs
Skljarevski, Oakes, Zhang, Ferguson, Martinez, Camporeale, Johnson, Shan,
Carter, and Schacht are full-time employees of Eli Lilly and Company and/or one
of its subsidiaries, and are stockholders. Dr Goadsby reports receiving
consultant fees from Allergan, Amgen, and Eli-Lilly and Company; and personal
fees from Akita Biomedical, Alder Biopharmaceuticals, Autonomic Technologies
Inc, Avanir Pharma, Cipla Ltd, Colucid Pharmaceuticals, Ltd, Dr Reddy's
Laboratories, eNeura, Electrocore LLC, Novartis, Pfizer Inc, Promius Pharma,
Quest Diagnostics, Scion, Teva Pharmaceuticals, Trigemina Inc; MedicoLegal work,
Journal Watch, UptoDate, and Oxford University Press. In addition, Dr Goadsby
has a patent magnetic stimulation for headache pending assigned to eNeura. Dr
Dodick has received compensation from serving on advisory boards and/or
consulting within the past 5 years for Allergan, Amgen, Alder, Arteaus, Pfizer,
Colucid, Merck, NuPathe, Eli Lilly and Company, Autonomic Technologies, Ethicon
J&J, Zogenix, Supernus, Labrys, Boston Scientific, Medtronic, St Jude,
Bristol-Myers Squibb, Lundbeck, Impax, MAP, Electrocore, Tonix, Novartis, Teva,
Alcobra, Zosano, Insys, GBS/Nocira, Acorda, eNeura, Charleston Laboratories,
Gore, Biohaven, Bioventric, Magellan, Theranica, Xenon, and Dr Reddy’s/Promius
Pharma. Dr Dodick owns equity in Epien, GBS/Nocira, Second Opinion, Healint, and
Theranica. Dr Dodick has received funding for travel, speaking, editorial
activities, or royalty payments from IntraMed, SAGE Publishing, Sun Pharma,
Allergan, Oxford University Press, American Academy of Neurology, American
Headache Society, West Virginia University Foundation, Canadian Headache
Society, HealthLogix, Universal Meeting Management, WebMD, UptoDate, Medscape,
Oregon Health Science Center, Albert Einstein University, University of Toronto,
Starr Clinical, Decision Resources, Synergy, MedNet LLC, Peer View Institute for
Medical Education, Medicom, Chameleon Communications, Academy for Continued
Healthcare Learning, Haymarket Medical Education, Global Scientific
Communications, HealthLogix, Miller Medical, MeetingLogiX, and Wiley Blackwell.
Dr Dodick, through his employer, has consulting use agreements with
NeuroAssessment Systems and Myndshft. He holds board of director positions with
King-Devick Technologies and Epien Inc. He holds the following Patent
17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine
Prophylaxis (no compensation). No other disclosures are reported. Background Safety findings from a Phase 2b study of galcanezumab, a humanized
monoclonal antibody against calcitonin gene-related peptide, for prevention of
migraine (NCT02163993) are reported here. Methods Patients aged 18-65 years with
episodic migraine were evaluated in this multicenter, double-blind, randomized
study. After randomization, 410 patients were administered 5, 50, 120 or 300 mg
of galcanezumab or placebo subcutaneously once every 4 weeks for 12 weeks,
followed by a post-treatment off-drug period lasting 12 weeks. Results
Treatment-emergent adverse events (TEAEs) were primarily rated as mild to
moderate. Serious adverse events reported in galcanezumab dose groups were
appendicitis, Crohn's disease, suicidal ideation, and congenital ankyloglossia
in an infant of a paternal pregcy; each of these were reported by one
patient. Adverse events leading to discontinuation with galcanezumab treatment
were abdominal pain, visual impairment, and upper limb fracture, each reported
by one patient. Treatment-emergent injection-site reactions were reported
significantly more frequently ( p = 0.013) with galcanezumab (13.9%) than with
placebo (5.8%). Injection-site pain was the most common injection-site reaction
(galcanezumab 11.4%; placebo 2.9%, p = 0.004). Upper respiratory tract infection
(galcanezumab 10.0%; placebo 8.8%) and nasopharyngitis (galcanezumab 7.0%;
placebo 2.2%) also occurred more frequently with galcanezumab treatment.
Potential hypersensitivity events were reported at similar frequencies in
galcanezumab (3.3%) and placebo (5.1%) groups. Incidence of treatment-emergent
anti-drug antibodies in galcanezumab dose groups (4.6% of patients during
treatment period) did not appear to have any meaningful effects on safety, the
pharmacokinetics of galcanezumab, or its ability to bind to the target ligand.
Conclusion The results from this 3-month Phase 2b study support the initiation
of larger Phase 3 trials of longer duration. PURPOSE OF REVIEW: Monoclonal antibodies (mAbs) targeting the
calcitonin-gene-related peptide (CGRP) pathway have been developed for episodic
and chronic migraine prevention, either through binding the CGRP ligand
(eptinezumab, fremanezumab, galcanezumab) or the CGRP receptor (erenumab). We
provide an update on published Phase 2 and Phase 3 trials, safety/tolerability
data, pharmacokinetics and mechanism of action of these biologicals.
RECENT FINDINGS: The efficacy data from Phase 2 trials are corroborated by those
from published Phase 3 trials, with a multitude of publications expected in
2018. Review of safety data concluded there was no difference in total adverse
events or main adverse events (including upper respiratory tract infection,
nasopharyngitis, nausea, injection-site pain and back pain) between the mAbs and
placebo injections except apparently for dizziness. The site of action of these
mAbs is not fully elucidated but current insight is that their effect resides in
the periphery; a contribution of central effect(s) can however not be excluded
at present.
SUMMARY: Although efficacy of all four drugs is modest over placebo in episodic
and chronic migraine prevention and overall comparable with available oral
preventive treatments, current tolerability and (short-term) safety data of this
new treatment approach certainly promise a major step forward for migraine
patients. Treatment of migraine is on the cusp of a new era with the development of drugs
that target the trigeminal sensory neuropeptide calcitonin gene-related peptide
(CGRP) or its receptor. Several of these drugs are expected to receive approval
for use in migraine headache in 2018 and 2019. CGRP-related therapies offer
considerable improvements over existing drugs as they are the first to be
designed specifically to act on the trigeminal pain system, they are more
specific and they seem to have few or no adverse effects. CGRP receptor
antagonists such as ubrogepant are effective for acute relief of migraine
headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab
and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine
attacks. As these drugs come into clinical use, we provide an overview of
knowledge that has led to successful development of these drugs. We describe the
biology of CGRP signalling, summarize key clinical evidence for the role of CGRP
in migraine headache, including the efficacy of CGRP-targeted treatment, and
synthesize what is known about the role of CGRP in the trigeminovascular system.
Finally, we consider how the latest findings provide new insight into the
central role of the trigeminal ganglion in the pathophysiology of migraine. The neuropeptide calcitonin gene-related peptide is well established as a key
player in the pathogenesis of migraine. Clinical studies show calcitonin
gene-related peptide levels correlate with migraine attacks, and decreases in
this neuropeptide can indicate antimigraine therapy effectiveness. Research has
revealed a wide distribution of expression sites for calcitonin gene-related
peptide in the central and peripheral nervous system. Of these, the calcitonin
gene-related peptide receptor, which binds calcitonin gene-related peptide with
high affinity, has attracted growing interest as a viable target for
antimigraine therapies. An incentive to pursue such research is the continuing
unmet medical need of patients. Triptans have offered some clinical benefit, but
many patients do not respond and these drugs have important safety
considerations. Initial calcitonin gene-related peptide-focused research led to
development of the "gepant" small-molecule calcitonin gene-related peptide
receptor blockers. Positive efficacy reports concerning the gepants have been
tempered by safety findings which led to the discontinuation of some of these
agents. Currently, there is considerable excitement regarding monoclonal
antibodies against calcitonin gene-related peptide (eptinezumab, galcanezumab,
fremanezumab) and the calcitonin gene-related peptide receptor (erenumab). To
date, these monoclonal antibodies have shown promising efficacy in clinical
trials, with no major safety concerns. If ongoing long-term studies show that
their efficacy can be maintained, this may herald a new era for effective
antimigraine therapies. OBJECTIVE: This meta-analysis was performed to evaluate the efficacy and safety
of monoclonal antibodies against calcitonin gene-related peptide (CGRP) for
episodic migraine prevention.
METHODS: MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched
from inception to April 2018. Studies considered to be eligible were randomized
controlled trials about efficacy and safety of calcitonin gene-related peptide
monoclonal antibody for episodic migraine prevention.
RESULTS: Eight randomized controlled trials involving 2292 patients were
included. The outcomes of this meta-analysis presented that CGRP monoclonal
antibodies for preventive treatment of episodic migraine significantly reduced
the monthly migraine days from baseline [weighted mean difference
(WMD) = - 1.52; 95%CI, - 1.92 to - 1.11; Z = 7.40; P < 0.001] and monthly acute
migraine-specific medication consumption from baseline [WMD = - 1.45; 95%CI,
- 2.17 to - 0.72; Z = 3.93; P < 0.001], as compared with placebo group. CGRP
monoclonal antibodies for preventive treatment of episodic migraine
significantly increased the ≥ 50% reduction from baseline in migraine days per
month [RR = 1.54; 95%CI, 1.38 to1.71; Z = 7.88; P < 0.001]. The adverse events
were similar between the CGRP monoclonal antibody group and placebo group
(P = 0.998). The outcomes of subgroup analysis showed that erenumab,
galcanezumab, and fremanezumab significantly reduced the monthly migraine days
from baseline and increased the ≥ 50% reduction from baseline in migraine days
per month. Both erenumab and fremanezumab significantly reduced from baseline.
CONCLUSIONS: Based on the results of this meta-analysis, CGRP monoclonal
antibodies significantly reduced the monthly migraine days and acute
migraine-specific medication. CGRP monoclonal antibodies were effective and safe
for preventive treatment of episodic migraine. OBJECTIVE: To characterize adult patients with episodic migraine who achieved
100% response to galcanezumab treatment.
BACKGROUND: Galcanezumab is a humanized monoclonal antibody that selectively
binds to the calcitonin gene-related peptide (CGRP) and has demonstrated
efficacy in reducing migraine headache days (MHD) in patients with episodic and
chronic migraine.
METHODS: A post hoc analysis of the proportion of patients with 100% response
(100% reduction from baseline in monthly MHD) was calculated for each month from
pooled data of 2 double-blind, 6-month galcanezumab studies in patients with
episodic migraine (4 to 14 MHD and ≥2 migraine attacks per month at baseline).
The patients were randomized (1:1:2) to monthly subcutaneous galcanezumab,
120 mg (after 240 mg initial loading dose) or 240 mg, or placebo. A generalized
linear mixed model with effects for baseline MHD, treatment, month, and
treatment-by-month interaction was used to estimate the mean monthly response
rate.
RESULTS: The analysis included 1739 patients treated with galcanezumab, 120 mg
(n = 436) or 240 mg (n = 428), or placebo (n = 875). The mean monthly 100%
response rate on an average month in the 6-month double-blind phase was greater
for galcanezumab 120 mg (13.5%) and 240 mg (14.3%) groups vs placebo (5.9%) with
odds ratios of 2.5 (95% confidence interval [CI] 1.9, 3.2) and 2.6 (95% CI 2.0,
3.4), respectively (P < .001). The rate of 100% monthly response increased at
each month over the 6-month double-blind phase with higher rates for
galcanezumab dose groups (9 to 21%) than placebo (2 to 10%) (P < .02).
Evaluation of 100% response by the number of months showed a greater proportion
of galcanezumab-treated patients in either dose group, compared to placebo, were
able to achieve a 100% response (P < .001 up to 3 months); however, though
greater than placebo, few galcanezumab patients had ≥4 months of 100% response
(P < .02). The proportions of patients with 100% response were greatest in the
last 3 months of the treatment. Considering the average number days between
nonconsecutive MHD across the 6-month period (not just during the times of 100%
response), the duration of migraine headache-free periods in the galcanezumab
groups was 29 days for those with at least 1 month of 100% response and 55 days
for those with at least 3 months of 100% response. This gap was approximately 6
to 11 times greater than the mean gap of 5 days observed at baseline.
CONCLUSIONS: More than a third of the patients with episodic migraine treated
with galcanezumab 120 mg or 240 mg achieved 100% response for at least 1 month.
More patients had 100% monthly response in the last 3 months of the 6-month
double-blind period. For those with 100% response for at least 1 month, the
average time between nonconsecutive MHD for the entire treatment period was
nearly 1 month and approached 2 months for patients with 3 or more months of
100% response. BACKGROUND: Galcanezumab, a humanized monoclonal antibody that selectively binds
to the calcitonin gene-related peptide, has demonstrated in previous Phase 2 and
Phase 3 clinical studies (≤6-month of treatment) a reduction in the number of
migraine headache days and improved patients' functioning. This study evaluated
the safety and tolerability, as well as the effectiveness of galcanezumab for up
to 12 months of treatment in patients with migraine.
METHODS: Patients diagnosed with episodic or chronic migraine, 18 to 65 years
old, that were not exposed previously to galcanezumab, were randomized to
receive galcanezumab 120 mg or 240 mg, administered subcutaneously once monthly
for a year. Safety and tolerability were evaluated by frequency of
treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and
adverse events (AEs) leading to study discontinuation. Laboratory values, vital
signs, electrocardiograms, and suicidality were also analyzed. Additionally,
overall change from baseline in the number of monthly migraine headache days,
functioning, and disability were assessed.
RESULTS: One hundred thirty five patients were randomized to each galcanezumab
dose group. The majority of patients were female (> 80%) and on average were
42 years old with 10.6 migraine headache days per month at baseline. 77.8% of
the patients completed the open-label treatment phase, 3.7% of patients
experienced an SAE, and 4.8% discontinued due to AEs. TEAEs with a
frequency ≥ 10% of patients in either dose group were injection site pain,
nasopharyngitis, upper respiratory tract infection, injection site reaction,
back pain, and sinusitis. Laboratory values, vital signs, or electrocardiograms
did not show anyclinically meaningful differences between galcanezumab
dosesOverall mean reduction in monthly migraine headache days over 12 months for
the galcanezumab dose groups were 5.6 (120 mg) and 6.5 (240 mg). Level of
functioning was improved and headache-related disability was reduced in both
dose groups.
CONCLUSION: Twelve months of treatment with self-administered injections of
galcanezumab was safe and associated with a reduction in the number of monthly
migraine headache days. Safety and tolerability of the 2 galcanezumab dosing
regimens were comparable.
TRIAL REGISTRATION: ClinicalTrials.gov as NCT02614287 , posted November 15,
2015. These data were previously presented as a poster at the International
Headache Congress 2017: PO-01-184, Late-Breaking Abstracts of the 2017
International Headache Congress. (2017). Cephalalgia, 37(1_suppl), 319-374. OBJECTIVE: To evaluate the efficacy and safety of galcanezumab, a humanized
monoclonal antibody that selectively binds to calcitonin gene-related peptide,
in the preventive treatment of chronic migraine.
METHODS: A phase 3, randomized, double-blind, placebo-controlled study of
LY2951742 in patients with chronic migraine (Evaluation of Galcanezumab in the
Prevention of Chronic Migraine [REGAIN]) was a phase 3 study with a 3-month
double-blind, placebo-controlled treatment phase and a 9-month open-label
extension. Eligible patients 18 to 65 years of age with chronic migraine were
randomized 2:1:1 to monthly subcutaneous injections of placebo (n = 558),
galcanezumab 120 mg (with a 240-mg loading dose, n = 278), or galcanezumab 240
mg (n = 277). The primary endpoint was the overall mean change from baseline in
the number of monthly migraine headache days (MHDs) during the 3-month
double-blind treatment phase.
RESULTS: Mean number of monthly MHDs at baseline was 19.4 for the total sample.
Both galcanezumab dose groups demonstrated greater overall mean reduction in the
number of monthly MHDs compared to placebo (placebo -2.7, galcanezumab 120 mg
-4.8, galcanezumab 240 mg -4.6) (p < 0.001 for each dose compared to placebo).
There were no clinically meaningful differences between galcanezumab doses and
placebo on any safety or tolerability outcome except for a higher incidence of
treatment-emergent injection-site reaction (p < 0.01), injection-site erythema
(p < 0.001), injection-site pruritus (p < 0.01), and sinusitis (p < 0.05) in the
galcanezumab 240-mg group relative to placebo.
CONCLUSIONS: Both doses of galcanezumab were superior to placebo in reducing the
number of monthly MHDs. Galcanezumab appears efficacious, safe, and well
tolerated for the preventive treatment of chronic migraine.
CLINICALTRIALSGOV IDENTIFIER: NCT02614261.
CLASSIFICATION OF EVIDENCE: This interventional study provides Class I evidence
that galcanezumab is superior to placebo in the reduction of the number of
monthly MHDs. |
Can mitochondria be inherited by both parents in humans? | Yes. A comprehensive exploration of mtDNA segregation in certain families shows biparental mtDNA transmission with an autosomal dominant-like inheritance mode. Although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. | Although there has been considerable debate about whether paternal mitochondrial
DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is
generally believed that mitochondria and mtDNA are exclusively maternally
inherited in humans. Here, we identified three unrelated multigeneration
families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a
total of 17 individuals. Heteroplasmy of mtDNA was independently examined by
high-depth whole mtDNA sequencing analysis in our research laboratory and in two
Clinical Laboratory Improvement Amendments and College of American
Pathologists-accredited laboratories using multiple approaches. A comprehensive
exploration of mtDNA segregation in these families shows biparental mtDNA
transmission with an autosomal domitlike inheritance mode. Our results
suggest that, although the central dogma of maternal inheritance of mtDNA
remains valid, there are some exceptional cases where paternal mtDNA could be
passed to the offspring. Elucidating the molecular mechanism for this unusual
mode of inheritance will provide new insights into how mtDNA is passed on from
parent to offspring and may even lead to the development of new avenues for the
therapeutic treatment for pathogenic mtDNA transmission. |
Can Diazepam be beneficial in the treatment of traumatic brain injury? | Diazepam treatment improved cognitive recovery and mortality in brain injured rats. | Glutamate-mediated excitotoxicity has been shown to contribute to cellular
dysfunction following traumatic brain injury (TBI). Increasing inhibitory
function through stimulation of gamma-aminobutyric acid (GABA(A)) receptors may
attenuate excitotoxic effects and improve outcome. The present experiment
examined the effects of diazepam, a positive modulator at the GABA(A) receptor,
on survival and cognitive performance in traumatically brain-injured animals. In
experiment 1, 15 min prior to central fluid percussion brain injury, rats (n=8
per group) were injected (i.p.) with saline or diazepam (5 mg/kg or 10 mg/kg).
Additional rats (n=8) were surgically prepared but not injured (sham-injury).
Rats pre-treated with the 5 mg/kg dose of diazepam had significantly lower
mortality (0%) than injured, saline-treated rats (53%). Also, diazepam-treated
(5 mg/kg) rats had significantly shorter latencies to reach the goal platform in
the Morris water maze test performed 11-15 days post-injury. In experiment 2, at
15 min post-injury, rats were given either saline (n=5) or 5 mg/kg diazepam
(n=6). Rats treated with diazepam did not differ in mortality from injured rats
treated with vehicle. However, rats treated with diazepam at 15 min post-injury
had significantly shorter latencies to reach the goal platform in the Morris
water maze than injured, vehicle-treated rats. In experiment 3, the post-injury
administration of bicuculline (1.5 mg/kg, n=8), a GABA(A) antagonist, increased
Morris water maze goal latencies compared to injured animals treated with saline
(n=8). These results suggest that enhancing inhibitory function during the acute
post-injury period produces beneficial effects on both survival and outcome
following experimental TBI. |
Name the algorithms for counting multi-mapping reads | RNA-Seq is currently used routinely, and it provides accurate information on gene transcription. However, the method cannot accurately estimate duplicated genes expression. Several strategies have been previously used (drop duplicated genes, distribute uniformly the reads, or estimate expression), but all of them provide biased results. Mmquant is a tool for computing gene expression, including duplicated genes. If a read maps at different positions, the tool detects that the corresponding genes are duplicated; it merges the genes and creates a merged gene. The counts of ambiguous reads is then based on the input genes and the merged genes. Other methods have been developed that use weighted allocation of read counts but these methods treat the different types of multi-reads equivalently. For instance a hierarchical approach was developed for allocation of read counts that first resolves ambiguities among genes, then among isoforms, and lastly between alleles. The model has been implemented in EMASE software (Expectation-Maximization for Allele Specific Expression) to estimate total gene expression, isoform usage and ASE based on this hierarchical allocation. | BACKGROUND: RNA-Seq is currently used routinely, and it provides accurate
information on gene transcription. However, the method cannot accurately
estimate duplicated genes expression. Several strategies have been previously
used (drop duplicated genes, distribute uniformly the reads, or estimate
expression), but all of them provide biased results.
RESULTS: We provide here a tool, called mmquant, for computing gene expression,
included duplicated genes. If a read maps at different positions, the tool
detects that the corresponding genes are duplicated; it merges the genes and
creates a merged gene. The counts of ambiguous reads is then based on the input
genes and the merged genes.
CONCLUSION: mmquant is a drop-in replacement of the widely used tools
htseq-count and featureCounts that handles multi-mapping reads in an unabiased
way. MOTIVATION: Allele-specific expression (ASE) refers to the differential
abundance of the allelic copies of a transcript. RNA sequencing (RNA-seq) can
provide quantitative estimates of ASE for genes with transcribed polymorphisms.
When short-read sequences are aligned to a diploid transcriptome, read-mapping
ambiguities confound our ability to directly count reads. Multi-mapping reads
aligning equally well to multiple genomic locations, isoforms or alleles can
comprise the majority (>85%) of reads. Discarding them can result in biases and
substantial loss of information. Methods have been developed that use weighted
allocation of read counts but these methods treat the different types of
multi-reads equivalently. We propose a hierarchical approach to allocation of
read counts that first resolves ambiguities among genes, then among isoforms,
and lastly between alleles. We have implemented our model in EMASE software
(Expectation-Maximization for Allele Specific Expression) to estimate total gene
expression, isoform usage and ASE based on this hierarchical allocation.
RESULTS: Methods that align RNA-seq reads to a diploid transcriptome
incorporating known genetic variants improve estimates of ASE and total gene
expression compared to methods that use reference genome alignments. Weighted
allocation methods outperform methods that discard multi-reads. Hierarchical
allocation of reads improves estimation of ASE even when data are simulated from
a non-hierarchical model. Analysis of RNA-seq data from F1 hybrid mice using
EMASE reveals widespread ASE associated with cis-acting polymorphisms and a
small number of parent-of-origin effects.
AVAILABILITY AND IMPLEMENTATION: EMASE software is available at
https://github.com/churchill-lab/emase.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online. |
In clinical trials, the H3 R antagonist CEP-26401 has a positive effect on cognition, yes or no? | The H3 R antagonist CEP-26401 had an effect on cognition. | CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3
receptor (H3R) antagonist, with potential therapeutic utility in cognition
enhancement. Two randomized, double-blind, placebo-controlled dose escalation
studies with single (0.02 to 5 mg) or multiple administration (0.02 to 0.5 mg
once daily) of CEP-26401 were conducted in healthy subjects. Plasma and urine
samples were collected to investigate CEP-26401 pharmacokinetics.
Pharmacodynamic endpoints included a subset of tasks from the Cambridge
Neuropsychological Test Automated Battery (CANTAB) and nocturnal
polysomnography. Population pharmacokinetic-pharmacodynamic modeling was
conducted on one CANTAB and one polysomnography parameter of interest. CEP-26401
was slowly absorbed (median tmax range 3-6 hours) and the mean terminal
elimination half-life ranged from 24-60 hours. Steady-state plasma
concentrations were achieved within six days of dosing. CEP-26401 exhibits dose-
and time-independent pharmacokinetics, and renal excretion is a major
elimination pathway. CEP-26401 had a dose-dependent negative effect on sleep,
with some positive effects on certain CANTAB cognitive parameters seen at lower
concentrations. The derived three compartment population pharmacokinetic model,
with first-order absorption and elimination, accurately described the available
pharmacokinetic data. CEP-26401 was generally well tolerated up to 0.5 mg/day
with most common treatment related adverse events being headache and insomnia.
Further clinical studies are required to establish the potential of low-dose
CEP-26401 in cognition enhancement. |
Fecal transplantation is used to treat infection with what bacteria? | Fecal microbiota transplantation is used to treat Clostridium difficile infection | Fecal microbiota transplantation (FMT) is becoming a more widely used technology
for treatment of recurrent Clostridum difficile infection (CDI). While previous
treatments used fresh fecal slurries as a source of microbiota for FMT, we
recently reported the successful use of standardized, partially purified and
frozen fecal microbiota to treat CDI. Here we report that high-throughput 16S
rRNA gene sequencing showed stable engraftment of gut microbiota following FMT
using frozen fecal bacteria from a healthy donor. Similar bacterial taxa were
found in post-transplantation samples obtained from the recipients and donor
samples, but the relative abundance varied considerably between patients and
time points. Post FMT samples from patients showed an increase in the abundance
of Firmicutes and Bacteroidetes, representing 75-80% of the total sequence
reads. Proteobacteria and Actinobacteria were less abundant (< 5%) than that
found in patients prior to FMT. Post FMT samples from two patients were very
similar to donor samples, with the Bacteroidetes phylum represented by a great
abundance of members of the families Bacteroidaceae, Rikenellaceae and
Porphyromonadaceae, and were largely comprised of Bacteroides, Alistipes and
Parabacteroides genera. Members of the phylum Firmicutes were represented by
Ruminococcaceae, Lachnospiraceae, Verrucomicrobiaceae and unclassified
Clostridiales and members of the Firmicutes. One patient subsequently received
antibiotics for an unrelated infection, resulting in an increase in the number
of intestinal Proteobacteria, primarily Enterobacteriaceae. Our results
demonstrate that frozen fecal microbiota from a healthy donor can be used to
effectively treat recurrent CDI resulting in restoration of the structure of gut
microbiota and clearing of Clostridum difficile. GOAL: By systematic review, we assessed the impact of fecal microbiota
transplantation (FMT) for the treatment of Clostridium difficile (CD)-associated
diarrhea.
BACKGROUND: Fecal microbiota microbiota transplantation from a healthy donor
into an individual with CD infection (CDI) can resolve symptoms.
STUDY: We conducted systematic searches in PubMed, SCOPUS, Web of Science, and
Cochrane Library. The last search was run on February 8, 2013. The following
Medical Subject Headings terms and keywords were used alone or in combination:
Clostridium difficile; Clostridium infection; pseudomembranous colitis; feces;
stools; fecal suspension; fecal transplantation; fecal transfer; fecal infusion;
microbiota; bacteriotherapy; enema; nasogastric tube; colonoscopy; gastroscopy;
fecal donation; donor. A critical appraisal of the clinical research evidence on
the effectiveness and safety of FMT for the treatment of patients with
CD-associated diarrhea was made.
RESULTS: Twenty full-text case series, 15 case reports, and 1 randomized
controlled study were included for the final analysis. Almost all patients
treated with donors' fecal infusion experienced recurrent episodes of
CD-associated diarrhea despite standard antibiotic treatment. Of a total of 536
patients treated, 467 (87%) experienced resolution of diarrhea. Diarrhea
resolution rates varied according to the site of infusion: 81% in the stomach;
86% in the duodenum/jejunum; 93% in the cecum/ascending colon; and 84% in the
distal colon. No severe adverse events were reported with the procedure.
CONCLUSIONS: FMT seems efficacious and safe for the treatment of recurrent CDI.
Hospitals should encourage the development of fecal transplantation programs to
improve therapy of local patients. Clostridium difficile infection is one of the most common health care-associated
infections, and up to 40% of patients suffer from recurrence of disease
following standard antibiotic therapy. Recently, fecal microbiota
transplantation (FMT) has been successfully used to treat recurrent C. difficile
infection. It is hypothesized that FMT aids in recovery of a microbiota capable
of colonization resistance to C. difficile. However, it is not fully understood
how this occurs. Here we investigated changes in the fecal microbiota structure
following FMT in patients with recurrent C. difficile infection, and imputed a
hypothetical functional profile based on the 16S rRNA profile using a predictive
metagenomic tool. Increased relative abundance of Bacteroidetes and decreased
abundance of Proteobacteria were observed following FMT. The fecal microbiota of
recipients following transplantation was more diverse and more similar to the
donor profile than the microbiota prior to transplantation. Additionally, we
observed differences in the imputed metagenomic profile. In particular, amino
acid transport systems were overrepresented in samples collected prior to
transplantation. These results suggest that functional changes accompany
microbial structural changes following this therapy. Further identification of
the specific community members and functions that promote colonization
resistance may aid in the development of improved treatment methods for C.
difficile infection.
IMPORTANCE: Within the last decade, Clostridium difficile infection has
surpassed other bacterial infections to become the leading cause of nosocomial
infections. Antibiotic use, which disrupts the gut microbiota and its capability
in providing colonization resistance against C. difficile, is a known risk
factor in C. difficile infection. In particular, recurrent C. difficile remains
difficult to treat with standard antibiotic therapy. Fecal microbiota
transplantation (FMT) has provided a successful treatment method for some
patients with recurrent C. difficile infection, but its mechanism and long-term
effects remain unknown. Our results provide insight into the structural and
potential metabolic changes that occur following FMT, which may aid in the
development of new treatment methods for C. difficile infection. D-lactic acidosis can occur in patients with short bowel syndrome (SBS) when
excessive malabsorbed carbohydrate (CHO) enters the colon and is metabolized by
colonic bacteria to D-lactate. D-lactate can be absorbed systemically, and
increased serum levels are associated with central nervous system toxicity
manifested by confusion, ataxia, and slurred speech. Current therapy, usually
directed toward suppressing intestinal bacterial overgrowth and limiting
ingested CHO, is not always successful. Fecal transplantation, the infusion of
donor feces into a recipient's intestinal tract, has been used for decades to
treat recurrent Clostridium difficile infection, and case reports document its
use in the successful treatment of constipation, diarrhea, and abdominal pain.
The exact mechanism of action is unknown, but it is surmised that the alteration
of the intestinal microbiome, as well as the reintroduction of potential
beneficial microbes, helps mediate disease. Here we present the case of a child
with SBS and recurrent, debilitating D-lactic acidosis, which was successfully
treated with fecal transplantation. OBJECTIVE: To assess the cost-effectiveness of six treatment strategies for
patients diagnosed with recurrent Clostridium difficile infection (CDI) in
Canada: 1. oral metronidazole; 2. oral vancomycin; 3.oral fidaxomicin; 4. fecal
transplantation by enema; 5. fecal transplantation by nasogastric tube; and 6.
fecal transplantation by colonoscopy.
PERSPECTIVE: Public insurer for all hospital and physician services.
SETTING: Ontario, Canada.
METHODS: A decision analytic model was used to model costs and lifetime health
effects of each strategy for a typical patient experiencing up to three
recurrences, over 18 weeks. Recurrence data and utilities were obtained from
published sources. Cost data was obtained from published sources and hospitals
in Toronto, Canada. The willingness-to-pay threshold was $50,000/QALY gained.
RESULTS: Fecal transplantation by colonoscopy dominated all other strategies in
the base case, as it was less costly and more effective than all alternatives.
After accounting for uncertainty in all model parameters, there was an 87%
probability that fecal transplantation by colonoscopy was the most beneficial
strategy. If colonoscopy was not available, fecal transplantation by enema was
cost-effective at $1,708 per QALY gained, compared to metronidazole. In
addition, fecal transplantation by enema was the preferred strategy if the
probability of recurrence following this strategy was below 8.7%. If fecal
transplantation by any means was unavailable, fidaxomicin was cost-effective at
an additional cost of $25,968 per QALY gained, compared to metronidazole.
CONCLUSION: Fecal transplantation by colonoscopy (or enema, if colonoscopy is
unavailable) is cost-effective for treating recurrent CDI in Canada. Where fecal
transplantation is not available, fidaxomicin is also cost-effective. Treatment options for multidrug-resistant (MDR) bacterial infections are limited
and often less effective. Non-pharmacologic approaches to preventing or treating
MDR infections are currently restricted to improved antimicrobial stewardship
and infection control practices. Fecal microbiota transplantation (FMT), a
highly effective treatment for recurrent Clostridium difficile infection, has
emerged as a promising therapy for intestinal MDR bacterial decolonization. A
total of eight case reports have been published showing FMT resulted in
intestinal decolonization of extended spectrum β-lactamase (ESBL)-producing and
carbapenemase-producing Enterobacteriaceae, vancomycin-resistant Enterococci, or
methicillin-resistant Staphylococcus aureus. The procedure has been shown to
work even in immunocompromised patients and those experiencing medical crises
without any adverse events. Five trials are currently underway to further
investigate the use of FMT for MDR bacterial decolonization. FMT is a completely
novel way to eradicate drug-resistant bacteria from the intestinal reservoir and
should be further investigated to address the global problem of
difficult-to-treat, MDR bacterial infections. Bacterial communities from subjects treated for recurrent Clostridium difficile
infection (rCDI) by fecal microbiota transplantation (FMT), using either
heterologous donor stool samples or autologous stool samples, were characterized
by Illumina next-generation sequencing. As previously reported, the success of
heterologous FMT (90%) was superior to that of autologous FMT (43%) (P = 0.019),
and post-FMT intestinal bacterial communities differed significantly between
treatment arms (P < 0.001). Subjects cured by autologous FMT typically had
greater abundances of the Clostridium XIVa clade and Holdemania bacteria prior
to treatment, and the relative abundances of these groups increased
significantly after FMT compared to heterologous FMT and pre-FMT samples. The
typical shift to post-FMT, donor-like assemblages, featuring high relative
abundances of genera within the Bacteroidetes and Firmicutes phyla, was not
observed in the autologous FMT subjects. Autologous FMT patient bacterial
communities were significantly different in composition than those for
heterologous FMT patients and donors (P < 0.001). The SourceTracker program,
which employs a Bayesian algorithm to determine source contributions to sink
communities, showed that patients initially treated by heterologous FMT had
significantly higher percentages of engraftment (i.e., similarity to donor
communities, mean value of 74%) compared to those who suffered recurrence
following autologous FMT (1%) (P ≤ 0.013). The findings of this study suggest
that complete donor engraftment may be not necessary if functionally critical
taxa are present in subjects following antibiotic therapy.
IMPORTANCE: This study provides a detailed characterization of fecal bacterial
communities in subjects who participated in a previously published randomized
clinical trial to treat recurrent C. difficile infection (rCDI). Bacterial
communities were characterized to determine differences between subjects who
received fecal bacteria either from healthy donor stool samples or their own
stool samples as "placebo" in order to determine which groups of bacteria were
most important in achieving a cure. The results of this study suggested that
bacteria associated with secondary bile acid metabolism could potentially
provide resistance to infection and that complete transfer of healthy donor
microorganisms was not necessary to resolve CDI following unsuccessful
antibiotic treatment. Fecal microbiota transplantation is a compelling treatment for recurrent
Clostridium difficile infections, with potential applications against other
diseases associated with changes in gut microbiota. But variability in fecal
bacterial communities-believed to be the therapeutic agent-can complicate or
undermine treatment efficacy. To understand the effects of transplant
preparation methods on living fecal microbial communities, we applied a
DNA-sequencing method (PMA-seq) that uses propidium monoazide (PMA) to
differentiate between living and dead fecal microbes, and we created an analysis
pipeline to identify individual bacteria that change in abundance between
samples. We found that oxygen exposure degraded fecal bacterial communities,
whereas freeze-thaw cycles and lag time between donor defecation and transplant
preparation had much smaller effects. Notably, the abundance of Faecalibacterium
prausnitzii-an anti-inflammatory commensal bacterium whose absence is linked to
inflammatory bowel disease-decreased with oxygen exposure. Our results indicate
that some current practices for preparing microbiota transplant material
adversely affect living fecal microbial content and highlight PMA-seq as a
valuable tool to inform best practices and evaluate the suitability of clinical
fecal material. Conflict of interest statement: CONFLICT OF INTEREST Guarantor of the article:
Alexander Khoruts, MD. Specific author contributions: Christopher Staley:
analysis and interpretation of data; critical revision of the manuscript for
intellectual content; statistical analysis. Matthew J. Hamilton: acquisition of
data; analysis and interpretation of data; critical revision of the manuscript
for intellectual content. Byron P. Vaughn: acquisition of data; critical
revision of the manuscript for intellectual content. Carolyn T. Graiziger:
acquisition of data; technical support. Krista M. Newman: acquisition of data.
Amanda J. Kabage: administrative and technical support. Michael J. Sadowsky:
study concept and design; analysis and interpretation of data; critical revision
of the manuscript for intellectual content; obtained funding; study supervision.
Alexander Khoruts: study concept and design; acquisition of data; analysis and
interpretation of data; drafting the manuscript; obtained funding; study
supervision. Ficial support: The study was supported by grants from the NIH
1R21-AI114722-01 (AK, MJS) to analyze the bacterial composition of the fecal
samples, CIPAC Limited (AK, MJS) to test various parameters for optimization of
microbiota preparation. Additional support for capsule preparation and
collection biological specimens was provided by the philanthropic support of
Achieving Cures Together, Ms. Emily Haller, and the Hubbard Foundation. None of
the sponsors had any roles (other than funding) in the study design, collection,
analysis, interpretation of data, or writing of the manuscript. Potential
competing interests: AK and MJS received research grant support from CIPAC
Limited. MJH, AJK, and MJS provided consulting services to CIPAC Limited and
Crestovo LLC. AK serves on the advisory board for Merck. BPV receives research
salary support from Roche and speaking consulting fees from Janssen and Abbvie.
The remaining authors declare no conflict of interest. The use of fecal microbiota transplantation in recurrent Clostridium difficile
infection and coexistent inflammatory bowel disease remains unclear. A
61-year-old man with ulcerative pancolitis was diagnosed with a third recurrence
of Clostridium difficile infection, previously treated with metronidazole,
vancomycin and fidaxomicin. Fecal microbiota transplantation of an unrelated
healthy donor was performed by the lower route. After a twelve month follow-up,
the patient remains asymptomatic without Clostridium difficile infection
relapses or inflammatory bowel disease flare-ups. Fecal microbiota
transplantation is relatively simple to perform, well-tolerated, safe and
effective in recurrent Clostridium difficile infection with ulcerative
pancolitis, as an alternative in case of antibiotic therapy failure. Rarely, in fulmit Clostridium difficile infection (CDI), the rectal stump is
persistently infected following total abdominal colectomy. We report cure of a
septic patient with proctitis by fecal microbiota transplant via rectal swabs
(mini-FMT). This novel procedure offers a management option for recurrent CDI
following total abdominal colectomy. OBJECTIVES: We aimed to assess the asymptomatic Clostridium difficile carriage
rates following fecal microbiota transplantation (FMT).
METHODS: All patients who underwent FMT for recurrent Clostridium difficile
infection (CDI) via colonoscopy or sigmoidoscopy between June 2013 and April
2015 and had a minimum of 8-week follow-up post FMT at two tertiary care
referral centres were included in the study. Patients were prospectively
followed both clinically and with stool assessments for 8 weeks post FMT.
Assessments occurred at 1 week and 4 weeks post FMT to assess for failure.
Failure was defined as presence of diarrhoeal symptoms and a positive CDI stool
test by polymerase chain reaction for toxin gene (PCR) at any time point during
the 8-week follow-up period. CDI stool testing using PCR was performed at weeks
1 and 4 post FMT in asymptomatic patients as well.
RESULTS: 167 patients were included. Twenty-eight patients (16.7% (28/167)) were
FMT failures throughout the 8-week period. At week 1, seven patients had already
failed the FMT. Of the remaining 160 patients, 144 were asymptomatic, and among
these, 141 were negative for C. difficile toxin gene by PCR. This resulted in an
asymptomatic carriage rate of 2.1% (3/144). At week 4, 143 patients had not yet
failed FMT. Of these patients 129 patients were asymptomatic and among those,
125 were negative by PCR, resulting in an asymptomatic carriage rate of 3%
(3/129).
CONCLUSIONS: Asymptomatic carriage after FMT is rare. This suggests that testing
for cure after FMT in asymptomatic patients is not necessary. Fecal microbiota transplant (FMT) has emerged as a highly efficacious treatment
for difficult cases of refractory and/or recurrent Clostridium difficile
infection (CDI). There have been many well-conducted randomized controlled
trials and thousands of patients reported in case series that describe success
rates of approximately 90% following one or more FMT. Although the exact
mechanisms of FMT have yet to be fully elucidated, replacement or restoration of
a 'normal' microbiota (or at least a microbiota resembling those who have never
had CDI) appears to have a positive effect on the gut dysbiosis that is thought
to exist in these patients. Furthermore, despite being aesthetically
unappealing, this 'ultimate probiotic' is a particularly attractive solution to
a difficult problem that avoids repeated courses of antibiotics. The lack of
clarity about the exact mechanism of action and the 'active ingredient' of FMT
(e.g., individual or communities of bacteria, bacteriophage, or bioactive
molecules such as bile acids) has hindered the ability to produce a standardized
and well-characterized FMT product. There is no standard method to produce
material for FMT, and there are a multitude of factors that can vary between
institutions that offer this therapy. Only a few studies have directly compared
clinical efficacy in groups of patients who have been treated with FMT prepared
differently (e.g., fresh vs. frozen) or administered by different route (e.g.,
by nasojejunal tube, colonoscopy or by oral administration of encapsulated
product). More of these studies should be undertaken to clarify the superiority
or otherwise of these variables. This review describes the methods and protocols
that two English NHS hospitals independently adopted over the same time period
to provide FMT for patients with recurrent CDI. There are several fundamental
differences in the methods used, including selection and testing of donors,
procedures for preparation and storage of material, and route of administration.
These methods are described in detail in this review highlighting differing
practice. Despite these significant methodological variations, clinical outcomes
in terms of cure rate appear to be remarkably similar for both FMT providers.
Although both hospitals have treated only modest numbers of patients, these
findings suggest that many of the described differences may not be critical
factors in influencing the success of the procedure. As FMT is increasingly
being proposed for a number of conditions other than CDI, harmonization of
methods and techniques may be more critical to the success of FMT, and thus it
will be important to standardize these as far as practically possible. |
Is pimavanserin effective for Parkinson's disease psychosis? | Yes. Pimavanserin is effective for treating Parkinson's disease psychosis. It is a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist. | BACKGROUND: Parkinson's disease psychosis, which includes hallucinations and
delusions, is frequent and debilitating in people with Parkinson's disease. We
aimed to assess safety and efficacy of pimavanserin, a selective serotonin
5-HT2A inverse agonist, in this population.
METHODS: In our 6 week, randomised, double-blind, placebo-controlled study, we
enrolled adults (aged ≥40 years) with Parkinson's disease psychosis.
Antipsychotic treatments were not permitted during the study, but controlled
antiparkinsonian medication or deep brain stimulation was allowed. Eligible
participants entered a 2 week non-pharmacological lead-in phase to limit the
placebo response, after which they were randomly allocated (1:1) to receive
pimavanserin 40 mg per day or matched placebo. The primary outcome was
antipsychotic benefit as assessed by central, independent raters with the
Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD)
in all patients who received at least one dose of study drug and had a SAPS
assessment at baseline and at least one follow-up. We assessed safety and
tolerability in all patients who received at least one dose of study drug. This
study is registered with ClinicalTrials.gov, number NCT01174004.
FINDINGS: Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199
patients to treatment groups. For 90 recipients of placebo and 95 recipients of
pimavanserin included in the primary analysis, pimavanserin was associated with
a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference
-3·06, 95% CI -4·91 to -1·20; p=0·001; Cohen's d 0·50). Ten patients in the
pimavanserin group discontinued because of an adverse event (four due to
psychotic disorder or hallucination within 10 days of start of the study drug)
compared with two in the placebo group. Overall, pimavanserin was well tolerated
with no significant safety concerns or worsening of motor function.
INTERPRETATION: Pimavanserin may benefit patients with Parkinson's disease
psychosis for whom few other treatment options exist. The trial design used in
this study to manage placebo response could have applicability to other studies
in neuropsychiatric disease.
FUNDING: ACADIA Pharmaceuticals. Pimavanserin (ACP-103) is a selective inverse agonist of the 5-hydroxytryptamine
2A (5-HT2A) receptor intended to treat patients with Parkinson's disease
psychosis (PDP). Currently there are no FDA-approved medications in the United
States for the treatment of PDP, although on September 2, 2014, the United
States Food and Drug Administration granted breakthrough therapy status to
pimavanserin, highlighting the unmet need for therapeutics in this class. Most
antipsychotic medications worsen motor dysfunction due to dopamine antagonism,
and all carry a black box warning for an increased risk of mortality in elderly
patients with dementia-related psychosis. Data from phase II and phase III
clinical trials suggest that pimavanserin is a safe and effective treatment
option for PDP. Trial results indicate a significant reduction in hallucinations
and delusions in patients with PDP without worsening motor symptoms. Additional
studies are ongoing for the treatment of Alzheimer's psychosis, schizophrenia
and insomnia. Such promising outcomes warrant a review of the available
literature regarding pimavanserin and its use in the treatment of PDP symptoms. Parkinson's disease psychosis (PDP) is a common and often very disturbing
component of Parkinson's disease (PD). PDP consists of hallucinations that are
mainly visual and delusions that are often of a paranoid nature. These symptoms
can be the most troubling and disruptive of all the manifestations of
Parkinson's disease. Current treatment methods include the reduction of
anti-Parkinson's medications, a strategy that may worsen the motor problems the
medications are prescribed to alleviate, and the introduction of selected
antipsychotic medications that carry with them the potential for troubling side
effects and serious consequences. Pimavanserin has been developed and studied in
clinical trials to specifically address Parkinson's disease psychosis and has
been submitted to the U.S. Food and Drug Administration for its approval for
this purpose. If this is granted, we believe the evidence of Pimavanserin
efficacy, safety and tolerability will position this medication as the first
choice for treatment of Parkinson's disease psychosis. INTRODUCTION: Parkinson´s disease (PD) is a synucleinopathy that affects
millions of people worldwide and leads to progressive disability. Psychosis is
highly prevalent in PD patients and is associated with poor prognosis. Until
April 2016, there were no licensed drugs available in the United States of
America (USA) for the treatment of PD psychosis (PDP). Pimavanserin is the first
Food and Drug Administration approved medicine for the treatment of
hallucinations and delusions associated with PDP.
AREAS COVERED: A MEDLINE literature search, publicly available information
provided by ACADIA Pharmaceuticals, and expert opinion were used for this
review. A review of PDP, its current treatment and limitations is followed by
the rationale for development of pimavanserin. The mechanism of action,
preclinical data, pharmacokinetics, pharmacodynamics, and clinical data
supporting the efficacy and safety of pimavanserin in PDP are reviewed. We also
describe the potential benefits of pimavanserin in other contexts such as
schizophrenia and sleep disorders.
EXPERT OPINION: Pimavanserin is an antipsychotic with a unique mechanism of
action (5-HT2A receptor inverse agonist) and no measurable dopaminergic
activity; it has been demonstrated to be efficacious, well tolerated and safe
for the treatment of PDP. The development of pimavanserin as an antipsychotic
represents a major breakthrough in the pharmacotherapy of psychotic symptoms
associated with PD. Parkinson disease psychosis (PDP) is a common phenomenon in Parkinson disease
(PD) patients treated with dopaminergic drugs, and is associated with high
morbidity and mortality. It also correlates with depression and dementia, and
can contribute to considerable caregiver stress and burnout. While symptoms can
be relieved by decreasing doses or number of anti-PD medications, this may lead
to an unacceptable worsening of motor function. When general medical or
psychiatric conditions have been ruled out, and decreasing dopaminergic agents
is not effective in treating psychosis, therapies include atypical
antipsychotics, primarily clozapine and quetiapine. Of these, clozapine is
effective but is associated with a poor side-effect profile and the necessity
for frequent blood draws. Clinicians prefer quetiapine for its theoretically
better safety profile, although there is no evidence for efficacy in treating
psychosis. All atypical antipsychotics are associated with increased mortality
in this patient population. Cholinesterase inhibitors can ameliorate psychosis
symptoms. The serotonin 5-HT2A receptor inverse agonist pimavanserin was
recently approved by the US FDA for the treatment of PDP and may prove to be a
more targeted therapy without the downsides of atypical antipsychotics. OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, and
place in therapy of pimavanserin for the treatment of hallucinations and
delusions of Parkinson's disease psychosis (PDP).
DATA SOURCES: A comprehensive PubMed search (1966 to January 2017) was conducted
using the search terms Parkinson's disease psychosis, hallucinations, delusions,
pimavanserin, and ACP-103. Additional data were obtained from references of
identified articles, governmental sources, manufacturer product labeling and
website, and Clinicaltrials.gov.
STUDY SELECTION AND DATA EXTRACTION: All English-language trials evaluating
pimavanserin in PDP were included. Data from review articles were included if
relevant to clinical practice. One phase II and 3 phase III trials are
discussed.
DATA SYNTHESIS: Pimavanserin was approved in April 2016 for the treatment of
delusions and hallucinations of PDP. One phase II and 2 phase III trials
reported no difference for primary outcomes when pimavanserin was compared with
placebo. The pivotal phase III ACP-103-020 trial adapted a scale to target more
specific symptoms prevalent in PDP and showed that least-squares mean
differences of the total PD-adapted Scale for the Assessment of Positive
Symptoms score were significantly improved for pimavanserin-treated patients as
compared with placebo-treated patients (difference = -3.06; 95% CI [-4.91 to
-1.20]; P = 0.0014]). Pimavanserin's adverse effect profile includes urinary
tract infections, falls, peripheral edema, hallucinations, confusion, nausea,
and headaches.
CONCLUSION: Pimavanserin is a novel 5-HT2A inverse agonist that has shown
promising results for managing hallucinations and delusions in patients with PDP
without worsening motor effects or orthostasis. Yet its high cost and specialty
pharmacy access may limit use in clinical practice. OBJECTIVE: To summarize and evaluate the existing literature regarding
medications to treat Parkinson's disease (PD) psychosis.
DATA SOURCES: MEDLINE (1946 to March 2017), EMBASE (1980 to March 2017), CINAHL
(1982 to March 2017), and PsychInfo (1887 to March 2017) were searched using the
following terms: Parkinson disease, Parkinson's disease, psychotic disorders,
psychosis, delusions, and hallucinations.
STUDY SELECTION AND DATA EXTRACTION: The search was limited to randomized
controlled trials (RCTs) reporting human outcomes. Data extracted included the
following: study design, population, setting, intervention, control, outcomes
related to psychosis and safety, and potential biases assessed using Cochrane
Collaboration's Risk of Bias Assessment Tool.
DATA SYNTHESIS: After assessment, 16 of 235 studies were included; 11 articles
reported comparisons between active drug and placebo, whereas 5 compared
clozapine and an active comparator. Placebo-controlled trials demonstrated
benefit for clozapine (n = 2) and pimavanserin (n = 2), with no firm benefits
observed for quetiapine (n = 4) or olanzapine (n = 3). Comparative studies
demonstrated improved efficacy in symptom scores when clozapine or comparator
agent (n = 2, quetiapine; n = 1, olanzapine; n = 1, risperidone; and n = 1,
ziprasidone) was assessed alone. However, no comparator data suggest that one
agent is better than another, and none are yet available for pimavanserin.
Overall risk of bias across all studies was moderate to high.
CONCLUSIONS: Despite lack of rigor in study designs, published data to date
suggest that clozapine and pimavanserin should be considered drugs of choice to
treat PD psychosis. OBJECTIVE: To summarize the US Food and Drug Administration's (FDA's) review of
the safety and effectiveness for pimavanserin, an atypical antipsychotic, for
the treatment of hallucinations and delusions associated with Parkinson's
disease psychosis. We describe the regulatory and clinical issues important to
the FDA's approval of this New Drug Application, with special focus on the
risk-benefit balance. We also describe a new labeling feature that presents
additional efficacy data to clinicians.
DATA SOURCES: Data sets for all relevant clinical trials of pimavanserin and the
Applicant's and FDA's analyses of these data were considered in this review.
Data were available from 616 patients with Parkinson's disease with
hallucinations and delusions who received at least 1 dose of pimavanserin, with
a total exposure of 825 patient-years in the Parkinson's disease psychosis
population.
RESULTS: Pimavanserin 34 mg/d was effective in treating hallucinations and
delusions associated with Parkinson's disease. In the Applicant's single pivotal
trial, 80.5% of pimavanserin patients experienced at least some improvement in
symptoms compared to 58.1% of patients taking placebo. Pimavanserin did not
worsen motor function, an adverse effect commonly observed with other
antipsychotics, probably because of a lack of consequential dopamine binding.
CONCLUSIONS: Pimavanserin is the only FDA-approved treatment for the
hallucinations and delusions seen in patients with psychosis of Parkinson's
disease. Although pimavanserin appears to have a pharmacologic mechanism that is
different from other atypical antipsychotics, concern remained that the
increased risk of death seen with antipsychotic use in elderly demented
patients, and described in all approved antipsychotic labels, would also occur
with pimavanserin. Pimavanserin bears the same boxed warning about the risk of
death associated with antipsychotic use in elderly patients with dementia. Pimavanserin, a 5-HT2A inverse agonist, was commercially released in the United
States in April 2016 for the treatment of Parkinson disease psychosis. No
"naturalistic" treatment results have yet been published. Charts from the
movement disorders clinic were reviewed for all patients who received this drug
as treatment for psychosis associated with primary parkinsonism due to
α-synucleinopathies. Data of 10 patients with idiopathic Parkinson disease,
including 1 with a long history of schizophrenia, 4 with dementia with Lewy
bodies, and 1 with multiple-system atrophy, were reviewed. There were no adverse
events reported. Ten patients improved and continue on the drug, whereas 5
stopped because of lack of benefit. Clozapine is an effective drug for treating psychosis in Parkinson's disease
(PDP) and is registered as such in the Netherlands. However, clozapine can have
adverse effects, including agranulocytosis. The new drug pimavanserin was
recently registered in the United States for the treatment of PDP.<br/> AIM: To
review the literature on pimavanserin and discuss the position it currently
occupies in the Netherlands as a potential treatment for PDP.<br/> METHOD:
Systematic search of the literature.<br/> RESULTS: We found reports on four
randomised controlled trials (RCTs), one review and six articles about the
pharmacokinetics and pharmacodynamics of pimavanserin. Pimavanserin is an
effective treatment for PDP, and, like clozapine, it has very few negative
effects on motor skills. However, all of the RCTs were funded by the
manufacturer of pimavanserin and the trials were conducted in a very selective
patient population. This means that results cannot be generalised. Long-term
results are not yet available. In earlier trials clozapine was shown to have a
greater and faster antipsychotic effect. Many clinicians and psychiatrists have
a great deal of experience with this drug. Another important point is that
no-one has yet conducted a trial comparing clozapine and pimavanserin.<br/>
CONCLUSION: Given that the current second drug of choice, namely quetiapine, has
not been found to be effective for PDP, we are of the opinion that - if
pimavanserin is registered in the Netherlands - pimavanserin could be used when
the current drug of choice, clozapine, is not completely effective or is poorly
tolerated. For patients who have cognitive impairments in addition to psychosis,
we advise testing the patient's reaction to a cholinesterase inhibitor before
starting the patient on a course of antipsychotics. Pimavanserin is the first FDA-approved atypical antipsychotic drug indicated for
the treatment of hallucinations and delusions associated with Parkinson's
disease psychosis (PDP). Areas covered: This review focuses on the preclinical
discovery of pimavanserin. It analyzes the pharmacological, behavioral and
molecular mechanisms of pimavanserin and their contribution to the therapeutic
advantages of the drug as reported in published preclinical and clinical
studies, press releases and product labels. Expert opinion: Pimavanserin
exhibits a unique pharmacological profile with omolar affinity at serotonin
5-HT2A and 5-HT2C receptors. Functionally, it acts as a potent inverse agonist
at 5-HT2A receptors, with selectivity over 5-HT2C receptors and no appreciable
activity at other neurotransmitter receptors. Behavioral studies found that
pimavanserin reversed impaired behaviors in animal models predictive of
antipsychotic activity, and with no impairment of motor functions. The drug
exhibits long plasma half-life (57 hours), which support its once/day
administration. A pivotal phase III clinical trial demonstrated significant
improvement in PDP symptoms in patients receiving pimavanserin compared to
placebo-treated patients. The drug also displayed relatively benign safety and
tolerability profiles. Pimavanserin's mechanism of action might contribute to
its unique psychopharmacological properties in the improved treatment of PDP,
and perhaps psychosis in other diseases including schizophrenia and
dementia-related psychosis. OBJECTIVE: Our aim was to describe the efficacy and tolerability of
pimavanserin, a highly selective serotonin 5-HT2A receptor inverse
agonist/antagonist indicated for the treatment of hallucinations and delusions
associated with Parkinson's disease psychosis (PDP), using the metrics of number
needed to treat (NNT) and number needed to harm (NNH).
METHODS: Categorical efficacy and tolerability data were extracted from the
clinical trial databases of the double-blind placebo-controlled studies of
pimavanserin in persons with PDP. NNT and NNH values were calculated with their
respective 95% confidence intervals. The likelihood to be helped or harmed (LHH)
was then calculated contrasting therapeutic response versus discontinuation
because of an adverse event.
RESULTS: NNT values for pimavanserin 34 mg/d versus placebo for several
definitions of clinical response are 10, and/or are not statistically
significant, and/or show an advantage for pimavanserin over placebo (such as for
postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times
more likely to result in clinical response (as measured by a ≥3 point decrease
from baseline on the Scale for the Assessment of Positive Symptoms adapted for
Parkinson's disease) versus discontinuation due to an adverse event.
CONCLUSIONS: Using the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for
the treatment of PDP appears to have a compelling benefit/risk profile. RATIONALE: Pimavanserin, a selective serotonin 2A receptor inverse agonist, is a
promising candidate for treating Parkinson's disease psychosis. Our previous
study revealed that there might be the presence of extensive metabolites of
pimavanserin in rats. However, the metabolic fate of pimavanserin in vivo
remains unknown. Thus, it is essential to develop an efficient method to
investigate the metabolic profile of pimavanserin in rats. Fourier transform ion
cyclotron resoce mass spectrometry (FT-ICR-MS) to date has the highest mass
measurement accuracy and resolution of any mass spectrometry platform.
METHODS: After a single intragastric administration of pimavanserin at a dose of
50 mg kg-1 , plasma, bile, urine and feces were collected from rats. A novel and
efficient strategy was developed to analyze the metabolic profile of
pimavanserin in vivo based on ultrahigh-performance liquid chromatography
(UHPLC) coupled with FT-ICR-MS.
RESULTS: A total of 23 metabolites were detected and tentatively identified
through comparing their mass spectrometry profiles with those of pimavanserin.
These metabolites were found in feces (22), bile (21), rat urine (16) and plasma
(15). Results demonstrated that metabolic pathways of pimavanserin in rats
included dehydrogenation, demethylation, deethylation, depropylation,
debutylation, hydroxylation, dihydroxylation and trihydroxylation.
CONCLUSIONS: A total of 22 phase I metabolites of pimavanserin were detected and
tentatively identified. This report presents the first study of screening and
identification of the metabolites of pimavanserin. The UHPLC/FT-ICR-MS method is
a powerful tool for exploring and identifying metabolites in complex biological
samples. PURPOSE OF REVIEW: In April 2016, the Food and Drug Administration (FDA)
approved a first-in-class atypical antipsychotic medication called pimavanserin
for the treatment of Parkinson disease psychosis (PDP). We aim to inform readers
about its indications, effectiveness, and safety profile.
RECENT FINDINGS: Pimavanserin acts as an inverse agonist at serotonin 5-HT2A
receptors and has negligible effects on other receptors, thereby avoiding the D2
receptor antagonism that can potentially worsen motor symptoms. Its FDA approval
was based primarily on the results of a single randomized, placebo-controlled
phase 3 trial.
SUMMARY: While pimavanserin appears to be a safe, effective, and well-tolerated
therapeutic option for PDP, additional clinical trials and open-label extension
studies are needed to determine the long-term safety and efficacy of this
promising therapy. In the meantime, prescribers need to be aware of the possible
adverse effects of pimavanserin including QT interval prolongation and a
potential to cause a paradoxical worsening of symptoms. Syndromes of delusional misidentification consist of disordered familiarity and
have been reported in diverse diagnoses, including Parkinson's disease. Although
the most common delusional misidentification is Capgras syndrome, in which the
sufferer believes a familiar person has been replaced by an identical imposter,
other forms have been also described. The pathogenesis of delusions of
misidentification appears to require dysfunction of or connection to a left
cerebral cortical area involved in recognition of familiarity, and also right
frontal cortex serving belief evaluation. Two cases of Parkinson's disease with
an unusual delusional misidentification, intermetamorphosis, are presented,
along with their improvement with pimavanserin, a novel atypical antipsychotic
medication. Objective: Pimavanserin is the first United States Food and Drug Administration
(FDA)-approved treatment for Parkinson's disease psychosis (PDP). This article
reviews the safety, efficacy, and pharmacology data for pimavanserin and its
role in therapy. Method of Research: Initial literature sources were identified
via MEDLINE search (1946-September 2016) of pimavanserin and ACP-103 (original
molecular designation). Reference review and search of FDA.gov and
clinicaltrials.gov yielded additional studies. English-language studies of
pimavanserin for PDP were evaluated. Animal studies were excluded. Randomized,
controlled trials (RCTs) were prioritized. Results: Four RCTs were identified.
In each, pimavanserin was well-tolerated with few adverse effects and no
worsening of motor symptoms. A Phase II trial displayed a nonsignificant trend
toward Scale for Assessment of Positive Symptoms (SAPS) improvement (p=0.09),
with significant benefits in secondary efficacy markers. However, two Phase III
trials, including one that was terminated early, failed to show significant SAPS
improvement. A third Phase III trial with an improved research design utilized a
nine-item subset of the SAPS, the SAPS-PD, as the primary outcome and
demonstrated that pimavanserin 40mg was effective in improving PDP compared to
placebo (p=0.0014, effect size=0.50). Secondary outcomes were also significantly
improved: Clinical Global Impression of Severity (CGI-S) (p=0.0007, effect
size=0.52) and Clinical Global Impression of Improvement (CGI-I) (p=0.0011,
effect size=0.51), caregiver burden (p=0.0016, effect size=0.50), nighttime
sleep (p=0.0446, effect size=0.31), and daytime wakefulness (p=0.012, effect
size=0.39). Conclusion: Evidence suggests pimavanserin attenuates PDP symptoms
with few adverse effects and little risk of worsening motor function. With
limited treatment options for PDP, pimavanserin represents an important
therapeutic innovation. INTRODUCTION: Pimavanserin (Nuplazid™) is an atypical antipsychotic currently
indicated for the treatment of hallucinations and delusions associated with
Parkinson disease psychosis. The antipsychotic effects of this new agent are
believed to occur via selective inverse agonist activity at serotonin 5-HT2a
receptors.
METHODS: Study authors completed a literature review of 2 published randomized
controlled trials of pimavanserin for the treatment of Parkinson disease
psychosis. The Food and Drug Administration Briefing Document by the
Psychopharmacologic Drugs Advisory Committee for the review of pimavanserin
dated March 29, 2016, was reviewed for additional information on 2 unpublished
trials.
RESULTS: Pimavanserin has demonstrated no worsening of motor symptoms of
Parkinson disease, but only 1 of 4 trials has shown consistent statistically
significant improvements in psychotic symptoms compared with placebo.
DISCUSSION: Options for the treatment of Parkinson disease psychosis are
limited. The selective receptor profile of pimavanserin offers advantages for
tolerability. Further studies are warranted to better provide clinicians and
patients with information regarding the clinical utility of this agent. Psychosis is common across dementia types with a prevalence of 20% to 70%.
Currently, no pharmacologic treatment is approved for dementia-related
psychosis. Atypical antipsychotics are frequently used to treat these disorders,
despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse
agonist/antagonist, was approved in the U.S. for treating hallucinations and
delusions associated with Parkinson's disease psychosis (PDP). Patients in the
pimavanserin group experienced a significant (p=0.001) improvement in Scale for
the Assessment of Positive Symptoms - Parkinson's disease (SAPS-PD) scores vs.
placebo. In a subgroup analysis of patients with cognitive impairment (MMSE
score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin
(N=50) was also significant (p=0.002) and larger than in the overall study
population without an adverse effect on cognition. In a Phase 2 study with
pimavanserin in Alzheimer's disease psychosis, pimavanserin significantly
(p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score
(PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a
substantively larger treatment effect (p=0.011) was observed vs. participants
with NPI-NH PS <12. The results of these studies in cognitively impaired
patients with PDP provided the scientific foundation for an ongoing study of
pimavanserin for treating patients with dementia-related psychosis associated
with the most common neurodegenerative disorders. The study uses a
relapse-prevention design with the endpoint of time-to-relapse of psychosis to
evaluate the long-term efficacy and safety of pimavanserin as a potential
treatment for hallucinations and delusions of dementia-related psychosis. |
When did delafloxacin receive its first approval in the USA for acute bacterial skin and skin structure infections? | Delafoxacin received approval in the USA for the treatment of acute bacterial skin and skin structure infections in 2017. | Delafloxacin (Baxdela™) is a fluoroquinolone antibacterial with activity against
both gram-positive and gram-negative pathogens being developed by Melinta
Therapeutics. The drug is being investigated or considered as a treatment for
various bacterial infections and in June 2017 received approval in the USA for
the treatment of acute bacterial skin and skin structure infections. This
article summarizes the milestones in the development of delafloxacin leading to
this first global approval for the treatment of acute bacterial skin and skin
structure infections. |
Erenumab, used to treat migraine headaches, binds to what protein? | Erenumab binds to the CGRP receptor to treat migraine headaches | Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP)
signaling are being explored as prophylactic treatments for migraine. Erenumab
(AMG 334) is the first potent, selective, and competitive human mAb antagonist
of the CGRP receptor. We report the data from two phase I studies assessing the
safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple
administrations of erenumab in healthy subjects and patients with migraine. The
results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg
and the linear portion of the clearance from 70 mg to 210 mg is consistent with
other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in
>75% inhibition of capsaicin-induced dermal blood flow, with no apparent
dose-dependency for erenumab ≥21 mg. Erenumab was generally well tolerated, with
an acceptable safety profile, supporting further clinical development of
erenumab for migraine prevention. BACKGROUND: We tested erenumab, a fully human monoclonal antibody that inhibits
the calcitonin gene-related peptide receptor, for the prevention of episodic
migraine.
METHODS: We randomly assigned patients to receive a subcutaneous injection of
either erenumab, at a dose of 70 mg or 140 mg, or placebo monthly for 6 months.
The primary end point was the change from baseline to months 4 through 6 in the
mean number of migraine days per month. Secondary end points were a 50% or
greater reduction in mean migraine days per month, change in the number of days
of use of acute migraine-specific medication, and change in scores on the
physical-impairment and everyday-activities domains of the Migraine Physical
Function Impact Diary (scale transformed to 0 to 100, with higher scores
representing greater migraine burden on functioning).
RESULTS: A total of 955 patients underwent randomization: 317 were assigned to
the 70-mg erenumab group, 319 to the 140-mg erenumab group, and 319 to the
placebo group. The mean number of migraine days per month at baseline was 8.3 in
the overall population; by months 4 through 6, the number of days was reduced by
3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as
compared with 1.8 days in the placebo group (P<0.001 for each dose vs. placebo).
A 50% or greater reduction in the mean number of migraine days per month was
achieved for 43.3% of patients in the 70-mg erenumab group and 50.0% of patients
in the 140-mg erenumab group, as compared with 26.6% in the placebo group
(P<0.001 for each dose vs. placebo), and the number of days of use of acute
migraine-specific medication was reduced by 1.1 days in the 70-mg erenumab group
and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the
placebo group (P<0.001 for each dose vs. placebo). Physical-impairment scores
improved by 4.2 and 4.8 points in the 70-mg and 140-mg erenumab groups,
respectively, as compared with 2.4 points in the placebo group (P<0.001 for each
dose vs. placebo), and everyday-activities scores improved by 5.5 and 5.9 points
in the 70-mg and 140-mg erenumab groups, respectively, as compared with 3.3
points in the placebo group (P<0.001 for each dose vs. placebo). The rates of
adverse events were similar between erenumab and placebo.
CONCLUSIONS: Erenumab administered subcutaneously at a monthly dose of 70 mg or
140 mg significantly reduced migraine frequency, the effects of migraines on
daily activities, and the use of acute migraine-specific medication over a
period of 6 months. The long-term safety and durability of the effect of
erenumab require further study. (Funded by Amgen and Novartis; STRIVE
ClinicalTrials.gov number, NCT02456740 .). PURPOSE OF REVIEW: Monoclonal antibodies (mAbs) targeting the
calcitonin-gene-related peptide (CGRP) pathway have been developed for episodic
and chronic migraine prevention, either through binding the CGRP ligand
(eptinezumab, fremanezumab, galcanezumab) or the CGRP receptor (erenumab). We
provide an update on published Phase 2 and Phase 3 trials, safety/tolerability
data, pharmacokinetics and mechanism of action of these biologicals.
RECENT FINDINGS: The efficacy data from Phase 2 trials are corroborated by those
from published Phase 3 trials, with a multitude of publications expected in
2018. Review of safety data concluded there was no difference in total adverse
events or main adverse events (including upper respiratory tract infection,
nasopharyngitis, nausea, injection-site pain and back pain) between the mAbs and
placebo injections except apparently for dizziness. The site of action of these
mAbs is not fully elucidated but current insight is that their effect resides in
the periphery; a contribution of central effect(s) can however not be excluded
at present.
SUMMARY: Although efficacy of all four drugs is modest over placebo in episodic
and chronic migraine prevention and overall comparable with available oral
preventive treatments, current tolerability and (short-term) safety data of this
new treatment approach certainly promise a major step forward for migraine
patients. Treatment of migraine is on the cusp of a new era with the development of drugs
that target the trigeminal sensory neuropeptide calcitonin gene-related peptide
(CGRP) or its receptor. Several of these drugs are expected to receive approval
for use in migraine headache in 2018 and 2019. CGRP-related therapies offer
considerable improvements over existing drugs as they are the first to be
designed specifically to act on the trigeminal pain system, they are more
specific and they seem to have few or no adverse effects. CGRP receptor
antagonists such as ubrogepant are effective for acute relief of migraine
headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab
and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine
attacks. As these drugs come into clinical use, we provide an overview of
knowledge that has led to successful development of these drugs. We describe the
biology of CGRP signalling, summarize key clinical evidence for the role of CGRP
in migraine headache, including the efficacy of CGRP-targeted treatment, and
synthesize what is known about the role of CGRP in the trigeminovascular system.
Finally, we consider how the latest findings provide new insight into the
central role of the trigeminal ganglion in the pathophysiology of migraine. The neuropeptide calcitonin gene-related peptide is well established as a key
player in the pathogenesis of migraine. Clinical studies show calcitonin
gene-related peptide levels correlate with migraine attacks, and decreases in
this neuropeptide can indicate antimigraine therapy effectiveness. Research has
revealed a wide distribution of expression sites for calcitonin gene-related
peptide in the central and peripheral nervous system. Of these, the calcitonin
gene-related peptide receptor, which binds calcitonin gene-related peptide with
high affinity, has attracted growing interest as a viable target for
antimigraine therapies. An incentive to pursue such research is the continuing
unmet medical need of patients. Triptans have offered some clinical benefit, but
many patients do not respond and these drugs have important safety
considerations. Initial calcitonin gene-related peptide-focused research led to
development of the "gepant" small-molecule calcitonin gene-related peptide
receptor blockers. Positive efficacy reports concerning the gepants have been
tempered by safety findings which led to the discontinuation of some of these
agents. Currently, there is considerable excitement regarding monoclonal
antibodies against calcitonin gene-related peptide (eptinezumab, galcanezumab,
fremanezumab) and the calcitonin gene-related peptide receptor (erenumab). To
date, these monoclonal antibodies have shown promising efficacy in clinical
trials, with no major safety concerns. If ongoing long-term studies show that
their efficacy can be maintained, this may herald a new era for effective
antimigraine therapies. Amgen and Novartis are developing erenumab (AIMOVIG™, erenumab-aooe)-a fully
human monoclonal antibody calcitonin gene-related peptide (CGRP) receptor
antagonist-for the prevention of migraine. CGRP is a vasodilatory neuropeptide
implicated in the pathophysiology of migraine and treatment with erenumab was
associated with significant reductions in migraine frequency in phase II and III
clinical trials. Based on these positive results erenumab was recently approved
in the US for the preventive treatment of migraine in adults and has received a
positive opinion in the EU for the prophylaxis of migraines in adults who have
at least 4 migraine days per month. This article summarizes the milestones in
the development of erenumab leading to this first approval. PURPOSE OF REVIEW: This article reviews the preventive therapy of migraine,
including indications, strategies for use, and available treatments.
RECENT FINDINGS: Lifestyle modifications and migraine trigger avoidance are
recommended as preventive measures for all individuals with migraine. The
decision to recommend additional migraine preventive therapy should consider the
frequency of migraine attacks and headaches, extent of migraine-associated
disability, frequency of using acute migraine treatments and the responsiveness
to such treatments, and patient preferences. Additional therapies include
prescription medications, nutraceuticals, neurostimulation, and behavioral
therapy. Considering evidence for efficacy and the risk of potential side
effects and adverse events, treatments with the most favorable profiles include
(in alphabetical order): amitriptyline, beta-blockers (several), biofeedback,
candesartan, coenzyme Q10, cognitive-behavioral therapy, magnesium citrate,
onabotulinumtoxinA (for chronic migraine only), relaxation therapy, riboflavin,
and topiramate. In addition, erenumab, a calcitonin gene-related peptide (CGRP)
receptor monoclonal antibody, received approval from the US Food and Drug
Administration (FDA) for the prevention of migraine in May 2018.
SUMMARY: Successful migraine preventive therapy reduces the frequency and burden
of attacks while causing limited side effects. Individual treatment
recommendations are determined based upon evidence for efficacy, side effect and
adverse event profiles, medication interactions, patient comorbidity, costs, and
patient preferences. Patients must be counseled on reasonable expectations for
their preventive therapy and the importance of adhering to the recommended
treatment plan for a period of time that is sufficient to determine outcomes. Background We evaluated the effect of erenumab, a fully human monoclonal
antibody that inhibits the canonical calcitonin gene-related peptide receptor,
on migraine-related disability, impact, and health-related quality of life among
patients with episodic migraine. Methods Patients enrolled in a phase 3,
6-month, double-blind, placebo-controlled study of once-monthly erenumab 70 and
140 mg for migraine prevention (STRIVE) used an eDiary during the baseline and
double-blind treatment phases to complete validated, specific questionnaires,
including the modified (monthly) Migraine Disability Assessment Questionnaire;
Headache Impact Test; and Migraine-Specific Quality of Life Questionnaire-role
function-restrictive (MSQ-RFR), -role function-preventive (MSQ-RFP), and
-emotional function (MSQ-EF). Results A total of 955 patients were randomized to
receive erenumab 70 mg (n = 317), erenumab 140 mg (n = 319), or placebo
(n = 319). Erenumab versus placebo resulted in significantly greater
improvements in all patient-reported outcomes; changes from baseline were
numerically higher with 140 mg erenumab. Improvements occurred rapidly and were
maintained over 6 months of treatment. Between-group differences from placebo
over months 4-6 for the 70- and 140-mg dose groups were, respectively, -2.1 and
-2.8 for modified (monthly) Migraine Disability Assessment Questionnaire, -2.1
and -2.3 for Headache Impact Test, 5.1 and 6.5 for MSQ-RFR, 4.2 and 5.4 for
MSQ-RFP, and 5.2 and 6.7 for MSQ-EF ( p < 0.001 for all). Erenumab also
significantly reduced the proportion of patients with severe and very severe
migraine-related disability and increased the proportion of patients with
clinically meaningful improvements in migraine-related impact and health-related
quality of life. Conclusion Erenumab reduced migraine disability and impact and
improved patients' health-related quality of life, reinforcing its role as a
promising new therapy for migraine prevention. BACKGROUND: A substantial proportion of patients with migraine does not respond
to, or cannot tolerate, oral preventive treatments. Erenumab is a novel
CGRP-receptor antibody with preventive efficacy in migraine. We assessed its
efficacy and tolerability in patients with episodic migraine in whom previous
treatment with two-to-four migraine preventives had been unsuccessful.
METHODS: LIBERTY was a 12-week, double-blind, placebo-controlled randomised
study at 59 sites in 16 countries. Eligible patients were aged 18-65 years and
had a history of episodic migraine with or without aura for at least 12 months,
had migraine for an average of 4-14 days per month during the 3 months before
screening, and had been treated unsuccessfully (in terms of either efficacy or
tolerability, or both) with between two and four preventive treatments. Eligible
participants were randomly assigned (1:1) to receive either erenumab 140 mg (via
two 70 mg injections) or placebo every 4 weeks subcutaneously for 12 weeks.
Randomisation was by interactive response technology and was stratified by
monthly frequency of migraine headache (4-7 vs 8-14 migraine days per month)
during the baseline phase. Cenduit generated the randomisation list and assigned
participants to groups. Participants, investigators, people doing various
assessments, and the study sponsor were masked to treatment assignment. The
primary endpoint was the proportion of patients achieving a 50% or greater
reduction in the mean number of monthly migraine days during weeks 9-12.
Efficacy was measured in the full analysis set, which included all randomly
assigned patients who started their assigned treatment and completed at least
one post-baseline monthly migraine day measurement. Safety and tolerability were
assessed by recording adverse events and by physical examination, assessment of
vital signs, clinical laboratory assessments, and electrocardiography. Safety
was assessed in all randomly assigned patients who received at least one dose of
study drug. This trial is registered with ClinicalTrials.gov, number
NCT03096834. The trial is closed to new participants, but the open-label
extension phase is ongoing.
FINDINGS: Between March 20, 2017, and Oct 27, 2017, 246 participants were
randomly assigned, 121 to the erenumab group and 125 to the placebo group. 95 of
246 (39%) participants had previously unsuccessfully tried two preventive drugs,
93 (38%) had tried three, and 56 (23%) had tried four. At week 12, 36 (30%)
patients in the erenumab had a 50% or greater reduction from baseline in the
mean number of monthly migraine days, compared with 17 (14%) in the placebo
group (odds ratio 2·7 [95% CI 1·4-5·2]; p=0·002). The tolerability and safety
profiles of erenumab and placebo were similar. The most frequent
treatment-emergent adverse event was injection site pain, which occurred in
seven (6%) participants in both groups.
INTERPRETATION: Compared with placebo, erenumab was efficacious in patients with
episodic migraine who previously did not respond to or tolerate between two and
four previous migraine preventive treatments. Erenumab might be an option for
patients with difficult-to-treat migraine who have high unmet needs and few
treatment options.
FUNDING: Novartis Pharma. BACKGROUND: Migraine prevention with erenumab and migraine induction by
calcitonin gene-related peptide (CGRP) both carry notable individual variance.
We wanted to explore a possible association between individual efficacy of
anti-CGRP treatment and susceptibility to migraine induction by CGRP.
METHODS: Thirteen migraine patients, previously enrolled in erenumab anti-CGRP
receptor monoclonal antibody trials, received CGRP in a double-blind,
placebo-controlled, randomized cross-over design to investigate their
susceptibility to migraine induction. A standardized questionnaire was used to
assess the efficacy of previous antibody treatment. The patients were stratified
into groups of high responders and poor responders. Primary outcomes were
incidence of migraine-like attacks and area under the curve of headache
intensity after infusion of CGRP and placebo. All interviews and experiments
were performed in laboratories at the Danish Headache Center, Copenhagen,
Denmark.
RESULTS: Ten high responders and three poor responders were included. CGRP
induced migraine-like attacks in ten (77%) patients, whereof two were poor
responders, compared to none after placebo (p = 0.002). The area under the curve
for headache intensity was greater after CGRP, compared to placebo, at 0-90 min
(p = 0.009), and 2-12 h (p = 0.014). The median peak headache intensity score
was 5 (5-9) after CGRP, compared to 2 (0-4) after placebo (p = 0.004).
CONCLUSIONS: Patients with an excellent effect of erenumab are highly
susceptible to CGRP provocation. If an association is evident, CGRP provocation
could prove a biomarker for predicting antibody treatment efficacy.
TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov with
identifier: NCT03481400 . |
What are the CADD scores? | Combined Annotation-Dependent Depletion (CADD) is a widely used measure of variant deleteriousness that can effectively prioritize causal variants in genetic analyses, particularly highly penetrant contributors to severe Mendelian disorders. CADD is an integrative annotation built from more than 60 genomic features, and can score human single nucleotide variants and short insertion and deletions anywhere in the reference assembly. | Next-generation sequencing in clinical diagnostics is providing valuable genomic
variant data, which can be used to support healthcare decisions. In silico tools
to predict pathogenicity are crucial to assess such variants and we have
evaluated a new tool, Combined Annotation Dependent Depletion (CADD), and its
classification of gene variants in Lynch syndrome by using a set of 2,210 DNA
mismatch repair gene variants. These had already been classified by experts from
InSiGHT's Variant Interpretation Committee. Overall, we found CADD scores do
predict pathogenicity (Spearman's ρ = 0.595, P < 0.001). However, we discovered
31 major discrepancies between the InSiGHT classification and the CADD scores;
these were explained in favor of the expert classification using population
allele frequencies, cosegregation analyses, disease association studies, or a
second-tier test. Of 751 variants that could not be clinically classified by
InSiGHT, CADD indicated that 47 variants were worth further study to confirm
their putative pathogenicity. We demonstrate CADD is valuable in prioritizing
variants in clinically relevant genes for further assessment by expert
classification teams. PURPOSE: Several in silico tools have been shown to have reasonable research
sensitivity and specificity for classifying sequence variants in coding regions.
The recently developed combined annotation-dependent depletion (CADD) method
generates predictive scores for single-nucleotide variants (SNVs) in all areas
of the genome, including noncoding regions. We sought for non-coding variants to
determine the clinical validity of common CADD scores.
METHODS: We evaluated 12,391 unique SNVs in 624 patient samples submitted for
germ-line mutation testing in a cancer-related gene panel. Stratifying by
genomic region, we compared the distributions of CADD scores of rare SNVs, SNVs
common in our patient population, and the null distribution of all possible
SNVs.
RESULTS: The median CADD scores of intronic and nonsynonymous variants were
significantly different between rare and common SNVs (P < 0.0001). Despite these
different distributions, no individual variants could be identified as plausibly
causative among the rare intronic variants with the highest scores. The
receiver-operating characteristics (ROC) area under the curve (AUC) for
noncoding variants is modest, and the positive predictive value of CADD for
intronic variants in panel testing was found to be 0.088.
CONCLUSION: Focused in silico scoring systems with much higher predictive value
will be necessary for clinical genomic applications.Genet Med 18 12, 1269-1275. |
What is a prolactinoma and where in the body would they be found? | Prolactinomas are the most common functional tumors of the pituitary gland. | Prolactinoma is the most common type of primary pituitary tumors. It occurs more
frequently in women than in men. Dopaminergic agonists are effective in the
shrinkage of prolactin-secreting pituitary tumor and are preferred in some
patients. However, pituitary radiotherapy may enable the long-term removal of
prolactin-secreting tumor cells. Recent evidence suggests that prolactinoma is a
heterogeneous disorder with complicated and multifactorial etiology and
pathogenesis. Apparently, a thorough understanding of prolactinoma tumorigenesis
would be important. To facilitate investigations on tumorigenesis of
prolactinoma, animal models for prolactinomas have been developed. These models
have expedited our progress in the recent years. Many researchers consider the
F(344) rat to be the most sensitive strain of rats to estrogen (E(2))-induced
prolactinoma formation. Nonetheless, E(2) treatment for 60 days also induces the
formation of pituitary prolactin-secreting adenoma in male Sprague-Dawley (SD)
rats. Evidently, the SD rat is also a good animal for prolactinoma
investigations. Following E(2) implantation, prolactinomas developed in the
eutopic adenohypophysis in situ and/or ectopic pituitary grafted under the renal
capsule in SD rats. These observations favor the hypothesis that prolactinoma
growth is the result of pathological changes in the adenohypophysis and/or
hypothalamus. In the latter case, abnormal release of hypothalamic dopamine,
GABA, or brain-gut peptides (such as cholecystokinin, vasoactive intestinal
polypeptide, galanin, angiotensin, opioid peptide, gastrin, gastrin-releasing
peptide, pancreatic polypeptide, and adrenocorticotropic hormone) results in
some of the pathological changes that may lead to hyperprolactinemia and/or
prolactinoma development. Dysregulation of prolactin synthesis and secretion may
be the result of prolactin gene modulation. In E(2)-induced rat prolactinomas,
prolactin mRNA contents and the expression of some proto-oncogenes, e.g. c-myc
and c-ras, TGFalpha and TGFbeta1 mRNA were significantly changed. The above
findings are consistent with results in human prolactinoma development. In
addition, in rats abnormal expression of the prolactin gene was correlated with
hypomethylated status of CpG sites in exons 1, 2 and 4 of the prolactin gene, as
well as the increase in hypersensitive sites to DNase 1 in the encoding region
of the prolactin gene. In E(2)-treated rats, a point mutation with a base
substitution from cytidine (C) to adenine (A) was found at the -36-bp site of
the proximal promoter of the prolactin gene in eutopic pituitary prolactinomas,
but no change was observed in the same sequence of the prolactin gene in ectopic
prolactinoma. The association of a base substitution with the hyperexpression of
the prolactin gene in eutopic prolactinomas suggests that different mechanisms
may mediate the formation of eutopic and ectopic prolactin-secreting tumors.
Melatonin decreases the expression of the prolactin gene in vitro suggesting
that this pineal hormone may be a potential anticarcinogen in vivo. It has also
been shown that MT(2) (Mel(1b)) melatonin receptors are expressed in anterior
pituitary cells. The use of melatonin as a preventive or therapeutic drug for
prolactinomas should be further investigated. In summary, improved knowledge on
tumorigenesis of prolactinomas, especially in the rat model, was noted. These
E(2)-induced rat prolactinoma models would facilitate future investigations, and
expected results shall be fruitful and exciting for the development of future
drug designs for the prevention and/or treatment of prolactin-secreting
pituitary tumors. Prolactinomas are the most common secretory pituitary adenoma. They typically
occur in women in the 3rd-6th decade of life and rarely in the pediatric
population or after menopause. Most women present with irregular menses and/or
infertility. Dopamine (DA) agonists, used in their treatment, are safe during
pregcy, but in most cases are discontinued at conception with close
monitoring for signs or symptoms of tumor growth. Breastfeeding is safe
postpartum, provided there was no significant growth during pregcy. Some
women will experience normalization of prolactin levels postpartum. Menopause
may also decrease prolactin levels and even those with macroprolactinomas may
consider discontinuing their DA agonist with close follow-up. Prolactinomas may
be associated with decreased quality of life scores in women, and play a role in
bone health and cardiovascular risk factors. This review discusses the current
literature and clinical understanding of prolactinomas throughout the entirety
of the female life cycle. |
Which integrin genes are activated by the immune system in inflammatory bowel disease? | ITGA4, ITGB8, ITGAL and ICAM1. In all four cases, the expression-increasing allele also increases disease risk. | Author information:
(1)Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
(2)Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge,
UK.
(3)Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne.
(4)Division of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard
Medical School, Boston, MA, USA.
(5)Program in Medical and Population Genetics, Broad Institute of Harvard and
MIT, Cambridge, MA, USA.
(6)Precision Medicine Exeter, University of Exeter, Exeter, UK.
(7)IBD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK.
(8)Wellcome Trust Centre for Human Genetics, University of Oxford, Headington,
UK.
(9)Christ Church, University of Oxford, St Aldates, UK.
(10)Gastrointestinal Unit, Wester General Hospital University of Edinburgh,
Edinburgh, UK.
(11)Department of Gastroenterology, Torbay Hospital, Torbay, Devon, UK.
(12)Department of Child Life and Health, University of Edinburgh, Edinburgh, UK.
(13)Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for
Sick Children,Edinburgh, UK.
(14)Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.
(15)Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, Department of
Gastroenterology, London, UK.
(16)Translational Gastroenterology Unit, John Radcliffe Hospital, University of
Oxford, Oxford OX3 9DS, UK.
(17)Human Immunology Unit, Weatherall Institute of Molecular Medicine,
University of Oxford, Oxford OX3 9DS, UK.
(18)Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children,
Edinburgh, UK.
(19)Child Life and Health, University of Edinburgh, Edinburgh, Scotland, UK.
(20)Gastroenterology & General Medicine, Norfolk and Norwich University
Hospital, Norwich, UK.
(21)Department of Medicine, St Mark's Hospital, Harrow, Middlesex, UK.
(22)Department of Medical and Molecular Genetics, Faculty of Life Science and
Medicine, King's College London, Guy's Hospital, London, UK.
(23)Sydney Brenner Institute for Molecular Bioscience, Faculty of Health
Sciences, University of Witwatersrand, South Africa.
(24)Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.
(25)The Manchester Centre for Genomic Medicine, University of Manchester,
Manchester, UK.
(26)Translational Gastroenterology Unit and the Department of Paediatrics,
University of Oxford, Oxford, United Kingdom.
(27)Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.
(28)Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
(#)Contributed equally |
Which is the database of somatic mutations in normal cells? | DSMNC is a database of somatic mutations in normal cells (http://dsmnc.big.ac.cn/) and provides a comprehensive catalogue of somatic SNVs in single cells from various normal tissues. In the current version, the database collected ∼0.8 million SNVs accumulated in ∼600 single normal cells (579 human cells and 39 mouse cells). The database interface supports the user-friendly capability of browsing and searching the SNVs and their annotation information. | |
Which drugs are included in the Lonsurf pill? | Lunsurf pill includes trifluridine and tipiracil. It is a novel form of chemotherapy for metastatic colorectal cancer. | Evolocumab (Repatha) for patients with hypercholesterolemia whose condition has
not been controlled by statins and other therapies; trifluridine/tipiracil
(Lonsurf) for metastatic colorectal cancer; and blood coagulation factor VIII
(Nuwiq) for adults and children with hemophilia A. Within the past several years, no chemotherapy has been sufficient to increase
the overall survival of patients with chemorefractory colorectal cancer. TAS-102
(Lonsurf) is an oral fluoropyrimidine that is formed by the combination of 2
active drugs: trifluridine (a nucleoside analog) and tipiracil hydrochloride (a
thymidine phosphorylase inhibitor). This drug extended the median overall
survival by approximately 2 months compared with placebo in a randomized phase
III trial composed of Asian and non-Asian patients with refractory (or
intolerant) metastatic colorectal cancer. The clinical development of TAS-102
began approximately a decade ago and included 2 pivotal randomized studies,
which are discussed in this review. This drug has just been approved in Japan,
and as soon as possible, it will be marketed in Western countries as well; it
will therefore become the standard of care for this patient population. The
optimal combination of TAS-102 with other agents, as well as the mechanism of
resistance to this regimen should be defined in the near future. Trifluridine/tipiracil (Lonsurf(®)) is a novel, orally active, antimetabolite
agent comprised of trifluridine, a thymidine-based nucleoside analogue, and
tipiracil, a potent thymidine phosphorylase inhibitor. Trifluridine is
incorporated into DNA via phosphorylation, ultimately inhibiting cell
proliferation. Tipiracil increases systemic exposure of trifluridine when
coadministered. Trifluridine/tipiracil has recently been approved for the
treatment of adult patients with metastatic colorectal cancer (mCRC) who are
refractory to or are not considered candidates for, current standard
chemotherapy and biological therapy in the EU and USA and in unresectable
advanced or recurrent CRC in Japan. The approved regimen of oral twice-daily
trifluridine/tipiracil (35 mg/m(2) twice daily on days 1-5 and 8-12 of each
28-day cycle) significantly improved overall survival and progression-free
survival and was associated with a significantly higher disease control rate
than placebo when added to best supportive care in the multinational, pivotal
phase III trial (RECOURSE) and a phase II Japanese trial. Trifluridine/tipiracil
was associated with an acceptable tolerability profile, with adverse events
generally being managed with dose reductions, temporary interruptions in
treatment or administration of granulocyte-colony stimulating factor. The most
common grade 3-4 adverse events (≥10 %) were anaemia, neutropenia,
thrombocytopenia and leukopenia. In conclusion, trifluridine/tipiracil is a
useful additional treatment option for the management of mCRC in patients who
are refractory to, or are not considered candidates for, currently available
therapies. BACKGROUND: Treatment-related adverse events (AEs) are common in patients with
metastatic colorectal cancer (mCRC) receiving chemotherapy. These AEs may affect
patient adherence, particularly with completely oral regimens, such as
trifluridine/tipiracil (TAS-102, Lonsurf®), an antimetabolite agent for patients
with mCRC refractory or intolerant to standard therapies.
.
OBJECTIVES: This article reviews strategies for promoting adherence and
educating patients and caregivers about oral therapy with
trifluridine/tipiracil.
.
METHODS: Recommended strategies for managing AEs are reviewed, with a focus on
the most common AEs reported in patients with mCRC receiving
trifluridine/tipiracil in clinical trials.
.
FINDINGS: Oncology nurses play an important role in educating and counseling
patients regarding treatment and its potential side effects. Among patients with
mCRC refractory or intolerant to standard therapies, trifluridine/tipiracil was
found to have a favorable safety profile. It is associated with hematologic AEs
as well as a low incidence of nausea, diarrhea, vomiting, anorexia, and fatigue. The National Institute for Health and Care Excellence (NICE) invited Servier,
the company manufacturing trifluridine and tipiracil (T/T; trade name:
Lonsurf®), to submit evidence for the clinical and cost effectiveness of T/T
compared with best supportive care (BSC) for metastatic colorectal cancer
(third-line or later). Kleijnen Systematic Reviews Ltd (KSR), in collaboration
with Maastricht University Medical Center, was commissioned as the Evidence
Review Group (ERG). This paper presents a summary of the company's submission
(CS), the ERG report and the development of the NICE guidance for the use of
this drug in England and Wales by the appraisal committee (AC). The ERG produced
a critical review of the clinical and cost effectiveness of T/T based upon the
CS. In the CS, pooled evidence of two trials (a phase II trial and RECOURSE)
showed that T/T resulted in a significant increase in overall survival [OS;
hazard ratio (HR) 0.67, 95% CI 0.58-0.78] and progression-free survival (PFS; HR
0.46, 95% CI 0.40-0.53). The AC considered the survival benefit of T/T
clinically meaningful although relatively small. The ERG highlighted that none
of the participants in the phase II trial and approximately half of the RECOURSE
participants (394 of 800) were from Europe, which might limit the applicability
of the study findings to the NHS. Moreover, the ERG's critical assessment of the
company's economic evaluation highlighted a number of concerns that resulted in
11 adjustments to the company's base-case analysis. The ERG adjustments that had
the largest impact were using the RECOURSE trial data only (instead of the
pooled evidence), fixing errors and violations and using the utilities from the
CORRECT trial (identified in the literature review) only. The ERG preferred to
use the RECOURSE trial data only given the suboptimal methodology used by the
company to pool the evidence. However, since there were no fundamental arguments
to prevent the two trials from being pooled, the ERG also presented its
base-case analysis based on the pooled effectiveness estimates. The company
base-case resulted in an incremental cost effectiveness ratio (ICER) of £44,032
per QALY gained while the ERG base-case resulted in ICERs of £52,695 and £49,392
per QALY gained based on the RECOURSE trial only and pooled evidence,
respectively. Since the AC concluded that the most plausible ICER was £49,392
per QALY gained, and that T/T meets end-of-life criteria, T/T was recommended as
a cost effective use of NHS resources. PURPOSE: Trifluridine/tipiracil (FTD/TPI; TAS-102, Lonsurf®), a novel form of
chemotherapy for metastatic colorectal cancer (mCRC), has shown clinical benefit
in the global, phase III RECOURSE trial, regardless of patient age. Here, we
report the safety and tolerability profile of FTD/TPI from an expanded-access
program (EAP) in the US patients with mCRC whose disease has progressed on the
standard therapies.
METHODS: A total of 549 patients (≥ 18 years) with histologically confirmed mCRC
following two or more regimens of standard therapy and an Eastern Cooperative
Oncology Group performance status of 0 or 1 participated in this open-label EAP.
During the 28-day treatment cycle, patients took FTD/TPI 35 mg/m2 twice daily
for 5 days followed by 2 days of rest for 2 weeks, with a 14-day rest period.
Data were collected for therapy duration, treatment discontinuation, and adverse
events. Age-based post hoc analysis was performed to determine the safety of
FTD/TPI in elderly (≥ 65 years) versus younger (< 65 years) patients.
RESULTS: FTD/TPI-treated patients in this EAP had a similar therapy duration and
time to treatment discontinuation to those in the RECOURSE trial. The safety
profile in elderly patients was consistent with that in younger patients, with
no unexpected safety concerns.
CONCLUSIONS: This USA-based, open-label EAP has confirmed a similar safety and
tolerability profile for FTD/TPI to that observed in the RECOURSE trial.
Furthermore, FTD/TPI is well tolerated and can be considered as a treatment
option in elderly patients with mCRC.
TRIAL REGISTRATION: NCT02286492. BACKGROUND: Trifluridine/tipiracil (TAS-102, Lonsurf®), a novel oral anti-tumor
agent combining an anti-neoplastic thymidine-based nucleoside analogue
(trifluridine, FTD) with a thymidine phosphorylase inhibitor (tipiracil
hydrochloride, TPI) presents a new treatment option for metastatic colorectal
cancer (mCRC) patients refractory or intolerant to standard therapies. FTD/TPI
was approved in the European Union (EU) in April 2016 and launched on the German
market in August 15, 2016.
METHODS: We investigated the characteristics of patients (pts) with mCRC treated
with FTD/TPI at 118 centers in Germany from January 12 to August 14, 2016 and
analyzed the safety in a clinical real-world setting.
RESULTS: In Germany, a total of 226 mCRC patients were included into a
compassionate-use-program (CUP) and received FTD/TPI. For 45.5% of patients
(n = 101), 253 adverse events (AE) were documented, most of them drug-related
(n = 135). From January 12 (2016) to March 2 (2017), 124 serious adverse events
(SAE) were reported (74 drug related). The most common serious adverse drug
reactions (SADR) were leukopenia (12 events), neutropenia (8 events), anemia (7
events), diarrhea and nausea (5 events each) (observation period January 12 2016
to October 7 2016). In total, 122 patients (54%) discontinued FTD/TPI treatment,
mostly due to progression (n = 75) followed by AEs (n = 21), deaths (n = 16),
and non-specified reasons (n = 16). Interestingly, 12 patients with ECOG PS ≥2
achieved up to 3 cycles of FTD/TPI and in this patient population only 3
treatment discontinuations due to AEs were documented and the safety profile was
comparable to the entire population.
CONCLUSION: The patient characteristics as well as the safety profile of FTD/TPI
documented in the German CUP were consistent with those reported in the pivotal
trial RECOURSE without unexpected safety signals. |
What is the association of epigallocatechin with the cardiovascular system? | The compound epigallocatechin-3-gallate (EGCG), the major polyphenolic compound present in green tea [Camellia sinensis (Theaceae], has shown numerous cardiovascular health promoting activity through modulating various pathways. EGCG was found to exhibit a wide range of therapeutic properties. | Reactive oxygen species (ROS) in the brain are involved in the pathogenesis of
hypertension. Epigallocatechin-3-O-gallate (EGCG), one of the active compounds
in green tea, has anti-oxidant, anti-inflammatory and vascular protective
properties. This study was designed to determine whether chronic infusion of
EGCG into the hypothalamic paraventricular nucleus (PVN) attenuates ROS and
sympathetic activity and delays the progression of hypertension by up-regulating
anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs) and
decreasing nuclear factor-kappa B (NF-κB) activity, as well as restoring the
neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR).
Adult normotensive Wistar-Kyoto (WKY) rats and SHR received bilateral PVN
infusion of EGCG (20μg/h) or vehicle via osmotic minipumps for 4 weeks. SHR
showed higher mean arterial pressure, plasma proinflammatory cytokines and
circulating norepinephrine (NE) levels compared with WKY rats. SHR also had
higher PVN levels of the subunit of NAD(P)H oxidase (gp91phox), ROS, tyrosine
hydroxylase, and PICs; increased NF-κB activity; and lower PVN levels of
interleukin-10 (IL-10) and 67kDa isoform of glutamate decarboxylase (GAD67) than
WKY rats. PVN infusion of EGCG attenuated all these changes in SHR. These
findings suggest that SHR have an imbalance between excitatory and inhibitory
neurotransmitters, as well as an imbalance between pro- and anti-inflammatory
cytokines in the PVN. Chronic inhibition of ROS in the PVN restores the balance
of neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive
response and sympathetic activity. Epigallocatechin gallate (EGCG), a bioactive ingredient of green tea, plays a
protective role in the cardiovascular system. Homocysteine (Hcy) is a major risk
factor for chronic kidney disease and cardiovascular disease. The present study
aimed to investigate the role of EGCG in Hcy-induced proliferation of vascular
smooth muscle cells (VSMCs) and its underlying mechanism. We also explored the
roles of rennin-angiotensin system (RAS), extracellular signal-regulated kinases
(ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) in this process.
Human aortic smooth muscle cells (HASMCs) were treated with different drugs for
different periods. The proliferation rate of HASMCs was detected using the CCK-8
and BrdU labeling assays. The Western blot assay was used to determine the
expression levels of angiotensin II type 1 receptor (AT-1R), ERK1/2, and p38
MAPK. Compared with the control group, the HASMCs treated with Hcy at different
doses (100, 200, 500, and 1000 µM) showed significantly increased proliferation.
Hcy increased the expression of AT-1R, whereas EGCG decreased the protein
expression of AT-1R. Furthermore, we found that Hcy-induced expression of
p-ERK1/2 and p-p38MAPK was dependent on AT-1R. Compared with Hcy
(500 µM)-treated cells, EGCG (20 µM)-treated cells showed decreased
proliferation as well as expression of AT-1R, p-ERK1/2, and p-p38MAPK. In
addition, HASMC proliferation was suppressed by the addition of an AT-1R blocker
(olmesartan), an ERK1/2 inhibitor (PD98059), and a p38MAPK inhibitor (SB202190).
EGCG can inhibit AT-1R and affect ERK1/2 and p38MAPK signaling pathways,
resulting in the decrease of VSMC proliferation induced by Hcy. The objective of the present study is to evaluate the effect of epigallocatechin
gallate (EGCG) on aging-mediated cardiac hypertrophy, fibrosis, and apoptosis.
The Wistar albino rats were divided into 4 groups (n = 18). Group I: young (3
months), group II: aged (24-26 months), group III: aged + EGCG (200 mg/kg for 30
days), and group IV: young + EGCG. At the end of 30 days, EGCG administration to
the aged animals showed significant (P < 0.001) reduction of low-density
lipoprotein, very low-density lipoprotein, triglyceride, total cholesterol with
concomitant increase of high-density lipoprotein (P < 0.001) when compared with
aged rats. Increased (P < 0.001) heart volume, weight with concomitant increase
of left ventricular wall thickness, and reduced ventricular cavity were observed
in aged rats supplemented with EGCG compared with aged animals. Histology and
histomorphometry study of aged animals treated with EGCG showed marked increases
in the diameter and volume of cardiomyocytes with concomitant reduction of
numerical density when compared with aged animals. Reduced reactive oxygen
species (P < 0.001) production with association of increased antioxidant defense
system (P < 0.001) in aged hearts supplemented with EGCG when compared with aged
animals. TUNEL staining and fibrosis showed a marked increase in apoptotic cell
death (P < 0.001) and collagen deposition (P < 0.001) in aged animals treated
with EGCG when compared with aged animals. Aged animals treated with EGCG showed
a marked increase in protein expression of TGFβ, TNFα, and nuclear factor kappa
B (NF-κB) and significant (P < 0.001) alteration in the gene expression of TGFβ,
TNFα, NF-κB, α-SMA, and Nrf2 when compared with aged animals. Taken together, it
is evident that EGCG may potentially inhibit aging-induced cardiac hypertrophy,
fibrosis, and apoptosis, thereby preserving cardiac function. The proposed
mechanism would be inhibition of reactive oxygen species-dependent activation of
TGFβ1, TNFα, and NF-κB signaling pathway. Hence, the present study suggests that
EGCG can be useful to fight against aging-induced cardiac hypertrophy, fibrosis,
and apoptosis. |
What is the mechanism of action of tucatinib? | Tucatinib is an oral, potent, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a novel treatment for ERBB2/HER2-positive breast cancer. | Approximately 50% of patients with advanced human epidermal growth factor 2
(HER2)-positive breast cancer and triple-negative breast cancer (TNBC)
ultimately develop breast cancer brain metastases (BCBM), which are associated
with significant morbidity and mortality. The advent of HER2-directed therapy
resulted in greatly improved survival outcomes, but unfortunately at the price
of an increased cumulative incidence of BCBM. We review challenges in the
management of BCBM, and potential treatment strategies, including novel agents
such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors
(olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors
(palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287).
The utility of human epidermal growth factor 2 (HER2)-directed
therapies-lapatinib, ado-trastuzumab emtansine (T-DM1), neratinib and
tucatinib-is also being studied in this setting. We address the need for
improved imaging techniques and innovation in clinical trial design. For
example, the current practice is to initially administer whole-brain
radiotherapy (WBRT) as treatment for patients with multiple BCBM. However, in
selected circumstances, first-line systemic treatment may be more appropriate in
order to avoid neurocognitive toxicities, and potential options should be
evaluated in window of opportunity trials. Other strategies that may aid
development of more effective clinical trials and expedite the development of
promising agents include the use of different clinical endpoints and different
imaging tools. Approximately 30-50% of advanced HER2-positive breast cancer patients will
develop central nervous system (CNS) metastases, with an annual risk of around
10%, and a half of them will die from brain progression. An increased risk of
brain metastases is also seen in patients with early HER2-positive breast cancer
administered curative therapy. Brain metastases in HER2-positive breast cancer
patients usually constitute the first site of recurrence. The administration of
anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, considerably delays
the onset of symptomatic brain disease: however, the limited penetration of
these compounds into the CNS hinders their efficacy. The small-molecule tyrosine
kinase inhibitors of epidermal growth factor receptors family have established
activity in HER2-positive breast cancer in both advanced disease and neoadjuvant
setting. Favorable physico-chemical properties of these compounds allow them for
a more efficient penetration through the blood-brain barrier, and hold the
promise for more effective prevention and treatment of brain metastases. In this
article we review the role of currently available or investigational HER2
tyrosine kinase inhibitors: lapatinib, neratinib, afatinib and tucatinib in the
treatment of brain metastases in HER2-positive breast cancer patients. BACKGROUND: Tucatinib is a potent and selective oral HER2 tyrosine kinase
inhibitor, with the potential to provide a well tolerated new treatment option
for patients whose disease has progressed on currently available therapies. We
aimed to determine the recommended phase 2 dose, safety, pharmacokinetics, and
preliminary activity of tucatinib in combination with capecitabine or
trastuzumab in patients with HER2-positive breast cancer with or without brain
metastases.
METHODS: In this non-randomised, open-label, phase 1b trial done in five sites
in the USA, we recruited patients aged 18 years or older with HER2-positive
progressive breast cancer who had been previously treated with trastuzumab,
pertuzumab, and trastuzumab emtansine. Eligible patients required
HER2-positivity assessed locally, evaluable lesions as defined per Response
Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative
Oncology Group performance status of 0 or 1. Tucatinib was administered twice a
day in conjunction with capecitabine 1000 mg/m2 orally twice a day for 14 days
of a 21-day cycle, trastuzumab 6 mg/kg intravenously once every 21 days, or
both. A modified 3 + 3 dose-escalation design was used to determine the
recommended phase 2 dose, starting with tucatinib in combination with
capecitabine or trastuzumab, and subsequently evaluating the triplet
combination. The primary endpoint was to establish the maximum tolerated dose
and recommended phase 2 dose of tucatinib, evaluated by toxicity assessments.
Efficacy was assessed in all patients by contrast CT of the body. Analyses
included all patients who had received at least one dose of study treatment. The
study is registered with ClinicalTrials.gov, number NCT02025192.
FINDINGS: Between Jan 15, 2014, and Dec 15, 2015, 60 patients were enrolled and
treated. The current report is from mature data as of June 30, 2017. The
tucatinib recommended phase 2 dose was determined to be 300 mg orally twice a
day, equivalent to single-agent maximum tolerated dose. Pharmacokinetic analysis
showed that there was no drug-drug interaction with capecitabine. Adverse events
seen at the recommended phase 2 dose regardless of causality, grade, and
treatment group included diarrhoea (35 [67%] of 52 patients), nausea (31 [60%]
patients), palmar-plantar erythrodysaesthesia syndrome (23 [44%] patients),
fatigue (20 [38%] patients), and vomiting (20 [38%] patients). In all patients,
treatment-related toxicities of grade 3 and worse included fatigue (five [8%]
patients), diarrhoea (four [7%] patients), and palmar-plantar
erythrodysaesthesia (four [7%] patients). No treatment-related deaths were
reported. The proportion of patients with measurable disease achieving objective
response was 83% (five of six patients) in the combination of tucatinib with
capecitabine, 40% (six of 15 patients) in the combination of tucatinib with
trastuzumab, and 61% (14 of 23 patients) in the combination of tucatinib with
both capecitabine and trastuzumab.
INTERPRETATION: Tucatinib in combination with capecitabine and trastuzumab had
acceptable toxicity and showed preliminary anti-tumour activity. Validation of
the current study results will be determined in the double-blinded randomised
study, HER2CLIMB (ONT-380-206; NCT02614794).
FUNDING: Cascadian Therapeutics, a wholly owned subsidiary of Seattle Genetics. IMPORTANCE: Treatment options for patients with disease progression after
treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1)
are limited. Tucatinib is an oral, potent, human epidermal growth factor
receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a
novel treatment for ERBB2/HER2-positive breast cancer.
OBJECTIVE: To determine the maximum tolerated dosage of tucatinib in combination
with T-DM1 in the treatment of patients with ERBB2/HER2-positive metastatic
breast cancer with and without brain metastases.
DESIGN, SETTING, AND PARTICIPANTS: In this phase 1b open-label, multicenter,
clinical trial, 57 participants enrolled between January 22, 2014, and June 22,
2015, were 18 years of age or older with ERBB2/HER2-positive metastatic breast
cancer previously treated with trastuzumab and a taxane. Data were analyzed
between January and March 2018.
INTERVENTIONS: Tucatinib 300 mg or 350 mg administered orally twice per day for
21 days and T-DM1 3.6 mg/kg administered intravenously once every 21 days.
MAIN OUTCOMES AND MEASURES: Safety assessments, pharmacokinetics, and response
were assessed using RECIST 1.1 every 2 cycles for 6 cycles, followed by every 3
cycles.
RESULTS: Fifty-seven T-DM1-naive patients (median [IQR] 51 [44.0-63.0] years of
age) who had undergone a median of 2 earlier HER2 therapies (range, 1-3) were
treated. The tucatinib maximum tolerated dosage was determined to be 300 mg
administered twice per day with dose-limiting toxic reactions seen at 350 mg
twice per day. Pharmacokinetic analysis showed that there was no drug-drug
interaction with T-DM1. Adverse events seen among the 50 patients treated at the
maximum tolerated dosage regardless of causality included nausea (36 patients;
72%), diarrhea (30 patients; 60%), fatigue (28 patients; 56%), epistaxis (22
patients; 44%), headache (22 patients; 44%), vomiting (21 patients; 42%),
constipation (21 patients; 42%), and decreased appetite (20 patients; 40%); the
majority of adverse events were grade 1 or 2. Tucatinib-related toxic reactions
that were grade 3 and above included thrombocytopenia (7 patients; 14%) and
hepatic transaminitis (6 patients; 12%).
CONCLUSIONS AND RELEVANCE: In this study, tucatinib in combination with T-DM1
appeared to have acceptable toxicity and to show preliminary antitumor activity
among heavily pretreated patients with ERBB2/HER2-positive metastatic breast
cancer with and without brain metastases.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01983501. |
Which enzyme is inhibited by a drug Lorlatinib? | Lorlatinib is anaplastic lymphoma kinase inhibitor. | Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the
orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase
domain that is physiologically related to anaplastic lymphoma kinase (ALK), and
is undergoing Phase I/II clinical trial investigations for non-small cell lung
cancers. An early goal is to measure the concentrations of this drug in brain
tumour lesions of lung cancer patients, as penetration of the blood-brain
barrier is important for optimal therapeutic outcomes. Here we prepare both 11C-
and 18F-isotopologues of lorlatinib to determine the biodistribution and
whole-body dosimetry assessments by positron emission tomography (PET).
Non-traditional radiolabelling strategies are employed to enable an automated
multistep 11C-labelling process and an iodonium ylide-based radiofluorination.
Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical
yields and shows reasonable tumour uptake in rodents. PET imaging in non-human
primates confirms that this radiotracer has high brain permeability. Lung toxicity is a potential fatal effect involving non-small-cell lung cancer
(NSCLC) patients exposed to tyrosine kinase inhibitors (TKIs). Moving from our
experience regarding a patient who developed lung toxicity while receiving 2
different anaplastic lymphoma kinase (ALK)-TKIs, we performed a systematic
review to assess the epidemiologic magnitude and the clinical significance of
such toxicity in NSCLC patients treated with ALK-TKIs. Studies were identified
using MEDLINE and additional sources (European Society for Medical Oncology,
American Society of Clinical Oncology, and World Conference on Lung Cancer
abstracts) in agreement with Preferred Reporting Items for Systematic Reviews
and Meta-Analyses and Cochrane guidelines. Lung toxicity was reported in 105 of
4943 NSCLC patients (2.1%). Crizotinib was responsible for pulmonary adverse
events (AEs) in 1.8% of exposed patients (49 of 2706). With the limit of a lower
number of treated patients (n = 359), brigatinib resulted as the most frequently
involved in lung toxicity (7%; n = 25). Pulmonary AEs during therapy with
ceritinib, alectinib, and lorlatinib occurred in 1.1%, 2.6%, and 1.8% of the
patients, respectively. Sixty-five percent of cases accounted for Grade 3 or 4
events, with a mortality rate of 9%. Radiological patterns of pneumonia were
reported in 25 patients, whereas imaging evocative of interstitial lung disease
in 37. Overall, 26 of 105 patients (25%) permanently discontinued treatment
because of lung toxicity. Lung toxicity is a rare albeit potentially severe side
effect in NSCLC patients receiving ALK-TKIs, apparently more frequent with
brigatinib. Its early recognition and treatment are crucial for the best outcome
of this subgroup of patients, whose overall prognosis is being improved by the
availability of several targeted agents. Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive
non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine
kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and
the benefit of TKIs is limited as a result of acquired resistance. Emerging data
suggest that the ALK fusion variant may affect clinical outcome, but the
molecular basis for this association is unknown. Patients and Methods We
identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK
resistance mutations and clinical outcomes on ALK TKIs were retrospectively
evaluated according to ALK variant. A Foundation Medicine data set of 577
patients with ALK-positive NSCLC was also examined. Results The most frequent
ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51
patients (40%). We analyzed 77 tumor biopsy specimens from patients with
variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were
significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023).
In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v
0%; P < .001). Analysis of the Foundation Medicine database revealed similar
associations of variant 3 with ALK resistance mutation and with G1202R ( P =
.010 and .015, respectively). Among patients treated with the third-generation
ALK TKI lorlatinib, variant 3 was associated with a significantly longer
progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to
0.79; P = .011). Conclusion Specific ALK variants may be associated with the
development of ALK resistance mutations, particularly G1202R, and provide a
molecular link between variant and clinical outcome. ALK variant thus represents
a potentially important factor in the selection of next-generation ALK
inhibitors. PURPOSE: ALK rearrangements predict for sensitivity to ALK tyrosine kinase
inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived.
Serial molecular analysis is an informative strategy for identifying genetic
mediators of resistance. Although multiple studies support the clinical benefits
of repeat tissue sampling, the clinical utility of longitudinal circulating
tumor DNA analysis has not been established in ALK-positive lung cancer.
METHODS: Using a 566-gene hybrid-capture next-generation sequencing (NGS) assay,
we performed longitudinal analysis of plasma specimens from 22 ALK-positive
patients with acquired resistance to ALK TKIs to track the evolution of
resistance during treatment. To determine tissue-plasma concordance, we compared
plasma findings to results of repeat biopsies.
RESULTS: At progression, we detected an ALK fusion in plasma from 19 (86%) of 22
patients, and identified ALK resistance mutations in plasma specimens from 11
(50%) patients. There was 100% agreement between tissue- and plasma-detected ALK
fusions. Among 16 cases where contemporaneous plasma and tissue specimens were
available, we observed 100% concordance between ALK mutation calls. ALK
mutations emerged and disappeared during treatment with sequential ALK TKIs,
suggesting that plasma mutation profiles were dependent on the specific TKI
administered. ALK G1202R, the most frequent plasma mutation detected after
progression on a second-generation TKI, was consistently suppressed during
treatment with lorlatinib.
CONCLUSIONS: Plasma genotyping by NGS is an effective method for detecting ALK
fusions and ALK mutations in patients progressing on ALK TKIs. The correlation
between plasma ALK mutations and response to distinct ALK TKIs highlights the
potential for plasma analysis to guide selection of ALK-directed therapies. BACKGROUND: Anaplastic lymphoma kinase (ALK) is a validated molecular target in
non-small-cell lung cancer (NSCLC). However, the clinical benefits of ALK
inhibitors are almost universally limited by the emergence of drug resistance.
METHODS: We monitored the plasma circulating tumor DNA (ctDNA) using
captured-based ultra-deep sequencing analysis of one patient with metastatic
ALK-positive NSCLC who had received therapies including first-, second- and
third-generation ALK inhibitors. Functional in vitro studies were further
undertaken to elucidate the mechanism of resistance.
RESULTS: ALK T1151Sins mutation was detected when the patient developed
resistance to ceritinib, and undetectable when she responded to lorlatinib. MET
amplification was present when the tumor developed resistance to lorlatinib, and
reduced when the patient received combination therapy of lorlatinib with
crizotinib, which corresponded to clinical radiologic responses. In addition,
further functional in vitro studies demonstrated that ALK harboring the
T1151Sins mutation, while conferring resistance to ceritinib, was inhibited by
lorlatinib.
CONCLUSIONS: Clinical evidence and in vitro validation revealed the clinical
usefulness of captured-base ultra-deep sequencing on longitudinal plasma ctDNA
in revealing the underlying resistance mechanism and guiding the precise
administration of ALK inhibitors in patients with advanced ALK-positive NSCLC. The identification of anaplastic lymphoma kinase (ALK), an oncogenetic driver
mutation, in lung cancer has paved the way for a new era in the treatment of
non-small cell lung cancer (NSCLC). Targeting ALK using tyrosine kinase
inhibitors (TKI) has dramatically improved the prognosis of patients with
ALK-rearranged NSCLC. However, most patients relapse on ALK-TKI therapy within a
few years because of acquired resistance. One mechanism of acquiring resistance
is a second mutation on the ALK gene, and the representative mutation is L1996M
in the gatekeeper residue. In particular, the solvent-front ALK G1202R mutation
is the common cause of resistance against first- and second-generation ALK-TKIs.
Another major concern regarding ALK-TKI is metastasis to the central nervous
system, commonly observed in patients relapsing after ALK-TKI therapy. The
next-generation ALK inhibitor lorlatinib (PF-06463922) has therefore been
developed to inhibit resistant ALK mutations, including ALK G1202R, and to
penetrate the blood-brain barrier. In a Phase I/II trial, the safety and
efficacy of lorlatinib were demonstrated in patients with advanced ALK-positive
NSCLC, most of whom had central nervous system metastases and had previous
ALK-TKI treatment. In this review, we discuss the structure, pharmacodynamics,
and pharmacokinetics of lorlatinib and compare its characteristics with those of
other ALK inhibitors. Furthermore, clinical trials for lorlatinib are
summarized, and future perspectives in the management of patients with
ALK-rearranged NSCLC are discussed. : Targeted therapy changed the standard of care in ALK-dependent tumors.
However, resistance remains a major challenge. Lorlatinib is a third-generation
ALK inhibitor that inhibits most ALK mutants resistant to current ALK
inhibitors. In this study, we utilize lorlatinib-resistant anaplastic large cell
lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cell
lines in vitro and in vivo to investigate the acquisition of resistance and its
underlying mechanisms. ALCL cells acquired compound ALK mutations G1202R/G1269A
and C1156F/L1198F in vitro at high drug concentrations. ALCL xenografts selected
in vivo showed recurrent N1178H (5/10 mice) and G1269A (4/10 mice) mutations.
Interestingly, intracellular localization of NPM/ALKN1178H skewed toward the
cytoplasm in human cells, possibly mimicking overexpression. RNA sequencing of
resistant cells showed significant alteration of PI3K/AKT and RAS/MAPK pathways.
Functional validation by small-molecule inhibitors confirmed the involvement of
these pathways in resistance to lorlatinib. NSCLC cells exposed in vitro to
lorlatinib acquired hyperactivation of EGFR, which was blocked by erlotinib to
restore sensitivity to lorlatinib. In neuroblastoma, whole-exome sequencing and
proteomic profiling of lorlatinib-resistant cells revealed a truncating NF1
mutation and hyperactivation of EGFR and ErbB4. These data provide an extensive
characterization of resistance mechanisms that may arise in different
ALK-positive cancers following lorlatinib treatment. SIGNIFICANCE:
High-throughput genomic, transcriptomic, and proteomic profiling reveals various
mechanisms by which multiple tumor types acquire resistance to the
third-generation ALK inhibitor lorlatinib. BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor
of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a
phase 1 study, activity was seen in patients with ALK-positive non-small-cell
lung cancer, most of whom had CNS metastases and progression after ALK-directed
therapy. We aimed to analyse the overall and intracranial antitumour activity of
lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.
METHODS: In this phase 2 study, patients with histologically or cytologically
ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or
without CNS metastases, with an Eastern Cooperative Oncology Group performance
status of 0, 1, or 2, and adequate end-organ function were eligible. Patients
were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK
and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally
once daily continuously in 21-day cycles. The primary endpoint was overall and
intracranial tumour response by independent central review, assessed in pooled
subgroups of ALK-positive patients. Analyses of activity and safety were based
on the safety analysis set (ie, all patients who received at least one dose of
lorlatinib) as assessed by independent central review. Patients with measurable
CNS metastases at baseline by independent central review were included in the
intracranial activity analyses. In this report, we present lorlatinib activity
data for the ALK-positive patients (EXP1-5 only), and safety data for all
treated patients (EXP1-6). This study is ongoing and is registered with
ClinicalTrials.gov, number NCT01970865.
FINDINGS: Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30
who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and
received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous
chemotherapy; 28 who were ALK positive and received one previous non-crizotinib
ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who
were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK
tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1
positive with any previous treatment (EXP6). One patient in EXP4 died before
receiving lorlatinib and was excluded from the safety analysis set. In
treatment-naive patients (EXP1), an objective response was achieved in 27
(90·0%; 95% CI 73·5-97·9) of 30 patients. Three patients in EXP1 had measurable
baseline CNS lesions per independent central review, and objective intracranial
responses were observed in two (66·7%; 95% CI 9·4-99·2). In ALK-positive
patients with at least one previous ALK tyrosine kinase inhibitor (EXP2-5),
objective responses were achieved in 93 (47·0%; 39·9-54·2) of 198 patients and
objective intracranial response in those with measurable baseline CNS lesions in
51 (63·0%; 51·5-73·4) of 81 patients. Objective response was achieved in 41
(69·5%; 95% CI 56·1-80·8) of 59 patients who had only received previous
crizotinib (EXP2-3A), nine (32·1%; 15·9-52·4) of 28 patients with one previous
non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6-48·5)
of 111 patients with two or more previous ALK tyrosine kinase inhibitors
(EXP4-5). Objective intracranial response was achieved in 20 (87·0%; 95% CI
66·4-97·2) of 23 patients with measurable baseline CNS lesions in EXP2-3A, five
(55·6%; 21·2-86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3-67·5) of 49
patients in EXP4-5. The most common treatment-related adverse events across all
patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43
[16%] grade 3-4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade
3-4). Serious treatment-related adverse events occurred in 19 (7%) of 275
patients and seven patients (3%) permanently discontinued treatment because of
treatment-related adverse events. No treatment-related deaths were reported.
INTERPRETATION: Consistent with its broad ALK mutational coverage and CNS
penetration, lorlatinib showed substantial overall and intracranial activity
both in treatment-naive patients with ALK-positive non-small-cell lung cancer,
and in those who had progressed on crizotinib, second-generation ALK tyrosine
kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors.
Thus, lorlatinib could represent an effective treatment option for patients with
ALK-positive non-small-cell lung cancer in first-line or subsequent therapy.
FUNDING: Pfizer. |
What periodontal disease associated bacteria is also associated with Alzheimer's disease? | Porphyromonas gingivalis, a keystone pathogen in chronic periodontitis, has been found to associate with remote body organ inflammatory pathologies, including atherosclerosis and Alzheimer's disease (AD). | BACKGROUND: Chronic inflammation in periodontal disease has been suggested as a
potential risk factor in Alzheimer's disease (AD). The purpose of this study was
to examine serum antibody levels to bacteria of periodontal disease in
participants who eventually converted to AD compared with the antibody levels in
control subjects.
METHODS: Serum samples from 158 participants in the Biologically Resilient
Adults in Neurological Studies research program at the University of Kentucky
were analyzed for immunoglobulin G antibody levels to seven oral bacteria
associated with periodontitis, including Aggregatibacter actinomycetemcomitans,
Porphyromonas gingivalis, Campylobacter rectus, Treponema denticola,
Fusobacterium nucleatum, Tannerella forsythia, and Prevotella intermedia. All
158 participants were cognitively intact at baseline venous blood draw. In all,
81 of the participants developed either mild cognitive impairment (MCI) or AD or
both, and 77 controls remained cognitively intact in the years of follow-up.
Antibody levels were compared between controls and subjects with AD at baseline
draw and after conversion and controls and subjects with MCI at baseline draw
and after conversion using the Wilcoxon rank-sum test. AD and MCI participants
were not directly compared. Linear regression models were used to adjust for
potential confounding.
RESULTS: Antibody levels to F nucleatum and P intermedia were significantly
increased (α = 0.05) at baseline serum draw in the patients with AD compared
with controls. These results remained significant when controlling for baseline
age, Mini-Mental State Examination score, and apolipoprotein epsilon 4 status.
CONCLUSIONS: This study provides initial data that demonstrate elevated
antibodies to periodontal disease bacteria in subjects years before cognitive
impairment and suggests that periodontal disease could potentially contribute to
the risk of AD onset/progression. Additional cohort studies profiling oral
clinical presentation with systemic response and AD and prospective studies to
evaluate any cause-and-effect association are warranted. Periodontitis is a chronic oral inflammatory disease produced by bacteria.
Gingival retraction and bone and connective tissues resorption are the hallmarks
of this disease. Chronic periodontitis may contribute to the risk of onset or
progression of neuroinflammatory pathological conditions, such as Alzheimer's
disease. The main goal of the present study was to investigate if the role of
epigenetic modulations is involved in periodontitis using human periodontal
ligament stem cells (hPDLSCs) as an in vitro model system. hPDLSCs were treated
with lipopolysaccharide of Porphyromonas gingivalis and the expression of
proteins associated with DNA methylation and histone acetylation, such as DNMT1
and p300, respectively, and inflammatory transcription factor NF-kB, were
examined. Immunofluorescence, Western blot and next generation sequencing
results demonstrated that P. gingivalis lipopolysaccharide significantly reduced
DNA methylase DNMT1, while it markedly upregulated the level of histone
acetyltransferase p300 and NF-kB in hPDLSCs. Our results showed that P.
gingivalis lipopolysaccharide markedly regulate the genes involved in epigenetic
mechanism, which may result in inflammation induction. We propose that P.
gingivalis lipopolysaccharide-treated hPDLSCs could be a potential in vitro
model system to study epigenetics modulations associated with periodontitis,
which might be helpful to identify novel biomarkers linked to this oral
inflammatory disease. Longitudinal monitoring of patients suggests a causal link between chronic
periodontitis and the development of Alzheimer's disease (AD). However, the
explanation of how periodontitis can lead to dementia remains unclear. A working
hypothesis links extrinsic inflammation as a secondary cause of AD. This
hypothesis suggests a compromised oral hygiene leads to a dysbiotic oral
microbiome whereby Porphyromonas gingivalis, a keystone periodontal pathogen,
with its companion species, orchestrates immune subversion in the host. Brushing
and chewing on teeth supported by already injured soft tissues leads to
bacteremias. As a result, a persistent systemic inflammatory response develops
to periodontal pathogens. The pathogens, and the host's inflammatory response,
subsequently lead to the initiation and progression of multiple metabolic and
inflammatory co-morbidities, including AD. Insufficient levels of essential
micronutrients can lead to microbial dysbiosis through the growth of periodontal
pathogens such as demonstrated for P. gingivalis under low hemin
bioavailability. An individual's diet also defines the consortium of microbial
communities that take up residency in the oral and gastrointestinal (GI) tract
microbiomes. Their imbalance can lead to behavioral changes. For example,
probiotics enriched in Lactobacillus genus of bacteria, when ingested, exert
some anti-inflammatory influence through common host/bacterial neurochemicals,
both locally, and through sensory signaling back to the brain. Early life
dietary behaviors may cause an imbalance in the host/microbial endocrinology
through a dietary intake incompatible with a healthy GI tract microbiome later
in life. This imbalance in host/microbial endocrinology may have a lasting
impact on mental health. This observation opens up an opportunity to explore the
mechanisms, which may underlie the previously detected relationship between
diet, oral/GI microbial communities, to anxiety, cognition and sleep patterns.
This review suggests healthy diet based interventions that together with
improved life style/behavioral changes may reduce and/or delay the incidence of
AD. |
Is deletion at 6q24.2-26 associated with longer survival of patients with high-grade serous ovarian carcinoma (HGSOCs)? | Yes. Loss at 6q24.2-26 was significantly associated with the cluster of longer survival independently from other confounding factors. The prognostic value of this deletion was validated in two independent series, one consisting of 36 HGSOCs analyzed by fluorescent in situ hybridization (P = 0.04) and another comprised of 411 HGSOCs from the Cancer Genome Atlas study (TCGA) (HR = 0.67, 95%CI = 0.48-0.93, Padj = 0.019). | Author information:
(1)Human Genetics Group, Spanish National Cancer Research Center (CNIO), C/
Melchor Fernández Almagro 3, 28029, Madrid, Spain.
(2)Structural Computational Biology Group, Spanish National Cancer Research
Center (CNIO), C/ Melchor Fernández Almagro 3 28029, Madrid, Spain.
(3)Cancer Epidemiology Centre, Cancer Council Victoria, 615 St Kilda Road,
Melbourne 3004, Australia; Center for Epidemiology and Biostatistics, Melbourne
School of Population and Global Health, The University of Melbourne, Level 3,
207 Bouverie Street Carlton, Melbourne 3010, Victoria, Australia.
(4)Molecular Cytogenetics Group, Spanish National Cancer Research Center (CNIO),
C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain.
(5)Departments of Genetics, Reproduction, and Fetal Medicine, IBIS, University
Hospital Virgen del Rocio/CSIC/University of Seville, Avda. Manuel Siurot, s/n.,
41013 Sevilla, Spain; Biomedical Network Research Centre on Rare Diseases
(CIBERER), Spain.
(6)Pathology Department, Fundación Jiménez Díaz, Avda. Reyes Católicos, 2, 28040
Madrid, Spain.
(7)Oncology Department, Hospital General de Albacete, Calle Hermanos Falco, 37,
02006 Albacete, Spain.
(8)Oncology Department, Fundación Hospital Alcorcón, Calle Valdelaguna, 1, 28922
Alcorcón, Spain.
(9)Medical Oncology Service, Oncologic Center Clara Campal, Calle Oña, 10, 28050
Madrid, Spain.
(10)Breast Cancer Clinical Research Unit, Spanish National Cancer Research
Center (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain.
(11)Medical Oncology Service, Hospital Sant Pau, Carrer de Sant Quintí, 89,
08026 Barcelona, Spain.
(12)Familial Cancer Unit and Medical Oncology Department, Hospital 12 de
Octubre, Avda de Córdoba, s/n, 28041 Madrid, Spain.
(13)Medical Oncology Service, Instituto de Investigación Sanitaria Gregorio
Marañón, Universidad Complutense, Calle Doctor Esquerdo, 46, 28007 Madrid,
Spain.
(14)Obstetrics and Gynecology Department, Institut Universitari Dexeus, Carrer
de Sabino Arana, 5, 08028 Barcelona, Spain.
(15)Laboratory of Genetics, Hospital Donostia, Calle Doctor Begiristain, 117,
20080 San Sebastián, Spain.
(16)Department of Internal Medicine, Hospital Severo Ochoa, Avd. de Orellana,
s/n., 28911 Madrid, Spain.
(17)Human Genetics Group, Spanish National Cancer Research Center (CNIO), C/
Melchor Fernández Almagro 3, 28029, Madrid, Spain; Biomedical Network Research
Centre on Rare Diseases (CIBERER), Spain.
(18)Familial Cancer Clinical Unit, Spanish National Cancer Research Center
(CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain; Biomedical Network
Research Centre on Rare Diseases (CIBERER), Spain.
(19)Molecular Cytogenetics Group, Spanish National Cancer Research Center
(CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain; Biomedical Network
Research Centre on Rare Diseases (CIBERER), Spain.
(20)Medical Oncology Department, University Hospital Virgen del Rocio, Avda.
Manuel Siurot s/n., 41013 Sevilla, Spain.
(21)Pathology Department, Hospital Universitario Ramón y Cajal, Ctra. de
Colmenar Viejo, km. 9,100, 28034 Madrid, Spain.
(22)Human Genetics Group, Spanish National Cancer Research Center (CNIO), C/
Melchor Fernández Almagro 3, 28029, Madrid, Spain; Biomedical Network Research
Centre on Rare Diseases (CIBERER), Spain. Electronic address: [email protected]. |
How does the Cholera toxin enter a cell? | Cholera toxin (CT), which is secreted by V. cholerae, can enter host cells by binding to GM1, a monosialoganglioside widely distributed on the plasma membrane surface of various animal epithelial cells. | Cholera is an acute diarrheal disease caused by infection in the
gastrointestinal tract by the gram-negative bacterium, Vibrio cholerae, and is a
serious public health threat worldwide. There has not been any effective
treatment for this infectious disease. Cholera toxin (CT), which is secreted by
V. cholerae, can enter host cells by binding to GM1, a monosialoganglioside
widely distributed on the plasma membrane surface of various animal epithelial
cells. The present study was undertaken to generate peptides that are
conformationally similar to the carbohydrate epitope of GM1 for use in the
treatment of cholera and related bacterial infection. For this purpose, we used
cholera toxin B (CTB) subunit to select CTB-binding peptides that structurally
mimic GM1 from a dodecamer phage-display library. Six GM1-replica peptides were
selected by biopanning based on CTB recognition. Five of the six peptides showed
inhibitory activity for GM1 binding to CTB. To test the potential of employing
the peptide mimics for intervening with the bacterial infection, those peptides
were examined for their binding capacity, functional inhibitory activity and in
vitro effects using a human intestinal epithelial cell line, Caco-2 cells. One
of the peptides, P3 (IPQVWRDWFKLP), was most effective in inhibiting cellular
uptake of CTB and suppressing CT-stimulated cyclic adenosine monophosphate
production in the cells. Our results thus provide convincing evidence that
GM1-replica peptides could serve as novel agents to block CTB binding on
epithelial cells and prevent the ensuing physiological effects of CT. The five B-subunits (CTB5) of the Vibrio cholerae (cholera) toxin can bind to
the intestinal cell surface so the entire AB5 toxin can enter the cell.
Simultaneous binding can occur on more than one of the
monosialotetrahexosylganglioside (GM1) units present on the cell surface. Such
simultaneous binding arising from the toxins multivalency is believed to enhance
its affinity. Thus, blocking the initial attachment of the toxin to the cell
surface using inhibitors with GM1 subunits has the potential to stop the
disease. Previously we showed that tetravalent GM1 molecules were sub-omolar
inhibitors of CTB5. In this study, we synthesized a pentavalent version and
compared the binding and potency of penta- and tetravalent cholera toxin
inhibitors, based on the same scaffold, for the first time. The pentavalent
geometry did not yield major benefits over the tetravalent species, but it was
still a strong inhibitor, and no major steric clashes occurred when binding the
toxin. Thus, systems which can adopt more geometries, such as those described
here, can be equally potent, and this may possibly be due to their ability to
form higher-order structures or simply due to more statistical options for
binding. |
Describe the mechanism of action of Lurbinectedin. | Lurbinectedin is a novel highly selective inhibitor of RNA polymerase II triggering caspase-dependent apoptosis of cancerous cells. It inhibits active transcription of protein-coding genes, causing DNA-break accumulation, apoptosis and modulation of the tumor microenvironment. | BACKGROUND AND OBJECTIVES: Lurbinectedin is an inhibitor of RNA polymerase II
currently under clinical development for intravenous administration as a single
agent and in combination with other anti-tumor agents for the treatment of
several tumor types. The objective of this work was to develop a
population-pharmacokinetic model in this patient setting and to elucidate the
main predictors to guide the late stages of development.
METHODS: Data from 443 patients with solid and hematologic maligcies treated
in six phase I and three phase II trials with lurbinectedin as a single agent or
combined with other agents were included in the analysis. The potential
influence of demographic, co-treatment, and laboratory characteristics on
lurbinectedin pharmacokinetics was evaluated.
RESULTS: The final population-pharmacokinetic model was an open
three-compartment model with linear distribution and linear elimination from the
central compartment. Population estimates for total plasma clearance, and
apparent volume at steady state were 11.2 L/h and 438 L, respectively.
Inter-individual variability was moderate for all parameters, ranging from 20.9
to 51.2%. High α-1-acid glycoprotein and C-reactive protein, and low albumin
reduced clearance by 28, 20, and 20%, respectively. Co-administration of
cytochrome P450 3A inhibitors reduced clearance by 30%. Combinations with other
anti-tumor agents did not modify the pharmacokinetics of lurbinectedin
significantly.
CONCLUSION: The population-pharmacokinetic model indicated neither a dose nor
time dependency, and no clinically meaningful pharmacokinetic differences were
found when co-administered with other anticancer agents. A chronic inflammation
pattern characterized by decreased albumin and increased C-reactive protein and
α-1-acid glycoprotein levels led to high lurbinectedin exposure.
Co-administration of cytochrome P450 3A inhibitors increased lurbinectedin
exposure. Trabectedin is an FDA-approved DNA minor groove binder that has activity against
translocation-associated sarcomas. Lurbinectedin is a next-generation minor
groove binder with preclinical activity against myeloid leukemia cells. A
dose-finding phase 1 clinical trial was performed in patients with acute myeloid
leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of
safety and tolerability. Forty-two patients with relapsed/refractory AML/MDS
received lurbinectedin administered as a 1-hour intravenous infusion in a 3 + 3
study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8
or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients
experienced dose-limiting toxicities of rhabdomyolysis (grade 4),
hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8
schedule. Otherwise, adverse events mainly consisted of gastrointestinal
manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary
toxicity (n = 2), and renal failure (n = 2). The most common laboratory
abnormalities observed were an increase in creatinine (93%) and anemia,
neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had
reduction in blasts in peripheral blood or bone marrow. One patient achieved a
partial response and 2 patients a morphologic leukemia-free state. Most (n = 30,
71%) were discontinued due to progressive disease. Early deaths occurred from
disease-related causes that were not attributable to lurbinectedin. Four
patients with a chromosome 11q21-23 abnormality had significantly greater bone
marrow blast reduction than those without such abnormality, with decrease of
31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall,
lurbinectedin was safe and tolerated using the schedules and dose levels tested.
While no sustained remissions were observed, single-agent lurbinectedin was
transiently leukemia suppressive for some patients. Conflict of interest statement: Ficial & competing interests disclosure AF
Farago received consulting fees from PharmaMar, Bayer, Loxo, Abbvie,
Abbvie/Stemcentrx and Genentech. The author further received research funding
from PharmaMar, Bayer, Loxo, AbbVie, AbbVie/Stemcentrx, Merck, BMS, AstraZeneca
and Novartis. BJ Drapkin received research funding from AstraZeneca, Novartis
and AbbVie. JAL-Vilarino de Ramos, CM Golmarini, R Nunez, C Kahatt are employees
of PharmaMar. L Paz-Ares gave scientific advice to Astra-Zeneca, BMS, MSD,
Roche, Incyte, Takeda, Lilly, Novartis, Pfizer, Pharmamar, Amgen and Genomica.
The manuscript arose, in whole or in part, from direct costs funded by NIH
(grant number: K12 CA087723). The authors have no other relevant affiliations or
ficial involvement with any organization or entity with a ficial interest
in or ficial conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed. No writing assistance was utilized in the
production of this manuscript. |
Can mogamulizumab be used for the treatment of cutaneous T-cell lymphoma? | Yes, mogamulizumab can be used for the treatment of cutaneous T-cell lymphoma. | In the large international phase III MAVORIC trial, patients with previously
treated cutaneous T-cell lymphoma who received the anti-CCR4 monoclonal antibody
mogamulizumab experienced significantly longer progression-free survival and
higher response rates, as well as better quality of life, than those who
received vorinostat, a standard therapy. |
Which enzymes are inhibited by Duvelisib? | Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ in late-stage clinical development for hematologic malignancy treatment. | Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated
signaling holds great promise for treating chronic lymphocytic leukemia (CLL).
Therefore we assessed three structurally related PI3K inhibitors targeting the
PI3K-δ isoform for their ability to inhibit the survival of freshly isolated CLL
cells. The purely PI3K-δ-selective inhibitor idelalisib was compared to
copanlisib (BAY 80-6946) and duvelisib (IPI-145), with isoform target profiles
that additionally include PI3K-α or PI3K-γ, respectively. The concentrations
leading to half-maximal reduction of the survival of CLL cells were more than
ten-fold lower for copanlisib than for idelalisib and duvelisib. At
concentrations reflecting the biological availability of the different
inhibitors, high levels of apoptotic response among CLL samples were attained
more consistently with copanlisib than with idelalisib. Copanlisib selectively
reduced the survival of CLL cells compared to T cells and to B cells from
healthy donors. In addition copanlisib and duvelisib impaired the migration of
CLL cells towards CXCL12 to a greater extent than equimolar idelalisib.
Similarly copanlisib and duvelisib reduced the survival of CLL cells in
co-cultures with the bone marrow stroma cell line HS-5 more strongly than
idelalisib. Survival inhibition by copanlisib and idelalisib was enhanced by the
monoclonal CD20 antibodies rituximab and obinutuzumab (GA101), while
antibody-dependent cellular cytotoxicity mediated by alemtuzumab and peripheral
blood mononuclear cells was not substantially impaired by both PI3K inhibitors
for the CLL-derived JVM-3 cell line as target cells. Taken together, targeting
the α- and δ- p110 isoforms with copanlisib may be a useful strategy for the
treatment of CLL and warrants further clinical investigation. Phosphoinositide-3-kinase (PI3K) is an enzyme group, known to regulate key
survival pathways in acute myeloid leukaemia (AML). It generates
phosphatidylinositol-3,4,5-triphosphate, which provides a membrane docking site
for protein kinaseB activation. PI3K catalytic p110 subunits are divided into 4
isoforms; α,β,δ and γ. The PI3Kδ isoform is always expressed in AML cells,
whereas the frequency of PI3Kγ expression is highly variable. The functions of
these individual catalytic enzymes have not been fully resolved in AML,
therefore using the PI3K p110δ and p110γ-targeted inhibitor IPI-145 (duvelisib)
and specific p110δ and p110γ shRNA, we analysed the role of these two p110
subunits in human AML blast survival. The results show that PI3Kδ and PI3Kγ
inhibition with IPI-145 has anti-proliferative activity in primary AML cells by
inhibiting the activity of AKT and MAPK. Pre-treatment of AML cells with IPI-145
inhibits both adhesion and migration of AML blasts to bone marrow stromal cells.
Using shRNA targeted to the individual isoforms we demonstrated that
p110δ-knockdown had a more significant anti-proliferative effect on AML cells,
whereas targeting p110γ-knockdown significantly inhibited AML migration. The
results demonstrate that targeting both PI3Kδ and PI3Kγ to inhibit AML-BMSC
interactions provides a biologic rationale for the pre-clinical evaluation of
IPI-145 in AML. Frontline chemotherapy is successful against chronic lymphocytic leukemia (CLL),
but results in untoward toxicity. Further, prognostic factors, cytogenetic
anomalies, and compensatory cellular signaling lead to therapy resistance or
disease relapse. Therefore, for the past few years, development of targeted
therapies is on the rise. PI3K is a major player in the B-cell receptor (BCR)
signaling axis, which is critical for the survival and maintece of B cells.
Duvelisib, a PI3K δ/γ dual isoform specific inhibitor that induces apoptosis and
reduces cytokine and chemokine levels in vitro, holds promise for CLL. Areas
covered: Herein, we review PI3K isoforms and their inhibitors in general, and
duvelisib in particular; examine literature on preclinical investigations,
pharmacokinetics and clinical studies of duvelisib either as single agent or in
combination, for patients with CLL and other lymphoid maligcies. Expert
opinion: Duvelisib targets the PI3K δ isoform, which is necessary for cell
proliferation and survival, and γ isoform, which is critical for cytokine
signaling and pro-inflammatory responses from the microenvironment. In phase I
clinical trials, duvelisib as a single agent showed promise for CLL and other
lymphoid maligcies. Phase II and III trials of duvelisib alone or in
combination with other agents are ongoing. Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase
(PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may
directly inhibit maligt T-cell growth, making duvelisib a promising candidate
for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma.
Inhibition of either isoform may also contribute to clinical responses by
modulating nonmaligt immune cells. We investigated these dual effects in a
TCL cohort from a phase 1, open-label study of duvelisib in patients with
relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and
in vivo models of TCL. The overall response rates in patients with PTCL and CTCL
were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses,
all among patients with PTCL. Activity was seen across a wide spectrum of
subtypes. The most frequently observed grade 3 and 4 adverse events were
transaminase increases (40% alanine aminotransferase, 17% aspartate
aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders
and nonresponders had markedly different changes in serum cytokine profiles
induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with
constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and
exceeded cell killing by the PI3K-δ-specific inhibitor idelalisib.
Administration of duvelisib to mice engrafted with a PTCL patient-derived
xenograft resulted in a shift among tumor-associated macrophages from the
immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In
summary, duvelisib demonstrated promising clinical activity and an acceptable
safety profile in relapsed/refractory TCL, as well as preclinical evidence of
both tumor cell-autonomous and immune-mediated effects. This trial was
registered at www.clinicaltrials.gov as #NCT01476657. Epstein-Barr virus (EBV) is a ubiquitous oncogenic virus that is associated with
B cell lymphomas, including Burkitt lymphoma and Hodgkin lymphoma. Previous
studies have shown that the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is
activated in EBV-associated lymphomas and can be a novel therapeutic target. An
oral dual inhibitor of PI3Kγ and PI3Kδ, duvelisib, is in clinical trials for the
treatment of lymphoid maligcies. In this study, we evaluated how duvelisib
affects the activity of the PI3K/Akt signaling pathway and if it has antitumor
effects in EBV-associated lymphoma cell lines. We found that the PI3K/Akt
signaling pathway was activated in most of the B and T cell lymphoma cell lines
tested. Additionally, duvelisib treatment inhibited cellular growth in the
tested cell lines. Overall, B cell lines were more susceptible to duvelisib than
T and NK cell lines in vitro regardless of EBV infection. However, the
additional influence of duvelisib on the tumor microenvironment was not
assessed. Duvelisib treatment induced both apoptosis and cell cycle arrest in
EBV-positive and -negative B cell lines, but not in T cell lines. Furthermore,
duvelisib treatment reduced the expression of EBV lytic genes (BZLF1 and
gp350/220) in EBV-positive B cell lines, suggesting that duvelisib suppresses
the lytic cycle of EBV induced by B cell receptor signaling. However, duvelisib
did not induce a remarkable change in the expression of EBV latent genes. These
results may indicate that there is therapeutic potential for duvelisib
administration in the treatment of EBV-associated B cell lymphomas and other B
cell maligcies. Duvelisib (IPI-145) is an oral dual inhibitor of phosphoinositide-3-kinase
(PI3K)-δ and -γ in clinical development for the treatment of hematologic
maligcies, including indolent non-Hodgkin lymphoma (iNHL). In a Phase 1,
open-label study to determine the maximum tolerated dose (MTD),
pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib
monotherapy in patients with advanced hematologic maligcies, duvelisib was
administered at eight dose levels (8-100 mg BID) in a dose-escalation phase (n
= 31 evaluable patients). Two dose-limiting toxicities (DLTs), Grade 3
transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD
was determined to be 75 mg BID. Across all doses, 58.1% of iNHL patients had a
response (19.4% complete, 35.5% partial, and 3.2% minor); median time to
response was 1.84 months and duration of response was 16.9 months. Median
progression-free survival was 14.7 months, and the probability of overall
survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included
elevated liver enzymes (38.7%), diarrhea (25.8%), and neutropenia (29.0%). Three
patients, all in the 75 mg BID cohort, experienced fatal AEs: E. coli sepsis,
acute respiratory failure, and fungal pneumonia. No iNHL patients experienced
Pneumocystis pneumonia. Duvelisib demonstrated favorable clinical activity and
an acceptable safety profile in these high-risk, heavily pretreated,
relapsed/refractory iNHL patients, with 25 mg BID selected for further clinical
development. Duvelisib is an orally active dual inhibitor of PI3K-δ and PI3K-γ in clinical
development in hematologic maligcies (HM). To identify novel pairings for
duvelisib in HM, it was evaluated alone and in combination with 35 compounds
comprising a diverse panel of standard-of-care agents and emerging drugs in
development for HM. These compounds were tested in 20 cell lines including
diffuse large B-cell, follicular, T-cell, and mantle cell lymphomas, and
multiple myeloma. Single agent activity was seen in fourteen cell lines, with a
median GI50 of 0.59 μM. A scalar measure of the strength of synergistic drug
interactions revealed a synergy hit rate of 19.3% across the matrix of drug
combinations and cell lines. Synergy with duvelisib was prominent in lymphoma
lines with approved and emerging drugs used to treat HM, including
dexamethasone, ibrutinib, and the BCL-2 inhibitor venetoclax. Western blotting
revealed that certain duvelisib-treated cell lines showed inhibition of
phosphorylated (p) AKT at serine 473 only out to 12 hours, with mTORC2 dependent
re-phosphorylation of pAKT evident at 24 hours. Combination with dexamethasone
or ibrutinib, however, prevented this reactivation leading to durable inhibition
of pAKT. The combination treatments also inhibited downstream signaling
effectors pPRAS40 and pS6. The combination of duvelisib with dexamethasone also
significantly reduced p-4EBP1, which controls cap dependent translation
initiation, leading to decreased levels of c-MYC 6 hours after treatment. In
support of the in vitro studies, in vivo xenograft studies revealed that
duvelisib in combination with the mTOR inhibitor everolimus led to greater tumor
growth inhibition compared to single agent administration. These data provide a
rationale for exploring multiple combinations in the clinic and suggest that
suppression of mTOR-driven survival signaling may be one important mechanism for
combination synergy. Duvelisib (IPI-145), an oral, dual inhibitor of phosphoinositide-3-kinase
(PI3K)-δ and -γ, was evaluated in a Phase 1 study in advanced hematologic
maligcies, which included expansion cohorts in relapsed/refractory (RR)
chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and
treatment-naïve (TN) CLL. Per protocol, TN patients were at least 65 years old
or had a del(17p)/TP53 mutation. Duvelisib was administered twice daily (BID) in
28-day cycles at doses of 8-75 mg in RR patients (n = 55) and 25 mg in TN
patients (n = 18.) Diarrhea was the most common nonhematologic AE (TN 78%, RR
47%); transaminase elevations the most frequent lab-abnormality AE (TN 33.3%, RR
30.9%); and neutropenia the most common ≥grade 3 AE (RR 44%, TN 33%). The
overall response rates were 56.4% for RR patients (1.8% CR, 54.5% PR) and 83.3%
for TN patients (all PRs); median response duration was 21.0 months in RR
patients but was not reached for TN patients. Based upon phase 1 efficacy,
pharmacodynamics, and safety, duvelisib 25 mg BID was selected for further
investigation in a phase 3 study in RR CLL/SLL. |
List search engines used in proteomics. | Mascot
X!Tandem
MS-GF
MS Amanda
MyriMatch
Comet
Tide
Andromeda
OMSSA | |
Is avelumab effective for bladder cancer? | Yes, avelumab is effective treatment of bladder cancer. | The treatment of bladder cancer has evolved over time to encompass not only the
traditional modalities of chemotherapy and surgery, but has been particularly
impacted by the use of immunotherapy. The first immunotherapy was the live,
attenuated bacterial Bacillus Calmette-Guérin vaccine, which has been the
standard of care non-muscle-invasive bladder cancer since 1990. Modern
immunotherapy has focused on inhibitors of checkpoint proteins, which are
molecules that impede immune function, thereby allowing tumor cells to grow and
proliferate unregulated. Several checkpoint targets (programmed death ligand-1
[PD-L1] programmed cell death protien-1 [PD-1], and cytotoxic T-lymphocyte
associated protein 4 [CTLA4]) have received the most attention in the treatment
of bladder cancer, and have inhibitor agents either approved or in late-stage
development. This review describes the most recent data on agents that inhibit
PD-L1, found on the surface of tumor cells, and PD-1 found on activated T and B
cells and macrophages. Atezolizumab is the only member of this class currently
approved for the treatment of bladder cancer, but nivolumab, pembrolizumab,
durvalumab, and avelumab all have positive results for this indication, and
approvals are anticipated in the near future. The checkpoint inhibitors offer an
effective alternative for patients for whom previously there were few options
for durable responses, including those who are ineligible for cisplatin-based
regimens or who are at risk of significant toxicity. Research is ongoing to
further categorize responses, define ideal patient populations, and investigate
combinations of checkpoint inhibitors to address multiple pathways in immune
system functioning. Cytotoxic chemotherapy has been the only systemic treatment of locally advanced
and metastatic urothelial carcinoma for decades. Long-term survival remains
stagt around 12-14 months for patients with advanced disease who have
progressed on or recurred after receiving first-line platinum-based
chemotherapy. Improving clinical outcomes for patients with urothelial carcinoma
in all disease settings requires the development of novel treatments, especially
for patients who failed on first-line chemotherapy. Since the discovery of
intravesical Bacillus-Calmette Guerin (BCG) in the 1970s for non-muscle invasive
disease, there have not been any major breakthrough drugs that exploit the
immune-sensitivity of bladder cancer until recently. Immune-checkpoint
inhibitors targeting the programmed death 1/programmed death-ligand 1
(PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways
have shown significant anti-tumor activity, tolerable safety profiles and
durable, long-term responses in clinical trials. Atezolizumab, avelumab,
durvalumab, nivolumab and pembrolizumab are promising PD-1/PD-L1 blockade drugs
under investigation that will redefine the standard of care for bladder cancer.
CTLA-4 inhibitors are also under investigation in this setting. Atezolizumab,
approved in May 2016, and nivolumab, approved in February 2017, are the first
Food and Drug Administration (FDA)-approved immune-checkpoint inhibitors in
bladder cancer for platinum-pretreated patients based on phase II data. On March
16, 2017, results from the phase III trial KEYNOTE-045 demonstrated that
survival was significantly longer in patients treated with pembrolizumab when
compared with the standard second-line chemotherapy. Research into biomarkers
such as PD-L1 expression, messenger RNA subtype, mutational and neoantigen load
and gene signature expression will be crucial to determining why some patients
respond to immunotherapy and others do not. This review article describes the
advances in immunotherapy since the development of BCG, presents results from
clinical trials investigating immune-checkpoint inhibitors and discusses
biomarkers and prognostic factors associated with response to these new drugs. Bladder cancer is the most common maligcy involving the genitourinary system
(Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). In the USA, it is the fifth
most common cancer and approximately 79,000 new cases will be diagnosed in 2017
(Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). The mortality from bladder
cancer is approximately 17,000 deaths each year (Siegel et al. in CA Cancer J
Clin, 66:7-30, 2016). The incidence rate for bladder cancer is higher in men
compared to women. Risk factors are predomitly related to tobacco smoking,
although infection with Schistosoma haematobium is another risk factor in
selected populations (Antoni et al. in Eur Urol, 71:96-108, 2017).
Cisplatin-based systemic chemotherapy regimens remain the standard of care in
both the neoadjuvant and metastatic setting for muscle-invasive bladder cancer
(Gupta et al. in Cancer, 9(15):1-14, 2017; Von der Maase et al. in J Clin Oncol,
23:4602-4608, 2005; De Santis et al. in J Clin Oncol, 30:191-199, 2012; Bellmunt
et al. in J Clin Oncol, 27: 4454-4461, 2009). There is an estimated overall
survival of 9-15 months in metastatic bladder cancer in those who receive the
standard of care platinum-based chemotherapy (Von der Maase et al. in J Clin
Oncol, 23:4602-4608, 2005; De Santis et al. in J Clin Oncol, 30:191-199, 2012).
The median survival, however, is significantly reduced after relapse in patient
treated with platinum chemotherapy to less than 7 months (Bellmunt et al. in J
Clin Oncol, 27: 4454-4461, 2009). Thus, this approach is preferred for patients
who can tolerate this treatment as first-line chemotherapy (Gupta et al. in
Cancer, 9(15):1-14, 2017). Until recently, there were few treatment options for
those patients with poor performance status who are ineligible to receive
cisplatin including renal insufficiency and multiple comorbidities or had
disease progression after receiving platinum-based chemotherapy (Gupta et al. in
Cancer, 9(15):1-14, 2017). With further understanding of tumor immune evasion,
systemic immunotherapy which utilizes the patient's own immune system directly
to eradicate and target neoplastic cells, has now been approved for urothelial
bladder cancer. Monoclonal antibodies that target programmed cell death protein
1 (PD-1), including Nivolumab and Pembrolizumab, and its ligand, PD-L1,
including Atezolizumab, Durvalumab, Avelumab, have all been investigated and
approved in the setting of metastatic refractory urothelial cancer (Gupta et al.
in Cancer, 9(15):1-14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602-4608,
2005; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174 ).
Atezolizumab and Pembrolizumab have also been approved as first-line therapy in
the setting of cisplatin-ineligible metastatic bladder cancer (Gupta et al. in
Cancer, 9(15):1-14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi:
10.1155/2017/5618174 ). Those that target cytotoxic T-lymphocyte-associated
protein 4, including Ipilimumab and Tremelimumab, have also been investigated
and further studies are being performed (Gupta et al. in Cancer, 9(15):1-14,
2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174 ).
This review outlines the systemic immunotherapies that have been approved or are
currently being investigated. This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive
urothelial bladder cancer, as substantial revisions were made in the 2017
updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab,
durvalumab, and avelumab. The complete version of the NCCN Guidelines for
Bladder Cancer addresses additional aspects of the management of bladder cancer,
including non-muscle-invasive urothelial bladder cancer and nonurothelial
histologies, as well as staging, evaluation, and follow-up. BACKGROUND: Avelumab has recently been approved by the Food and Drug
Administration for the therapy of Merkel cell carcinoma and urothelial
carcinoma. M7824 is a novel first-in-class bifunctional fusion protein
comprising a monoclonal antibody against programmed death-ligand 1 (PD-L1,
avelumab), fused to the extracellular domain of human transforming growth factor
beta (TGFβ) receptor 2, which functions as a TGFβ "trap." Advanced urothelial
tumors have been shown to express TGFβ, which possesses immunosuppressive
properties that promote cancer progression and metastasis. The rationale for a
combined molecule is to block the PD-1/PD-L1 interaction between tumor cells and
immune cell infiltrate and simultaneously reduce or eliminate TGFβ from the
tumor microenvironment. In this study, we explored the effect of M7824 on
invasive urothelial carcinoma cell lines.
METHODS: Human urothelial (transitional cell) carcinoma cell lines HTB-4, HTB-1,
and HTB-5 were treated with M7824, M7824mut (M7824 that is mutated in the
anti-PD-L1 portion of the molecule and thus does not bind PD-L1), anti-PD-L1
(avelumab), or IgG1 isotype control monoclonal antibody, and were assessed for
gene expression, cell-surface phenotype, and sensitivity to lysis by TRAIL,
antigen-specific cytotoxic T lymphocytes and natural killer cells.
RESULTS: M7824 retains the ability to mediate antibody-dependent cellular
cytotoxicity of tumor cells, although in some cases to a lesser extent than
anti-PD-L1. However, compared to anti-PD-L1, M7824 increases (A) gene expression
of molecules involved in T-cell trafficking in the tumor (e.g., CXCL11), (B)
TRAIL-mediated tumor cell lysis, and (C) antigen-specific CD8+ T-cell-mediated
lysis of tumor cells.
CONCLUSIONS: These studies demonstrate the immunomodulatory properties of M7824
on both tumor cell phenotype and immune-mediated lysis. Compared to anti-PD-L1
or M7824mut, M7824 induces immunogenic modulation of urothelial carcinoma cell
lines, rendering them more susceptible to immune-mediated recognition and lysis.
These findings show the relevance of the dual blockade of PD-L1 and TGFβ in
urothelial carcinoma cell lines and thus support the rationale for future
clinical studies of M7824 in patients with urothelial cancer. Our expanding knowledge of immunotherapy for solid tumors has led to an
explosion of clinical trials aimed at urothelial carcinoma. The primary strategy
is centered on unleashing the immune system by releasing the inhibitory signals
propagated by programmed cell death-1 (PD-1) and its ligand programmed cell
death ligand-1 (PD-L1). Many antibody constructs have been developed to block
these interactions and are used in clinical trials. The Food and Drug
Administration has already approved a number of checkpoint inhibitors such as
anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies
including ipilimumab; anti-PD-1 monoclonal antibodies including nivolumab and
pembrolizumab; anti-PD-L1 antibodies including atezolizumab, avelumab, and
durvalumab. One of the latest inhibitors is durvalumab, which is a high-affinity
human immunoglobulin G1 kappa monoclonal antibody and blocks the interaction of
PD-L1 with PD-1 and CD80. Currently, there are a number of ongoing trials in
advanced urothelial carcinoma both using durvalumab monotherapy and in
combination with other targeted therapies. In addition, durvalumab is being
investigated in the non-muscle-invasive urothelial carcinoma, which is centered
around intravenous formulations. These exciting developments have added a
significant number of therapies in a previously limited treatment landscape. Metastatic urothelial carcinoma (UC) remains an aggressive disease associated
with limited treatment options and a reduced survival. In spite of this, the
first-line treatment based on platinum-based combinations has remained virtually
unchanged for the last 20-30 years. Similarly, before the advent of the immune
checkpoint inhibitors, there were no FDA-approved drugs for second-line therapy.
In the last few years, impressive signs of anti-tumor activity have been
reported with several immunotherapy agents targeting the programmed cell death-1
(PD-1) pathway. Avelumab, a PD-1 ligand (PD-L1) inhibitor, is currently being
investigated for the treatment of UC. Areas covered: This article will review
the pharmacological characteristics of avelumab, the efficacy studies which led
to its approval, its safety profile, as well as its place within the management
of urothelial carcinoma with immunotherapy. For that matter, we undertook a
literature review of all the studies assessing the pharmacology of avelumab and
its efficacy within clinical trials. Expert commentary: Avelumab has shown
promising antitumor activity and a manageable safety profile in patients with
UC. Its dual mechanism of action, blocking the interaction between PD-L1 and
PD-1 and promoting antibody-dependent cell-mediated cytotoxicity could
potentially be of great interest since it could produce synergistic clinical
efficacy. PURPOSE OF REVIEW: Advanced urothelial carcinoma (aUC) has long been treated
preferably with cisplatin-based chemotherapy, but many patients are
cisplatin-ineligible whereas for those who progress on a platinum-based regimen
treatment options are limited. We review key recent data regarding immune
checkpoint inhibitors that are changing this treatment landscape.
RECENT FINDINGS: Since May 2016, five different agents targeting the PD-1/PD-L1
pathway (atezolizumab, pembrolizumab, nivolumab, avelumab, durvalumab) have
received FDA approval for the treatment of aUC in the platinum-refractory
setting, while pembrolizumab and atezolizumab are FDA-approved for
cisplatin-ineligible patients in the first-line setting. Clinical outcomes and
safety profiles of these agents appear relatively comparable across separate
trials; however, only pembrolizumab is supported by level I evidence from a
large randomized phase III trial showing overall survival benefit over
conventional cytotoxic salvage chemotherapy in the platinum-refractory setting.
Pembrolizumab has the highest level of evidence in platinum-refractory aUC,
whereas pembrolizumab and atezolizumab have comparable level of evidence in the
frontline setting in cisplatin-ineligible patients. Ongoing research is
evaluating novel agents, various rational combinations, and sequences, as well
as predictive and prognostic biomarkers. Urothelial carcinoma is the predomit histologic type of bladder cancer. After
30 years of minimal progress in the treatment of advanced-stage disease, recent
advances in the genomic characterization of urothelial cancer and breakthroughs
in bladder cancer therapeutics have rejuvenated the field. Nivolumab,
pembrolizumab, atezolizumab, durvalumab, and avelumab are among the exciting
recent novel therapeutic advances gaining approvals by the FDA for treatment of
advanced-stage urothelial carcinoma. Yet the challenge for clinicians is to
determine the optimal choice of agents as first-line or second-line therapy and
which offers the best chance for overall survival for the individual patient in
this rapidly changing field. |
Is cabozantinib effective for Hepatocellular Carcinoma? | Yes, cabozantinib is approved as second line agent for treatment of Hepatocellular Carcinoma. | PURPOSE: MET signaling has been suggested a potential role in hepatocellular
carcinoma (HCC) and associated with prometastasis during antiangiogenesis
therapy. We investigated the potential association between MET expression and
therapeutic response to sorafenib in patients with HCC. Antitumor effects of
cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC
cells as well as in vivo models.
EXPERIMENTAL DESIGN: Total MET and phosphorylated MET (p-MET) were measured in
29 resected HCC specimens, and correlated with response to sorafenib as
postoperative adjuvant therapy. In the second set of experiments using cultured
HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib
were examined.
RESULTS: High level of p-MET in resected HCC specimens was associated with
resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed
p-MET, cabozantinib inhibited the activity of MET and its downstream effectors,
leading to G1-phase arrest. Cabozantinib inhibited tumor growth in
p-MET-positive and p-MET-negative HCC by decreasing angiogenesis, inhibiting
proliferation, and promoting apoptosis, but it exhibited more profound efficacy
in p-MET-positive HCC xenografts. Cabozantinib blocked the hepatocyte growth
factor (HGF)-stimulated MET pathway and inhibited the migration and invasion of
the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in
the lung and liver in the experimental metastatic mouse model.
CONCLUSIONS: Patients with HCC with high level of p-MET are associated with
resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET
by cabozantinib has significant antitumor activities in HCC, and the activation
of MET in HCC may be a promising efficacy-predicting biomarker. Clin Cancer Res;
20(11); 2959-70. ©2014 AACR. Aberrant c-Met activity has been implicated in the development of hepatocellular
carcinoma (HCC), suggesting that c-Met inhibition may have therapeutic
potential. However, clinical trials of nonselective kinase inhibitors with c-Met
activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with
HCC have failed so far to demonstrate significant efficacy. This lack of
observed efficacy is likely due to several factors, including trial design, lack
of patient selection according to tumor c-Met status, and the prevalent
off-target activity of these agents, which may indicate that c-Met inhibition is
incomplete. In contrast, selective c-Met inhibitors (tepotinib, capmatinib) can
be dosed at a level predicted to achieve complete inhibition of tumor c-Met
activity. Moreover, results from early trials can be used to optimize the design
of clinical trials of these agents. Preliminary results suggest that selective
c-Met inhibitors have antitumor activity in HCC, with acceptable safety and
tolerability in patients with Child-Pugh A liver function. Ongoing trials have
been designed to assess the efficacy and safety of selective c-Met inhibition
compared with standard therapy in patients with HCC that were selected based on
tumor c-Met status. Thus, c-Met inhibition continues to be an active area of
research in HCC, with well-designed trials in progress to investigate the
benefit of selective c-Met inhibitors. (Hepatology 2018;67:1132-1149). Chemotherapy is one of the most important treatment modalities for advanced
hepatocellular carcinoma (HCC). On the basis of the results of two pivotal Phase
III placebo-controlled studies, sorafenib is currently acknowledged worldwide as
the standard therapeutic agent for advanced HCC. Following the introduction of
sorafenib for the treatment of HCC, Phase III trials of numerous other agents as
first-line or second-line chemotherapy have been conducted to determine if any
of these agents might offer superior survival benefit to sorafenib. In 2016, a
clear survival benefit of regorafenib over placebo was demonstrated in HCC
patients showing disease progression after sorafenib treatment. A year later, in
2017, lenvatinib has been shown to be non-inferior to sorafenib, in terms of the
overall survival, in chemo-naïve patients with advanced HCC. More recently,
promising outcomes have also been reported with new agents, such as nivolumab
and cabozantinib. At present, various novel combination regimens including these
agents are currently under development. Hepatic arterial infusion chemotherapy
(HAIC) is frequently adopted for the treatment of locally advanced HCC in Japan,
based on reports of high response rates and favorable long-term outcomes.
Although some randomized controlled trials of HAIC plus sorafenib vs. sorafenib
alone as first-line therapy have been conducted in patients with advanced HCC,
no firm evidence of the superiority of one over the other has been established
yet. In the future, demonstration of the survival advantage of HAIC and the
recognition of HAIC as one of the standard treatments for patients with advanced
HCC are expected. Cabozantinib is an oral small-molecule multitargeted tyrosine kinase inhibitor
(TKI) that may confer an advantage over other TKIs that target a single
receptor. It was approved by the U.S. Food and Drug Administration for the
treatment of both advanced renal cell carcinoma and progressive metastatic
medullary thyroid cancer, and it is being investigated for a wide array of other
maligcies. Rationale for use, clinical trial data, and current
recommendations for cabozantinib in renal cell cancer, thyroid cancer, prostate
cancer, hepatocellular cancer, and lung cancer are detailed in this article.
Common adverse events are reviewed, and management strategies for select adverse
events are discussed. Implications for contemporary practitioners are also
provided because use of this novel agent is likely to increase as more studies
are completed. Hepatocellular carcinomas (HCCs) are characterised by considerable phenotypic
and molecular heterogeneity. Treating HCC and designing clinical trials are
particularly challenging because co-existing liver disease, present in most
patients, limits aggressive therapeutic options. Positive results in recent
phase III clinical trials have confirmed the high value of anti-angiogenic
therapies for HCC in both first (sorafenib and lenvatinib) and second line
(regorafenib and cabozantinib) treatment modalities. However, failure of several
large randomised controlled clinical trials over the last 10 years underlines
the necessity for innovative treatment strategies and implementation of
translational findings to overcome the unmet clinical need. Furthermore, the
promising results from novel immunotherapies are likely to complement the
landscape of active compounds for HCC and will require a completely different
approach to patients, as well as the development of prognostic/predictive
biomarkers. Given our increasing understanding of the most abundant molecular
alterations in HCC, effective enrichment of patients based on clinical and
molecular biomarkers, as well as adaptive clinical trials, are now feasible and
should be implemented. Herein, we aim to review important aspects of precision
medicine approaches in HCC that might contribute to improving the molecular
subclassification of patients in a clinical trial setting and pave the way for
novel therapeutic strategies. The hepatocellular carcinoma (HCC) treatment landscape changed a decade ago,
with sorafenib demonstrating survival benefit in the first-line setting and
becoming the first systemic therapy to be approved for HCC. More recently,
regorafenib and nivolumab have received approval in the second-line setting
after sorafenib, with further positive phase 3 studies emerging in the first
line (lenvatinib non-inferior to sorafenib) and second line versus placebo
(cabozantinib and ramucirumab). A key recommendation in the management of
patients receiving sorafenib is to promote close communication between the
patient and the physician so that adverse events (AEs) are detected early and
severe AEs can be prevented. Sorafenib-related AEs have been identified as
clinical biomarkers for sorafenib efficacy. Healthcare professionals have become
more efficient in managing AEs, identifying patients who are likely to benefit
from treatment, and assessing response to treatment, resulting in a trend
towards increased overall survival in the sorafenib arms of clinical studies.
The rapidly changing treatment landscape due to the emergence of new treatment
options (sorafenib and lenvatinib equally effective in first line; regorafenib,
cabozantinib, and ramucirumab showing OS benefit in second line with nivolumab
approved by the FDA based on response rate) underscores the importance of
re-assessing the role of the first approved systemic agent in HCC, sorafenib. Publisher: AKTUELLER STAND UND ALLGEMEINES: Die Leitlinien für das
hepatozelluläre Karzinom (HCC) sind derzeit unter Revision, Neuauflagen werden
2018 erwartet. Patienten mit chronischen Lebererkrankungen oder Leberzirrhose
müssen mittels Ultraschall alle 6 Monate in Bezug auf die Entwicklung eines HCC
gescreent werden. Die chirurgische Resektion oder die Lebertransplantation sind
kurative Optionen im frühen Stadium. LOKOREGIONäRE THERAPIEN: Die selektive
interne Radiotherapie (SIRT) wird zunehmend häufiger als lokoregionäre Therapie
eingesetzt. Die Studiendaten sprechen für eine gute Verträglichkeit, aber keine
überlegene Wirksamkeit gegenüber transarterieller Chemoembolisation (TACE) oder
Systemtherapie mit Sorafenib.
NEUE ZIELGERICHTETE THERAPIEN: Regorafenib stellt bei Patienten mit Progress
unter Sorafenib eine neu zugelassene Alternative in der Zweitlinientherapie dar.
Positive Phase-III-Studien wurden für Lenvatinib in der Erst- und Cabozantinib
in der Zweitlinientherapie publiziert.
IMMUNTHERAPIE: Der Checkpoint-Inhibitor Nivolumab ist in den USA in der
Zweitlinientherapie aufgrund guter Phase-I/II-Daten zugelassen worden. Daten zu
einer Phase-III-Studie in der Erstlinientherapie vs. Sorafenib werden 2018
erwartet. INTRODUCTION: Many clinical trials have been conducted with chemotherapies in
patients with advanced hepatocellular carcinoma (HCC). However, few agents have
shown efficacy. It is thought that the efficacy of some agents might have
resulted from the heterogeneity of tumors, insufficient dosages due to liver
cirrhosis, and post-therapy effects. In recent years, immune checkpoint
inhibitors have shown promising clinical activity and safety in patients with
advanced HCC.
AREAS COVERED: The authors provide an overview of chemotherapies used for the
treatment of HCC, including ongoing trials. The authors also provide their
expert opinion on the subject area and provide their future perspectives.
EXPERT OPINION: Based on favorable phase III clinical trial data, sorafenib and
lenvatinib are considered promising agents for HCC as first-line systemic
chemotherapy. Moreover, regorafenib and cabozantinib are useful second-line
therapies after the failure of sorafenib. Furthermore, in early phase clinical
trials, immune checkpoint inhibitors and the combinations of these inhibitors
and molecular targeted agents have demonstrated promising activity. Therefore,
better survival results are expected from future phase III clinical trials. BACKGROUND: Cabozantinib inhibits tyrosine kinases, including vascular
endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are
implicated in the progression of hepatocellular carcinoma and the development of
resistance to sorafenib, the standard initial treatment for advanced disease.
This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared
with placebo in previously treated patients with advanced hepatocellular
carcinoma.
METHODS: A total of 707 patients were randomly assigned in a 2:1 ratio to
receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients
had received previous treatment with sorafenib, had disease progression after at
least one systemic treatment for hepatocellular carcinoma, and may have received
up to two previous systemic regimens for advanced hepatocellular carcinoma. The
primary end point was overall survival. Secondary end points were
progression-free survival and the objective response rate.
RESULTS: At the second planned interim analysis, the trial showed significantly
longer overall survival with cabozantinib than with placebo. Median overall
survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard
ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005).
Median progression-free survival was 5.2 months with cabozantinib and 1.9 months
with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36
to 0.52; P<0.001), and the objective response rates were 4% and less than 1%,
respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients
in the cabozantinib group and in 36% in the placebo group. The most common
high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib
vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate
aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs.
2%).
CONCLUSIONS: Among patients with previously treated advanced hepatocellular
carcinoma, treatment with cabozantinib resulted in longer overall survival and
progression-free survival than placebo. The rate of high-grade adverse events in
the cabozantinib group was approximately twice that observed in the placebo
group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426 .). BACKGROUND: The approval of the tyrosine kinase inhibitor sorafenib in 2007
marked a milestone in the treatment of hepatocellular carcinoma, as sorafenib
was the first systemic therapy to show a survival benefit in patients with
advanced hepatocellular carcinoma. Since then many drugs failed in the first-
and second-line setting and it took almost another decade until further tyrosine
kinase inhibitors succeeded in phase III trials.
AIM: To summarise the evolving field of systemic therapy of hepatocellular
carcinoma.
METHODS: We reviewed recently published studies identified from PubMed and data
presented at recent meetings. Main search terms included hepatocellular
carcinoma, tyrosine kinase inhibitors, immunotherapy, immune checkpoint
inhibitors, sorafenib, regorafenib, lenvatinib, cabozantinib, ramucirumab, and
nivolumab.
RESULTS: We discuss the evolution of targeted therapies since the approval of
sorafenib including failures and recent advances. We also elaborate the unmet
need of biomarkers to guide treatment decisions and discuss the emerging field
of immunotherapy in hepatocellular carcinoma.
CONCLUSIONS: The tyrosine kinase inhibitors sorafenib (first line) and
regorafenib (second line) have been approved for hepatocellular carcinoma, and
the immune checkpoint inhibitor nivolumab obtained conditional approval for
sorafenib-experienced patients in the United States. With lenvatinib in the
first line, and cabozantinib and ramucirumab in sorafenib-experienced patients,
three more targeted therapies reached their primary endpoint in phase III trials
and may soon be added to the treatment armamentarium. BACKGROUND: Prognosis is very poor for advanced HCC patients partially due to
lack of effective systemic treatment. Sorafenib was the only approved agent for
advanced HCC since 2007 until recent breakthroughs. In this article, we will
review the newer approved and promising agents in the treatment of advanced HCC
in the first line setting and beyond progression.
MAIN BODY: The Food and Drug Administration approved sorafenib as it
demonstrated 3 months overall survival benefit compared to placebo in the first
line setting over 10 years ago. Multiple single agent and combination therapies
have been studied but failed to show benefit. Chemotherapy has limited role in
patients with advanced HCC given poor hepatic reserve due to underlying
cirrhosis. A new era of treatment for advanced HCC arrived recently with
exciting data presented for lenvatinib, regorafenib, cabozantinib, nivolumab,
ramucirumab and several other promising clinical trials.
CONCLUSION: Advanced HCC patients are difficult to treat with poor outcomes.
After initial approval of sorafenib in 2007, we recently have multiple new
agents that showed benefit and promising activity, and are set to change the
landscape of HCC treatment. Transcatheter arterial therapies for hepatocellular carcinoma (HCC) have
developed during the last decade. A fine powder formulation of cisplatin and the
new platinum agent miriplatin became standard medicines in addition to
anthracyclines in transcatheter arterial chemoembolization (TACE) in Japan.
Recent prospective and retrospective studies supported the usefulness of
platinum agents as a chemotherapeutic at the time of varied TACE therapy.
Although balloon-occluded TACE is an effective therapy for localized HCC and
drug-eluting microspheres seemed to show a higher response rate in certain HCCs,
the definite advantages of those procedures still remain uncertain. Intermediate
stage HCC, or Barcelona Clinic Liver Cancer stage B, is regarded as a
heterogeneous category with a wide spectrum of tumors and patients, and several
subclassifications of the stage have been proposed to show different prognoses;
there are also different recommended therapies in each subgroup. Authors have
subclassified patients based on combinations of tumor size, tumor number, and
liver function, with or without performance status. Because of differences of
available medical resources and techniques in treatment procedures between
countries, the most ideal and useful subgrouping remains inconclusive at
present. Recently, a few systemic chemotherapies proved to be effective for
advanced stage HCC in phase III studies: lenvatinib as the first line of
therapy, and regorafenib, cabozantinib, and ramucirumab as second-line therapy.
Other molecular-targeted and immune-oncological medicines are expected to follow
in the near future. Some studies have suggested an advantage of early
introduction of molecular-targeted therapy for TACE-resistant HCC in the
intermediate stage. The principal advancements in the treatment of hepatocellular carcinoma (HCC)
are the use of new systemic treatments, such as lenvatinib in first-line
treatment and regorafenib, cabozantinib, and ramucirumab in second-line
treatment, because of their benefits in terms of overall survival. In addition,
nivolumab as a second-line agent was approved by the US Food and Drug
Administration in 2017 based on improved radiological response data. Physicians
and patients alike will greatly benefit from this expanded arsenal of treatments
once all these new drugs for the treatment of HCC finally become available.
Unfortunately, in our review of the available data, we found a conspicuous lack
of approved systemic treatments for HCC in the distinct setting of after liver
transplantation (LT). Careful evaluation of the clinical trials for approved
systemic treatments of HCC is crucial when considering the best options for
those with HCC recurrence after LT. Although several first-line or second-line
treatments have been shown to be effective for HCC, each of these trials was
composed of its own specific populations, and those with HCC recurrence after LT
were excluded. We have also summarized from a critical and clinical point of
view the issues involved in the management of patients who are candidates for
systemic treatment in this era of multiple drugs for the same indication. |
De novo mutations in which novel genes are involved in systemic lupus erythematosus? | DNMT3A, PRKCD, and C1QTNF4. | The omnigenic model of complex disease stipulates that the majority of the
heritability will be explained by the effects of common variation on genes in
the periphery of core disease pathways. Rare variant associations, expected to
explain far less of the heritability, may be enriched in core disease genes and
thus will be instrumental in the understanding of complex disease pathogenesis
and their potential therapeutic targets. Here, using complementary whole-exome
sequencing, high-density imputation, and in vitro cellular assays, we identify
candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE).
Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE
parent-affected-offspring trios and identified 14 genes with missense de novo
mutations (DNM), none of which are within the >80 SLE susceptibility loci
implicated through genome-wide association studies. In a follow-up cohort of 10,
995 individuals of matched European ancestry, we imputed genotype data to the
density of the combined UK10K-1000 genomes Phase III reference panel across the
14 candidate genes. Gene-level analyses indicate three functional candidates:
DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD
associated with SLE risk (P = 0.0028), and across DNMT3A associated with two
severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further
characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on
NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our
results identify three novel genes in SLE susceptibility and support
extreme-phenotype sampling and DNM gene discovery to aid the search for core
disease genes implicated through rare variation. |
Is there a link between BCL11B haploinsufficiency and syndromic neurodevelopmental delay? | No. Mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. | |
What is the mechanism of action of motolimod? | Motolimod is the toll-like receptor 8 (TLR8) agonist that stimulates innate and adaptive immunity. | PURPOSE: Immunotherapy as a treatment for cancer holds the promise of complete
and durable tumor remission, yet the immunosuppressive environment created by
many tumors, advanced patient age, and previous treatments with cytotoxic agents
may limit the approach. The activity of motolimod (VTX-2337), a potent and
selective Toll-like receptor 8 (TLR8) agonist, was therefore assessed in the
context of advanced, late-stage cancer patients.
EXPERIMENTAL DESIGN: The repertoire of mediators induced from human peripheral
blood mononuclear cells in response to motolimod was characterized.
Translational studies in cynomolgus monkeys elucidated the activity of motolimod
on an intact immune system, identified biomarkers of TLR8 activation, and
defined the relationship between the pharmacokinetic and pharmacodynamic (PK/PD)
response. The PK/PD relationship for motolimod in cancer patients was assessed,
compared with preclinical findings, and contrasted with activity in healthy
volunteers.
RESULTS: In late-stage cancer patients, plasma levels of multiple biomarkers,
including IL6, G-CSF, MCP-1, and MIP1-β, increased with increasing motolimod
dose. The magnitude and breadth of the biomarker response closely aligned with
the response seen in preclinical studies, demonstrating that advanced cancer
patients remained responsive to TLR8 activation. In addition, the PK/PD response
in cancer patients closely aligned with the activity of motolimod seen in
healthy volunteers.
CONCLUSIONS: Late-stage cancer patients are highly sensitive to TLR8 activation
by motolimod. Tumor burden, advanced age, and prior treatment history with
cytotoxic agents did not moderate or modify the response predicted by
nonclinical studies and confirmed in healthy volunteers. Clin Cancer Res;
21(24); 5445-52. ©2015 AACR. VTX-2337 (USAN: motolimod) is a selective toll-like receptor 8 (TLR8) agonist,
which is in clinical development as an immunotherapy for multiple oncology
indications, including squamous cell carcinoma of the head and neck (SCCHN).
Activation of TLR8 enhances natural killer cell activation, increases
antibody-dependent cell-mediated cytotoxicity, and induces Th1 polarizing
cytokines. Here, we show that VTX-2337 stimulates the release of mature IL-1β
and IL-18 from monocytic cells through coordinated actions on both TLR8 and the
NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome complex. In
vitro, VTX-2337 primed monocytic cells to produce pro-IL-1β, pro-IL-18, and
caspase-1, and also activated the NLRP3 inflammasome, thereby mediating the
release of mature IL-1β family cytokines. Inhibition of caspase-1 blocked
VTX-2337-mediated NLRP3 inflammasome activation, but had little impact on
production of other TLR8-induced mediators such as TNFα. IL-18 activated natural
killer cells and complemented other stimulatory pathways, including FcγRIII and
NKG2D, resulting in IFNγ production and expression of CD107a. NLRP3 activation
in vivo was confirmed by a dose-related increase in plasma IL-1β and IL-18
levels in cynomolgus monkeys administered VTX-2337. These results are highly
relevant to clinical studies of combination VTX-2337/cetuximab treatment.
Cetuximab, a clinically approved, epidermal growth factor receptor-specific
monoclonal antibody, activates NK cells through interactions with FcγRIII and
facilitates ADCC of tumor cells. Our preliminary findings from a Phase I
open-label, dose-escalation, trial that enrolled 13 patients with recurrent or
metastatic SCCHN show that patient NK cells become more responsive to
stimulation by NKG2D or FcγRIII following VTX-2337 treatment. Together, these
results indicate that TLR8 stimulation and inflammasome activation by VTX-2337
can complement FcγRIII engagement and may augment clinical responses in SCCHN
patients treated with cetuximab.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01334177. Erratum in
Author's view on original publication: Dietsch GN, Randall TD, Gottardo R,
Northfelt DW, Ramanathan RK, Cohen PA, Manjarrez KL, Newkirk M, Bryan JK,
Hershberg RM. Late Stage Cancer Patients Remain Highly Responsive to Immune
Activation by the Selective TLR8 Agonist Motolimod (VTX–2337). Clin Cancer Res
2015; 21(24):5445-52; PMID: ; http:/dx.doi.org/10.1158/1078-0432.CCR–15–0578. Purpose: Immunotherapy is an emerging paradigm for the treatment of cancer, but
the potential efficacy of many drugs cannot be sufficiently tested in the mouse.
We sought to develop a rational combination of motolimod-a novel Toll-like
receptor 8 (TLR8) agonist that stimulates robust innate immune responses in
humans but diminished responses in mice-with pegylated liposomal doxorubicin
(PLD), a chemotherapeutic that induces immunogenic cell death.Experimental
Design: We followed an integrative pharmacologic approach including healthy
human volunteers, non-human primates, NSG-HIS ("humanized immune system") mice
reconstituted with human CD34+ cells, and patients with cancer to test the
effects of motolimod and to assess the combination of motolimod with PLD for the
treatment of ovarian cancer.Results: The pharmacodynamic effects of motolimod
monotherapy in NSG-HIS mice closely mimicked those in non-human primates and
healthy human subjects, whereas the effects of the motolimod/PLD combination in
tumor-bearing NSG-HIS mice closely mimicked those in patients with ovarian
cancer treated in a phase Ib trial (NCT01294293). The NSG-HIS mouse helped
elucidate the mechanism of action of the combination and revealed a positive
interaction between the two drugs in vivo The combination produced no
dose-limiting toxicities in patients with ovarian cancer. Two subjects (15%) had
complete responses and 7 subjects (53%) had disease stabilization. A phase II
study was consequently initiated.Conclusions: These results are the first to
demonstrate the value of pharmacologic approaches integrating the NSG-HIS mouse,
non-human primates, and patients with cancer for the development of novel
immunomodulatory anticancer agents with human specificity. Clin Cancer Res;
23(8); 1955-66. ©2016 AACR. Purpose: As Toll-like receptors (TLR) are key mediators of immune responses, TLR
agonists may be important for augmenting the efficacy of therapies for squamous
cell carcinoma of the head and neck (SCCHN). Motolimod (VTX-2337), a selective
small-molecule agonist of TLR8, stimulates natural killer (NK) cells, dendritic
cells, and monocytes. A phase Ib clinical trial assessed the safety and
antitumor activity of motolimod in combination with cetuximab in patients with
SCCHN. Correlative biomarkers of immune activity were explored.Experimental
Design: Thirteen patients with recurrent or metastatic SCCHN were enrolled in
this open-label, dose-escalation study using a standard 3 + 3 design. Doses of
motolimod (2.5, 3.0, or 3.5 mg/m2) were given on days 1, 8, and 15, in
combination with fixed weekly doses of cetuximab in 28-day cycles.Results: There
were no protocol-defined dose-limiting toxicities, drug-related deaths, or
evidence of synergistic toxicities between motolimod and cetuximab. Clinical
tolerability at the 3.5 mg/m2 dose level was not optimal for repeated dosing and
3.0 mg/m2 was identified as the MTD. Two patients achieved partial responses for
an overall response rate of 15%. Five patients had disease stabilization
equating to a disease control rate of 54%. Statistically significant increases
in plasma cytokines and in the frequency and activation of circulating NK cells
were observed.Conclusions: Motolimod can be safely administered in combination
with cetuximab with an acceptable toxicity profile. Encouraging antitumor
activity and robust pharmacodynamic responses were observed. Motolimod is being
further investigated in a phase II trial in patients with SCCHN
(ClinicalTrials.gov ID: NCT01836029). Clin Cancer Res; 23(10); 2442-50. ©2016
AACR. BACKGROUND: A phase 2, randomized, placebo-controlled trial was conducted in
women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and
safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust
innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a
chemotherapeutic that induces immunogenic cell death.
PATIENTS AND METHODS: Women with ovarian, fallopian tube, or primary peritoneal
carcinoma were randomized 1 : 1 to receive PLD in combination with blinded
motolimod or placebo. Randomization was stratified by platinum-free interval (≤6
versus >6-12 months) and Gynecologic Oncology Group (GOG) performance status (0
versus 1). Treatment cycles were repeated every 28 days until disease
progression.
RESULTS: The addition of motolimod to PLD did not significantly improve overall
survival (OS; log rank one-sided P = 0.923, HR = 1.22) or progression-free
survival (PFS; log rank one-sided P = 0.943, HR = 1.21). The combination was
well tolerated, with no synergistic or unexpected serious toxicity. Most
patients experienced adverse events of fatigue, anemia, nausea, decreased white
blood cells, and constipation. In pre-specified subgroup analyses,
motolimod-treated patients who experienced injection site reactions (ISR) had a
lower risk of death compared with those who did not experience ISR.
Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8
stimulation predicted OS outcomes in patients receiving motolimod on study.
Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide
polymorphisms, mutational status in BRCA and other DNA repair genes, and
autoantibody biomarkers did not correlate with OS or PFS.
CONCLUSIONS: The addition of motolimod to PLD did not improve clinical outcomes
compared with placebo. However, subset analyses identified statistically
significant differences in the OS of motolimod-treated patients on the basis of
ISR and in vitro immune responses. Collectively, these data may provide
important clues for identifying patients for treatment with immunomodulatory
agents in novel combinations and/or delivery approaches.
TRIAL REGISTRATION: Clinicaltrials.gov, NCT 01666444. Head and neck squamous cell carcinoma (HNSCC) is now the seventh most common
cancer worldwide. The median overall survival for patients with recurrent and/or
metastatic (R/M) HNSCC remains <1 year despite modern systemic chemotherapy and
targeted agents. Palliative systemic therapy for patients with R/M HNSCC
typically includes a platinum-based doublet, with an understanding that the
increase in efficacy compared with single agents is primarily related to
improved response rate, and not survival. Till date, the only systemic therapy
regimen to demonstrate survival superiority over platinum-5-fluorouracil (5-FU)
doublet is platinum, FU, and cetuximab. Epidermal growth factor receptor
inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors, have
achieved only a modest success in R/M HNSCC. Immunotherapy represents an
attractive treatment option for R/M HNSCC, with encouraging preliminary data
from studies involving immune checkpoint inhibitors (e.g., pembrolizumab,
nivolumab) and toll-like receptor agonists (e.g., motolimod). Given the poor
prognosis of R/M HNSCC, enrollment of patients into clinical trials to
investigate novel systemic agents, is necessary for further improvement of
oncologic outcomes in this patient population. IMPORTANCE: Immunotherapy for recurrent and/or metastatic (R/M) squamous cell
carcinoma of the head and neck (SCCHN) is promising. The toll-like receptor 8
(TLR8) agonist motolimod may stimulate innate and adaptive immunity.
OBJECTIVE: To determine whether motolimod improves outcomes for R/M SCCHN when
combined with standard therapy.
DESIGN, SETTING, AND PARTICIPANTS: The Active8 study was a multicenter,
randomized, double-blind, placebo-controlled clinical trial enrolling adult
patients (age ≥18 years) with histologically confirmed R/M SCCHN of the oral
cavity, oropharynx, hypopharynx, or larynx between October 2013 and August 2015.
Follow-up ended September 2016. Analysis for the present report was conducted
between June 2016 and December 2017.
INTERVENTIONS: Combination treatment with platinum (carboplatin or cisplatin),
fluorouracil, cetuximab (the EXTREME regimen), and either placebo or motolimod,
each administered intravenously every 3 weeks. Patients received a maximum of 6
chemotherapy cycles, after which patients received weekly cetuximab with either
placebo or motolimod every 4 weeks.
MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS) as determined by
independent central review using immune-related RECIST (Response Evaluation
Criteria in Solid Tumors). Key secondary end points included overall survival
(OS) and safety.
RESULTS: Of 195 patients enrolled, 85% were men (n = 166); 82% were white
(n = 159); median age was 58 years (range 23-81 years). Median PFS was 6.1 vs
5.9 months (hazard ratio [HR], 0.99; 1-sided 90% CI, 0.00-1.22; P = .47), and
median OS was 13.5 vs 11.3 months (HR, 0.95; 1-sided 90% CI, 0.00-1.22; P = .40)
for motolimod vs placebo. Increased incidence of injection site reactions,
pyrexia, chills, anemia, and acneiform rash were noted with motolimod. Of 83
cases oropharyngeal cancer, 52 (63%) were human papillomavirus (HPV) positive.
In a prespecified subgroup analysis of HPV-positive participants, motolimod vs
placebo resulted in significantly longer PFS (7.8 vs 5.9 months; HR, 0.58;
1-sided 90% CI, 0.00-0.90; P = .046) and OS (15.2 vs 12.6 months; HR, 0.41;
1-sided 90% CI, 0.00-0.77; P = .03). In an exploratory analysis, patients with
injection site reactions had longer PFS and OS (median PFS, 7.1 vs 5.9 months;
HR, 0.69; 1-sided 90% CI, 0.00-0.93; P = .06; and median OS, 18.7 vs 12.6; HR,
0.56; 1-sided 90% CI, 0.00-0.81; P = .02).
CONCLUSIONS AND RELEVANCE: Adding motolimod to the EXTREME regimen was well
tolerated but did not improve PFS or OS in the intent-to-treat population.
Significant benefit was observed in HPV-positive patients and those with
injection site reactions, suggesting that TLR8 stimulation may benefit subset-
and biomarker-selected patients.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01836029. |
Is Lasmiditan effective for migraine? | Yes, Lasmiditan is effective for treatment of migraine. This has been demonstrated in clinical trials. | INTRODUCTION: Lasmiditan (COL-144; LY573144) is a novel, highly selective and
potent agonist at 5-HT(1F) receptors that lacks vasoconstrictor activity.
Preclinical and early clinical experiments predict acute antimigraine efficacy
of COL-144 that is mediated through a non-vascular, primarily neural, mechanism.
SUBJECTS AND METHODS: In a randomised, multicentre, placebo-controlled,
double-blind, group-sequential, adaptive treatment-assignment, proof-of-concept
and dose-finding study, we treated 130 subjects in-hospital during a migraine
attack. Subjects were allocated to an intravenous dose level of lasmiditan or
placebo in small cohorts. The starting dose was 2.5 mg. Subsequent doses were
adjusted, up or down, according to the safety and efficacy seen in the preceding
cohort. The primary outcome measure was headache response defined as improvement
from moderate or severe headache at baseline to mild or no headache at 2 h
post-dose. The study was designed to explore the overall dose response
relationship but was not powered to differentiate individual doses from placebo,
nor to detect effect differences for other migraine symptoms.
RESULTS: Forty-two subjects received placebo and 88 received lasmiditan in doses
of 2.5-45 mg. Subjects were observed in the clinic for 4 h after treatment and
used a diary card to record symptoms and adverse events for up to 24 h. The
study was terminated when the 20 mg dose met predefined efficacy stopping rules.
Of subjects treated in the 10, 20, 30 and 45 mg lasmiditan dose groups, 54-75%
showed a 2 h headache response, compared to 45% in the placebo group (P = 0.0126
for the linear association between response rates and dose levels). Patient
global impression at 2 h and lack of need for rescue medication also showed
statistically significant linear correlations with dose. Lasmiditan was
generally well tolerated. Adverse events were reported by 65% of subjects on
lasmiditan and by 43% on placebo and were generally mild. Dizziness, paresthesia
and sensations of heaviness (usually limb) were more common on lasmiditan.
CONCLUSIONS: At intravenous doses of 20 mg and higher, lasmiditan proved
effective in the acute treatment of migraine. Further studies to assess the
optimal oral dose and full efficacy and tolerability profile are under way. The
non-vascular, neural mechanism of action of lasmiditan may offer an alternative
means to treat migraine especially in patients who have contra-indications for
agents with vasoconstrictor activity. The clinicaltrials.gov identifier for this
study is NCT00384774. Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both
scientifically and clinically relevant to review whether a 5-HT(1F) receptor
agonist is effective in the acute treatment of migraine. Two RCTs in the phase
II development of lasmiditan was reviewed. In the intravenous placebo-controlled
RCT, lasmiditan doses of 2.5-45 mg were used, and there was a linear association
between headache relief (HR) rates and dose levels (P < 0.02). For lasmiditan
20 mg, HR was 64 % and for placebo it was 45 % (NS). In the oral
placebo-controlled RCT, lasmiditan doses of 50, 100, 200 and 400 mg were used.
For HR, all doses of lasmiditan were superior to placebo (P < 0.05). For
lasmiditan 400 mg, HR was 64 % and it was 25 % for placebo. Adverse events (AEs)
emerging from the treatment were reported by 22 % of the patients receiving
placebo and by 65, 73, 87 and 87 % of patients receiving 50, 100, 200 and
400 mg, respectively. The majority of AEs after lasmiditan 100 and 400 mg were
moderate or severe. For the understanding of migraine pathophysiology, it is
very important to note that a selective 5-HT(1F) receptor agonist like
lasmiditan is effective in the acute treatment of migraine. Thus, migraine can
be treated with a drug that has no vasoconstrictor ability. While lasmiditan
most likely is effective in the treatment of migraine attacks it had,
unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed
in larger studies in phase III, this might adversely limit the use of this
highly specific non-vascular acute treatment of migraine. Larger studies
including the parameters of patients' preferences are necessary to accurately
position this new treatment principle in relation to the triptans. BACKGROUND: Lasmiditan (COL-144) is a novel, centrally acting, highly selective
5-HT(1F) receptor agonist without vasoconstrictor activity that seemed effective
when given as an intravenous infusion in a proof-of-concept migraine study. We
aimed to assess the efficacy and safety of oral lasmiditan for the acute
treatment of migraine.
METHODS: In this multicentre, double-blind, parallel-group, dose-ranging study
in 43 headache centres in five European countries, patients with migraine with
and without aura and who were not using prophylaxis were randomly assigned
(1:1:1:1:1) to treat one moderate or severe attack at home with 50 mg, 100 mg,
200 mg, or 400 mg lasmiditan, or placebo. Study drug and placebo were supplied
in identical numbered tablet packs. The randomisation code was generated by an
independent statistician. Patients and investigators were masked to treatment
allocation. The primary endpoint was dose response for headache relief (moderate
or severe becoming mild or none) at 2 h. The primary analysis was done in the
modified intention-to-treat population. This study is registered with
ClinicalTrials.gov, number NCT00883051.
FINDINGS: Between July 8 2009, and Feb 18, 2010, 512 patients were randomly
assigned to treatment, 391 of whom received treatment. 86 patients received
placebo (81 included in primary analysis) and 305 received lasmiditan (50 mg
n=79, 100 mg n=81, 200 mg n=69, and 400 mg n=68 included in primary analysis).
There was a linear association between headache response rate at 2 h and
lasmiditan dose (Cochran-Armitage test p<0·0001). Every lasmiditan treatment
dose significantly improved headache response at 2 h compared with placebo
(lasmiditan 50 mg: difference 17·9%, 95% CI 3·9-32·1, p=0·022; 100 mg: 38·2%,
24·1-52·4, p<0·0001; 200 mg: 28·8%, 9·6-39·9, p=0·0018; 400 mg: 38·7%,
23·9-53·6, p<0·0001). The proportion of patients with treatment-emergent adverse
events increased with increasing doses (53/82 [65%], 59/82 [72%], 61/71 [86%],
and 59/70 [84%] for lasmiditan 50, 100, 200, and 400 mg, respectively vs 19/86
[22%] for placebo). Most adverse events were mild or moderate in intensity, with
16 of 82 (20%), 23 of 82 (28%), 28 of 71 (39%), and 31 of 70 (44%) of patients
on lasmiditan 50, 100, 200, and 400 mg, respectively reporting a severe adverse
event compared with five of 86 (6%) on placebo. The most common adverse events
were CNS related and included dizziness, fatigue, vertigo, paraesthesia, and
somnolence.
INTERPRETATION: Oral lasmiditan seems to be safe and effective in the acute
treatment of migraine. Further assessment in larger placebo-controlled and
triptan-controlled trials are needed to assess the potential role of lasmiditan
in acute migraine therapy.
FUNDING: CoLucid Pharmaceuticals. Research has focused on serotonin (5-HT) 5-HT1D and 5-HT1F receptors to develop
drugs acting through non-vasoconstrictive mechanisms for treating acute migraine
and those targeting 5-HT2B and 5-HT7 receptors for preventing migraine. Areas
covered: This paper reviews antimigraine drugs targeting 5-HT receptors in one
phase I trial (sumatriptan iontophoretic transdermal system, TDS) and five phase
II clinical trials (PNU-142633, LY334370, lasmiditan, NOX-188). Expert opinion:
Data from our overview on investigational drugs in phase I and II clinical
trials using the 5-HT1B/1D receptor agonist (sumatriptan TDS), 5-HT1D receptor
agonist (PNU-142633), 5-HT1F receptor agonists (LY334370, lasmiditan) and a
combined 5-HT1B/1D receptor agonist with nNOS inhibition (NOX-188) provided
encouraging data for sumatriptan TDS and lasmiditan, disappointing results for
PNU-142633, and promising findings for NOX-188. The 5-HT1F receptor agonist
lasmiditan, a drug acting through non-vasoconstrictive mechanisms, represents a
promising safe, effective and tolerated acute migraine therapy also for patients
at cardiovascular risk. Upcoming phase III trials should clarify the optimal
lasmiditan dose and eventual clinical advantages over triptans. The negative
results for the PNU-142633 trial prompt further studies using specific compounds
more precisely targeting 5-HT1D receptors. Antagonism at 5-HT2B and 5-TH7
receptors, a promising strategy to prevent migraine, is still limited to
experimental migraine models. Migraine remains one of the most disabling disorders worldwide. The high
prevalence in the general population and the often-delicate treatment of
patients account for that. Therapeutic management of migraine relies mainly on
non-specific medical treatment and is affected by low patient adherence to the
treatment regimens applied. The introduction of specific anti-migraine treatment
occurred over 20 years ago when the first triptan was approved by regulatory
authorities (sumatriptan, 28 December 1992). Triptan use is limited by side
effects, time- and frequency-restricted application, and the risk of developing
medication overuse headache. Within the past few years, new and promising drugs
such as more specific 5-HT 1F receptor agonists (that is, lasmiditan) and
monoclonal calcitonin gene-related peptide (CGRP) receptor antibodies entered
advanced development phases while non-invasive neuromodulatory approaches were
suggested to be potentially effective as non-pharmaceutical interventions for
migraine. Migraine is an important socioeconomic burden and is ranked the sixth cause of
years of life lost because of disability in the general population and the third
cause of years of life lost in people younger than 50 years. The cornerstone of
pharmacological treatment is represented by the acute therapy. The serotonin
(5-hydroxytryptamine [5-HT]) receptor subtype 1B/1D agonists, called triptans,
are nowadays the first-line acute therapy for patients who experience
moderate-to-severe migraine attacks. Unfortunately, a high percentage of
patients are not satisfied with this acute treatment, either for lack of
response or side effects. Moreover, their mechanism of action based on
vasoconstriction makes them unsuitable for patients with previous cardio- and
cerebrovascular diseases and for those with uncontrolled hypertension. Since the
introduction of triptans, no other acute drug class has passed all developmental
stages. The research for a new drug lacking vasoconstrictive effects led to the
development of lasmiditan, a highly selective 5-HT1F receptor agonist with
minimized interactions with other 5-HT receptor subtypes. Lasmiditan is
considered to be the first member of a new drug category, the neurally acting
anti-migraine agent (NAAMA). Phase II and III trials had shown superiority
compared to placebo and absence of typical triptan-associated adverse events
(AEs). Most of the AEs were related to the central nervous system, depending on
the high permeability through the blood-brain barrier and mild to moderate
severity. The results of ongoing long-term Phase III trials will determine
whether lasmiditan will become available in the market, and then active triptan
comparator studies will assess patients' preference. Future studies could then
explore the safety during pregcy and breastfeeding or the risk that overuse
of lasmiditan leads to medication overuse headache. Now that the vascular hypothesis of migraine is no longer the prevailing theory
of migraine pathogenesis, there is interest in developing acute migraine
treatments that act exclusively on non-vascular targets. There is a large
percentage of non-responders to current acute migraine treatments and the
vasoconstriction associated with triptans limit their use in patients with
pre-existing cardiovascular risk factors. Preferential 5-HT1F agonists have
shown promising results in in vitro and early proof-of-concept trials.
Lasmiditan, a highly selective 5-HT1F agonist, has completed two Phase III
randomized, double blind, placebo-controlled clinical trials, with a third - a
long-term, open-label safety study - still underway. Research to date suggests
lasmiditan lacks vasoconstrictive properties and may be a safe and effective
treatment option in patients refractory to current acute migraine medications or
who have cardiovascular risk factors. OBJECTIVE: To assess the efficacy and safety of lasmiditan in the acute
treatment of migraine.
METHODS: Adult patients with migraine were randomized (1:1:1) to a double-blind
dose of oral lasmiditan 200 mg, lasmiditan 100 mg, or placebo and were asked to
treat their next migraine attack within 4 hours of onset. Over 48 hours after
dosing, patients used an electronic diary to record headache pain and the
presence of nausea, phonophobia, and photophobia, one of which was designated
their most bothersome symptom (MBS).
RESULTS: Of the 1,856 patients who treated an attack, 77.9% had ≥1
cardiovascular risk factors in addition to migraine. Compared with placebo, more
patients dosed with lasmiditan 200 mg were free of headache pain at 2 hours
after dosing (32.2% vs 15.3%; odds ratio [OR] 2.6, 95% confidence interval [CI]
2.0-3.6, p< 0.001), similar to those dosed with lasmiditan 100 mg (28.2%; OR
2.2, 95% CI 1.6-3.0, p< 0.001). Furthermore, compared with those dosed with
placebo, more patients dosed with lasmiditan 200 mg (40.7% vs 29.5%; OR 1.6, 95%
CI 1.3-2.1, p< 0.001) and lasmiditan 100 mg (40.9%; OR 1.7, 95% CI, 1.3-2.2, p<
0.001) were free of their MBS at 2 hours after dosing. Adverse events were
mostly mild or moderate in intensity.
CONCLUSIONS: Lasmiditan dosed at 200 and 100 mg was efficacious and well
tolerated in the treatment of acute migraine among patients with a high level of
cardiovascular risk factors.
CLINICALTRIALSGOV IDENTIFIER: NCT02439320.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for adult
patients with migraine, lasmiditan increases the proportion of subjects who are
headache pain free at 2 hours after treating a migraine attack. |
List drugs included in the TRIUMEQ pill. | Triumeq is a single-tablet regimen for patients with HIV infection comprising dolutegravir, abacavir and lamivudine. | We report this case to highlight the possibility of a severe hypersensitivity
reaction as an important potential consequence of couples, living with HIV,
sharing anti-retroviral treatment. An HIV-1 positive and carrier of HLA-B*57:01
allele, treatment experienced man was commenced one pill Regimen Stribild
(tenofovir, emtricitabine, elvitegravir and cobicistat) in July 2015. On running
short of medication, he admitted to sharing his partner's treatment (Triumeq;
abacavir, lamivudine and dolutegravir). On the second occasion, re-introduction
resulted in whole body rash 4 h post dose and was associated with fever,
respiratory symptoms, headache and vomiting. On examination, he was pyrexic,
tachyponeic, tachycardiac and hypotensive. Hypersensitivity to abacavir can
cause significant morbidity. Re-challenge can result in a more rapid, severe and
potentially life-threatening reaction. This potentially could become an
increasing problem with more couples, living with HIV, sharing medication. Drug-induced liver injury related to Triumeq (abacavir/lamivudine/dolutegravir)
has not been reported in clinical trials. We report a case of hepatotoxicity
related to Triumeq exposure in a human immunodeficiency virus-infected patient.
Clinicians should remain aware of the risk for acute and late-onset hepatitis
with these agents. Close monitoring is recommended. Antiretroviral (ART) therapy for the treatment of human immunodeficiency virus
(HIV) infection has undergone significant changes over the past 30 years. Many
single-tablet regimens (STRs), including newer fixed-dose combination (FDC)
tablets, are available, offering patients several options for choosing a
treatment regimen that works best for them. Given these changes, patients are
more likely to adhere to treatment, achieve better clinical outcomes, and
experience both fewer side effects and drug-drug interactions. Newer STRs
include dolutegravir (DTG)/lamivudine (3TC)/abacavir (ABC) (Triumeq; Viiv
Healthcare, Research Triangle Park, NC), rilpivirine (RPV)/emtricitabine
(FTC)/tenofovir alafenamide (TAF) (Odefsey; Gilead, Foster City, CA),
RPV/FTC/tenofovir disoproxil fumarate (TDF) (Complera; Gilead), elvitegravir
(EVG)/cobicistat (COBI)/FTC/TDF (Stribild; Gilead), and EVG/COBI/FTC/TAF
(Genvoya; Gilead). Recently approved FDCs, such as atazanavir (ATV)/COBI
(Evotaz; Bristol-Myers Squibb, Princeton, NJ), darunavir (DRV)/COBI (Prezcobix;
Janssen Products, Titusville NJ), and FTC/TAF (Descovy; Gilead), are also now
available. The Department of Health and Human Services treatment guidelines for
HIV recommend many of these integrase strand transfer inhibitor (INSTI) STRs as
a preferred choice for initiation of treatment in both ART-naive and
-experienced patients because they offer comparably faster rates of virologic
suppression, reduced rates of resistance development (especially with DTG), and
overall better adherence than protease inhibitors or NNRTIs. Numerous phase 3
clinical trials support these recommendations including several switch or
simplification clinical trials. Notably, the novel pharmacokinetic booster COBI,
with its water soluble properties, has enabled the development and coformulation
of a few of these STRs and FDCs. Also, a newer tenofovir salt formulation, TAF,
has an advantageous pharmacokinetic profile, contributing to better overall
renal and bone tolerability compared with TDF. Further simplification regimens
comprising dual ART therapies are currently being explored. This review provides
an overview of the clinical efficacy and safety data for these coformulated
agents, highlighting the relative impact on comparative adverse events,
assessing the potential for experiencing fewer drug-drug interactions, and
discussing the clinical implications regarding adherence to treatment. Triumeq is a single-tablet regimen for patients with HIV infection comprising
dolutegravir, abacavir and lamivudine. Overdoses with Triumeq have not been
reported previously. We present a case of a 26-year-old man who presented to our
hospital after intentionally ingesting 30 tablets of Triumeq. An intoxication
with Triumeq can lead to several side effects. An overdose of abacavir and
lamivudine can cause mitochondrial toxicity and lactic acidosis. An intoxication
with dolutegravir appears to be relatively harmless. As Triumeq will be used on
a regular basis as treatment for patients with HIV-1 infection, these
intoxications are expected to be encountered more often. BACKGROUND: If HIV patients are unconscious or cannot swallow tablets for other
reasons, antiretroviral medication is crushed and dissolved prior to
administration. Crushing can alter drug exposure, possibly leading to treatment
failure, development of resistance or toxicity. Currently, there is no
information about crushing of the branded fixed-dose combination of
dolutegravir/abacavir/lamivudine (Triumeq®, referred to as TRI); therefore,
crushing of TRI is not recommended.
OBJECTIVES: To investigate whether the TRI fixed-dose combination tablet can be
crushed and combined with enteral nutrition without influencing pharmacokinetics
(PK).
METHODS: We carried out an open-label, three-period, randomized, single-dose,
crossover trial in 22 healthy adult volunteers. Subjects randomly received
whole-tablet TRI with fasting (reference), crushed and suspended TRI with
fasting or crushed and suspended TRI with oral intake of enteral nutrition.
Bioequivalence criteria (80%-125% acceptance range) of AUC0-∞ and Cmax were
used. ClinicalTrials.gov: NCT02569346.
RESULTS: Crushing TRI leads to higher dolutegravir exposure (AUC0-∞: +26% and
Cmax: +30%) and, if crushed TRI is combined with enteral nutrition, to a
decrease in abacavir Cmax (-17%). Lamivudine concentrations were not affected as
geometric mean ratios with 90% CIs fell within the 80%-125% range.
CONCLUSIONS: Bioequivalence could not be demonstrated for a crushed and
suspended tablet or a crushed and suspended tablet with oral intake of enteral
nutrition compared with whole-tablet TRI with fasting. Both scenarios led to
higher dolutegravir exposure, but this did not exceed exposure after intake with
food or in twice-daily dosing. In our opinion, TRI can be crushed for patients
with swallowing difficulties and can be simultaneously administered with enteral
nutrition. |
Are there graph kernel libraries available implemented in JAVA? | No. Measuring the similarity of graphs is a fundamental step in the analysis of graph-structured data, which is omnipresent in computational biology. Graph kernels have been proposed as a powerful and efficient approach to this problem of graph comparison. Graphkernels are the first R and Python graph kernel libraries including baseline kernels such as label histogram based kernels, classic graph kernels such as random walk based kernels, and the state-of-the-art Weisfeiler-Lehman graph kernel. The core of all graph kernels is implemented in C ++ for efficiency. Using the kernel matrices computed by the package, one can perform tasks such as classification, regression and clustering on graph-structured samples. | SUMMARY: Measuring the similarity of graphs is a fundamental step in the
analysis of graph-structured data, which is omnipresent in computational
biology. Graph kernels have been proposed as a powerful and efficient approach
to this problem of graph comparison. Here we provide graphkernels, the first R
and Python graph kernel libraries including baseline kernels such as label
histogram based kernels, classic graph kernels such as random walk based
kernels, and the state-of-the-art Weisfeiler-Lehman graph kernel. The core of
all graph kernels is implemented in C ++ for efficiency. Using the kernel
matrices computed by the package, we can easily perform tasks such as
classification, regression and clustering on graph-structured samples.
AVAILABILITY AND IMPLEMENTATION: The R and Python packages including source code
are available at https://CRAN.R-project.org/package=graphkernels and
https://pypi.python.org/pypi/graphkernels.
CONTACT: [email protected] or [email protected].
SUPPLEMENTARY INFORMATION: Supplementary data are available online at
Bioinformatics. |
What organism causes hepatic capillariasis? | Hepatic capillariasis is a rare and neglected parasitic disease caused by infection with Capillaria hepatica in human liver. | Capillaria hepatica (C. hepatica) is a parasitic nematode causing hepatic
capillariasis in numerous mammals. Ecologic studies showed that the first hosts
of C. hepatica were rodents, among which rats had relatively high infection
rates, which explains why C. hepatica spreads globally. Anatomical studies
showed that the liver was the principal site of colonization by these parasites
and physical damage tended to occur. Although C. hepatica might lead to serious
liver disorders, relevant clinical reports were rare, because of the
non-specific nature of clinical symptoms, leading to misdiagnosis. This review
mainly focuses on the biological characteristics and epidemiology of C. hepatica
in China and histopathologic changes in the liver, with expectation of gaining a
better understanding of the disease and seeking more effective treatment. Capillaria hepatica which accidentally infects humans is a zoonotic parasite of
mammalian liver, primarily rodents and causes hepatic capillariasis. The
diagnosis is difficult because of the non-specific nature of clinical symptoms,
leading to misdiagnosis and can be confirmed only through liver biopsy or on
autopsy results. This paper is written with an objective to report a new case of
hepatic capillariasis as a rare differential for peripheral eosinophilia and an
imaging dilemma for abdominal lymphadenopathy. Zoonotic infections are increasingly becoming public health menaces and are
usually transmitted to humans due to unsuitable environmental conditions. One of
them is hepatic capillariasis, caused by the parasite Capillaria hepatica,
primarily a disease of rodents, with hepatic manifestations in humans. Although
its prevalence is very low, it can cause significant morbidity and mortality,
with cases reported from all over the world. The main infective form for humans
is the embryonated egg of the parasite, which hatches in the intestine and
ultimately colonize the liver. The larvae mature and reproduce, and eventually
form embryonated eggs, which cause chronic focal inflammation and septal hepatic
fibrosis. Clinical presentation mainly consists of fever, abdominal pain,
hepatomegaly and eosinophilia. Spurious infection with unembryonated eggs cause
gastrointestinal symptoms. Diagnostic modalities include liver biopsy,
ultrasonography, CT scan, immunological tests like ELISA and IIFT. The infection
can be treated mainly with a combination of benzimidazoles like thiabendazole,
mebendazole and albendazole; with corticosteroids. The study emphasizes the need
for hepatic capillariasis to be considered as a differential diagnosis in cases
of suspected hepatitis, leptospirosis, abdominal lymphadenopathy or other
hepatic or parasitic infections prevalent in the region concerned; and
meticulously assess the cases to facilitate early diagnosis and prompt
treatment, thus reducing the distress faced by patients. |
Cerliponase alfa is apprived for treatment of which disease? | Cerliponase alfa is a recombinant human tripeptidyl peptidase-1 (TPP1) approved for use in patients with neuronal ceroid lipofuscinosis type 2 (CLN2), a paediatric neurodegenerative disease caused by a deficiency in TPP1. | Cerliponase alfa (Brineura™) is a recombit human tripeptidyl peptidase-1
(TPP1) being developed by BioMarin Pharmaceutical Inc. for use in patients with
neuronal ceroid lipofuscinosis type 2 (CLN2), a paediatric neurodegenerative
disease caused by a deficiency in TPP1. CLN2 is characterised by progressive
impairment of motor function, language deficiencies, seizures, ataxia, blindness
and early death, and intracerebroventricular infusion of cerliponase alfa has
been shown to reduce the progression of functional decline. This article
summarizes the milestones in the development of cerliponase alfa leading to its
first global approval in the USA for the treatment of motor function loss in
paediatric patients ≥3 years of age with CLN2, and subsequent approval in the EU
for CLN2 in all ages. Sarilumab (Kevzara) for moderately to severely active rheumatoid arthritis;
valbenazine (Ingrezza), the first approval for tardive dyskinesia; and
cerliponase alpha (Brineura) for late infantile neuronal ceroid lipofuscinosis
type-2 disease. BACKGROUND: Recombit human tripeptidyl peptidase 1 (cerliponase alfa) is an
enzyme-replacement therapy that has been developed to treat neuronal ceroid
lipofuscinosis type 2 (CLN2) disease, a rare lysosomal disorder that causes
progressive dementia in children.
METHODS: In a multicenter, open-label study, we evaluated the effect of
intraventricular infusion of cerliponase alfa every 2 weeks in children with
CLN2 disease who were between the ages of 3 and 16 years. Treatment was
initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received
the 300-mg dose for at least 96 weeks. The primary outcome was the time until a
2-point decline in the score on the motor and language domains of the CLN2
Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function
and 3 representing normal function in each of the two domains), which was
compared with the time until a 2-point decline in 42 historical controls. We
also compared the rate of decline in the motor-language score between the two
groups, using data from baseline to the last assessment with a score of more
than 0, divided by the length of follow-up (in units of 48 weeks).
RESULTS: Twenty-four patients were enrolled, 23 of whom constituted the efficacy
population. The median time until a 2-point decline in the motor-language score
was not reached for treated patients and was 345 days for historical controls.
The mean (±SD) unadjusted rate of decline in the motor-language score per
48-week period was 0.27±0.35 points in treated patients and 2.12±0.98 points in
42 historical controls (mean difference, 1.85; P<0.001). Common adverse events
included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure
of the intraventricular device. In 2 patients, infections developed in the
intraventricular device that was used to administer the infusion, which required
antibiotic treatment and device replacement.
CONCLUSIONS: Intraventricular infusion of cerliponase alfa in patients with CLN2
disease resulted in less decline in motor and language function than that in
historical controls. Serious adverse events included failure of the
intraventricular device and device-related infections. (Funded by BioMarin
Pharmaceutical and others; CLN2 ClinicalTrials.gov numbers, NCT01907087 and
NCT02485899 .). Treatment with intracerebroventricular (ICV)-delivered cerliponase alfa enzyme
replacement therapy (ERT) in a Phase 1/2 study of 24 subjects with CLN2 disease
resulted in a meaningful preservation of motor and language (ML) function and
was well tolerated. Treatment was associated with anti-drug antibody (ADA)
production in the cerebrospinal fluid (CSF) of 6/24 (25%) and in the serum of
19/24 (79%) of clinical trial subjects, respectively, over a mean exposure of
96.4 weeks (range 0.1-129 weeks). Neutralizing antibodies (NAb) were not
detected in the CSF of any of the subjects. No events of anaphylaxis were
reported. Neither the presence of serum ADA nor drug-specific immunoglobulin E
was associated with the incidence or severity of hypersensitivity adverse
events. Serum and CSF ADA titers did not correlate with change in ML score.
Therefore, the development of an ADA response to cerliponase alfa is not
predictive of an adverse safety profile or poor treatment outcome. |
Is baricitinib effective for rheumatoid arthritis? | Yes, baricitinib is effective treatment of rheumatoid arthritis. | INTRODUCTION: The JAK kinases are a family of four tyrosine receptor kinases
that play a pivotal role in cytokine receptor signalling pathways via their
interaction with signal transducers and activators of transcription proteins.
Selective inhibitors of JAK kinases are viewed as of considerable potential as
disease-modifying anti-inflammatory drugs for the treatment of rheumatoid
arthritis.
AREAS COVERED: This article provides a review of the clinical development and
available clinical results for those JAK inhibitors currently under
investigation. Phase II data for four JAK inhibitors (baricitinib, decernotinib,
filgotinib and INCB-039110) are contrasted with that reported for the recently
approved JAK inhibitor tofacitinib. The preclinical data on these, in addition
to peficitinib, ABT-494, INCB-047986 and AC-410 are also discussed, as are some
of the inhibitors in preclinical development.
EXPERT OPINION: JAK inhibitors are effective in the treatment of rheumatoid
arthritis as evidenced by several inhibitors enabling the majority of treated
patients to achieve ACR20 responses, with baricitinib and INCB-039110 both
effective when administered once daily. JAK inhibitors differ in isoform
specificity profiles, with good efficacy achievable by selective inhibition of
either JAK1 (filgotinib or INCB-039110) or JAK3 (decernotinib). It remains to be
seen what selectivity provides the optimal side-effect profile and to what
extent inhibition of JAK2 should be avoided. INTRODUCTION: Rheumatoid arthritis (RA) is characterized by systemic synovitis
causing joint destruction. With the development of biological disease-modifying
anti-rheumatic drugs (bDMARDs) and combination of conventional DMARDs, clinical
remission is perceived as an appropriate and realistic goal in many patients.
However, bDMARDs require intravenous or subcutaneous injection and some patients
fail to respond to bDMARDs or lose their primary response. Under the
circumstances, targeted synthetic DMARDs (tsDMARDs), which are orally available
low-molecular weight products, have been emerging. Five phase 3 trials of
Baricitinib, a JAK1 and JAK2 inhibitor, have been performed and showed high
clinical efficacy in patients with active RA and naïve to sDMARDs or an
inadequate response to sDMARDs, MTX or bDMARDs. There was a favorable response
for clinical and functional parameters in studies with placebo, MTX and
adalimumab as comparator. It is also reported that safety was tolerable within
the limited study period.
AREAS COVERED: We here review the recent progress in the development of
baricitinib and its potential for the treatment of RA. Expert commentary:
Although baricitinib is only one of the highly effective DMARDs that has a new
mode of action, it will bring new concepts for rheumatology in the future. OBJECTIVE: This study aimed to assess the relative efficacy and safety of
once-daily baricitinib 2 mg and 4 mg administration in patients with active
rheumatoid arthritis (RA).
METHODS: In this network meta-analysis, randomized controlled trials (RCTs)
examining the efficacy and safety of baricitinib in patients with active RA were
included. A Bayesian network meta-analysis was conducted to combine the direct
and indirect evidence from the RCTs.
RESULTS: Seven RCTs involving 3461 patients met the inclusion criteria. There
were ten pairwise comparisons, including seven direct comparisons and five
interventions. The ACR20 response rate was significantly higher in the
baricitinib 4 mg in combination with disease-modifying antirheumatic drugs
(DMARD) group than in the placebo+DMARD group (odds ratio, OR 3.13; 95% credible
interval, CrI 2.32-4.33). Compared with the placebo+DMARD group, the baricitinib
4 mg, baricitinib 2 mg + DMARD, and adalimumab 40 mg + methotrexate (MTX) groups
showed a significantly higher ACR20 response rate. The ranking probability based
on the surface under the cumulative ranking curve (SUCRA) indicated that
baricitinib 4 mg + DMARD was likely to elicit the best ACR20 response rate
(SUCRA = 0.7930), followed by baricitinib 4 mg (SUCRA = 0.7034), baricitinib
2 mg + DMARD (SUCRA = 0.6304), adalimumab 40 mg + MTX (SUCRA = 0.3687), and
placebo+DMARD (SUCRA = 0.0045). By contrast, the safety based on the number of
treatment-emergent adverse events (TEAEs) did not differ significantly among the
five interventions.
CONCLUSION: Baricitinib 2 mg and 4 mg administered once daily, in combination
with DMARD, were efficacious interventions for active RA that had no significant
risk of TEAE development. BACKGROUND: Baricitinib is an oral, reversible inhibitor of the Janus kinases
JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid
arthritis.
METHODS: We conducted a 52-week, phase 3, double-blind, placebo- and
active-controlled trial in which 1307 patients with active rheumatoid arthritis
who were receiving background therapy with methotrexate were randomly assigned
to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib
after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an
anti-tumor necrosis factor α monoclonal antibody) every other week. End-point
measures evaluated after adjustment for multiplicity included 20% improvement
according to the criteria of the American College of Rheumatology (ACR20
response) (the primary end point), the Disease Activity Score for 28 joints
(DAS28), the Health Assessment Questionnaire-Disability Index, and the
Simplified Disease Activity Index at week 12, as well as radiographic
progression of joint damage as measured by the van der Heijde modification of
the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating
greater structural joint damage) at week 24.
RESULTS: More patients had an ACR20 response at week 12 with baricitinib than
with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary
objectives were met, including inhibition of radiographic progression of joint
damage, according to the mTSS at week 24 with baricitinib versus placebo (mean
change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response
rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014).
Adverse events, including infections, were more frequent through week 24 with
baricitinib and adalimumab than with placebo. Cancers were reported in five
patients (two who received baricitinib and three who received placebo).
Baricitinib was associated with reductions in neutrophil counts and increases in
levels of creatinine and low-density lipoprotein cholesterol.
CONCLUSIONS: In patients with rheumatoid arthritis who had had an inadequate
response to methotrexate, baricitinib was associated with significant clinical
improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and
Incyte; ClinicalTrials.gov number, NCT01710358 .). OBJECTIVES: To evaluate efficacy/safety of baricitinib for rheumatoid arthritis
(RA) in Japanese subpopulations from four phase 3 studies, and assess whether
results in these subpopulations are consistent with the overall study
populations.
METHODS: Subgroup analyses (394 patients) of four phase 3 randomized controlled
trials: RA-BEGIN [no or limited treatment with disease-modifying antirheumatic
drugs (DMARDs)], RA-BEAM [inadequate response (IR) to methotrexate], RA-BUILD
[IR to conventional synthetic DMARDs (csDMARDs)], and RA-BEACON (IR to tumor
necrosis factor inhibitors receiving csDMARDs).
RESULTS: For American College of Rheumatology 20% improvement (ACR20) response
rate, Japanese patients receiving baricitinib 4-mg showed similar improvement
compared to methotrexate at Week 24 (72 versus 69%; RA-BEGIN), and greater
improvement compared with placebo at Week 12 (67 versus 34%; RA-BEAM). Japanese
patients receiving baricitinib 4-mg also showed greater improvement compared
with placebo at Week 12 in RA-BUILD and RA-BEACON. Across all studies,
baricitinib was well-tolerated, with no deaths and one maligcy. In RA-BEGIN
and RA-BEAM, herpes zoster rates were higher for Japanese patients than for
overall populations; all events were mild/moderate.
CONCLUSION: Data for baricitinib, with/without methotrexate, in Japanese
subpopulations across all stages of the RA treatment continuum accord with the
efficacy/safety profile in overall study populations. Baricitinib appears to be
similarly effective in Japanese patients. OBJECTIVE: RA patients who have failed biologic DMARDs (bDMARDs) represent an
unmet medical need. We evaluated the effects of baseline characteristics,
including prior bDMARD exposure, on baricitinib efficacy and safety.
METHODS: RA-BEACON patients (previously reported) had moderate to severe RA with
insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to
once-daily placebo or 2 or 4 mg baricitinib. Prior bDMARD use was allowed. The
primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4
mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated
efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI)
⩽10. An interaction P-value ⩽0.10 was considered significant, with significance
at both weeks 12 and 24 given more weight.
RESULTS: The odds ratios predomitly favored baricitinib over placebo and were
generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and
24, respectively). Significant quantitative interactions were observed for
baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect
Europe) and CDAI ⩽10 by disease duration (larger effect ⩾10 years). No
significant interactions were consistently observed for ACR20 by age; weight;
disease duration; seropositivity; corticosteroid use; number of prior bDMARDs,
TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor.
Treatment-emergent adverse event rates, including infections, appeared somewhat
higher across groups with greater prior bDMARD use.
CONCLUSION: Baricitinib demonstrated a consistent, beneficial treatment effect
in bDMARD-refractory patients across subgroups based on baseline characteristics
and prior bDMARD use.
TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/),
NCT01721044. Two different Janus kinase (JAK) inhibitors-baricitinib and tofacitinib-are
effective and licensed in active rheumatoid arthritis (RA). There have been
recent concerns about potential thromboembolic risks with these drugs. Concerns
about baricitinib focus on clinical trial findings. Using all publically
available data, we estimate thromboembolic risks are approximately five events
per 1000 patient years with 4 mg baricitinib daily. Concerns about tofacitinib
have been raised by analyses of the Federal Drug Administration Adverse Event
Reporting System (FAERs). These show some evidence of increased risks of
pulmonary thrombosis, though not pulmonary embolism or venous thrombosis.
Observational studies suggest in the general population and non-RA controls
there are one to four thromboembolic events per 1000 patient years. In RA,
thromboembolic risks increase to three to seven per 1000 patient years. The
impact of biologics and disease-modifying anti-rheumatic drugs (DMARDs) on
disease risk appears minimal, and the number of thromboembolic events is between
four and eight per 1000 patient years. In the short term, full details of
thromboembolic events in trials of JAK inhibitors need to be published. As the
numbers of thromboembolic events will be small and patients enrolled in trials
are not representative of all RA patients who may receive JAK inhibitors, this
information is unlikely to provide definitive answers. Consequently, in the
longer term, large observational studies are needed to accurately quantify
thromboembolic risks attributable to JAK inhibitors and other drugs used to
treat RA, and differentiate these from risks attributable to RA itself and its
comorbidities. Baricitinib (Olumiant®) is an oral, targeted synthetic DMARD that inhibits JAK1
and JAK2, which are implicated in the pathogenesis of rheumatoid arthritis (RA).
This novel, small molecule is approved for use as monotherapy, or in combination
with methotrexate, for the treatment of adults with moderate to severe active RA
who responded inadequately to or were intolerant of ≥ 1 DMARD. In pivotal
multinational trials, once-daily baricitinib 4 mg, with/without methotrexate
(± another csDMARD), improved the signs and symptoms of RA, disease activity and
physical function in DMARD-naive patients and in patients with an inadequate
response to methotrexate, csDMARDs or TNF inhibitors; baricitinib treatment also
slowed structural joint damage in DMARD-naive patients and in those with an
inadequate response to methotrexate and csDMARDs. Baricitinib plus methotrexate
was more effective than adalimumab plus methotrexate in patients with an
inadequate response to methotrexate. The onset of these benefits was generally
rapid and sustained over time. Baricitinib was generally well tolerated during
up to 5.5 years' treatment; the most commonly reported adverse drug reactions
were upper respiratory tract infections, increased LDL cholesterol, nausea and
thrombocytosis. Thus, once-daily baricitinib, as monotherapy or in combination
with methotrexate, is an effective and generally well tolerated emerging
treatment for patients with moderate to severe active RA who have responded
inadequately to or are intolerant of ≥ 1 DMARD, and extends the options
available for this population. OBJECTIVE: Baricitinib is an orally administered inhibitor of JAK1 and JAK2 that
has been shown to be effective in treating rheumatoid arthritis (RA). This study
was undertaken to analyze changes in lymphocyte cell subsets during baricitinib
treatment and to correlate these changes with clinical outcomes.
METHODS: An integrated analysis was conducted by pooling data from 3 completed
phase III trials comparing placebo with baricitinib treatment (RA-BEAM,
RA-BUILD, and RA-BEACON) and 1 ongoing long-term extension study (RA-BEYOND) in
patients with active RA (n = 2,186).
RESULTS: Baricitinib treatment was associated with an early transient increase
in total lymphocyte count at week 4, which returned to baseline by week 12.
Transient changes within normal reference ranges in T cells and subsets were
observed with baricitinib treatment, up to week 104. B cells and relevant
subpopulations increased after 4 weeks of baricitinib treatment, with no further
increases noted through 104 weeks of treatment. Natural killer (NK) cells
temporarily increased after 4 weeks of baricitinib treatment, before decreasing
below baseline levels and then stabilizing over time. With baricitinib
treatment, few correlations were observed between changes in lymphocyte subsets
and clinical end points, and most correlations were also observed within the
placebo group. A modest potential association between low NK cell numbers and
treatment-emergent infections was observed in the baricitinib 4 mg/day treatment
group, but not for serious infections or herpes zoster.
CONCLUSION: Overall, these findings demonstrate that changes in lymphocyte
subsets were largely within normal reference ranges across the baricitinib phase
III RA clinical program and were not associated with increased risk of serious
infections. OBJECTIVES: Oral targeted synthetic disease-modifying anti-rheumatic drugs
(DMARDs), including the Janus kinase inhibitors tofacitinib and baricitinib, are
the latest addition to the therapeutic options for rheumatoid arthritis (RA).
Tofacitinib 5 mg, twice daily, is approved for treatment, with or without
methotrexate, of moderate to severe active RA in adults not adequately
responding to, or not tolerating one or more DMARDs. In this narrative review we
aimed to provide an overview of the real-world evidence for tofacitinib in RA.
METHODS: The literature was reviewed up to March 2018 for studies regarding the
efficacy and safety of tofacitinib for the treatment of RA. The focus was mainly
on real-world studies with implications for every day clinical practice.
RESULTS: The efficacy and safety of tofacitinib have been comprehensively
assessed in a wide programme of randomised controlled trials. Extensive
observational research on tofacitinib in RA is also ongoing worldwide and a
substantial body of post-marketing real-world data from clinical practice is
becoming available. There was a degree of consistency across the real-world
studies reviewed. Tofacitinib tends to be used as monotherapy more frequently
than bDMARDS and appears to be effective without background methotrexate. The
data show a manageable safety profile, with no new safety signals and a
discontinuation rate from safety issues <10%. Patients initiating tofacitinib
usually have longer disease duration and have been exposed to longer bDMARDs
than patients initiating a bDMARD.
CONCLUSIONS: Real-world data are a key component of the evidence supporting the
effectiveness of this novel drug and are of interest to all stakeholders.
Treatment persistence and adherence to tofacitinib are good overall and similar
to those seen for bDMARDs. OBJECTIVES: The relative efficacy and safety of tofacitinib and baricitinib were
assessed in patients with rheumatoid arthritis (RA) with an inadequate response
to disease-modifying anti-rheumatic drugs (DMARDs) or biologics.
METHODS: We performed a Bayesian network meta-analysis to combine direct and
indirect evidence from randomized controlled trials (RCTs) to examine the
efficacy and safety of tofacitinib and baricitinib in combination with DMARDs in
RA patients with an inadequate DMARD or biologic response.
RESULTS: Twelve RCTs including 5883 patients met the inclusion criteria. There
were 15 pairwise comparisons including 10 direct comparisons of 6 interventions.
Tofacitinib 10 mg + methotrexate (MTX) and baricitinib 4 mg + MTX were among the
most effective treatments for active RA with an inadequate DMARD or biologic
response, followed by baricitinib 2 mg + MTX, tofacitinib 5 mg + MTX, and
adalimumab + MTX. The ranking probability based on the surface under the
cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg + MTX had the
highest probability of being the best treatment to achieve the ACR20 response
rate (SUCRA = 0.865), followed by baricitinib 4 mg + MTX (SUCRA = 0.774),
baricitinib 2 mg + MTX (SUCRA = 0.552), tofacitinib 5 mg + MTX (SUCRA = 0.512),
adalimumab + MTX (SUCRA = 0.297), and placebo + MTX (SUCRA <0.001). No
significant differences were observed in the incidence of serious adverse events
after treatment with tofacitinib + MTX, baricitinib + MTX, adalimumab + MTX, or
placebo + MTX.
CONCLUSIONS: In RA patients with an inadequate response to DMARDs or biologics,
tofacitinib 10 mg + MTX and baricitinib 4 mg + MTX were the most efficacious
interventions and were not associated with a significant risk of serious adverse
events. Author information:
(1)From the Division of Rheumatology, Department of Medicine, Medical University
of Vienna, Vienna, Austria; Division of Immunology and Rheumatology, Stanford
University Medical Center, Palo Alto, California, USA; Division of Rheumatology,
Department of Internal Medicine, Keio University, Tokyo, Japan; Lilly Research
Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA; Lilly Research
Laboratories, Eli Lilly and Co., Kobe, Japan; Oregon Health Sciences University,
Portland, Oregon, USA. [email protected].
(2)J.S. Smolen, MD, Division of Rheumatology, Department of Medicine, Medical
University of Vienna; M.C. Genovese, MD, Division of Immunology and
Rheumatology, Stanford University Medical Center; T. Takeuchi, MD, PhD, Division
of Rheumatology, Department of Internal Medicine, Keio University; D.L. Hyslop,
MD, Lilly Research Laboratories, Eli Lilly and Co., USA; W. Macias, MD, PhD,
Lilly Research Laboratories, Eli Lilly and Co., USA; T. Rooney, MD, Lilly
Research Laboratories, Eli Lilly and Co., USA; L. Chen, MD, PhD, Lilly Research
Laboratories, Eli Lilly and Co., USA; C.L. Dickson, BS Pharm, Lilly Research
Laboratories, Eli Lilly and Co., USA; J. Riddle Camp, BA, Lilly Research
Laboratories, Eli Lilly and Co., USA; T.E. Cardillo, MSN, Lilly Research
Laboratories, Eli Lilly and Co., USA; T. Ishii, MD, PhD, Lilly Research
Laboratories, Eli Lilly and Co., Japan; K.L. Winthrop, MD, MPH, Oregon Health
Sciences University. [email protected].
(3)From the Division of Rheumatology, Department of Medicine, Medical University
of Vienna, Vienna, Austria; Division of Immunology and Rheumatology, Stanford
University Medical Center, Palo Alto, California, USA; Division of Rheumatology,
Department of Internal Medicine, Keio University, Tokyo, Japan; Lilly Research
Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA; Lilly Research
Laboratories, Eli Lilly and Co., Kobe, Japan; Oregon Health Sciences University,
Portland, Oregon, USA.
(4)J.S. Smolen, MD, Division of Rheumatology, Department of Medicine, Medical
University of Vienna; M.C. Genovese, MD, Division of Immunology and
Rheumatology, Stanford University Medical Center; T. Takeuchi, MD, PhD, Division
of Rheumatology, Department of Internal Medicine, Keio University; D.L. Hyslop,
MD, Lilly Research Laboratories, Eli Lilly and Co., USA; W. Macias, MD, PhD,
Lilly Research Laboratories, Eli Lilly and Co., USA; T. Rooney, MD, Lilly
Research Laboratories, Eli Lilly and Co., USA; L. Chen, MD, PhD, Lilly Research
Laboratories, Eli Lilly and Co., USA; C.L. Dickson, BS Pharm, Lilly Research
Laboratories, Eli Lilly and Co., USA; J. Riddle Camp, BA, Lilly Research
Laboratories, Eli Lilly and Co., USA; T.E. Cardillo, MSN, Lilly Research
Laboratories, Eli Lilly and Co., USA; T. Ishii, MD, PhD, Lilly Research
Laboratories, Eli Lilly and Co., Japan; K.L. Winthrop, MD, MPH, Oregon Health
Sciences University. |
What is the function of PARP1? | parp1 is the most abundant and best-characterized member of the family of parp enzymes. the poly(adp-ribose) polymerases (parps) catalyze poly(adp-ribosyl)ation, a post-translational modification of proteins. | Asbestos is known to induce maligt mesothelioma (MM) and other
asbestos-related diseases. It is directly genotoxic by inducing DNA strand
breaks and cytotoxic by promoting apoptosis in lung target cells.
Poly(ADP-ribose) polymerase-1 (PARP1) is a nuclear zinc-finger protein with a
function as a DNA damage sensor. To determine whether PARP1 is involved in
asbestos-induced carcinogenesis, PARP1 expression and activity as well as DNA
damage and repair were evaluated in circulating cells of asbestos-exposed
subjects, MM patients and age-matched controls. PARP1 expression and activity
were also evaluated in pleural biopsies of MM patients and compared with normal
tissue. Accumulation of the pre-mutagenic 8-hydroxy-2'-deoxyguanosine and
elevated PARP1 expression were found both in asbestos-exposed subjects and MM
patients. Although PARP1 was highly expressed, its activity was relatively low.
Low DNA repair efficiency was observed in lymphocytes from MM patients. High
expression of PARP1 associated with low PARP activity was also found in MM
biopsies. To mimic PARP1 dysfunction, PARP1 expression and activity were induced
in immortalised mesothelial cells by their exposure to asbestos in the presence
of a PARP1 inhibitor, which resulted in transformation of the cells. We propose
that exposure to asbestos inhibits the PARP1 activity possibly resulting in
higher DNA instability, thus causing maligt transformation. Poly(ADP-ribose)polymerase-1 (PARP1) is a chromatin-associated enzyme that was
described to affect chromatin compaction. Previous reports suggested a dynamic
modulation of the chromatin landscape during adipocyte differentiation. We thus
hypothesized that PARP1 plays an important transcriptional role in adipogenesis
and metabolism and therefore used adipocyte development and function as a model
to elucidate the molecular action of PARP1 in obesity-related diseases. Our
results show that PARP1-dependent ADP-ribose polymer (PAR) formation increases
during adipocyte development and, at late time points of adipogenesis, is
involved in the sustained expression of PPARγ2 and of PPARγ2 target genes.
During adipogenesis, PARP1 was recruited to PPARγ2 target genes such as CD36 or
aP2 in a PAR-dependent manner. Our results also reveal a PAR-dependent decrease
in repressory histone marks (e.g. H3K9me3) and an increase in stimulatory marks
(e.g. H3K4me3) at the PPARγ2 promoter, suggesting that PARP1 may exert its
regulatory function during adipogenesis by altering histone marks.
Interestingly, activation of PARP1 enzymatic activity was prevented with a
topoisomerase II inhibitor. These data hint at topoisomerase II-dependent,
transient, site-specific double-strand DNA breaks as the cause for
poly(ADP)-ribose formation, adipogenic gene expression, and adipocyte function.
Together, our study identifies PARP1 as a critical regulator of PPARγ2-dependent
gene expression with implications in adipocyte function and obesity-related
disease models. Poly(ADP-ribose) polymerase 1 (PARP1, also known as ARTD1) is an abundant
nuclear enzyme that plays important roles in DNA repair, gene transcription, and
differentiation through the modulation of chromatin structure and function. In
this work we identify a physical and functional poly(ADP-ribose)-mediated
interaction of PARP1 with the E3 ubiquitin ligase UHRF1 (also known as NP95,
ICBP90) that influences two UHRF1-regulated cellular processes. On the one hand,
we uncovered a cooperative interplay between PARP1 and UHRF1 in the accumulation
of the heterochromatin repressive mark H4K20me3. The absence of PARP1 led to
reduced accumulation of H4K20me3 onto pericentric heterochromatin that coincided
with abnormally enhanced transcription. The loss of H4K20me3 was rescued by the
additional depletion of UHRF1. In contrast, although PARP1 also seemed to
facilitate the association of UHRF1 with DNMT1, its absence did not impair the
loading of DNMT1 onto heterochromatin or the methylation of pericentric regions,
possibly owing to a compensating interaction of DNMT1 with PCNA. On the other
hand, we showed that PARP1 controls the UHRF1-mediated ubiquitination of DNMT1
to timely regulate its abundance during S and G2 phase. Together, this report
identifies PARP1 as a novel modulator of two UHRF1-regulated
heterochromatin-associated events: the accumulation of H4K20me3 and the
clearance of DNMT1. The latent infection of Epstein-Barr virus (EBV) is associated with 1% of human
cancer incidence. Poly(ADP-ribosyl)ation (PARylation) is a posttranslational
modification catalyzed by poly(ADP-ribose) polymerases (PARPs) that mediate EBV
replication during latency. In this study, we detail the mechanisms that drive
cellular PARylation during latent EBV infection and the effects of PARylation on
host gene expression and cellular function. EBV-infected B cells had higher PAR
levels than EBV-negative B cells. Moreover, cellular PAR levels were up to
2-fold greater in type III than type I latently infected EBV B cells. We
identified a positive association between expression of the EBV genome-encoded
latency membrane protein 1 (LMP1) and PAR levels that was dependent upon PARP1.
PARP1 regulates gene expression by numerous mechanisms, including modifying
chromatin structure and altering the function of chromatin-modifying enzymes.
Since LMP1 is essential in establishing EBV latency and promoting tumorigenesis,
we explored the model that disruption in cellular PARylation, driven by LMP1
expression, subsequently promotes epigenetic alterations to elicit changes in
host gene expression. PARP1 inhibition resulted in the accumulation of the
repressive histone mark H3K27me3 at a subset of LMP1-regulated genes. Inhibition
of PARP1, or abrogation of PARP1 expression, also suppressed the expression of
LMP1-activated genes and LMP1-mediated cellular transformation, demonstrating an
essential role for PARP1 activity in LMP1-induced gene expression and cellular
transformation associated with LMP1. In summary, we identified a novel mechanism
by which LMP1 drives expression of host tumor-promoting genes by blocking
generation of the inhibitory histone modification H3K27me3 through PARP1
activation.
IMPORTANCE: EBV is causally linked to several maligcies and is responsible
for 1% of cancer incidence worldwide. The EBV-encoded protein LMP1 is essential
for promoting viral tumorigenesis by aberrant activation of several well-known
intracellular signaling pathways. We have identified and defined an additional
novel molecular mechanism by which LMP1 regulates the expression of
tumor-promoting host genes. We found that LMP1 activates the cellular protein
PARP1, leading to a decrease in a repressive histone modification, accompanied
by induction in expression of multiple cancer-related genes. PARP1 inhibition or
depletion led to a decrease in LMP1-induced cellular transformation. Therefore,
targeting PARP1 activity may be an effective treatment for EBV-associated
maligcies. |
Is Semagacestat effective for treatment of Alzheimer's disease? | No. In clinical trial semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. | The recent failure of semagacestat in two large Phase III studies questions the
value of γ-secretase inhibitors in treating Alzheimer's disease. Understanding
the reasons of this setback may be important for the future research on
effective treatments for this devastating disease. Neurological and psychiatric disorders are frequently associated with disruption
of various cognitive functions, but development of effective drug treatments for
these conditions has proven challenging. One of the main obstacles is the poor
predictive validity of our preclinical animal models. In the present study the
effects of the γ-secretase inhibitor semagacestat was evaluated in preclinical
in vivo electrophysiological models. Recently disclosed Phase III findings on
semagacestat indicated that Alzheimer's disease (AD) patients on this drug
showed significantly worsened cognitive function compared to those treated with
placebo. Since previous studies have shown that drugs impairing cognitive
function (including scopolamine, NMDA (N-methyl-D-aspartate) receptor
antagonists, and nociceptin receptor agonists) disrupt or decrease power of
elicited theta oscillation in the hippocampus, we tested the effects of acute
and sub-chronic administration of semagacestat in this assay. Field potentials
were recorded across the hippocampal formation with NeuroNexus multi-site
silicon probes in urethane anesthetized male C57BL/6 mice; hippocampal CA1 theta
oscillation was elicited by electrical stimulation of the brainstem nucleus
pontis oralis. Sub-chronic administration of semagacestat twice daily over 12
days at a dose known to reduce beta-amyloid peptide (Aβ) level [100 mg/kg, p.o.
(per oral)] diminished power of elicited hippocampal theta oscillation. Acute,
subcutaneous administration of semagacestat (100 mg/kg) produced a similar
effect on hippocampal activity. We propose that the disruptive effect of
semagacestat on hippocampal function could be one of the contributing mechanisms
to its worsening of cognition in patients with AD. As it has been expected, both
acute and sub-chronic administrations of semagacestat significantly decreased
Aβ40 and Aβ42 levels but the current findings do not reveal the mode of action
of semagacestat in disrupting hippocampal oscillation. BACKGROUND: Alzheimer's disease is characterized by the presence of cortical
amyloid-beta (Aβ) protein plaques, which result from the sequential action of
β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a
small-molecule γ-secretase inhibitor that was developed as a potential treatment
for Alzheimer's disease.
METHODS: We conducted a double-blind, placebo-controlled trial in which 1537
patients with probable Alzheimer's disease underwent randomization to receive
100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in
cognition from baseline to week 76 were assessed with the use of the cognitive
subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog),
on which scores range from 0 to 70 and higher scores indicate greater cognitive
impairment, and changes in functioning were assessed with the Alzheimer's
Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which
scores range from 0 to 78 and higher scores indicate better functioning. A
mixed-model repeated-measures analysis was used.
RESULTS: The trial was terminated before completion on the basis of a
recommendation by the data and safety monitoring board. At termination, there
were 189 patients in the group receiving placebo, 153 patients in the group
receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg
of semagacestat. The ADAS-cog scores worsened in all three groups (mean change,
6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the
study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07,
respectively, for the comparison with placebo). The ADCS-ADL scores also
worsened in all groups (mean change at week 76, -9.0 points in the placebo
group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group;
P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients
treated with semagacestat lost more weight and had more skin cancers and
infections, treatment discontinuations due to adverse events, and serious
adverse events (P<0.001 for all comparisons with placebo). Laboratory
abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins,
albumin, total protein, and uric acid and elevated levels of eosinophils,
monocytes, and cholesterol; the urine pH was also elevated.
CONCLUSIONS: As compared with placebo, semagacestat did not improve cognitive
status, and patients receiving the higher dose had significant worsening of
functional ability. Semagacestat was associated with more adverse events,
including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov
number, NCT00594568.) OBJECTIVE: Semagacestat, a γ-secretase inhibitor, demonstrated an unfavorable
risk-benefit profile in a Phase 3 study of patients with Alzheimer's disease
(IDENTITY trials), and clinical development was halted. To assist in future
development of γ-secretase inhibitors, we report detailed safety findings from
the IDENTITY study, with emphasis on those that might be mechanistically linked
to γ-secretase inhibition.
RESEARCH DESIGN AND METHODS: The IDENTITY trial was a double-blind,
placebo-controlled trial of semagacestat (100 mg and 140 mg), in which 1537
patients age 55 years and older with probable Alzheimer's disease were
randomized. Treatment-emergent adverse events (TEAEs) are reported by body
system along with pertinent laboratory, vital sign, and ECG findings.
RESULTS: Semagacestat treatment was associated with increased reporting of
suspected Notch-related adverse events (gastrointestinal, infection, and skin
cancer related). Other relevant safety findings associated with semagacestat
treatment included cognitive and functional worsening, skin-related TEAEs, renal
and hepatic changes, increased QT interval, and weight loss. With few
exceptions, differences between semagacestat and placebo treatment groups were
no longer significant after cessation of treatment with active drug.
CONCLUSIONS: Many of these safety findings can be attributed to γ-secretase
inhibition, and may be valuable to researchers developing γ-secretase
inhibitors. BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase
inhibitor (semagacestat) was associated with poorer cognitive outcomes in
Alzheimer's disease (AD).
OBJECTIVE: We sought to examine the effect of semagacestat treatment on
neuropsychiatric symptoms (NPS).
METHODS: 1,537 participants with mild to moderate AD were randomized to 76
weeks' treatment with placebo versus two doses of semagacestat. NPS were
assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains).
Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive
(first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the
effects of treatment assignment on change in NPI-total and subdomains over time.
Survival analysis was used to assess the treatment effect on time to first
worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or
minor NPS at baseline.
RESULTS: Participants on high dose semagecestat (140 mg) had greater increase in
NPI-Total and greater risk of incident first worsening in NPI-Total and in
subdomains of aberrant motor behavior, appetite, depression/dysphoria, and
sleep. ADAS11 increased more in participants whose NPI-Total increased.
CONCLUSION: In participants with mild to moderate AD, high dose semagacestat
treatment was associated with greater severity and faster worsening of NPS in a
pattern resembling an agitated depression. Increased NPS was associated with
cognitive decline regardless of treatment assignment. These findings suggest
that greater NPS may be the result of gamma-secretase treatment and emphasize
the importance of monitoring NPS as potential adverse events in trials of novel
treatments for AD. Author information:
(1)Neuropsychiatry, Department of Integrated Medicine, Division of Internal
Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871,
Japan.
(2)Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha
University, Kizugawa, Kyoto 619-0225, Japan.
(3)Neuropsychiatry, Department of Integrated Medicine, Division of Internal
Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871,
Japan; Pain and Neurology, Shionogi & Co. Ltd., Osaka, Osaka 561-0825, Japan.
(4)Department of Molecular Virology, Research Institute for Microbial Diseases,
Osaka University, Suita, Osaka 565-0871, Japan.
(5)Departments of Neurology and Molecular Genetics, Brain Research Institute,
Niigata University, Niigata, Niigata 951-8520, Japan.
(6)Pain and Neurology, Shionogi & Co. Ltd., Osaka, Osaka 561-0825, Japan.
(7)Department of Psychiatry, Osaka University Health Care Center, Toyonaka,
Osaka 560-0043, Japan.
(8)Neuropsychiatry, Department of Integrated Medicine, Division of Internal
Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871,
Japan. Electronic address: [email protected]. |
Which molecule is inhibited by ivosidenib? | Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. It used an effective treatment of leukemia. | PURPOSE OF REVIEW: Hypomethylating agents (HMAs) are the standard of care for
patients with myelodysplastic syndromes (MDS). Although these agents induce
responses in up to 40% of patients, most patients ultimately experience loss of
response. The purpose of this review is to provide an overview of the different
therapies under development for MDS after HMA therapy.
RECENT FINDINGS: Recent advances in the understanding of MDS pathogenesis have
led to the development of new potential therapies after HMA failure. Newer HMAs,
less susceptible to in-vivo deamination, such as guadecitabine or ASTX727 have
shown activity. Alterations of immune checkpoints in MDS have led to multiple
clinical trials evaluating the activity of monoclonal antibodies targeting these
proteins (pembrolizumab, nivolumab, ipilimumab). Different combinations and new
formulations of cytotoxic agents, such as clofarabine or CPX-351, are newer
options for specific subsets of patients. Finally, targeted agents inhibiting
multiple kinases (rigosertib), BCL2 (venetoclax) or mutant IDH1 (ivosidenib),
IDH2 (enasidenib), FLT3 (sorafenib, midostaurin) or spliceosome components
(H3B-8800) are other novel options.
SUMMARY: Despite the poor prognosis associated with HMA failure, clinical
trials, new cytotoxic agents and allogeneic stem-cell transplantation, can offer
therapeutic opportunities for these patients for whom there is no standard of
care. Somatic point mutations at a key arginine residue (R132) within the active site
of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of
function in cancer cells, resulting in the production of d-2-hydroxyglutarate
(2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic
alterations and impaired cellular differentiation. IDH1 mutations have been
described in an array of hematologic maligcies and solid tumors. Here, we
report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant
enzyme that exhibits profound 2-HG lowering in tumor models and the ability to
effect differentiation of primary patient AML samples ex vivo. Preliminary data
from phase 1 clinical trials enrolling patients with cancers harboring an IDH1
mutation indicate that AG-120 has an acceptable safety profile and clinical
activity. A phase I study suggests that ivosidenib can induce remission in patients with
relapsed or refractory acute myeloid leukemia characterized by IDH1 mutations.
The drug spurred complete remission or complete remission with partial
hematologic recovery in 30.4% of patients. The most common side effects of at
least grade 3 were prolonged QT interval and IDH differentiation syndrome. Author information:
(1)Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer
Center, New York, NY, USA.
(2)Center for Hematologic Maligcies, Memorial Sloan Kettering Cancer Center,
New York, NY, USA.
(3)Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
(4)Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY,
USA.
(5)Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
(6)Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center,
New York, NY, USA.
(7)Computational & Systems Biology Program, Memorial Sloan Kettering Cancer
Center, New York, NY, USA.
(8)Gerstner Sloan Kettering Graduate School, Memorial Sloan Kettering Cancer
Center, New York, NY, USA.
(9)The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial
Sloan Kettering Cancer Center, New York, NY, USA.
(10)Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer
Center, New York, NY, USA.
(11)Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New
York, NY, USA.
(12)Department of Pathology, Memorial Sloan Kettering Cancer Center, New York,
NY, USA.
(13)Feil Family Brain and Mind Research Institute, Weill Cornell Medical
College, New York, New York, USA.
(14)Agios Pharmaceuticals, Inc, Cambridge, MA, USA.
(15)Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center,
New York, NY, USA. [email protected].
(16)Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer
Center, New York, NY, USA. [email protected].
(17)Center for Hematologic Maligcies, Memorial Sloan Kettering Cancer Center,
New York, NY, USA. [email protected].
(18)Department of Medicine, Memorial Sloan Kettering Cancer Center, New York,
NY, USA. [email protected].
(19)Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
[email protected].
(20)Department of Medicine, Memorial Sloan Kettering Cancer Center, New York,
NY, USA. [email protected].
(21)Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
[email protected]. The FDA approved ivosidenib for patients with IDH1-mutant relapsed/refractory
acute myeloid leukemia. The approval was based on results of a phase I trial in
which 32.8% of patients treated with the drug had a complete remission or a
complete remission with a partial hematologic recovery. Ivosidenib (Tibsovo®) is a small molecule, orally available inhibitor of mutated
cytosolic isocitrate dehydrogenase 1 (IDH1) that is being developed by Agios
Pharmaceuticals for the treatment of cancer in patients with IDH1 mutations. The
mutated form of the IDH1 enzyme produces a metabolite, 2-hydroxyglutarate
(2-HG), which is thought to play a role in the formation and progression of
acute myeloid leukaemia (AML), gliomas and other cancers. Elevated 2-HG levels
interfere with cellular metabolism and epigenetic regulation, thereby
contributing to oncogenesis. Ivosidenib targets the IDH1 metabolic pathway to
prevent a build-up of the oncometabolite 2-HG. This article summarizes the
milestones in the development of ivosidenib leading to this first approval in
the USA for the treatment of patients with relapsed or refractory AML with a
susceptible IDH1 mutation. Clinical development for AML, cholangiocarcinoma,
glioma, myelodysplastic syndromes and solid tumours is ongoing worldwide. |
What is COG112? | COG112 is a a modified apoE-mimetic peptide, that results from the fusion of COG133 to a protein transduction domain. COG112 has significantly enhanced anti-inflammatory bioactivities in vitro. | |
List the four advances integrated into the SHERLOCKv2 platform. | SHERLOCKv2 presents with four distinct advances: (i) four-channel single-reaction multiplexing with orthogonal CRISPR enzymes; (ii) quantitative measurement of input as low as 2 attomolar; (iii) 3.5-fold increase in signal sensitivity by combining Cas13 with Csm6, an auxiliary CRISPR-associated enzyme; and (iv) lateral-flow readout. | Rapid detection of nucleic acids is integral for clinical diagnostics and
biotechnological applications. We recently developed a platform termed SHERLOCK
(specific high-sensitivity enzymatic reporter unlocking) that combines
isothermal preamplification with Cas13 to detect single molecules of RNA or DNA.
Through characterization of CRISPR enzymology and application development, we
report here four advances integrated into SHERLOCK version 2 (SHERLOCKv2) (i)
four-channel single-reaction multiplexing with orthogonal CRISPR enzymes; (ii)
quantitative measurement of input as low as 2 attomolar; (iii) 3.5-fold increase
in signal sensitivity by combining Cas13 with Csm6, an auxiliary
CRISPR-associated enzyme; and (iv) lateral-flow readout. SHERLOCKv2 can detect
Dengue or Zika virus single-stranded RNA as well as mutations in patient liquid
biopsy samples via lateral flow, highlighting its potential as a multiplexable,
portable, rapid, and quantitative detection platform of nucleic acids. |
Does Rhamnose have any effect on aging? | Yes, Rhamnose does have an effect on aging. | Skin is the most voluminous organ of the body. It assumes several important
physiological functions and represents also a "social interface" between an
individual and other members of society. This is the main reason its
age-dependent modifications are in the forefront of dermatological research and
of the "anti-aging" cosmetic industry. Here we concentrate on some aspects only
of skin aging, as far as the cellular and extracellular matrix components of
skin are concerned. Most well studied mechanisms of skin aging can be situated
at the postgenetic level, both epigenetic and post-translational mechanisms
being involved. Some of these mechanisms will be reviewed as well as the
capacity of fucose- and rhamnose-rich oligo- and polysaccharides (FROP and RROP)
to counteract several of the mechanisms involved in skin aging. This study was designed to investigate the antioxidant and anti-aging effects of
D-galatose-induced (D-gal-induced) aging mice as well as monosaccharide
compositions of acidic-extractable polysaccharides (AcAPS) and its major
purified fractions (AcAPS-1, AcAPS-2 and AcAPS-3) from the fruiting body of
Agaricus bisporus. In the in vitro assays, AcAPS-2 showed superior scavenging
activities on hydroxyl (82.98±4.67%) and DPPH (64.47±4.05%) radicals at the
concentration of 1.0mg/mL than AcAPS and other polysaccharides fractions. For in
vivo anti-aging analysis, AcAPS-2 showed superior effects on hepatic and nephric
protection by improving serum enzyme activities, biochemical levels, lipid
contents and antioxidant status, respectively. The monosaccharide analysis
showed that rhamnose (Rha) and glucose (Glu) may play vital roles in maintaining
the antioxidant and anti-aging activities. The results suggested that both AcAPS
and its purified fractions might be suitable for functional foods and natural
drugs in preventing the acute aging-associated diseases. |
Is there any approved treatment for NAFLD? | No,
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. | Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent
forms of chronic liver disease worldwide, reflecting the epidemic of global
obesity. Those with the progressive variant of NAFLD, non-alcoholic
steatohepatitis (NASH), are at significantly increased risk of multisystem
morbidity and mortality. However, there are currently no approved pharmacologic
therapies for NASH. Given the disease burden, there is an important unmet need
for pharmacologic treatment options for this patient population. The underlying
pathophysiologic mechanisms that contribute to the development and progression
of NAFLD and NASH are complex and reflected by the myriad of therapies, with
different targets, currently under investigation. In broad strokes, drug
development has focused on modulation of metabolic pathways, inflammatory
cascades, and/or mechanisms impacting fibrosis. Although much progress has been
made in enhancing our understanding of NAFLD pathogenesis, development of
pharmacologic treatments has been hindered by challenges in clinical trial
enrollment and complexities in clinical trial design. The compounds in phase IIa
have provided promising results in terms of potential benefits on various
aspects of histopathology. Agents in later stages of development have shown
fairly modest results in terms of reduction of hepatic steatosis,
necroinflammation and fibrosis. If longer term safety and efficacy are
established among heterogeneous cohorts, these medications may help mitigate
potential morbidity and mortality for this burgeoning patient population. Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease
worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E
and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a
progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently
approved for use in diabetes, have shown early efficacy in NASH, and also have
beneficial cardiovascular or renal effects. Innovative NASH therapies include
four main pathways. The first approach is targeting hepatic fat accumulation.
Medications in this approach include modulation of peroxisome
proliferator-activator receptors (e.g., pemafibrate, elafibranor), medications
targeting farnesoid X receptor axis [obeticholic acid; OCA)], inhibitors of de
novo lipogenesis (aramchol, ACC inhibitor), and fibroblast growth factor-21
analogues. A second target is oxidative stress, inflammation, and apoptosis.
This class of drug includes apoptosis signaling kinase 1 (ASK1) inhibitor and
emricasan (an irreversible caspase inhibitor). A third target is intestinal
microbiomes and metabolic endotoxemia. Several agents are in ongoing trials,
including IMMe124, TLR4 antagonist, and solithromycin (macrolide antibiotics).
The final target is hepatic fibrosis, which is strongly associated with
all-cause or liver-related mortality in NASH. Antifibrotic agents are a
cysteine-cysteine motif chemokine receptor-2/5 antagonist (cenicriviroc; CVC)
and galectin 3 antagonist. Among a variety of medications in development, four
agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being
evaluated in an international phase 3 trial for the treatment of NASH. Within
the next few years, the availability of therapeutic options for NASH will
hopefully curb the rising trend of NASH-related diseases. Nonalcoholic fatty liver disease (NAFLD) has an increasing prevalence worldwide.
At present, no specific pharmacotherapy is approved for NAFLD. Simple steatosis
and nonalcoholic steatohepatitis (NASH) can progress to liver fibrosis that is
associated with mortality in NAFLD. The recruitment of inflammatory monocytes
and macrophages via chemokine receptor CCR2 as well as of lymphocytes and
hepatic stellate cells via CCR5 promote the progression of NASH to fibrosis.
Areas covered: I summarize preclinical and clinical data on the efficacy and
safety of the dual CCR2/CCR5 inhibitor cenicriviroc (CVC, also TBR-652 or
TAK-652) for the treatment of NASH and fibrosis. In animal models of liver
diseases, CVC potently inhibits macrophage accumulation in the liver and
ameliorates fibrosis. In a phase 2b clinical trial (CENTAUR) on 289 patients
with NASH and fibrosis, CVC consistently demonstrated liver fibrosis improvement
after 1 year of therapy and had an excellent safety profile, leading to the
implementation of a phase 3 trial (AURORA). Expert opinion: Preclinical and
clinical data support the development of CVC as a safe and potent antifibrotic
agent. However, open questions around CVC are the durability of antifibrotic
responses, divergent effects on NASH versus fibrosis, potential long-term
concerns and the expected path to approval. BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading chronic
hepatic condition worldwide and new approaches to management and treatment are
limited.
SUMMARY: L-ornithine L-aspartate (LOLA) has hepatoprotective properties in
patients with fatty liver of diverse etiology and results of a multicenter
randomized clinical trial reveal that 12 weeks treatment with oral LOLA (6-9
g/d) results in a dose-related reduction in activities of liver enzymes and
triglycerides together with significant improvements of liver/spleen CT ratios.
A preliminary report described improvements of hepatic microcirculation in
patients with non-alcoholic steatohepatitis (NASH) following treatment with
LOLA. Mechanisms responsible for the beneficial effects of LOLA in NAFLD/NASH
involve, in addition to its established ammonia-lowering effect, metabolic
transformations of the LOLA-constituent amino acids L-ornithine and L-aspartate
into L-glutamine, L-arginine, and glutathione. These metabolites have
well-established actions implicated in the prevention of lipid peroxidation,
improvement of hepatic microcirculation in addition to anti-inflammatory, and
anti-oxidant properties. Key Messages: (1) LOLA is effective for the treatment
of key indices in NAFLD/NASH. (2) Mechanisms other than LOLA's ammonia-lowering
action have been postulated. (3) Further assessments in the clinical setting are
now required. |
Can pazopanib be used for treatment von Hippel-Lindau disease? | Yes, pazopanib is used for treatment von Hippel-Lindau disease. | Hemangioblastoma is a rare benign neoplasm, accounting for less than 2% of all
primitive brain tumors. It may arise sporadically in a solitary form, or
associated with Von Hippel-Lindau (VHL) disease with multiple tumors. Surgery is
the mainstay treatment, but management is challenging in case of recurrent
and/or multiple tumors. VHL protein is defective in both forms of
hemangioblastoma, leading to the accumulation of hypoxia-inducible factor,
stimulating angiogenesis via VEGF and PDGF mainly. Here, we report a 37-year-old
woman's case with recurrent and rapidly progressive VHL-associated
hemangioblastomas, causing severe disability. She was treated 24 months with
pazopanib, a multityrosine kinase inhibitor (TKI) targeting VEGF and PDGF-β
pathways. Despite moderate radiological changes, progressive improvement in her
clinical condition persisting over 3 years was observed. Inhibiting angiogenesis
is a therapeutic option that may improve the quality of life and the autonomy of
VHL patients disabled with multiple hemangioblastomas. Von Hippel-Lindau (VHL) disease is a multisystem genetic disease, the cardinal
manifestations of which include central nervous system hemangioblastomas (CNS
HB), renal cell carcinomas (RCC), and pheochromocytoma. Tumorigenesis in VHL of
both RCC and CNS HB occurs secondary to downstream effects of a mutated or
absent VHL protein. Treatment of RCCs with tyrosine kinase inhibitors (TKIs)
such as Pazopanib is now first line therapy, but their effect on VHL-associated
CNS HBs remains unknown. We report the use of Pazopanib in a patient with VHL
disease for treatment of RCC who also harbored multiple CNS HBs. Following
initiation of treatment, a large cervical and a lumbar spinal HB regressed in
size while the remaining CNS HBs exhibited stable or progressive disease. These
findings highlight the multiplicity of factors contributing to hemangioblastoma
development, even among tumors with a common germline mutation, and the
potential limitations of TKIs, but additionally this report supports the
conservative management of asymptomatic VHL patients with spinal HBs whereby
tumor response to TKI treatment may alleviate or postpone the need for surgery. BACKGROUND: No approved systemic therapy exists for von Hippel-Lindau disease,
an autosomal domit disorder with pleiotropic organ manifestations that
include clear cell renal cell carcinomas; retinal, cerebellar, and spinal
haemangioblastomas; pheochromocytomas; pancreatic serous cystadenomas; and
pancreatic neuroendocrine tumours. We aimed to assess the activity and safety of
pazopanib in patients with von Hippel-Lindau disease.
METHODS: In this non-randomised, single-centre, open-label, phase 2 trial, adult
patients with clinical manifestations of von Hippel-Lindau disease were
recruited from the University of Texas MD Anderson Cancer Center (Houston, TX,
USA) and were treated with pazopanib (800 mg orally daily) for 24 weeks, with an
option to continue treatment if desired by the patient and treating physician.
Primary endpoints were the proportion of patients who achieved an objective
response and safety in the per-protocol population. The objective response was
measured for each patient and each lesion type. Radiographic assessments were
done at baseline and every 12 weeks throughout the study. Activity and safety
were assessed with continuous monitoring and a Bayesian design. This study is
registered with ClinicalTrials.gov, number NCT01436227, and is closed to
accrual.
FINDINGS: Between Jan 18, 2012, and Aug 10, 2016, we screened 37 patients with
genetically confirmed or clinical features consistent with von Hippel-Lindau
disease, of whom 31 eligible patients were treated with pazopanib. The
proportion of patients who achieved an objective response was 42% (13 of 31
patients). By lesion sites responses were observed in 31 (52%) of 59 renal cell
carcinomas, nine (53%) of 17 pancreatic lesions, and two (4%) of 49 CNS
haemangioblastomas. Seven (23%) of 31 patients chose to stay on the treatment
after 24 weeks. Four (13%) of 31 patients withdrew from the study because of
grade 3 or 4 transaminitis, and three (10%) discontinued study treatment because
of treatment intolerance with multiple intercurrent grade 1-2 toxicities.
Treatment-related serious adverse events included one case each of appendicitis
and gastritis and one patient had a fatal CNS bleed.
INTERPRETATION: Pazopanib was associated with encouraging preliminary activity
in von Hippel-Lindau disease, with a side-effect profile consistent with that
seen in previous trials. Pazopanib could be considered as a treatment choice for
patients with von Hippel-Lindau disease and growing lesions, or to reduce the
size of unresectable lesions in these patients. The safety and activity of
pazopanib in this setting warrants further investigation.
FUNDING: Novartis Inc and NIH National Cancer Institute core grant. |
Which ploidy-agnostic method has been developed for estimating telomere length from whole genome sequencing data? | Telomerecat is a ploidy-agnostic method for estimating telomere length from whole genome sequencing data. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. | |
What happens to retrotransposons during ageing? | Retrotransposons are activated as organisms age | Cellular senescence, an irreversible growth arrest triggered by a variety of
stressors, plays important roles in normal physiology and tumor suppression, but
accumulation of senescent cells with age contributes to the functional decline
of tissues. Senescent cells undergo dramatic alterations to their chromatin
landscape that affect genome accessibility and their transcriptional program.
These include the loss of DNA-nuclear lamina interactions, the distension of
centromeres, and changes in chromatin composition that can lead to the
activation of retrotransposons. Here we discuss these findings, as well as
recent advances in microscopy and genomics that have revealed the importance of
the higher-order spatial organization of the genome in defining and maintaining
the senescent state. |
What is the function of Taraxasterol in rheumatoid arthritis? | Taraxasterol suppresses inflammation in rheumatoid arthritis. | Taraxasterol is an effective component of dandelion that has anti-inflammatory
effects in vivo and in vitro. The present study was performed to explore whether
taraxasterol exhibits a protective effect against rheumatoid arthritis through
the modulation of inflammatory responses in mice. Eight-week-old CCR9-deficient
mice were injected with a collagen II monoclonal antibody cocktail to create a
rheumatoid arthritis model. In the experimental group, arthritic model mice were
treated with 10 mg/kg taraxasterol once per day for 5 days. Treatment with
taraxasterol significantly increased the pain thresholds and reduced the
clinical arthritic scores of the mice in the experimental group compared with
those of the model group. Furthermore, treatment with taraxasterol significantly
suppressed tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and nuclear
factor-κB protein expression levels compared with those in the rheumatoid
arthritis model mice. Taraxasterol treatment also significantly reduced nitric
oxide, prostaglandin E2 and cyclooxygenase-2 levels compared with those in the
rheumatoid arthritis model group. These observations indicate that the
protective effect of taraxasterol against rheumatoid arthritis is mediated via
the modulation of inflammatory responses in mice. |
Is Netrin-1 a secreted protein? | Yes,
netrin-1 is a secreted protein. | Netrins are a family of secreted protein related to laminin and act as tropic
cues directing axon growth and cell migration during neural development.
Netrin-4 is a novel member of netrin family recently identified in the
vertebrate with neuritis elongation promoting activity; however, the receptors
for netrin-4 are still unknown. To better understand the function and signal
transduction pathway of netrin-4, the potential receptors for netrin-4 were
studied in this paper. The netrin-4 protein was prepared by introducing a
eukaryotic expression vector with a secretable alkaline phosphatase tag (AP4)
into COS7 cells to allow the expression of AP4-netrin4 fusion protein. Axon
guidance activity of netrin-4 was confirmed by using the cortical explants.
After incubation with cultured primary cortical neurons, the neurons were
distinctly labeled by the AP4-coupled netrin-4 ligands. In contrast, the binding
activity of AP4-netrin4 to neurons could be completely competed by the
exogenously expressed netrin-4 protein without AP4 tag, indicating specificity
of netrin-4 binding to the potential receptors. Moreover, netrin-4 could also
bind to CHO cells transfected with the plasmids expressing two known receptors
for netrin-1, Deleted in Colorectal Cancer (DCC) and UNC5 homolog 1 (UNC5H1)
respectively. As there are three domains in netrin-4, we further tried to narrow
down the region containing binding sites with the receptors. Interestingly, only
the N-terminal domain (LNT) could bind to DCC and UNC5H1. A further
ligand-receptor binding analysis showed that both the N- and the C-terminal
domain (NCT) but not the EGF-like (EGFL) domain of netrin-4 could bind to the
surface of cultured primary neurons, indicating the existence of novel receptors
for netrin-4. After competed by netrin-4, we confirmed that the binding of AP
tagged netrin-4 domains to neurons were also netrin-4 dependent. The binding
activity of the N-terminal domain of netrin-4 is about 3-fold higher than that
for the C-terminal domain. In summary, our data here indicated that the two
known receptors for netrin-1, DCC and UNC5H1, are also receptors for netrin-4,
while only LNT but not EGFL and NCT is the key domain for specific binding. In
addition, there are novel receptors for netrin-4, where both LNT and NCT but not
EGFL are key domains for binding. CONTEXT: The axon guidance cues netrin-1 is a secreted protein overexpressed in
many different cancer tissues.
OBJECTIVES: To determine whether plasma netrin-1 can be used as a diagnostic
biomarker of human cancer.
MATERIALS AND METHODS: A total of 300 cancer plasma samples from breast, renal,
prostate, liver, meningioma, pituitary adenoma, glioblastoma, lung, pancreatic
and colon cancer patients were compared against 138 control plasma samples.
Netrin-1 levels were quantified by ELISA and immunohistochemistry.
RESULTS: Plasma netrin-1 levels were significantly increased in breast, renal,
prostate, liver, meningioma, pituitary adenoma, and glioblastoma cancers as
compared to control samples.
DISCUSSION AND CONCLUSION: Our results suggest that plasma netrin-1 can be used
as a diagnostic biomarker for many human cancers. BACKGROUND: Netrin-1 is a laminin-related secreted protein, is highly induced
after tissue injury, and may serve as a marker of injury. However, the
regulation of netrin-1 production is not unknown. Current study was carried out
in mouse and mouse kidney cell line (TKPTS) to determine the signaling pathways
that regulate netrin-1 production in response to injury.
METHODS AND PRINCIPAL FINDINGS: Ischemia reperfusion injury of the kidney was
induced in mice by clamping renal pedicle for 30 minutes. Cellular stress was
induced in mouse proximal tubular epithelial cell line by treating with
pervanadate, cisplatin, lipopolysaccharide, glucose or hypoxia followed by
reoxygenation. Netrin-1 expression was quantified by real time RT-PCR and
protein production was quantified using an ELISA kit. Cellular stress induced a
large increase in netrin-1 production without increase in transcription of
netrin-1 gene. Mitogen activated protein kinase, ERK mediates the drug induced
netrin-1 mRNA translation increase without altering mRNA stability.
CONCLUSION: Our results suggest that netrin-1 expression is suppressed at the
translational level and MAPK activation leads to rapid translation of netrin-1
mRNA in the kidney tubular epithelial cells. Netrin-1 is a secreted protein that directs long-range axon guidance during
early stages of neural circuit formation and continues to be expressed in the
mammalian forebrain during the postnatal period of peak synapse formation. Here
we demonstrate a synaptogenic function of netrin-1 in rat and mouse cortical
neurons and investigate the underlying mechanism. We report that netrin-1 and
its receptor DCC are widely expressed by neurons in the developing mammalian
cortex during synapse formation and are enriched at synapses in vivo. We detect
DCC protein distributed along the axons and dendrites of cultured cortical
neurons and provide evidence that newly translated netrin-1 is selectively
transported to dendrites. Using gain and loss of function manipulations, we
demonstrate that netrin-1 increases the number and strength of excitatory
synapses made between developing cortical neurons. We show that netrin-1
increases the complexity of axon and dendrite arbors, thereby increasing the
probability of contact. At sites of contact, netrin-1 promotes adhesion, while
locally enriching and reorganizing the underlying actin cytoskeleton through Src
family kinase signaling and m-Tor-dependent protein translation to locally
cluster presynaptic and postsynaptic proteins. Finally, we demonstrate using
whole-cell patch-clamp electrophysiology that netrin-1 increases the frequency
and amplitude of mEPSCs recorded from cortical pyramidal neurons. These findings
identify netrin-1 as a synapse-enriched protein that promotes synaptogenesis
between mammalian cortical neurons. Yes-associated protein (YAP), a transcription coactivator, is the major
downstream effector of the Hippo pathway, which plays a critical role in organ
size control and cancer development. However, how YAP is regulated by
extracellular stimuli in tumorigenesis remains incompletely understood.
Netrin-1, a laminin-related secreted protein, displays proto-oncogenic activity
in cancers. Nonetheless, the downstream signaling mediating its oncogenic
effects is not well defined. Here we show that netrin-1 via its transmembrane
receptors, deleted in colorectal cancer and uncoordinated-5 homolog,
up-regulates YAP expression, escalating YAP levels in the nucleus and promoting
cancer cell proliferation and migration. Inactivating netrin-1, deleted in
colorectal cancer, or uncoordinated-5 homolog B (UNC5B) decreases YAP protein
levels, abrogating cancer cell progression by netrin-1, whereas knockdown of
mammalian STE20-like protein kinase 1/2 (MST1/2) or large tumor suppressor
kinase 1/2 (Lats1/2), two sets of upstream core kinases of the Hippo pathway,
has no effect in blocking netrin-1-induced up-regulation of YAP. Netrin-1
stimulates phosphatase 1A to dephosphorylate YAP, which leads to decreased
ubiquitination and degradation, enhancing YAP accumulation and signaling. Hence,
our findings support that netrin-1 exerts oncogenic activity through YAP
signaling, providing a mechanism coupling extracellular signals to the nuclear
YAP oncogene. |
Which enzyme is deficient in Wolman disease? | Deficiency of lysosomal acid lipase (LAL) causes Wolman disease. | Previous studies have shown that cultured fibroblasts derived from patients with
genetic defects in lysosomal acid lipase (i. e. the Wolman Syndrome and
Cholesteryl Ester Storage Disease) are defective in their ability to hydrolyze
the cholesteryl esters contained in plasma low density lipoprotein (LDL). As a
result, these mutant cells show a reduced responsiveness to the regulatory
actions of LDL, as evidenced by a decreased LDL-mediated suppression of the
activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase and by a decreased
LDL-mediated activation of cellular cholesteryl ester formation. In the current
studies, the Wolman Syndrome and Cholesteryl Ester Storage Disease cells were
grown in the same Petri dish with mutant fibroblasts derived from a patient with
the homozygous form of Familial Hypercholesterolemia. Whereas pure monolayers of
either the Familial Hypercholesterolemia cells (lacking cell surface LDL
receptors) or the acid lipase-deficient cells (lacking cholesteryl ester
hydrolase activity) responded poorly to LDL, the mixed monolayers developed
lipoprotein responsiveness as measured by an enhancement of both LDL-mediated
suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and
LDL-mediated stimulation of cholesteryl ester formation. This effect was shown
to result from the release of the lysosomal acid lipase from the Familial
Hypercholesterolemia homozygote cells into the culture medium and its subsequent
uptake by the acid lipase-deficient cells. The acquisition of this acid lipase
activity enhanced the ability of the Wolman Syndrome and Cholesteryl Ester
Storage Disease cells to respond to the lipoprotein by suppression of
3-hydroxy-3-methylglutaryl coenzyme A reductase and activation of cellular
cholesteryl ester formation. These data emphasize the importance of the
lysosomal acid lipase in the cellular metabolism of LDL cholesteryl esters and,
in addition, demonstrate that delivery of this enzyme to genetically deficient
cells can enhance the regulatory response to the lipoprotein. Pyrenemethyl laurate (PMLes), a fluorogenic substrate for determining in vitro
lipase activity [Nègre, Salvayre, Dagan and Gatt (1989) Biochim. Biophys. Acta
1006, 84-88], has been administered to cultured lymphoblastoid cells from normal
subjects and from a patient affected with Wolman disease, which is characterized
by a deficiency of lysosomal acid lipase. The intracellular degradation of PMLes
was dependent on the mode of administration of the substrate into the cells, and
occurred by two separate pathways involving lysosomal and extra-lysosomal
hydrolases. PMLes incorporated into LDL was taken up by normal lymphoblastoid
cells through the apolipoprotein-B/E-receptor-mediated pathway and degraded in
the lysosomal compartment, as suggested by the degradation block in Wolman
cells. In contrast, when PMLes dissolved in 2% dimethyl sulphoxide was added
directly to the culture medium, its hydrolysis was similar in lymphoblastoid
cells from controls and from patients affected with Wolman disease, neutral
lipid storage disease or familial hypercholesterolaemia. This suggested that the
administered PMLes was degraded by a non-lysosomal enzyme which is not deficient
in Wolman cells. This enzyme also differs from the neutral lipase system which
is deficient in lymphoblastoid cells from patients with neutral lipid storage
disease. When pyrenemethanol was administered directly to the cell culture, it
was only poorly acylated and was rapidly released into the culture medium. These
results and the fluorescence properties of PMLes ('monomeric' emission in a
hydrophobic environment and 'excimeric' emission in a hydrophilic environment)
and pyrenemethanol ('monomeric' emission in a hydrophilic environment) allowed
us to design a 'direct reading' procedure by monitoring (without any lipid
extraction) the fluorescence of intact living cells and that of the culture
medium during pulse-chase experiments. This method allowed the direct evaluation
of the time course of in situ degradation of PMLes. In pulse-chase experiments
with LDL-PMLes, the fluorescence of normal cells decreased relatively rapidly
with time whereas the fluorescence of the culture medium increased
concomitantly. With Wolman cells, the cellular fluorescence decreased only very
slightly, whereas that of the culture medium remained at the basal level; this
demonstrates the catabolic block in intact living cells from patients with
Wolman disease. In vitro degradation of PMLes indicated the existence of two
PMLes-degrading enzymes in lymphoblastoid cell homogenates: one is the acid
lipase which is involved in PMLes degradation in the lysosomal compartment (and
is deficient in Wolman cells), while the second is a cytoplasmic enzyme (not
deficient in Wolman cells). Lysosomal acid lipase (LAL) is a hydrolase essential for the intracellular
degradation of cholesteryl esters and triglycerides. We previously reported a
rat model of Wolman's disease (Wolman rat) that is deficient for LAL activity.
In this study, we cloned rat LAL (RLAL) cDNA and investigated abnormal LAL gene
expression in the Wolman rat. We cloned the RLAL gene from a cDNA library made
from normal rat liver mRNA using the human LAL cDNA as a probe, subcloned the
RLAL cDNA into pBlueScript vector, and sequenced it. Next, we constructed a cDNA
library from a Wolman rat liver, and used the RLAL cDNA as a probe to isolate
the Wolman RLAL cDNA for comparison. The normal RLAL cDNA contains 3150 bp
including an 1194 bp open reading frame and three poly A signals at the 3' end.
The deduced amino acid sequence contained 397 amino acids, showed 79.9% homology
with human LAL, and had the same functional domains at the same sites as human
LAL. Northern blot analysis revealed that the RLAL mRNA from normal rat was 3.2
kb in length, while the RLAL mRNA from Wolman rat was only 1.4 kb. Nucleotide
sequence analysis showed that Wolman rat LAL cDNA had the same sequence as a
RLAL cDNA from the 5'-untranslated region to nt 1101, followed by a 60 bp
replacement from nt 1102 to nt 1161 with poly A signal and a 3' 1.8 kb deletion.
The deduced amino acid sequence demonstrated the substitution of 367Ile to Asn,
368Pro to stop codon, and deletion of the C-terminal 29 amino acids. Genomic
Southern blot analysis disclosed a large deletion at the 3' end of the gene.
These results identify the molecular defect in the Wolman RLAL, and suggest that
the C-terminus of RLAL is essential for the activity and/or stability of the
enzyme. Cholesteryl ester storage disease (CESD) and Wolman disease (WD) are both
autosomal recessive disorders associated with reduced activity and genetic
defects of lysosomal acid lipase (LAL). The strikingly more severe course of WD
is caused by genetic defects of LAL that leave no residual enzymatic activity.
Mutations at the exon 8/intron 8 transition of the LAL gene have been identified
in several CESD and WD patients and are responsible for the manifestation of the
disease. We have determined the genetic defect in a 3-month-old boy of African
origin affected by WD. No enzymatic activity of the lysosomal acid lipase was
detectable in white blood cells and cultured fibroblasts. Analysis of his LAL
cDNA and genomic DNA revealed that he was homozygous for a mutation at position
-3 of the exon 8 splice donor site. A C-->T transition leads to a nonsense codon
and to a premature termination of the LAL protein at amino acid 277. Due to this
mutation, a shorter LAL mRNA species was also generated that lacked exon 8 and
was deficient of the nonsense codon. As a consequence, the protein synthesis
proceeded to the natural termination codon, but the enzyme generated had an
internal deletion of 24 amino acids (254-277) and was also inactive. These
findings, together with our previous observations when analyzing the mutations
in WD and CESD patients lead to the conclusion that the more severe WD is due to
mutations that absolutely abolish lysosomal acid lipase (LAL) enzyme activity
and the cholesteryl ester storage disease phenotype is due to mutations that
allow some residual LAL activity to be manifested. Wolman disease is characterized by severe diarrhea and malnutrition leading to
death during infancy. Lysosomal acid lipase deficiency is the cause of the
symptoms and signs. It is inherited in an autosomal recessive manner. All Wolman
disease patients have adrenal gland calcification. Previous therapeutic attempts
have failed to provide remission. We report successful long-term bone marrow
engraftment in a patient with Wolman disease resulting in continued
normalization of peripheral leukocyte lysosomal acid lipase enzyme activity.
Diarrhea is no longer present. Now, at 4 years of age, this patient is gaining
developmental milestones. Cholesterol and triglyceride levels are normal. Liver
function is normal. This is the first long-term continued remission reported for
Wolman disease. Cholesteryl ester storage disease (CESD, OMIM #278000) and Wolman disease (OMIM
#278000) are autosomal recessive lysosomal storage disorders caused by a
deficient activity of lysosomal acid lipase (cholesteryl ester hydrolase, LAL).
Human lysosomal acid lipase is essential for the metabolism of cholesteryl
esters and triglycerides. In Wolman disease, LAL activity is usually absent,
whereas CESD usually presents some residual LAL activity. In infants, poor
weight gain, massive hepatosplenomegaly, calcified adrenal glands (present about
2/3 of the time), vomiting, diarrhea and failure to thrive are indicative of
Wolman disease. The clinical picture is more variable in CESD. Hepatomegaly
and/or elevation of liver transaminases are almost always present. Hepatic
steatosis often leads to fibrosis and cirrhosis. Other signs often include
splenomegaly, high total cholesterol and LDL-cholesterol, elevated
triglycerides, and low HDL-cholesterol. The diagnosis of LAL deficiency requires
clinical experience and specialized laboratory tests. The diagnosis is based on
finding deficient activity of acid lipase and/or molecular tests. Pilot
screening projects using dried blood spot testing in 1) children with atypical
fatty liver disease in the absence of overweight, 2) patients with dyslipidaemia
and presence of hepatomegaly and/or elevated transaminases, 3) newborns/neonates
with hepatomegaly and abdominal distension/failure to thrive/elevated
transaminases are currently underway. Early diagnosis is particularly important
for the enzyme replacement therapy. Human trials with recombit LAL are
currently ongoing, raising the prospect for specific correction of LAL
deficiency in this progressive and often debilitating disorder. No published case of Wolman's disease has described the prenatal sonographic
findings. We present a case in which a third-trimester sonographic examination
demonstrated fetal hepatomegaly and bilateral adrenal echogenicity suggestive of
diffuse calcification. Wolman's disease, also known as lysosomal acid lipase
(LIPA) deficiency, is a rare autosomal-recessive disorder characterized by
complete absence of the LIPA enzyme. The diagnosis of Wolman's disease was made
postnatally by biochemical testing, which indicated absence of LIPA enzyme
activity and gene sequencing, which confirmed homozygosity for the G66V mutation
within the LIPA gene. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:66-68,
2018. BACKGROUND: Wolman disease (WD) is a rare lysosomal storage disorder that is
caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL).
Deficiency in LAL function causes accumulation of cholesteryl esters and
triglycerides in lysosomes. Fatality usually occurs within the first year of
life. While an enzyme replacement therapy has recently become available, there
is currently no small-molecule drug treatment for WD.
RESULTS: We have generated induced pluripotent stem cells (iPSCs) from two WD
patient dermal fibroblast lines and subsequently differentiated them into neural
stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of
neutral lipid accumulation, severely deficient LAL activity, and increased
LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the
WD phenotype in these cells. In addition, δ-tocopherol (DT) and
hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in
WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy.
CONCLUSION: The results demonstrate that these WD NSCs are valid cell-based
disease models with characteristic disease phenotypes that can be used to
evaluate drug efficacy and screen compounds. DT and HPBCD both reduce
LysoTracker dye staining in WD cells. The cells may be used to further dissect
the pathology of WD, evaluate compound efficacy, and serve as a platform for
high-throughput drug screening to identify new compounds for therapeutic
development. Although only a small proportion of cholesterol in the body is esterified, in
several diseases marked expansion of the esterified cholesterol (EC) pool
occurs. These include Wolman disease (WD) and Cholesteryl Ester Storage Disease
(CESD) which both result from mutations in LIPA, the gene that encodes lysosomal
acid lipase (LAL). The respective contributions that our three cholesterol
esterifying enzymes make to EC production, especially in disorders like CESD,
are not well defined. The current studies represent a detailed exploration of
our earlier findings in young male LAL-deficient mice also missing sterol
O-acyltransferase 2 (SOAT2, also called ACAT2). Here we show that, even as they
aged, male and female Lal-/-: Soat2- /- mice, compared to Lal-/-: Soat2+/+
littermates, had appreciably less hepatomegaly as well as a marked reduction in
the level of sequestration of EC, in liver transaminase activities, and in
hepatic mRNA expression levels for markers of inflammation. Loss of SOAT2
function also dramatically curtailed EC entrapment in the small intestine of the
LAL-deficient mice. Together, these data imply that SOAT2 inhibition, if applied
concurrently with enzyme replacement therapy for LAL deficiency, may blunt the
re-esterification of newly released unesterified cholesterol thereby improving
clinical outcomes. BACKGROUND: Lysosomal acid lipase deficiency is an autosomal recessive metabolic
disease with a wide range of severity from Wolman Disease to Cholesterol Ester
Storage Disease. Recently enzyme replacement therapy with sebelipase alpha has
been approved by drug agencies for treatment of this lysosomal disease.
Ezetimibe is an azetidine derivative which blocks Niemann Pick C1-Like 1
Protein; as its consequence, plasmatic concentration of low density lipoproteins
and other apoB-containing lipoproteins, that are the substrate of lysosomal acid
lipase, are decreased. Furthermore, ezetimibe acts by blocking inflammasome
activation which is the cause of liver fibrosis in steatohepatitis and in
lysosomal storage diseases.
RESULTS: Two patients with Cholesterol Ester Storage Disease were treated with
ezetimibe for 9 years and a third patients for 10 years. Treatment was
supplemented with low dose of atorvastatin in the first two patients during the
last 6 years. All patients showed a significant reduction of alanine
aminotransferase, cholesterol and triglyceride. Furthermore, no progression of
liver fibrosis was demonstrated.
CONCLUSION: In this observational case series, ezetimibe is effective, safe, and
sustainable treatment for lysosomal acid lipase deficiency. Further studies are
warranted to demonstrate that ezetimibe is an alternative therapy to enzyme
replacement therapy. PURPOSE OF REVIEW: Lysosomal acid lipase (LAL), encoded by the LIPA gene, is an
essential lysosomal enzyme that hydrolyzes cholesteryl ester and triglyceride
delivered to the lysosome. This review highlights the novel pathophysiological
role of LAL, the functional genomic discoveries of LIPA as a risk locus for
coronary heart diseases (CHD), and the clinical advance in therapies for LAL
deficiency.
RECENT FINDINGS: The essential role of LAL in lipid metabolism has been
confirmed in human and mice with LAL deficiency. In humans, loss-of-function
mutations of LIPA cause rare lysosomal disorders, Wolman disease, and
cholesteryl ester storage disease, in which LAL enzyme replacement therapy has
shown significant benefits in a phase 3 clinical trial. Recent studies have
revealed the role of LAL-mediated lysosomal lipolysis in regulating macrophage
M2 polarization, lipid mediator production, VLDL secretion, lysosomal function
and autophagy, extracellular degradation of aggregated-LDL, and adipose tissue
lipolysis. Genome-wide association studies and functional genomic studies have
identified LIPA as a risk locus for CHD, but the causal variants and mechanisms
remain to be determined.
SUMMARY: Despite years of research, our understanding of LAL is incomplete.
Future studies will continue to focus on the key pathophysiological functions of
LAL in health and diseases including CHD. |
Is the yeast (Saccharomyces cerevisiae) genome organized into topologically associated domains (TADs)? | Yes. By analyzing Hi-C data for budding yeast, 200-kb scale topologically associated domains (TADs) have been identified, whose boundaries are enriched for transcriptional activity. | The genome of metazoan cells is organized into topologically associating domains
(TADs) that have similar histone modifications, transcription level, and DNA
replication timing. Although similar structures appear to be conserved in
fission yeast, computational modeling and analysis of high-throughput chromosome
conformation capture (Hi-C) data have been used to argue that the small, highly
constrained budding yeast chromosomes could not have these structures. In
contrast, herein we analyze Hi-C data for budding yeast and identify 200-kb
scale TADs, whose boundaries are enriched for transcriptional activity.
Furthermore, these boundaries separate regions of similarly timed replication
origins connecting the long-known effect of genomic context on replication
timing to genome architecture. To investigate the molecular basis of TAD
formation, we performed Hi-C experiments on cells depleted for the Forkhead
transcription factors, Fkh1 and Fkh2, previously associated with replication
timing. Forkhead factors do not regulate TAD formation, but do promote
longer-range genomic interactions and control interactions between origins near
the centromere. Thus, our work defines spatial organization within the budding
yeast nucleus, demonstrates the conserved role of genome architecture in
regulating DNA replication, and identifies a molecular mechanism specifically
regulating interactions between pericentric origins. Recent advances in our understanding of the three-dimensional organization of
the eukaryotic nucleus have rendered the spatial distribution of genes
increasingly relevant. In a recent work (Tsochatzidou et al., Nucleic Acids Res
45:5818-5828, 2017), we proposed the existence of a functional
compartmentalization of the yeast genome according to which, genes occupying the
chromosomal regions at the nuclear periphery have distinct structural,
functional and evolutionary characteristics compared to their
centromeric-proximal counterparts. Around the same time, it was also shown that
the genome of Saccharomyces cerevisiae is organized in topologically associated
domains (TADs), which are largely associated with the replication timing. In
this work, we proceed to investigate whether such units of three-dimensional
genomic organization can be linked to transcriptional activity as a driving
force for the shaping of genomic architecture. Through the application of a
simple boundary-calling criterion in genome-wide 3C data, we define ~100
TAD-like domains which can be clustered in six different classes with radically
different nucleosomal organizations, significant variations in transcription
factor binding and uneven chromosomal distribution. Approximately ~20% of the
genome is found to be confined in regions with "closed" chromatin structure
around gene promoters. Most interestingly, we find both "open" and "closed"
regions to be segregated, in the sense that they tend to avoid inter-chromosomal
interactions. Our data further enforce the notion of a marked
compartmentalization of the yeast genome in isolated territories, with
implications in its function and evolution. |
What is MOV10? | MOV10 is an RNA helicase | BACKGROUND: Mov10 is an RNA helicase that modulates access of Argonaute 2 to
microRNA recognition elements in mRNAs. We examined the role of Mov10 in Xenopus
laevis development and show a critical role for Mov10 in gastrulation and in the
development of the central nervous system (CNS).
RESULTS: Knockdown of maternal Mov10 in Xenopus embryos using a translation
blocking morpholino led to defects in gastrulation and the development of
notochord and paraxial mesoderm, and a failure to neurulate. RNA sequencing of
the Mov10 knockdown embryos showed significant upregulation of many mRNAs when
compared with controls at stage 10.5 (including those related to the
cytoskeleton, adhesion, and extracellular matrix, which are involved in those
morphogenetic processes). Additionally, the degradation of the miR-427 target
mRNA, cyclin A1, was delayed in the Mov10 knockdowns. These defects suggest that
Mov10's role in miRNA-mediated regulation of the maternal to zygotic transition
could lead to pleiotropic effects that cause the gastrulation defects.
Additionally, the knockdown of zygotic Mov10 showed that it was necessary for
normal head, eye, and brain development in Xenopus consistent with a recent
study in the mouse.
CONCLUSIONS: Mov10 is essential for gastrulation and normal CNS development.
Developmental Dynamics 247:660-671, 2018. © 2017 Wiley Periodicals, Inc. |
As of Feb 2019, are major brain gangliosides a target for the treatment of Alzheimer's disease? | As of Feb 2019, major brain gangliosides are proposed as a target for the treatment of Alzheimer's disease. | Gangliosides are glycosphingolipids localized to the outer leaflet of the plasma
membrane of vertebrate cells. The highest ganglioside concentration of any organ
is found in the mammalian brain, where the gangliosides are enriched in the
neuronal membrane, particularly in the synapses. There are four major brain
gangliosides with the same neutral tetrasaccharide core to which one to three
sialic acids are linked--the simplest being the GM1-ganglioside. These
gangliosides have been shown to have neuritogenic and neuronotrophic activity
and to facilitate repair of neuronal tissue after mechanical, biochemical or
toxic injuries. Mixtures of native bovine brain gangliosides were adopted for
pharmacological use in the treatment of peripheral nerve damage, and
GM1-ganglioside has been applied for the treatment of CNS injuries and diseases.
Beneficial effects of GM1 have been documented in the treatment of stroke and
spinal cord injuries, particularly when the treatment has been initiated within
a few hours of the acute event. Continuous intraventricular infusion of GM1 has
recently been shown to have a significant beneficial effect in Alzheimer disease
of early onset (AD Type I). Conversion of the soluble, nontoxic amyloid β-protein (Aβ) into an aggregated,
toxic form rich in β-sheets is a key step in the onset of Alzheimer's disease
(AD). It has been suggested that Aβ induces changes in neuronal membrane
fluidity as a result of its interactions with membrane components such as
cholesterol, phospholipids, and gangliosides. Gangliosides are known to bind Aβ.
A complex of GM1 and Aβ, termed "GAβ", has been identified in AD brains.
Abnormal ganglioside metabolism also may occur in AD brains. We have reported an
increase of Chol-1α antigens, GQ1bα and GT1aα, in the brain of transgenic mouse
AD model. GQ1bα and GT1aα exhibit high affinities to Aβs. The presence of
Chol-1α gangliosides represents evidence for genesis of cholinergic neurons in
AD brains. We evaluated the effects of GM1 and Aβ1-40 on mouse neuroepithelial
cells. Treatment of these cells simultaneously with GM1 and Aβ1-40 caused a
significant reduction of cell number, suggesting that Aβ1-40 and GM1
cooperatively exert a cytotoxic effect on neuroepithelial cells. An
understanding of the mechanism on the interaction of GM1 and Aβs in AD may
contribute to the development of new neuroregenerative therapies for this
disorder. |
Which cancer is associated with increased levels of Serum alpha fetoprotein (AFP) ? | Serum alpha fetoprotein (AFP) is a marker of germ cell neoplasms,
Serum α-Fetoprotein (AFP) is a widely used diagnostic biomarker, but it has limited sensitivity and is not elevated in all HCC cases. | Advanced hepatocellular carcinoma (HCC) has limited treatment options and poor
survival, therefore early detection is critical to improving the survival of
patients with HCC. Current guidelines for high-risk patients include ultrasound
screenings every six months, but ultrasounds are operator dependent and not
sensitive for early HCC. Serum α-Fetoprotein (AFP) is a widely used diagnostic
biomarker, but it has limited sensitivity and is not elevated in all HCC cases
so, we incorporate a second blood-based biomarker, des'γ carboxy-prothrombin
(DCP), that has shown potential as a screening marker for HCC. The data from the
Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a
valuable source of data to study biomarker screening for HCC. We assume the
trajectories of AFP and DCP follow a joint hierarchical mixture model with
random changepoints that allows for distinct changepoint times and subsequent
trajectories of each biomarker. The changepoint indicators are jointly modeled
with a Markov Random Field distribution to help detect borderline changepoints.
Markov chain Monte Carlo methods are used to calculate posterior distributions,
which are used in risk calculations among future patients and determine whether
a patient has a positive screen. The screening algorithm was compared to
alternatives in simulations studies under a range of possible scenarios and in
the HALT-C Trial using cross-validation. Ovarian Sertoli-Leydig cell tumors (SLCTs) are uncommon neoplasms that are
occasionally associated with an elevated level of serum alpha fetoprotein (AFP),
a marker of germ cell neoplasms, particularly yolk sac tumor (YST). We report 7
cases of ovarian SLCT (3 moderately differentiated, 2 poorly differentiated, 2
retiform) with heterologous intestinal-type glands, 6 of which were associated
with elevated serum AFP. The intestinal-type mucinous glands were immunoreactive
for SALL4 (4 cases), AFP (4 cases), glypican 3 (1 case), CDX2 (6 cases), and
villin (7 cases), markers that are commonly expressed in YSTs, although the
latter 2 markers would be expected to be positive in intestinal-type glands. We
show that heterologous intestinal-type glands in ovarian SLCTs often have an
endodermal sinus-like (YST-like) immunophenotype and stress that these should
not be misinterpreted as microscopic foci of endodermal-type YST. Cases of
ovarian SLCT with elevated serum AFP should be sampled extensively to look for
foci of intestinal-type glands, the likely source of the AFP elevation in some
of these neoplasms. Cirrhosis in patients with chronic hepatitis C increases the risk of
hepatocellular carcinoma (HCC), and surveillance with ultrasound (US) and
alpha-fetoprotein (AFP) is recommended. This study aimed to estimate changes in
the HCC incidence rate (IR) over time, HCC stage and prognosis, and AFP and US
performed in patients with hepatitis C and cirrhosis. Eligible patients were
identified in the Danish Database for Hepatitis B and C, and data from national
health registries and patient charts were obtained. Tumour stage was based on
Barcelona-Clinic Liver Cancer stage, TNM classification and size and number of
lesions combined into stages 0-3. We included 1075 patients with hepatitis C and
cirrhosis, free of HCC and liver transplant at baseline. During 4988 person
years (PY), 115 HCC cases were diagnosed. The HCC incidence rate increased from
0.8/100 PY [CI95% 0.4-1.5] in 2002-2003 to 2.9/100 PY [2.4-3.4] in 2012-2013.
One-year cumulative incidence of at least one AFP or US was 53% among all
patients. The positive predictive value of an AFP ≥ 20 ng mL-1 was 17%.
Twenty-three (21%) patients were diagnosed with early-stage HCC (stage 0/1) and
84 (79%) with late stage. Median survival after HCC for early-stage HCC disease
was 30.1 months and 7.4 months for advanced HCC (stage 2/3). The incidence rate
of HCC increased over time among patients with hepatitis C and cirrhosis in
Denmark. Application of AFP and US was suboptimal, and most patients were
diagnosed with advanced HCC with a poor prognosis. BACKGROUND & AIMS: Outcomes of liver transplantation for hepatocellular
carcinoma (HCC) are determined by cancer-related and non-related events.
Treatments for hepatitis C virus infection have reduced non-cancer events among
patients receiving liver transplants, so reducing HCC-related death might be an
actionable end point. We performed a competing-risk analysis to evaluate factors
associated with survival of patients with HCC and developed a prognostic model
based on features of HCC patients before liver transplantation.
METHODS: We performed multivariable competing-risk regression analysis to
identify factors associated with HCC-specific death of patients who underwent
liver transplantation. The training set comprised 1018 patients who underwent
liver transplantation for HCC from January 2000 through December 2013 at 3
tertiary centers in Italy. The validation set comprised 341 consecutive patients
who underwent liver transplantation for HCC during the same period at the Liver
Cancer Institute in Shanghai, China. We collected pretransplantation data on
etiology of liver disease, number and size of tumors, patient level of
α-fetoprotein (AFP), model for end-stage liver disease score, tumor stage,
numbers and types of treatment, response to treatments, tumor grade,
microvascular invasion, dates, and causes of death. Death was defined as
HCC-specific when related to HCC recurrence after transplantation, disseminated
extra- and/or intrahepatic tumor relapse and worsened liver function in presence
of tumor spread. The cumulative incidence of death was segregated for hepatitis
C virus status.
RESULTS: In the competing-risk regression, the sum of tumor number and size and
of log10 level of AFP were significantly associated with HCC-specific death (P <
.001), returning an average c-statistic of 0.780 (95% confidence interval,
0.763-0.798). Five-year cumulative incidence of non-HCC-related death was 8.6%
in HCV-negative patients and 18.1% in HCV-positive patients. For patients with
HCC to have a 70% chance of HCC-specific survival 5 years after transplantation,
their level of AFP should be <200 ng/mL and the sum of number and size of tumors
(in centimeters) should not exceed 7; if the level of AFP was 200-400 ng/mL, the
sum of the number and size of tumors should be ≤5; if their level of AFP was
400-1000 ng/mL, the sum of the number and size of tumors should be ≤4. In the
validation set, the model identified patients who survived 5 years after liver
transplantation with 0.721 accuracy (95% confidence interval, 0.648%-0.793%).
Our model, based on patients' level of AFP and HCC number and size, outperformed
the Milan; University of California, San Francisco; Shanghai-Fudan; Up-to-7
criteria (P < .001); and AFP French model (P = .044) to predict which patients
will survive for 5 years after liver transplantation.
CONCLUSIONS: We developed a model based on level of AFP, tumor size, and tumor
number, to determine risk of death from HCC-related factors after liver
transplantation. This model might be used to select end points and refine
selection criteria for liver transplantation for patients with HCC. To predict
5-year survival and risk of HCC-related death using an online calculator, please
see www.hcc-olt-metroticket.org/. ClinicalTrials.gov ID NCT02898415. PURPOSE: To evaluate the diagnostic performance of the combination of tumor
markers [alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9)] and
imaging features in differentiating combined hepatocellular-cholangiocarcinoma
(CHC) from hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC).
METHODS: Forty consecutive patients with pathologically proven CHC were
retrospectively evaluated with contrast-enhanced ultrasound (CEUS).
Additionally, 40 HCC and 40 CC patients who were randomly selected from the same
period served as a control group. Images were classified as HCC-like or CC-like
pattern according to CEUS guidelines recommended by World and European
Federation for Ultrasound in Medicine and Biology (WFUMB-EFSUMB). The diagnostic
criteria of CHC were defined as follows: (1) both AFP and CA19-9 are
simultaneously elevated (AFP > 20 ng/ml and CA19-9 > 100 units/ml); or (2)
elevated AFP with a CC-like pattern on CEUS and without elevated CA19-9 level;
or (3) elevated CA19-9 with an HCC-like pattern on CEUS and without elevated AFP
level. The diagnostic tests were performed with calculation of the sensitivity,
specificity, accuracy, positive predictive value (PPV), negative predictive
value (NPV), and area under the receiver operating characteristic curve (AUC).
RESULTS: For the 40 CHC patients, the rates of elevated AFP and CA19-9 serology
were 55.0 and 30.0%, respectively. Twenty-three (57.5%) patients exhibited an
HCC-like pattern, and 15 (37.5%) showed a CC-like pattern. After applying the
above diagnostic criteria of CHC in the 120 patients, the sensitivity,
specificity, PPV, NPV, accuracy, and AUC were 32.5, 93.8, 72.2, 73.5, 73.3, and
0.631%, respectively. When the actual prevalence rate (0.4-14.3%) was taken into
account, the PPV and NPV were modified from 2.1 to 46.7% and 89.3 to 99.7%,
respectively.
CONCLUSION: The combination of enhancement patterns on CEUS and serum tumor
markers (AFP and CA19-9) may be a potentially specific diagnostic method to
differentiate CHC from HCC and CC. |
Is Miller-Dieker syndrome associated with abnormalities of chromosome 1? | No. Miller-Dieker syndrome is caused by a heterozygous deletion of chromosome 17p13.3 involving the genes LIS1 and YWHAE and leads to malformations during cortical development. | Profilin is a conserved actin-monomer-binding protein which is found in all
eukaryotes, including yeast. Although amino acid sequence analysis and RNase
protection analysis suggest a single profilin isoform in mammalian cells,
Southern blot analysis of human and somatic cell hybrid DNA indicates several
loci in the human genome which hybridize with the profilin cDNA. We therefore
isolated human genomic clones to analyze these genetic loci in detail. Only one
of the cloned loci has typical features of a functional gene, including upstream
transcriptional elements and typical exon-intron structure. Four other isolated
loci are all diverged, intronless pseudogenes and are likely to be
nonfunctional. The functional gene was localized to human chromosome band 17p13
by analysis of somatic cell hybrids and by in situ chromosomal localization. The
Miller-Dieker syndrome (MDS), a rare congenital disorder manifested by
characteristic facial abnormalities and lissencephaly (smooth brain), is
associated with microdeletions of the distal 17p region. RFLP analysis of a
patient with MDS, and analysis of somatic cell hybrids containing partially
deleted chromosomes 17 from patients with MDS, using the profilin gene probe,
indicate that profilin is localized to chromosome subband 17p13.3. These results
also indicate that profilin is the first identified cloned gene which is part of
the genetic material deleted in some patients with MDS but that other patients
have smaller deletions not affecting the profilin locus. Thus, single allelic
deletion of the profilin locus may contribute to the clinical phenotype of the
MDS in some patients but does not play a major role in the essential phenotype. The Miller-Dieker syndrome (MDS), a syndrome with lissencephaly, distinctive
craniofacial features, growth impairment, and profound developmental failure,
has been associated with a deletion of the distal part of chromosome band 17p13.
A minority of patients with the syndrome do not have a deletion detectable with
current cytogenetic techniques. Using three highly polymorphic DNA probes
(pYNZ22, pYNH37.3, and p144D6) we have detected microdeletions in three MDS
patients, two of whom had no visible abnormalities of chromosome 17. Loci
defined by two of the DNA probes, pYNZ22 and pYNH37.3, were deleted in all three
patients. The most distal locus, defined by p144D6, was present in one MDS
patient, possibly defining the distal limits of the MDS region in band 17p13.3.
None of these loci were absent in one case of lissencephaly without MDS. Miller-Dieker syndrome (MDS), a disorder manifesting the severe brain
malformation lissencephaly ("smooth brain"), is caused, in the majority of
cases, by a chromosomal microdeletion of the distal short arm of chromosome 17.
Using human chromosome 17-specific DNA probes, we have begun a molecular
dissection of the critical region for MDS. To localize cloned DNA sequences to
the MDS critical region, a human-rodent somatic cell hybrid panel was
constructed which includes hybrids containing the abnormal chromosome 17 from
three MDS patients with deletions of various sizes. Three genes (myosin heavy
chain 2, tumor antigen p53, and RNA polymerase II) previously mapped to 17p were
excluded from the MDS deletion region and therefore are unlikely to play a role
in its pathogenesis. In contrast, three highly polymorphic anonymous probes,
YNZ22.1 (D17S5), YNH37.3 (D17S28), and 144-D6 (D17S34), were deleted in each of
four patients with visible deletions, including one with a ring chromosome 17
that is deleted for a portion of the single telomeric prometaphase subband
p13.3. In two MDS patients with normal chromosomes, a combination of somatic
cell hybrid, RFLP, and densitometric studies demonstrated deletion for YNZ22.1
and YNH37.3 in the paternally derived 17's of both patients, one of whom is also
deleted for 144-D6. The results indicate that MDS can be caused by
submicroscopic deletion and raises the possibility that all MDS patients will
prove to have deletions at a molecular level. The two probes lie within a
critical region of less than 3,000 kb and constitute potential starting points
in the isolation of genes implicated in the severe brain maldevelopment in MDS. Recently it has been shown that most cases of the Miller-Dieker syndrome (MDS)
are caused by deletion 17p13.3. All familial cases have been associated with a
balanced reciprocal translocation in a carrier parent and unbalanced
translocations in their affected offspring. We report a new case of familial MDS
in whom the mother carries a pericentric inversion of chromosome 17. She has had
two children with MDS, one of whom was shown to carry a recombit 17
consisting of dup(17q) and del(17p). The high frequency of familial MDS and its
consistent association with balanced chromosomal rearrangements in one of the
parents makes it important to do high-resolution chromosome analysis on all
patients with MDS and possibly all patients with lissencephaly. Finding a
familial balanced rearrangement makes prenatal diagnosis of this condition
feasible. We studied after death a 3-month-old girl whose karyotype was
45,XX,-15,-17,+der(17),t(15;17)(q13;p13.3) and thus combines abnormalities of
chromosome 15 associated with the Prader-Willi syndrome and of chromosome 17
associated with the Miller-Dieker syndrome. This infant had several
manifestations of the Prader-Willi syndrome in infancy but none of the
Miller-Dieker syndrome. We propose that essentially no loss of 17p material has
occurred and confirm previous reports that the critical region for the
production of the Miller-Dieker phenotype is located subterminally in the
17p13.3 region. Miller-Dieker syndrome, which includes lissencephaly and a characteristic
phenotypic appearance, has been reported to have an autosomal recessive pattern
of inheritance. However, we have found abnormalities of chromosome 17 in two of
three unrelated patients with this syndrome, one with a ring chromosome 17 and
the other with an unbalanced translocation resulting in partial monosomy of
17p13. A review of the literature revealed five additional patients in three
families, who had Miller-Dieker syndrome and an abnormality of 17p. Thus, we
propose that monosomy of distal 17p may be the cause of Miller-Dieker syndrome
in some patients. Miller-Dieker syndrome (MDS) is a multiple malformation syndrome characterized
by classical lissencephaly and a characteristic facies. It is associated with
visible or submicroscopic deletions within chromosome band 17p13.3.
Lissencephaly without facial dysmorphism has also been observed and is referred
to as isolated lissencephaly sequence (ILS). Apparently partial and
non-overlapping deletions of the 5' or 3' end of a candidate gene LIS1 in one
ILS and one MDS patient had suggested that MDS was a single gene disorder, and
that LIS1 spans in excess of 400 kb. However, the originally presumed 5' end of
LIS1 was found to belong to the 14-33 epsilon gene residing more distally on
17p13.3. We have now isolated the correct 5' end of LIS1, constructed a
approximately 500 kb genomic contig encompassing LIS1, and estimated its gene to
be approximately 80 kg. Fluorescence in situ hybridization analysis of an ILS
patient with a de novo balanced translocation, as well as analysis of several
other key MDS and ILS deletion patients, localizes the lissencephaly critical
region within the LIS1 gene. Therefore, LIS1 remains the strongest candidate
gene for the lissencephaly phenotype in ILS and MDS. Our analyses also suggest
that additional genes distal to LIS1 may be responsible for the facial
dysmorphology and other abnormalities seen in MDS but not in ILS patients,
supporting our original concept MDS as a contiguous gene deletion syndrome. Trisomy 5p and Miller-Dieker syndromes frequently are the result of unbalanced
segregations of reciprocal translocations of chromosomes 5 and 17 with other
autosomes. The critical regions for the expression of the mentioned syndromes
have been mapped to 5p13-->pter, and 17p13.3-->pter. In this report, we describe
an 8-year-old girl with mental retardation, postnatal growth deficiency,
generalized muscular hypotonia, seizures, microcephaly, cortical atrophy,
partial agenesis of corpus callosum, cerebral ventriculomegaly, facial
anomalies, patent ductus arteriosus, pectus excavatum, long fingers, and
bilateral talipes equinovarus caused by the presence of a
46,XX,der(17)t(5;17)(p13.1;p13.3)mat chromosome complement. Cytogenetic studies
of the family confirmed a balanced reciprocal translocation (5;17)(p13.1;p13.3)
in her mother, maternal grandfather, maternal aunt, and a female first cousin.
Fluorescence in situ hybridization studies on the mother and the proposita using
three probes, which map to distal 17p, confirmed the reciprocal translocation in
the mother and a terminal deletion in the patient, which resulted in the
retention of LIS1 and D17S379 loci and deletion of the 17p telomere. These
findings and the phenotype of the proposita, strongly suggest that genes
telomeric to LIS1 and locus D17S379 are involved in many clinical findings,
including the minor facial anomalies of the Miller-Dieker syndrome. HIC1 is a candidate tumor suppressor gene which is frequently hypermethylated in
human tumors, and its location within the Miller-Dieker syndrome's critical
deletion region at chromosome 17p13.3 makes it a candidate gene for involvement
in this gene deletion syndrome. To study the function of murine Hic1 in
development, we have created Hic1 -deficient mice. These animals die perinatally
and exhibit varying combinations of gross developmental defects throughout the
second half of development, including acrania, exencephaly, cleft palate, limb
abnormalities and omphalocele. These findings demonstrate a role for Hic1 in the
development of structures affected in the Miller-Dieker syndrome, and provide
functional evidence to strengthen its candidacy as a gene involved in this
disorder. The Miller-Dieker syndrome (type I lissencephaly) is a neuronal migration
disorder which is associated with microdeletions in the short arm of chromosome
17. Neurofibromatosis type I (NF1) is an autosomal domit condition associated
with mutations in the long arm of chromosome 17, and characterised by
neurofibromas, café-au-lait spots and axillary freckling. The neonatal period
for a female infant born at 39 weeks gestation by emergency Caesarean section
was complicated by frequent epileptic seizures as well as hypotonia. A computed
tomography scan revealed evidence of lissencephaly, and chromosomal analysis
showed a microdeletion on the short arm of chromosome 17 (17p13.3), confirming
the diagnosis as Miller-Dieker syndrome. The child died at the age of 4 years
and examination of the brain confirmed lissencephaly with a thickened cortex,
deficient white matter, and grey matter heteropias. The mother had café-au-lait
spots, and axillary freckling. In addition, the mother's and maternal
grandmother's genetic analysis showed identical mutations in the
neurofibromatosis I gene on the long arm of chromosome 17, confirming the
diagnosis of NF1. The child did not possess the mutation. This case illustrates
a rare neuronal migration disorder appearing in a child from a family with a
history of NF1. Epilepsy is among the most frequent findings in many, especially autosomal,
chromosome aberrations. Its incidence, however, is very variable, and there are
very few aberrations in which epilepsy is a constant finding. Even siblings and
monozygotic twins with the same aberration are often discordant for seizure
disorders. Similar observations can be made for congenital (major) malformations
in chromosome aberrations. The common explanation is that in these instances
epilepsy is not caused by the action of a single gene in single or triple dose,
but is influenced by the combined action of a number of genes within and outside
of the aneuploid segment. The situation is comparable to a polygenic model of
inheritance. Gene mutations associated with epilepsy are known, to date, only
for two disorders: the lissencephaly 1 gene in Miller-Dieker syndrome and
mutations in the UBE3A gene in Angelman syndrome. Chromosome aberrations in
which epilepsy is a major and consistent finding include Angelman syndrome due
to loss of the maternal 15q11.2-q12 segment, tetrasomy of the maternal segment
15pter-q13 due to an additional inv dup chromosome, Miller-Dieker syndrome due
to deletion of the 17p13.3 segment including the lissencephaly1 gene, ring
chromosome 20, and Wolf-Hirschhorn syndrome due to deletion of at least the
4p16.3 segment. BACKGROUND: Deletions in the 17p13.3 region are associated with abnormal
neuronal migration. Point mutations or deletion copy number variants of the
PAFAH1B1 gene in this genomic region cause lissencephaly, whereas extended
deletions involving both PAFAH1B1 and YWHAE result in Miller-Dieker syndrome
characterised by facial dysmorphisms and a more severe grade of lissencephaly.
The phenotypic consequences of YWHAE deletion without deletion of PAFAH1B1 have
not been studied systematically.
METHODS: We performed a detailed clinical and molecular characterization of five
patients with deletions involving YWHAE but not PAFAH1B1, two with deletion
including PAFAH1B1 but not YWHAE, and one with deletion of YWHAE and mosaic for
deletion of PAFAH1B1.
RESULTS: Three deletions were terminal whereas five were interstitial. Patients
with deletions including YWHAE but not PAFAH1B1 presented with significant
growth restriction, cognitive impairment, shared craniofacial features, and
variable structural abnormalities of the brain. Growth restriction was not
observed in one patient with deletion of YWHAE and TUSC5, implying that other
genes in the region may have a role in regulation of growth with CRK being the
most likely candidate. Using array based comparative genomic hybridisation and
long range polymerase chain reaction, we have delineated the breakpoints of
these nonrecurrent deletions and show that the interstitial genomic
rearrangements are likely generated by diverse mechanisms, including the
recently described Fork Stalling and Template Switching (FoSTeS)/Microhomology
Mediated Break Induced Replication (MMBIR).
CONCLUSIONS: Microdeletions of chromosome 17p13.3 involving YWHAE present with
growth restriction, craniofacial dysmorphisms, structural abnormalities of brain
and cognitive impairment. The interstitial deletions are mediated by diverse
molecular mechanisms. Miller-Dieker syndrome involves a severe type of lissencephaly, which is caused
by defects in the lissencephaly gene (LIS1). We report the case of a female
infant with der(17)t(12;17)(q24.33;p13.3)pat caused by an unbalanced segregation
of the parental balanced translocation of 17p with other chromosomes. The
proband presented with facial dysmorphism, arthrogryposis, and intrauterine
growth retardation. Most cases of Miller-Dieker syndrome have a de novo deletion
involving 17p13.3. When Miller-Dieker syndrome is caused by an unbalanced
translocation, mild-to-severe phenotypes occur according to the extension of the
involved partner chromosome. However, a pure partial monosomy derived from a
paternal balanced translocation is relatively rare. In this case, the
submicroscopic cryptic deletion in the proband was initially elucidated by FISH,
and karyotype analysis did not reveal additional chromosome abnormalities such
as translocation. However, a family history of recurrent pregcy abnormalities
strongly suggested familial translocation. Sequential G-banding and FISH
analysis of the father's chromosomes showed that the segment of 17p13.3→pter was
attached to the 12qter. Thus, we report a case that showed resemblance to the
findings in cases of a nearly pure 17p deletion, derived from t(12;17), and
delineated by whole genome array comparative genomic hybridization (CGH). If
such cases are incorrectly diagnosed as Miller-Dieker syndrome caused by de novo
17p13.3 deletion, the resultant improper genetic counseling may make it
difficult to exactly predict the potential risk of recurrent lissencephaly for
successive pregcies. OBJECTIVE: To perform molecular cytogenetic study on two fetuses with abnormal
ultrasound findings and analyze their genotype-phenotype correlation.
METHODS: G-banded karyotyping, single nucleotide polymorphism array (SNP array)
and fluorescence in situ hybridization (FISH) were performed on amniotic fluid
cells from both fetuses and peripheral blood samples from their parents. Results
of SNP array were analyzed with bioinformatics software.
RESULTS: G-banded karyotyping failed to detect any abnormalities in both fetuses
and their parents. SNP array detected a 2.484 Mb terminal deletion at 17p13.3
[arr[hg19] 17p13.3 (83 035-2 567 405)×1] in fetus 1 and a 3.295 Mb terminal
deletion at 17p13.3p13.2 [arr[hg19] 17p13.3p13.2 (83 035- 3 377 560)×1] in fetus
2. Both deletions have overlapped with the critical region of Miller-Dieker
syndrome (MDS) and involved candidate genes such as PAFAH1B1, YWHAE and CRK. In
addition, SNP array and FISH analyses on the parental peripheral blood samples
demonstrated that both 17p13.3 and 17p13.3p13.2 deletions were of de novo
origin. Metaphase FISH performed on amniotic fluid cells confirmed the presence
of 17p13.3 and 17p13.3p13.2 deletions detected by the SNP array, while metaphase
FISH performed on the parents excluded any potential chromosome rearrangements.
CONCLUSION: Abnormal ultrasound features for fetuses with MDS mainly include
central nervous system anomalies. SNP array can efficiently detect 17p13.3
microdeletions underlying MDS, and accurately map the breakpoints and involved
genes, which may facilitate understanding of the genotype and phenotype
correlations for MDS. Miller-Dieker syndrome (MDS) is caused by a heterozygous deletion of chromosome
17p13.3 involving the genes LIS1 and YWHAE (coding for 14.3.3ε) and leads to
malformations during cortical development. Here, we used patient-specific
forebrain-type organoids to investigate pathological changes associated with
MDS. Patient-derived organoids are significantly reduced in size, a change
accompanied by a switch from symmetric to asymmetric cell division of
ventricular zone radial glia cells (vRGCs). Alterations in microtubule network
organization in vRGCs and a disruption of cortical niche architecture, including
altered expression of cell adhesion molecules, are also observed. These
phenotypic changes lead to a non-cell-autonomous disturbance of the
N-cadherin/β-catenin signaling axis. Reinstalling active β-catenin signaling
rescues division modes and ameliorates growth defects. Our data define the role
of LIS1 and 14.3.3ε in maintaining the cortical niche and highlight the utility
of organoid-based systems for modeling complex cell-cell interactions in vitro. Chromosome 17p13.3 is a region of genomic instability that is linked to
different rare neurodevelopmental genetic diseases, depending on whether a
deletion or duplication of the region has occurred. Chromosome microdeletions
within 17p13.3 can result in either isolated lissencephaly sequence (ILS) or
Miller-Dieker syndrome (MDS). Both conditions are associated with a smooth
cerebral cortex, or lissencephaly, which leads to developmental delay,
intellectual disability, and seizures. However, patients with MDS have larger
deletions than patients with ILS, resulting in additional symptoms such as poor
muscle tone, congenital anomalies, abnormal spasticity, and craniofacial
dysmorphisms. In contrast to microdeletions in 17p13.3, recent studies have
attracted considerable attention to a condition known as a 17p13.3
microduplication syndrome. Depending on the genes involved in their
microduplication, patients with 17p13.3 microduplication syndrome may be
categorized into either class I or class II. Individuals in class I have
microduplications of the YWHAE gene encoding 14-3-3ε, as well as other genes in
the region. However, the PAFAH1B1 gene encoding LIS1 is never duplicated in
these patients. Class I microduplications generally result in learning
disabilities, autism, and developmental delays, among other disorders.
Individuals in class II always have microduplications of the PAFAH1B1 gene,
which may include YWHAE and other genetic microduplications. Class II
microduplications generally result in smaller body size, developmental delays,
microcephaly, and other brain malformations. Here, we review the phenotypes
associated with copy number variations (CNVs) of chromosome 17p13.3 and detail
their developmental connection to particular microdeletions or
microduplications. We also focus on existing single and double knockout mouse
models that have been used to study human phenotypes, since the highly limited
number of patients makes a study of these conditions difficult in humans. These
models are also crucial for the study of brain development at a mechanistic
level since this cannot be accomplished in humans. Finally, we emphasize the
usefulness of the CRISPR/Cas9 system and next generation sequencing in the study
of neurodevelopmental diseases. A complete ophthalmic examination is not routinely performed on infants with
Miller-Dieker syndrome (MDS, chromosome 17p13.3 microdeletion). The authors
present the cases of four cousins with MDS who also carried a 16p13.3
microduplication (not associated with Rubinstein-Taybi syndrome). Retinopathy of
prematurity-like proliferative peripheral retinopathy (PPR) was detected in two
male first cousins, but was not detected in the female half-cousins. PPR in the
first infant resolved by 4 months, but the second infant's PPR progressed,
requiring photocoagulation followed by lens-sparing vitrectomy. While ocular
abnormalities are more prevalent and severe in other lissencephalopathies, the
PPR in these MDS infants underscores the sight-saving potential of performing an
ophthalmologic exam with early molecular testing for all lissencephaly infants. |
List clinical symptoms of the MECOM-associated syndrome | Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. The clinical picture included radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal malformations, B-cell deficiency, and presenile hearing loss. No single clinical manifestation was detected in all patients affected by MECOM mutations. Radioulnar synostosis and B-cell deficiency were observed only in patients with mutations affecting a short region in the C-terminal zinc finger domain of EVI1. | Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported
to be causative of a rare association of congenital amegakaryocytic
thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with
congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations
(including 10 novel mutations). The mutations affected different functional
domains of the EVI1 protein. The spectrum of phenotypes was much broader than
initially reported for the first 3 patients; we found familial as well as
sporadic cases, and the clinical spectrum ranged from isolated radioulnar
synostosis with no or mild hematological involvement to severe bone marrow
failure without obvious skeletal abnormality. The clinical picture included
radioulnar synostosis, bone marrow failure, clinodactyly, cardiac and renal
malformations, B-cell deficiency, and presenile hearing loss. No single clinical
manifestation was detected in all patients affected by MECOM mutations.
Radioulnar synostosis and B-cell deficiency were observed only in patients with
mutations affecting a short region in the C-terminal zinc finger domain of EVI1.
We propose the term MECOM-associated syndrome for this heterogeneous hereditary
disease and inclusion of MECOM sequencing in the diagnostic workup of congenital
bone marrow failure. |
Does the interaction of MOV10 and RNASEH2 promote L1 retrotransposition? | MOV10 interacts with RNASEH2, and their interplay is crucial for restricting L1 retrotransposition. | Long interspersed nuclear element 1 is an autonomous non-long terminal repeat
retrotransposon that comprises ∼17% of the human genome. Its spontaneous
retrotransposition and the accumulation of heritable L1 insertions can
potentially result in genome instability and sporadic disorders. Moloney
leukemia virus 10 homolog (MOV10), a putative RNA helicase, has been implicated
in inhibiting L1 replication, although its underlying mechanism of action
remains obscure. Moreover, the physiological relevance of MOV10-mediated L1
regulation in human disease has not yet been examined. Using a proteomic
approach, we identified RNASEH2 as a binding partner of MOV10. We show that
MOV10 interacts with RNASEH2, and their interplay is crucial for restricting L1
retrotransposition. RNASEH2 and MOV10 co-localize in the nucleus, and RNASEH2
binds to L1 RNAs in a MOV10-dependent manner. Small hairpin RNA-mediated
depletion of either RNASEH2A or MOV10 results in an accumulation of L1-specific
RNA-DNA hybrids, suggesting they contribute to prevent formation of vital L1
heteroduplexes during retrotransposition. Furthermore, we show that
RNASEH2-MOV10-mediated L1 restriction downregulates expression of the rheumatoid
arthritis-associated inflammatory cytokines and matrix-degrading proteinases in
synovial cells, implicating a potential causal relationship between them and
disease development in terms of disease predisposition. |
What is the role of CD28 with respect to bacterial superantigen toxins? | CD28 is a direct receptor of bacterial superantigen toxins. | Bacterial superantigens, a diverse family of toxins, induce an inflammatory
cytokine storm that can lead to lethal shock. CD28 is a homodimer expressed on T
cells that functions as the principal costimulatory ligand in the immune
response through an interaction with its B7 coligands, yet we show here that to
elicit inflammatory cytokine gene expression and toxicity, superantigens must
bind directly into the dimer interface of CD28. Preventing access of the
superantigen to CD28 suffices to block its lethality. Mice were protected from
lethal superantigen challenge by short peptide mimetics of the CD28 dimer
interface and by peptides selected to compete with the superantigen for its
binding site in CD28. Superantigens use a conserved β-strand/hinge/α-helix
domain of hitherto unknown function to engage CD28. Mutation of this
superantigen domain abolished inflammatory cytokine gene induction and
lethality. Structural analysis showed that when a superantigen binds to the T
cell receptor on the T cell and major histocompatibility class II molecule on
the antigen-presenting cell, CD28 can be accommodated readily as third
superantigen receptor in the quaternary complex, with the CD28 dimer interface
oriented towards the β-strand/hinge/α-helix domain in the superantigen. Our
findings identify the CD28 homodimer interface as a critical receptor target for
superantigens. The novel role of CD28 as receptor for a class of microbial
pathogens, the superantigen toxins, broadens the scope of pathogen recognition
mechanisms. Every adaptive immune response requires costimulation through the B7/CD28 axis,
with CD28 on T-cells functioning as principal costimulatory receptor.
Staphylococcal and streptococcal superantigen toxins hyperstimulate the
T-cell-mediated immune response by orders of magnitude, inducing a lethal
cytokine storm. We show that to elicit an inflammatory cytokine storm and
lethality, superantigens must bind directly to CD28. Blocking access of the
superantigen to its CD28 receptor with peptides mimicking the contact domains in
either toxin or CD28 suffices to protect mice effectively from lethal shock. Our
finding that CD28 is a direct receptor of superantigen toxins broadens the scope
of microbial pathogen recognition mechanisms. |
What is the exoproteome? | Exoproteomics aims at describing and quantifying the proteins found outside of the cells. | Pathogens are known to release in their environment a large range of toxins and
other virulence factors. Their pathogenicity relies on this arsenal of
exoproteins and their orchestrated release upon changing environmental
conditions. Exoproteomics aims at describing and quantifying the proteins found
outside of the cells, thus takes advantage of the most recent methodologies of
next-generation proteomics. This approach has been applied with great success to
a variety of pathogens increasing the fundamental knowledge on pathogenicity. In
this chapter, we describe how the exoproteome should be prepared and handled for
high-throughput identification of exoproteins and their quantitation by
label-free shotgun proteomics. We also mentioned some bioinformatics tools for
extracting information such as toxin similarity search. Wound-colonizing microorganisms can form complex and dynamic polymicrobial
communities where pathogens and commensals may co-exist, cooperate or compete
with each other. The present study was aimed at identifying possible
interactions between different bacteria isolated from the same chronic wound of
a patient with the genetic blistering disease epidermolysis bullosa (EB).
Specifically, this involved two different isolates of the human pathogen
Staphylococcus aureus, and isolates of Bacillus thuringiensis and Klebsiella
oxytoca. Particular focus was attributed to interactions of S. aureus with the
two other species, because of the high staphylococcal prevalence among chronic
wounds. Intriguingly, upon co-cultivation, none of the wound isolates inhibited
each other's growth. Since the extracellular proteome of bacterial pathogens is
a reservoir of virulence factors, the exoproteomes of the staphylococcal
isolates in monoculture and co-culture with B. thuringiensis and K. oxytoca were
characterized by Mass Spectrometry to explore the inherent relationships between
these co-exisiting bacteria. This revealed a massive reduction in the number of
staphylococcal exoproteins upon co-culturing with K. oxytoca or B.
thuringiensis. Interestingly, this decrease was particularly evident for
extracellular proteins with a predicted cytoplasmic localization, which were
recently implicated in staphylococcal virulence and epidemiology. Furthermore,
our exoproteome analysis uncovered potential cooperativity between the two
different S. aureus isolates. Altogether, the observed exoproteome variations
upon co-culturing are indicative of unprecedented adaptive mechanisms that set
limits to the production of secreted staphylococcal virulence factors. Proteins that mediate cellular and subcellular membrane fusion are key factors
in vesicular trafficking in all eukaryotic cells, including the secretion and
transport of plant pathogen virulence factors. In this study, we identified
vesicle-fusion components that included 22 soluble N-ethylmaleimide-sensitive
factor attachment protein receptors (SNAREs), four Sec1/Munc18 (SM) family
proteins, and 10 Rab GTPases encoded in the genome of the vascular wilt pathogen
Verticillium dahliae Vd991. Targeted deletion of two SNARE-encoding genes in V.
dahliae, VdSec22 and VdSso1, significantly reduced virulence of both mutants on
cotton, relative to the wild-type Vd991 strain. Comparative analyses of the
secreted protein content (exoproteome) revealed that many enzymes involved in
carbohydrate hydrolysis were regulated by VdSec22 or VdSso1. Consistent with a
role of these enzymes in plant cell-wall degradation, pectin, cellulose, and
xylan utilization were reduced in the VdSec22 or VdSso1 mutant strains along
with a loss of exoproteome cytotoxic activity on cotton leaves. Comparisons with
a pathogenicity-related exoproteome revealed that several known virulence
factors were not regulated by VdSec22 or VdSso1, but some of the proteins
regulated by VdSec22 or VdSso1 displayed different characteristics, including
the lack of a typical signal peptide, suggesting that V. dahliae employs more
than one secretory route to transport proteins to extracellular sites during
infection. |
List features of the Triple A syndrome. | Triple A (Allgrove) syndrome is a rare autosomal recessive disorder characterized by cardinal features of adrenal insufficiency, achalasia, and alacrimia. It is frequently associated with neurological manifestations like polyneuropathy. | The triple A syndrome or Allgrove syndrome (MIM*231550) is characterized by
adrenocorticotropic hormone (ACTH) resistant Adrenal insufficiency, Achalasia of
the cardia and Alacrima. In addition to the main features, patients frequently
suffer from neurological disturbances. Dermatological abnormalities such as
palmoplantar hyperkeratosis as well as other signs like short stature,
microcephaly and osteoporosis point to the multisystemic character of the
disorder. The molecular defect of the autosomal recessively inherited triple A
syndrome is not known. We initially performed a systematic genome linkage scan
in eight triple A families and were able to map the syndrome to a 6 cM interval
on human chromosome 12q13 near the type II keratin gene cluster. A refinement of
the triple A critical region was achieved by detailed haplotype analysis in a
further 37 families from different ethnic backgrounds. There was no indication
of genetic heterogeneity. The achalasia-alacrima (AA) syndrome which has been
defined as a distinct clinical entity (MIM 200440) is most likely a variant of
the triple A syndrome as shown by haplotype analysis in three AA families. We
constructed a high-resolution BAC/PAC-based transcript map of the region which
will greatly facilitate the identification of the triple A syndrome gene. The
considerable intra- and interfamilial variability of the severity of the
disorder implies a variable expression of an impaired pleiotropically acting
gene. BACKGROUND: The triple A syndrome is characterized by the main features adrenal
insufficiency, achalasia and alacrima. Other organ systems can be involved in a
variable manner.
PATIENT: We report clinical and novel molecular findings in a 6.8-year-old
Kurdish boy, who presented with relapsing vomiting and failure to thrive. He was
diagnosed as having achalasia and primary adrenocortical hypofunction. History
and clinical examination showed that the boy was unable to produce tears. In
addition, a large number of associated neurological and dermatological features
was present in this patient. Thus, the clinical diagnosis of triple A syndrome
was made.
RESULTS: Initial molecular marker analysis supported linkage to the triple A
critical region on chromosome 12q13. Further, a homozygous G -->A transition in
exon 9 of the newly identified AAAS gene, resulting in a stop codon (W295X) and
predicting a truncated protein with loss of function, confirmed the diagnosis.
This new mutation was also detected in another family of Kurdish origin. In
turned out that both families were related. The triple A syndrome (MIM*231550) is a rare autosomal recessive disorder
characterized by adrenocorticotropic hormone (ACTH) resistant adrenal failure,
achalasia, alacrima and a variety of neurological and dermatological features.
Adrenal insufficiency usually presents in the first decade of life, however in
some patients it may occur later in life or may even lack completely. Recently,
we and others identified a novel gene on chromosome 12q13, designated AAAS
(Achalasia-Addisonianism-Alacrima-Syndrome gene) which is mutated in patients
with triple A syndrome. We investigated n=84 families including 111 patients
with clinically suggested triple A syndrome and identified homozygous or
compound heterozygous AAAS mutations in 78 families. Genotype/phenotype analyses
revealed a highly variable occurrence, age of onset and severity of all clinical
symptoms between patients with the same AAAS mutation. The obvious lack of a
genotype/phenotype relationship is suggestive of modifying genes/factors which
need to be determined. The AAAS protein function is unknown. With four WD
repeats it belongs to the family of WD repeat-containing proteins which may
exhibit a high degree of functional diversity. The subcellular localization of
the protein and the determination of its putative binding partners will shed
light on the role of the AAAS protein for the development and function of the
adrenal gland and other neuroendocrine structures. The triple A or Allgrove syndrome is an autosomal-recessive disease (MIM*231550)
characterized by the triad of achalasia, alacrima and adrenocorticotropic
hormone (ACTH)-resistant adrenal insufficiency. Associated features of the
syndrome are neurological and dermatological abnormalities. Until the discovery
of the AAAS gene as the responsible gene in triple A syndrome, the diagnosis was
based on characteristic clinical features. Here we present the clinical and
molecular genetic data which demonstrated the marked phenotypic variability in
three unrelated patients with triple A syndrome. The final diagnosis of triple A
syndrome was confirmed by molecular analysis. In one patient with isolated
achalasia, the diagnosis of triple A syndrome could only be made on the basis of
the molecular genetic analysis of the AAAS gene. We therefore suggest that the
diagnosis of triple A syndrome should be considered in patients who exhibit only
one or two of the main symptoms (i.e. alacrima, achalasia or adrenal
insufficiency). These patients require careful neurological investigation, and
mutation analysis of the AAAS gene should be performed. The triple A syndrome (MIM#231550) is a rare autosomal recessive disorder
characterized by adrenocorticotropic hormone (ACTH) resistant adrenal failure,
achalasia, alacrima, and a variety of neurological and dermatological features.
The triple A syndrome is caused by mutations in the AAAS gene, which encodes a
protein known as ALADIN (ALacrima Achalasia aDrenal Insufficiency Neurologic
disorder). ALADIN is a new WD-repeat protein that has no significant homology to
any previously identified WD-repeat protein. It has been shown that it
colocalizes with nuclear pore complexes (NPCs), a finding that strongly suggests
an involvement of ALADIN in nucleocytoplasmic transport. An investigation of 110
families with triple A syndrome disclosed mutation hot spots including Q15K
(exon 1), and S293P (exon 8), which occur in 17 and 21 families from different
geographical regions, respectively. The variable phenotype of all patients
cannot be correlated with the localization and the nature of the ALADIN
mutations. Thus, modifying genes/factors may be involved in the progression of
this neurodegenerative disease. The lack of AAAS mutations in eight patients and
negative linkage to chromosome 12q13 in three families are suggestive of genetic
heterogeneity. To examine the cellular localization of ALADIN mutants causing
triple A syndrome, we investigated nine different ALADIN-mutants: 2 nonsense
(W84X, Q456X), 2 frameshift (F157fsX171, G397fsX414) and 5 point mutations
(Q15K, L25P, H160R, S263P, L381R) by transfection experiments with green
fluorescence protein. Mutants were predomitly localized in the cytoplasm, but
also found in the nucleus indicating that ALADIN is essential for NPC targeting.
To investigate physiological functions of ALADIN in vivo, we generated and
analysed Aaas-/- knockout mice by homologous recombination in embryonic stem
cells. Surprisingly, required animals lack any gross abnormality in adrenal and
nervous system function. Further studies have to investigate the role of ALADIN
at NPCs and to identify interacting proteins. Functional analyses of ALADIN may
permit further understanding of its role for adrenocortical function and
neurodevelopment. Allgrove syndrome (triple A syndrome) is a rare autosomal recessive disorder
characterized by achalasia, alacrima, adrenal insufficiency,
and--occasionally--autonomic instability. Disease causing mutations have been
found in the AAAS gene on 12q13, but no strong phenotype-genotype correlation
could be found. We present a 28 year-old woman with classical systemic features
of triple A syndrome with prominent neurological dysfunctions/deficits,
including distal muscular atrophy, progressive muscle weakness and wasting of
both legs, sensibility dysfunction, hyperreflexia and autonomic dysfunction
presented with excessive sweating. DNA sequencing of the AAAS gene revealed
compound heterozygosity for previously reported mutations. A similar genotype
was previously reported, but with a remarkably different phenotype. The triple A syndrome is a rare autosomal recessive disease that is
characterised by the triad of adrenocorticotropin (ACTH)-resistant adrenal
insufficiency, achalasia and alacrima. In most patients, neurological and
dermatological abnormalities are associated features. We report on the first
Bosnian patient with triple A syndrome. Endocrine investigation confirmed
primary adrenal insufficiency at the age of 5.8 years. Two months later,
achalasia was diagnosed, and in the presence of alacrima, the patient satisfies
the diagnostic criteria of triple A syndrome. In addition, a large number of
associated neurological and dermatological features were present in this
patient. Moreover, he has dysmorphic facial features, which have not been
previously described in triple A syndrome. Triple A syndrome was confirmed by
molecular analysis, revealing a nonsense mutation p.W84X in the AAAS gene. The
parents are both heterozygous carriers of the mutation. The affected twin
brother unfortunately died from hypoglycaemic shock, despite a normal cortisol
rise in an ACTH stimulation test. Further, triple A syndrome patients carrying
the identical homozygous p.W84X mutation have to be studied to assess a
genotype-phenotype relationship for this mutation. Triple-A or Allgrove syndrome is a rare multisystem disease classically
associated with esophageal achalasia, adrenal insufficiency and alacrima. Here,
we describe the poorly understood neurological characteristics often associated
with this condition, through the clinical and electrophysiological analysis of
eight patients. All patients were genetically confirmed and had a mutation in
the ALADIN gene. They all displayed a classical picture of Triple-A syndrome:
all suffered from achalasia and alacrima and half of them from adrenal
insufficiency. However, all harbored a neurological picture characterized by a
recognizable pattern of peripheral neuropathy. Other neurological features
included cognitive deficits, pyramidal syndrome, cerebellar dysfunction,
dysautonomia, neuro-ophthalmological signs and bulbar and facial symptoms. This
neurological picture was prominent in all patients and misled the initial
diagnosis in six of them, which had a late onset. We then review the previous
neurological reports of this disease, to improve the understanding of this rare
condition. Diagnosis of late-onset Triple-A syndrome is difficult when the
clinical picture is mainly neurological and when endocrine or gastrointestinal
signs are minor. The characteristics of the peripheral neuropathy, among other
neurological signs, can be of help. Allgrove (Triple A) syndrome is a rare autosomal recessive disorder
characterized by cardinal features of adrenal insufficiency due to
adrenocorticotropic hormone (ACTH) resistance, achalasia, and alacrimia. It is
frequently associated with neurological manifestations like polyneuropathy.
Since its first description by Allgrove in 1978, approximately 100 cases have
been reported in the literature. Here we report an 18-year-old boy diagnosed as
having Allgrove syndrome, with ACTH resistant adrenal insufficiency, achalasia,
alacrimia, and severe motor polyneuropathy. Alacrimia was the earliest feature
evident at the age of 8 years. He presented with achalasia and adrenal
insufficiency at 12 and 18 years respectively and developed neurological
symptoms in the form of severe muscle wasting at the age of 15 years. Patients
with Allgrove syndrome usually manifest adrenal insufficiency and achalasia
during first decade of life. Our patient manifested adrenal insufficiency and
achalasia in the second decade and manifested neurological dysfunction before
adrenal dysfunction. Triple A syndrome (TAS) or Allgrove syndrome (OMIM #231550) is a rare autosomal
recessive disorder characterised by adrenocorticotropic hormone-resistant
adrenal insufficiency, alacrima, achalasia, and neurological and dermatological
abnormalities. Mutations in the AAAS gene on chromosome 12q13 encoding the
nuclear pore protein ALADIN have been reported in these patients. Between 2006
and 2017, we evaluated six patients with a clinical diagnosis of TAS, based on
the presence of at least two symptoms, usually adrenal insufficiency and
alacrima. In all cases, genetic analysis revealed homozygous mutations in the
AAAS gene. One novel mutation was detected: a homozygous 10-bp deletion
(c.1264_1273del, p.Q422NfsX126) in exon 14 of the AAAS gene that caused a
frameshift that introduced an aberrant stop codon after 126 amino acids. This
genetic variant is likely to be pathogenic because it caused a significant
change in protein structure. A precise genotype-phenotype correlation was
impossible to establish.
CONCLUSIONS: Based on our experience, we recommend that molecular analysis
should be performed in the presence of alacrima and at least one more symptom of
TAS. Our cases share many clinical features of TAS and underline the variability
in this syndrome, as well as the need for thorough investigation following a
multidisciplinary approach. What is known: • Triple A syndrome is characterised
by achalasia, alacrima, adrenal insufficiency, neurological impairment, and
dermatological abnormalities. • A precise genotype-phenotype correlation has
proved impossible to establish. What is new: • These cases add to a large number
of similar case reports with limited novel information. • The newly identified
AAAS gene mutation was reported. Allgrove or triple A syndrome (AS or AAA) is a rare autosomal recessive syndrome
with variable phenotype due to mutations in AAAS gene which encodes a protein
called ALADIN. Generally, it's characterized by of adrenal insufficiency in
consequence of adrenocorticotropic hormone (ACTH) resistance, besides of
achalasia, and alacrimia. Neurologic features are varied and have been the
subject of several case reports and reviews. A few cases of Allgrove syndrome
with motor neuron disease have been already described. A 25-year-old white man,
at the age of four, presented slowly progressive distal amyotrophy and weakness,
autonomic dysfunction, dysphagia and lack of tears. He suffered later of
orthostatic hypotension and erectile dysfunction. He presented distal amytrophy
in four limbs, tongue myofasiculations, alacrimia, hoarseness and dysphagia due
to achalasia. The ENMG showed generalized denervation with normal conduction
velocities. Genetic testing revealed 2 known pathogenic variants in the AAAS
gene (c.938T>C and c.1144_1147delTCTG). Our case presented a distal spinal
amyotrophy with slow evolution and symptoms and signs of AS with a mutation in
AAAS gen. Some cases of motor neuron disease, as ours, may be due to AAS. Early
diagnosis is extremely important for symptomatic treatment. |
What is the mechanism of the drug CRT0066101? | Recently developed small molecule PKD inhibitors, CID755673 and CRT0066101, provide potentially important pharmacological approaches to further investigate the effect of PKD in pancreatitis therapy | Invasive ductal carcinomas (IDC) of the breast are associated with altered
expression of hormone receptors (HR), amplification or overexpression of HER2,
or a triple-negative phenotype. The most aggressive cases of IDC are
characterized by a high proliferation rate, a great propensity to metastasize,
and their ability to resist to standard chemotherapy, hormone therapy, or
HER2-targeted therapy. Using progression tissue microarrays, we here demonstrate
that the serine/threonine kinase protein kinase D3 (PKD3) is highly upregulated
in estrogen receptor (ER)-negative (ER(-)) tumors. We identify direct binding of
the ER to the PRKD3 gene promoter as a mechanism of inhibition of PKD3
expression. Loss of ER results in upregulation of PKD3, leading to all hallmarks
of aggressive IDC, including increased cell proliferation, migration, and
invasion. This identifies ER(-) breast cancers as ideal for treatment with the
PKD inhibitor CRT0066101. We show that similar to a knockdown of PKD3, treatment
with this inhibitor targets all tumorigenic processes in vitro and decreases
growth of primary tumors and metastasis in vivo. Our data strongly support the
development of PKD inhibitors for clinical use for ER(-) breast cancers,
including the triple-negative phenotype. AMP-activated protein kinase (AMPK) is an energy-sensing enzyme whose activity
is inhibited in settings of insulin resistance. Exposure to a high glucose
concentration has recently been shown to increase phosphorylation of AMPK at
Ser(485/491) of its α1/α2 subunit; however, the mechanism by which it does so is
not known. Diacylglycerol (DAG), which is also increased in muscle exposed to
high glucose, activates a number of signaling molecules including protein kinase
(PK)C and PKD1. We sought to determine whether PKC or PKD1 is involved in
inhibition of AMPK by causing Ser(485/491) phosphorylation in skeletal muscle
cells. C2C12 myotubes were treated with the PKC/D1 activator phorbol
12-myristate 13-acetate (PMA), which acts as a DAG mimetic. This caused dose-
and time-dependent increases in AMPK Ser(485/491) phosphorylation, which was
associated with a ∼60% decrease in AMPKα2 activity. Expression of a
phosphodefective AMPKα2 mutant (S491A) prevented the PMA-induced reduction in
AMPK activity. Serine phosphorylation and inhibition of AMPK activity were
partially prevented by the broad PKC inhibitor Gö6983 and fully prevented by the
specific PKD1 inhibitor CRT0066101. Genetic knockdown of PKD1 also prevented
Ser(485/491) phosphorylation of AMPK. Inhibition of previously identified
kinases that phosphorylate AMPK at this site (Akt, S6K, and ERK) did not prevent
these events. PMA treatment also caused impairments in insulin-signaling through
Akt, which were prevented by PKD1 inhibition. Finally, recombit PKD1
phosphorylated AMPKα2 at Ser(491) in cell-free conditions. These results
identify PKD1 as a novel upstream kinase of AMPKα2 Ser(491) that plays a
negative role in insulin signaling in muscle cells. One of the properties of human breast cancer cells is cancer stemness, which is
characterized by self-renewal capability and drug resistance. Protein kinase D1
(PRKD1) functions as a key regulator of many cellular processes and is
downregulated in invasive breast cancer cells. In this study, we found that
PRKD1 was upregulated in MCF-7-ADR human breast cancer cells characterized by
drug resistance. Additionally, we discovered that PRKD1 expression was
negatively regulated by miR-34a binding to the PRKD1 3'-UTR. PRKD1 expression
increased following performance of a tumorsphere formation assay in MCF-7-ADR
cells. We also found that reduction of PRKD1 by ectopic miR-34a expression or
PRKD1 siRNA treatment resulted in suppressed self-renewal ability in breast
cancer stem cells. Furthermore, we confirmed that the PRKD1 inhibitor CRT0066101
reduced phosphorylated PKD/PKCμ, leading to suppression of breast cancer
stemness through GSK3/β-catenin signaling. PRKD1 inhibition also influenced
apoptosis initiation in MCF-7-ADR cells. Tumors from nude mice treated with
miR-34a or CRT0066101 showed suppressed tumor growth, proliferation, and induced
apoptosis. These results provide evidence that regulation of PRKD1, a novel
miR-34a target, contributes to overcoming cancer stemness and drug resistance in
human breast cancer. Agonist-evoked endocytosis of G protein-coupled receptors has been extensively
studied. The mechanisms by which agonists stimulate mobilization and plasma
membrane translocation of G protein-coupled receptors from intracellular stores
are unexplored. Protease-activated receptor-2 (PAR2) traffics to lysosomes, and
sustained protease signaling requires mobilization and plasma membrane
trafficking of PAR2 from Golgi stores. We evaluated the contribution of protein
kinase D (PKD) and Gβγ to this process. In HEK293 and KNRK cells, the PAR2
agonists trypsin and 2-furoyl-LIGRLO-NH2 activated PKD in the Golgi apparatus,
where PKD regulates protein trafficking. PAR2 activation induced translocation
of Gβγ, a PKD activator, to the Golgi apparatus, determined by bioluminescence
resoce energy transfer between Gγ-Venus and giantin-Rluc8. Inhibitors of PKD
(CRT0066101) and Gβγ (gallein) prevented PAR2-stimulated activation of PKD.
CRT0066101, PKD1 siRNA, and gallein all inhibited recovery of PAR2-evoked Ca(2+)
signaling. PAR2 with a photoconvertible Kaede tag was expressed in KNRK cells to
examine receptor translocation from the Golgi apparatus to the plasma membrane.
Irradiation of the Golgi region (405 nm) induced green-red photo-conversion of
PAR2-Kaede. Trypsin depleted PAR2-Kaede from the Golgi apparatus and repleted
PAR2-Kaede at the plasma membrane. CRT0066101 inhibited PAR2-Kaede translocation
to the plasma membrane. CRT0066101 also inhibited sustained protease signaling
to colonocytes and nociceptive neurons that naturally express PAR2 and mediate
protease-evoked inflammation and nociception. Our results reveal a major role
for PKD and Gβγ in agonist-evoked mobilization of intracellular PAR2 stores that
is required for sustained signaling by extracellular proteases. Nuclear factor-kappa B (NF-κB) activation is a key early signal regulating
inflammatory and cell death responses in acute pancreatitis. Our previous in
vitro studies with molecular approaches on AR42J cell showed that protein kinase
D (PKD/PKD1) activation was required in NF-κB activation induced by
cholecystokinin 8 (CCK) or carbachol (CCh) in pancreatic acinar cells. Recently
developed small molecule PKD inhibitors, CID755673 and CRT0066101, provide
potentially important pharmacological approaches to further investigate the
effect of PKD in pancreatitis therapy. The aim of this study was to explore
whether CID755673 and CRT0066101 block NF-κB activation with in vitro and in
vivo models of experimental pancreatitis and whether the small molecule PKD
inhibitors have therapeutic effects when given before or after the initiation of
experimental pancreatitis. Freshly prepared pancreatic acini were incubated with
CID755673 or CRT006101, followed by hyperstimulation with CCK or CCh. For in
vivo experimental pancreatitis, rats were treated with intraperitoneal injection
of CID755673 or CRT0066101 prior to or after administering cerulein or saline.
PKD activation and NF-κB-DNA binding activity in nuclear extracts from
pancreatic acini and tissue were measured. The effects of PKD inhibitors on
pancreatitis responses were evaluated. Our results showed that both CID755673 or
CRT0066101 selectively and specifically inhibited PKD without effects on related
protein kinase Cs. Inhibition of PKD resulted in significantly attenuation of
NF-κB activation in both in vitro and in vivo models of experimental
pancreatitis. NF-κB inhibition by CID755673 was associated with decreased
inflammatory responses and attenuated severity of the disease, which were
indicated by less inflammatory cell infiltration, reduced pancreatic
interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), decreased
intrapancreatic trypsin activation, and alleviation in pancreatic necrosis,
edema and vacuolization. Furthermore, PKD inhibitor CID755673, given after the
initiation of pancreatitis in experimental rat model, significantly attenuated
the severity of acute pancreatitis. Therapies for acute pancreatitis are
limited. Our results indicate that small chemical PKD inhibitors have
significant potential as therapeutic interventions by suppressing NF-κB
activation. |
Which protein is the Mitochondrial carrier homolog 2 (MTCH2) receptor for? | Mitochondrial Carrier Homolog 2 (MTCH2) acts as a receptor for the BH3 interacting-domain death agonist (BID) in the mitochondrial outer membrane. | BID, a proapoptotic BCL-2 family member, plays an essential role in the tumor
necrosis factor alpha (TNF-alpha)/Fas death receptor pathway in vivo. Activation
of the TNF-R1 receptor results in the cleavage of BID into truncated BID (tBID),
which translocates to the mitochondria and induces the activation of BAX or BAK.
In TNF-alpha-activated FL5.12 cells, tBID becomes part of a 45-kDa
cross-linkable mitochondrial complex. Here we describe the biochemical
purification of this complex and the identification of mitochondrial carrier
homolog 2 (Mtch2) as part of this complex. Mtch2 is a conserved protein that is
similar to members of the mitochondrial carrier protein family. Our studies with
mouse liver mitochondria indicate that Mtch2 is an integral membrane protein
exposed on the surface of mitochondria. Using blue-native gel electrophoresis we
revealed that in viable FL5.12 cells Mtch2 resides in a protein complex of ca.
185 kDa and that the addition of TNF-alpha to these cells leads to the
recruitment of tBID and BAX to this complex. Importantly, this recruitment was
partially inhibited in FL5.12 cells stably expressing BCL-X(L). These results
implicate Mtch2 as a mitochondrial target of tBID and raise the possibility that
the Mtch2-resident complex participates in the mitochondrial apoptotic program. Recent studies report mitochondrial carrier homolog 2 (MTCH2) as a novel and
uncharacterized protein that acts as a receptor-like protein for the truncated
BH3-interacting domain death agonist (tBID) protein in the outer membrane of
mitochondria. These studies, using mouse embryonic stem cells and fibroblasts as
well as mice with a conditional knockout of MTCH2 in the liver, showed that
deletion of MTCH2 hindered recruitment of tBID to the mitochondria with
subsequent reductions in the activation of pro-apoptotic proteins, mitochondrial
outer membrane permeabilization and apoptosis. Sequence analysis shows that
MTCH2 is present in all examined multicellular Metazoa as well as unicellular
Choanoflagellata, and is a highly derived member of the mitochondrial carrier
family. Mitochondrial carriers are monomeric transport proteins that are usually
found in the inner mitochondrial membrane, where they exchange small substrates
between the mitochondrial matrix and intermembrane space. There are extensive
differences between the protein sequences of MTCH2 and other mitochondrial
carriers that may explain the ability of MTCH2 to associate with tBID and thus
its role in apoptosis. We review the experimental evidence for the role of MTCH2
in apoptosis and suggest that the original transport function of the ancestral
MTCH2 mitochondrial carrier has been co-opted by the apoptotic machinery to
provide a receptor and signaling mechanism. During apoptosis, proapoptotic BAX and BAK trigger mitochondrial outer membrane
(MOM) permeabilization by a mechanism that is not yet fully understood. BH3-only
proteins such as tBID, together with lipids of the MOM, are thought to play a
key role in BAX and BAK activation. In particular, cardiolipin (CL) has been
shown to stimulate tBID-induced BAX activation in vitro. However, it is still
unclear whether this process also relies on CL in the cell, or whether it is
more dependent on MTCH2, a proposed receptor for tBID present in the MOM. To
address this issue, we deleted both alleles of cardiolipin synthase in human
HCT116 cells by homologous recombination, which resulted in a complete absence
of CL. The CL-deficient cells were fully viable in glucose but displayed
impaired oxidative phosphorylation and an inability to grow in galactose. Using
these cells, we found that CL was not required for either tBID-induced BAX
activation, or for apoptosis in response to treatment with TRAIL. Downregulation
of MTCH2 in HCT116 cells also failed to prevent recruitment of tBID to
mitochondria in apoptotic conditions. However, when both CL and MTCH2 were
depleted, a significant reduction in tBID recruitment was observed, suggesting
that in HCT116 cells, CL and MTCH2 can have redundant functions in this process. Author information:
(1)Department of Pharmacy, National University of Singapore, Singapore 117543,
Singapore.
(2)Department of Pharmacy, National University of Singapore, Singapore 117543,
Singapore; School of Life Sciences, Xiamen University, Xiamen 361102, China.
(3)Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
169857, Singapore.
(4)Division of iHOPE, Department of Pediatrics, Faculty of Medicine and
Dentistry, Women and Children's Research Institute and Cancer Research Institute
of Northern Alberta, University of Alberta, Edmonton, AB T6G 2N8, Canada.
(5)Department of Microbiology and Immunology, Yong Loo Lin School of Medicine,
National University of Singapore, Singapore 117545, Singapore.
(6)Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
169857, Singapore; Division of Cellular and Molecular Research, Humphrey Oei
Institute of Cancer Research, National Cancer Centre, Singapore 169610,
Singapore.
(7)School of Life Sciences, Xiamen University, Xiamen 361102, China.
(8)Department of Pharmacy, National University of Singapore, Singapore 117543,
Singapore. Electronic address: [email protected]. |
What is PhenomeCentral? | The discovery of disease-causing mutations typically requires confirmation of the variant or gene in multiple unrelated individuals, and a large number of rare genetic diseases remain unsolved due to difficulty identifying second families. The PhenomeCentral portal (https://phenomecentral.org) enables the secure sharing of case records by clinicians and rare disease scientists. PhenomeCentral identifies similar patients in the database based on semantic similarity between clinical features, automatically prioritized genes from whole-exome data, and candidate genes entered by the users, enabling both hypothesis-free and hypothesis-driven matchmaking. Users can then contact other submitters to follow up on promising matches. PhenomeCentral incorporates data for over 1,000 patients with rare genetic diseases, contributed by the FORGE and Care4Rare Canada projects, the US NIH Undiagnosed Diseases Program, the EU Neuromics and ANDDIrare projects, as well as numerous independent clinicians and scientists. Though the majority of these records have associated exome data, most lack a molecular diagnosis. PhenomeCentral has already been used to identify causative mutations for several patients, and its ability to find matching patients and diagnose these diseases will grow with each additional patient that is entered. | The discovery of disease-causing mutations typically requires confirmation of
the variant or gene in multiple unrelated individuals, and a large number of
rare genetic diseases remain unsolved due to difficulty identifying second
families. To enable the secure sharing of case records by clinicians and rare
disease scientists, we have developed the PhenomeCentral portal
(https://phenomecentral.org). Each record includes a phenotypic description and
relevant genetic information (exome or candidate genes). PhenomeCentral
identifies similar patients in the database based on semantic similarity between
clinical features, automatically prioritized genes from whole-exome data, and
candidate genes entered by the users, enabling both hypothesis-free and
hypothesis-driven matchmaking. Users can then contact other submitters to follow
up on promising matches. PhenomeCentral incorporates data for over 1,000
patients with rare genetic diseases, contributed by the FORGE and Care4Rare
Canada projects, the US NIH Undiagnosed Diseases Program, the EU Neuromics and
ANDDIrare projects, as well as numerous independent clinicians and scientists.
Though the majority of these records have associated exome data, most lack a
molecular diagnosis. PhenomeCentral has already been used to identify causative
mutations for several patients, and its ability to find matching patients and
diagnose these diseases will grow with each additional patient that is entered. |
What organism causes Rhombencephalitis? | Rhombencephalitis caused by Listeria monocytogenes | We report a case of Listeria rhombencephalitis in a previously healthy
60-year-old man. Listeria rhombencephalitis is a rare but well-defined clinical
syndrome of lower brain-stem involvement caused by Listeria monocytogenes.
Contrary to other listerioses, rhombencephalitis has been mainly observed in
patients without predisposing conditions. In our case, however, findings of a
detailed immunologic study, performed three months and one year, respectively,
after clinical onset of Listeria rhombencephalitis manifestations, showed a
transient cellular immunity defect, not associated with any other apparent
disease. Rhombencephalitis due to Listeria monocytogenes is a frequent complication of
human listeriosis, inducing a high mortality and severe neurological sequelae
despite antibiotic therapy. However, there is no animal model which consistently
reproduces clinical rhombencephalitis. Here, we present a model of Listeria
rhombencephalitis in gerbils. Animals were inoculated in the middle ears with a
low infective dose of L. monocytogenes, thus creating prolonged otitis media
with persistent bacteremia. Gerbils developed a severe rhombencephalitis with
circling syndrome, paresia, ataxia, rolling movements. The invasion of the
central nervous system was visualized on living animals by resoce magnetic
imaging and characterized by bacterial growth in the brain, reaching about 10(7)
bacteria in the rhombencephalum by day 12 of infection. The histological lesions
were mainly located in the brainstem, and consisted in coalescent, necrotic
abscesses with perivascular sheaths, mimicking those observed in human
rhombencephalitis. Bacteria were detected by electronmicroscopy inside
infectious foci, either free in necrotic material or inside inflammatory cells,
mainly polymorphonuclear cells. This gerbil model of Listeria rhombencephalitis
will be useful to study the molecular mechanisms allowing bacteria to cross the
blood-brain barrier, and to evaluate the intracerebral efficacy of antibiotics. INTRODUCTION: Listeria monocytogenes is a gram-positive bacillus which causes
sporadic infections in immunocompromised humans, with a special propensity for
the central nervous system, in the form of acute, subacute or chronic
meningitis, rhombencephalitis or abscesses in the brain or spinal cord. The
final diagnosis is established by germ culture in blood or in cerebrospinal
fluid (CSF). Preferred treatment is ampicillin in association with
aminoglycosides.
CASE REPORT: We report the case of a 70-year-old male patient with a history of
arterial hypertension and chronic lymphatic leukaemia with no specific
treatment, who suffered meningoencephalitis and brain abscesses caused by L.
monocytogenes. Symptoms were a 48-hour history of headache and a febrile
condition. The CSF showed lymphocytic pleocytosis with hypoglycorrhachia.
Magnetic resoce scans of the brain revealed areas of cerebritis and multiple
brain abscesses in the right frontal lobe. Specific treatment was established
with ampicillin for 13 weeks, associated with gentamicin and vancomycin during
the first few weeks, until x-rays showed the lesions to be resolved.
CONCLUSIONS: L. monocytogenes infections must be investigated in all patients
with cellular immunosuppression who present febrile symptoms. The central
nervous system may be the only area of the body infected. Moreover, this site
will need studying in patients who present neurological focus data or an
alteration in the state of consciousness and bacteraemia due to L.
monocytogenes. Establishing suitable treatment as early as possible can improve
the prognosis. Infection of the central nervous system due to Listeria monocytogenes is
uncommon. The treatment of choice is ampicillin. We describe in this report a
case of rhombencephalitis caused by Listeria monocytogenes successfully treated
with linezolid. To the best of our knowledge, this is the first case in which
linezolid was used to treat infection of the central nervous system caused by
this organism. Listeriosis is an emerging zoonotic infection of humans and rumits worldwide
caused by Listeria monocytogenes (LM). In both host species, CNS disease
accounts for the high mortality associated with listeriosis and includes
rhombencephalitis, whose neuropathology is strikingly similar in humans and
rumits. This review discusses the current knowledge about listeric
encephalitis, and involved host and bacterial factors. There is an urgent need
to study the molecular mechanisms of neuropathogenesis, which are poorly
understood. Such studies will provide a basis for the development of new
therapeutic strategies that aim to prevent LM from invading the brain and spread
within the CNS. Rhombencephalitis (RE) is a syndrome of multiple causes and multiple outcomes.
Most authors now use the terms "rhombencephalitis" and "brainstem encephalitis"
interchangeably even though anatomically they are slightly different. The
etiologic categories of RE include infections, autoimmune diseases, and
paraneoplastic syndromes (PNS). Listeria is the most common cause of infectious
RE. Listeria RE primary occurs in healthy young adults. It usually occurs as a
biphasic time course with a flu-like syndrome followed by brainstem dysfunction;
75% of patients have a cerebrospinal fluid (CSF) pleocytosis, and almost 100%
have an abnormal brain MRI scan. Positive CSF and blood cultures are the most
specific for diagnosis. Treatment primarily is with ampicillin. Enterovirus 71
is probably the second most common infectious cause of RE; however, 95% of cases
have occurred in the Asian-Pacific region and there is no specific treatment.
Herpes simplex virus (HSV) is the third most common infectious cause of RE, and
about 80% of cases are caused by HSV1 and 20% by HSV2. About 50% only had
involvement of the brainstem whereas the other 50% also had supratentorial
involvement of the temporal and frontal lobes. Mortality with acyclovir
treatment was 22% versus those not on acyclovir 75%. Epstein-Barr virus (EBV)
and human herpesvirus 6 (HHV6) have caused a few cases. The most common
autoimmune etiology is Behçet disease. Over 90% of those with Behçet RE had
abnormal MRI scans and 94% had a CSF pleocytosis. Treatment is with
corticosteroids and immunosuppressive agents, but only 25% have complete
recovery. Paraneoplastic causes are the third category of RE. Brain MRIs are
usually normal; there is usually a CSF pleocytosis but the protein is usually
normal. Often anti-neuronal antibodies can be found. Prognosis is poor and
treatment is only partially beneficial. Because Listeria and HSV are the most
common treatable acute causes of RE, we recommend empiric therapy with
ampicillin and acyclovir for all cases after samples have been obtained from CSF
and blood for cultures and the polymerase chain reaction (PCR). Antibiotics can
be changed based upon MRI, culture results, PCR results, and antibody studies. Listeria monocytogenes is a gram-positive bacillus that exhibits predilection to
infect the central nervous system in immunocompromised individuals; the most
common manifestations are meningitis and rhombencephalitis. Listerial brain
abscesses are rare. We report here two brain abscess cases caused by L.
monocytogenes in patients receiving immunosuppressive agents. The first patient
presented with left hemiparesis mimicking stroke and the second patient
presented with neurological symptoms without fever, which was indistinguishable
from brain tumor. In both cases, magnetic resoce spectroscopy (MRS) was
performed to differentiate infectious processes from other causes. Diagnosis was
made with a positive blood culture in both cases. Listerial DNA was detected in
the pus aspirated from the abscess in the first case. Both patients were
successfully treated with intravenous ampicillin followed by oral amoxicillin.
MRS was useful in differentiating infectious processes from non-infectious
causes. The term rhombencephalitis refers to inflammatory diseases affecting the
hindbrain (brainstem and cerebellum). Rhombencephalitis has a wide variety of
etiologies, including infections, autoimmune diseases, and paraneoplastic
syndromes. Infection with bacteria of the genus Listeria is the most common
cause of rhombencephalitis. Primary rhombencephalitis caused by infection with
Listeria spp. occurs in healthy young adults. It usually has a biphasic time
course with a flu-like syndrome, followed by brainstem dysfunction; 75% of
patients have cerebrospinal fluid pleocytosis, and nearly 100% have an abnormal
brain magnetic resoce imaging scan. However, other possible causes of
rhombencephalitis must be borne in mind. In addition to the clinical aspects,
the patterns seen in magnetic resoce imaging can be helpful in defining the
possible cause. Some of the reported causes of rhombencephalitis are potentially
severe and life threatening; therefore, an accurate initial diagnostic approach
is important to establishing a proper early treatment regimen. This pictorial
essay reviews the various causes of rhombencephalitis and the corresponding
magnetic resoce imaging findings, by describing illustrative confirmed cases. Listeria monocytogenes is associated with rhombencephalitis. However, the exact
mechanisms of brainstem invasion remains poorly understood. Here, we demonstrate
clinical and radiological data suggesting that Listeria may invade the brainstem
via the trigeminal nerve. Three females (41, 64 and 70 years) with culture
proven L. monocytogenes bacteremia and rhombencephalitis were investigated in
the period of 2014-16. T2-weighted and contrast-enhanced T1-weighted MRI
revealed a cerebellopontine abscess in all three patients, including the
involvement of the trigeminal nerve root. In two patients, MRI also revealed
selective contrast enhancement of the sensory trigeminal tract in the pons and
medulla oblongata. Prior to any other neurological symptoms, two patients
complained of hypoesthesia and a tingling sensation in the ipsilateral half of
the face, consistent with sensory trigeminal nerve dysfunction on that side. In
addition, we identified another 120 cases of Listeria rhombencephalitis
following a systematic review. Cranial nerves VII, V, IX, and X, respectively,
medulla oblongata, cerebellum and pons, were the most frequently involved brain
structures. The present clinical and radiological findings corroborate earlier
data from animal experiments, indicating that L. monocytogenes may be capable of
retrograde intra-axonal migration along the cranial nerves. We suggest that in a
subset of patients with rhombencephalitis L. monocytogenes enters the
cerebellopontine angle through the trigeminal nerve, invading the brainstem via
the sensory trigeminal nuclei. Listeria rhombencephalitis is caused by infection with Listeria monocytogenes
and is associated with a high mortality rate in humans and rumits. Little is
known about the metabolic changes associated with neurolisteriosis in particular
and infectious central nervous system (CNS) diseases in general. The purpose of
our study was to investigate the metabolic changes associated with listeria
rhombencephalitis in small rumits (goats and sheep) as a model for
inflammatory CNS disease by 1 H high-resolution magic angle spinning nuclear
magnetic resoce (1 H HR-MAS NMR) spectroscopy of brain biopsies obtained from
the brainstem and thalamus. Statistical analysis revealed distinct differences
in the metabolic profile of brainstem biopsies, the primary location of listeria
rhombencephalitis with moderate or severe inflammatory changes.
N-Acetylaspartate (NAA), N-acetylaspartylglutamate, choline, myo-inositol and
scyllo-inositol were decreased, and glycine, phosphocholine, taurine and lactate
were increased, in the diseased group (n = 13) in comparison with the control
group (n = 12). In the thalamus, which showed no or only mild inflammatory
changes in the majority of animals, no statistically significant metabolic
changes were observed. However, trends for metabolic alterations were partly the
same as those found in the brainstem, including NAA, choline and lactate. This
may be an indicator of metabolic changes occurring in the early stages of the
disease. Therefore, further research with a larger number of animals is needed
to evaluate the presence of subtle metabolic changes associated with mild
inflammatory changes in the thalamus. In conclusion, 1 H HR-MAS NMR
investigation of listeria rhombencephalitis identified brain metabolite changes,
offering new insights into the disease pathophysiology. A 46-year-old previously healthy man presented with 1 week of headache, nausea,
vomiting and dizziness. He was found to have cranial nerve deficits, his
cerebrospinal fluid (CSF) demonstrated a lymphocytic pleocytosis and brain MRI
suggested rhombencephalitis. Although Gram stains and cultures of his CSF did
not identify a pathogen, Listeria monocytogenes DNA was detected by the
FilmArray Meningitis/Encephalitis panel within 2 hours of performing a lumbar
puncture. He was treated with ampicillin and gentamicin and had a near-complete
recovery. This case highlights the importance of recognising L. monocytogenes
infection as a cause of acute cranial nerve impairment with MRI findings
suggestive of brainstem encephalitis. It also highlights the frequently atypical
CSF profile and low yield of culture in L. monocytogenes rhombencephalitis and
the value of multiplex PCR testing of CSF to rapidly identify this pathogen and
permit targeted therapy. |
Has the protein SIRT2 been associated to cervical cancer? | Yes.
A progressive increase in the expression of both SIRT2 and SIRT7 was noted during cancer progression in the following order: normal < preneoplasia < cancer. | RhoGDIα is a key regulator of Rho proteins, coordinating their GTP/GDP and
membrane/cytosol cycle. Recently, it was demonstrated by quantitative mass
spectrometry that RhoGDIα is heavily targeted by post-translational lysine
acetylation. For one site in its N-terminal domain, namely K52, we reported
earlier that acetylation completely switches off RhoGDIα function. Herein we
show that K52-acetylated RhoGDIα is specifically deacetylated by the sirtuin
deacetylase Sirt2. We show that acetylation at K52 decelerates cervical cancer
cell proliferation, suggesting RhoGDIα acetylation to be a promising therapeutic
target. We demonstrate that treatment of cervical cancer cells with a
RhoGDIα-derived K52-trifluoroacetylated, substrate-derived peptidic sirtuin
inhibitor severely impairs cell proliferation. Finally, we conclude that the
potency of substrate-derived sirtuin inhibitors depends on structural features,
the substrate-derived amino acid sequence as a determit for selectivity, as
well as the presence of an acetyl-lysine analogue to increase its potency. These
data reveal a prospective therapeutic potential for novel substrate-derived
sirtuin inhibitors. |
Which receptor is targeted by Erenumab? | Erenumab is a human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, is being evaluated for migraine prevention. | BACKGROUND: The calcitonin gene-related peptide (CGRP) pathway is important in
migraine pathophysiology. We assessed the efficacy and safety of erenumab, a
fully human monoclonal antibody against the CGRP receptor, in patients with
chronic migraine.
METHODS: This was a phase 2, randomised, double-blind, placebo-controlled,
multicentre study of erenumab for adults aged 18-65 years with chronic migraine,
enrolled from 69 headache and clinical research centres in North America and
Europe. Chronic migraine was defined as 15 or more headache days per month, of
which eight or more were migraine days. Patients were randomly assigned (3:2:2)
to subcutaneous placebo, erenumab 70 mg, or erenumab 140 mg, given every 4 weeks
for 12 weeks. Randomisation was centrally executed using an interactive voice or
web response system. Patients, study investigators, and study sponsor personnel
were masked to treatment assignment. The primary endpoint was the change in
monthly migraine days from baseline to the last 4 weeks of double-blind
treatment (weeks 9-12). Safety endpoints were adverse events, clinical
laboratory values, vital signs, and anti-erenumab antibodies. The efficacy
analysis set included patients who received at least one dose of investigational
product and completed at least one post-baseline monthly measurement. The safety
analysis set included patients who received at least one dose of investigational
product. The study is registered with ClinicalTrials.gov, number NCT02066415.
FINDINGS: From April 3, 2014, to Dec 4, 2015, 667 patients were randomly
assigned to receive placebo (n=286), erenumab 70 mg (n=191), or erenumab 140 mg
(n=190). Erenumab 70 mg and 140 mg reduced monthly migraine days versus placebo
(both doses -6·6 days vs placebo -4·2 days; difference -2·5, 95% CI -3·5 to
-1·4, p<0·0001). Adverse events were reported in 110 (39%) of 282 patients, 83
(44%) of 190 patients, and 88 (47%) of 188 patients in the placebo, 70 mg, and
140 mg groups, respectively. The most frequent adverse events were
injection-site pain, upper respiratory tract infection, and nausea. Serious
adverse events were reported by seven (2%), six (3%), and two (1%) patients,
respectively; none were reported in more than one patient in any group or led to
discontinuation. 11 patients in the 70 mg group and three in the 140 mg group
had anti-erenumab binding antibodies; none had anti-erenumab neutralising
antibodies. No clinically significant abnormalities in vital signs, laboratory
results, or electrocardiogram findings were identified. Of 667 patients randomly
assigned to treatment, 637 completed treatment. Four withdrew because of adverse
events, two each in the placebo and 140 mg groups.
INTERPRETATION: In patients with chronic migraine, erenumab 70 mg and 140 mg
reduced the number of monthly migraine days with a safety profile similar to
placebo, providing evidence that erenumab could be a potential therapy for
migraine prevention. Further research is needed to understand long-term efficacy
and safety of erenumab, and the applicability of this study to real-world
settings.
FUNDING: Amgen. Calcitonin gene-related peptide (CGRP) is a signaling neuropeptide released from
activated trigeminal sensory afferents in headache and facial pain disorders.
There are a handful of CGRP-targeted therapies currently in phase 3 studies for
migraine acute treatment or prevention. Currently, 4 monoclonal antibodies
targeting either the CGRP ligand or receptor are being studied for migraine
prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab),
and TEV-48125 (fremanezumab). Meanwhile, 1 small-molecule CGRP receptor
antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute
treatment of migraine. Two of these anti-CGRP monoclonal antibodies are in
clinical trials for cluster headache prevention as well. Several other
small-molecular CGRP receptor antagonists are in earlier stages of development
for acute migraine treatment or prevention. In this review, we will discuss the
growing body of clinical trials studying CGRP-targeted therapies for migraine
and cluster headache. Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP)
signaling are being explored as prophylactic treatments for migraine. Erenumab
(AMG 334) is the first potent, selective, and competitive human mAb antagonist
of the CGRP receptor. We report the data from two phase I studies assessing the
safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple
administrations of erenumab in healthy subjects and patients with migraine. The
results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg
and the linear portion of the clearance from 70 mg to 210 mg is consistent with
other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in
>75% inhibition of capsaicin-induced dermal blood flow, with no apparent
dose-dependency for erenumab ≥21 mg. Erenumab was generally well tolerated, with
an acceptable safety profile, supporting further clinical development of
erenumab for migraine prevention. BACKGROUND: We tested erenumab, a fully human monoclonal antibody that inhibits
the calcitonin gene-related peptide receptor, for the prevention of episodic
migraine.
METHODS: We randomly assigned patients to receive a subcutaneous injection of
either erenumab, at a dose of 70 mg or 140 mg, or placebo monthly for 6 months.
The primary end point was the change from baseline to months 4 through 6 in the
mean number of migraine days per month. Secondary end points were a 50% or
greater reduction in mean migraine days per month, change in the number of days
of use of acute migraine-specific medication, and change in scores on the
physical-impairment and everyday-activities domains of the Migraine Physical
Function Impact Diary (scale transformed to 0 to 100, with higher scores
representing greater migraine burden on functioning).
RESULTS: A total of 955 patients underwent randomization: 317 were assigned to
the 70-mg erenumab group, 319 to the 140-mg erenumab group, and 319 to the
placebo group. The mean number of migraine days per month at baseline was 8.3 in
the overall population; by months 4 through 6, the number of days was reduced by
3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as
compared with 1.8 days in the placebo group (P<0.001 for each dose vs. placebo).
A 50% or greater reduction in the mean number of migraine days per month was
achieved for 43.3% of patients in the 70-mg erenumab group and 50.0% of patients
in the 140-mg erenumab group, as compared with 26.6% in the placebo group
(P<0.001 for each dose vs. placebo), and the number of days of use of acute
migraine-specific medication was reduced by 1.1 days in the 70-mg erenumab group
and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the
placebo group (P<0.001 for each dose vs. placebo). Physical-impairment scores
improved by 4.2 and 4.8 points in the 70-mg and 140-mg erenumab groups,
respectively, as compared with 2.4 points in the placebo group (P<0.001 for each
dose vs. placebo), and everyday-activities scores improved by 5.5 and 5.9 points
in the 70-mg and 140-mg erenumab groups, respectively, as compared with 3.3
points in the placebo group (P<0.001 for each dose vs. placebo). The rates of
adverse events were similar between erenumab and placebo.
CONCLUSIONS: Erenumab administered subcutaneously at a monthly dose of 70 mg or
140 mg significantly reduced migraine frequency, the effects of migraines on
daily activities, and the use of acute migraine-specific medication over a
period of 6 months. The long-term safety and durability of the effect of
erenumab require further study. (Funded by Amgen and Novartis; STRIVE
ClinicalTrials.gov number, NCT02456740 .). Migraine is a highly disabling neurological condition, and preventative
treatment still remains problematic, due to aspecificity of the majority of the
currently available prophylactic drugs. Calcitonin-gene-related peptide (CGRP)
plays a crucial role in migraine pathophysiology; agents aimed at blocking its
activity have, therefore, been developed in recent years, among which are
monoclonal antibodies (mAbs) against CGRP, to prevent migraine. Erenumab is the
only mAb that targets the CGRP receptor instead of the ligand, with high
specificity and affinity of binding. This review will report on the most recent
data on erenumab characteristics and on the results of clinical trials on its
employment in the prevention of episodic migraine (4-14 monthly migraine days):
one Phase II and two Phase III trials (completed) and one Phase III trial
(ongoing). Monthly subcutaneous administration (70 mg or 140 mg) of erenumab vs
placebo for 3-6 months showed significantly higher efficacy in reducing the mean
monthly number of migraine days and the use of migraine-specific medication, and
in decreasing physical impairment and impact of migraine on everyday activities
(P<0.001). A favorable safety profile was demonstrated by the lack of
significant differences in the occurrence of adverse events in erenumab-treated
vs placebo-treated patients. Global results so far obtained point to erenumab as
a new promising candidate for the preventative treatment of episodic migraine.
Licence applications for erenumab were recently submitted to the Food and Drug
Administration in the USA and European Medicines Agency in Europe (May/June
2017). Erratum: Calcitonin gene-related peptide receptor as a novel target for the
management of people with episodic migraine: current evidence and safety profile
of erenumab [Corrigendum]. PURPOSE OF REVIEW: Monoclonal antibodies (mAbs) targeting the
calcitonin-gene-related peptide (CGRP) pathway have been developed for episodic
and chronic migraine prevention, either through binding the CGRP ligand
(eptinezumab, fremanezumab, galcanezumab) or the CGRP receptor (erenumab). We
provide an update on published Phase 2 and Phase 3 trials, safety/tolerability
data, pharmacokinetics and mechanism of action of these biologicals.
RECENT FINDINGS: The efficacy data from Phase 2 trials are corroborated by those
from published Phase 3 trials, with a multitude of publications expected in
2018. Review of safety data concluded there was no difference in total adverse
events or main adverse events (including upper respiratory tract infection,
nasopharyngitis, nausea, injection-site pain and back pain) between the mAbs and
placebo injections except apparently for dizziness. The site of action of these
mAbs is not fully elucidated but current insight is that their effect resides in
the periphery; a contribution of central effect(s) can however not be excluded
at present.
SUMMARY: Although efficacy of all four drugs is modest over placebo in episodic
and chronic migraine prevention and overall comparable with available oral
preventive treatments, current tolerability and (short-term) safety data of this
new treatment approach certainly promise a major step forward for migraine
patients. Treatment of migraine is on the cusp of a new era with the development of drugs
that target the trigeminal sensory neuropeptide calcitonin gene-related peptide
(CGRP) or its receptor. Several of these drugs are expected to receive approval
for use in migraine headache in 2018 and 2019. CGRP-related therapies offer
considerable improvements over existing drugs as they are the first to be
designed specifically to act on the trigeminal pain system, they are more
specific and they seem to have few or no adverse effects. CGRP receptor
antagonists such as ubrogepant are effective for acute relief of migraine
headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab
and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine
attacks. As these drugs come into clinical use, we provide an overview of
knowledge that has led to successful development of these drugs. We describe the
biology of CGRP signalling, summarize key clinical evidence for the role of CGRP
in migraine headache, including the efficacy of CGRP-targeted treatment, and
synthesize what is known about the role of CGRP in the trigeminovascular system.
Finally, we consider how the latest findings provide new insight into the
central role of the trigeminal ganglion in the pathophysiology of migraine. The neuropeptide calcitonin gene-related peptide is well established as a key
player in the pathogenesis of migraine. Clinical studies show calcitonin
gene-related peptide levels correlate with migraine attacks, and decreases in
this neuropeptide can indicate antimigraine therapy effectiveness. Research has
revealed a wide distribution of expression sites for calcitonin gene-related
peptide in the central and peripheral nervous system. Of these, the calcitonin
gene-related peptide receptor, which binds calcitonin gene-related peptide with
high affinity, has attracted growing interest as a viable target for
antimigraine therapies. An incentive to pursue such research is the continuing
unmet medical need of patients. Triptans have offered some clinical benefit, but
many patients do not respond and these drugs have important safety
considerations. Initial calcitonin gene-related peptide-focused research led to
development of the "gepant" small-molecule calcitonin gene-related peptide
receptor blockers. Positive efficacy reports concerning the gepants have been
tempered by safety findings which led to the discontinuation of some of these
agents. Currently, there is considerable excitement regarding monoclonal
antibodies against calcitonin gene-related peptide (eptinezumab, galcanezumab,
fremanezumab) and the calcitonin gene-related peptide receptor (erenumab). To
date, these monoclonal antibodies have shown promising efficacy in clinical
trials, with no major safety concerns. If ongoing long-term studies show that
their efficacy can be maintained, this may herald a new era for effective
antimigraine therapies. Amgen and Novartis are developing erenumab (AIMOVIG™, erenumab-aooe)-a fully
human monoclonal antibody calcitonin gene-related peptide (CGRP) receptor
antagonist-for the prevention of migraine. CGRP is a vasodilatory neuropeptide
implicated in the pathophysiology of migraine and treatment with erenumab was
associated with significant reductions in migraine frequency in phase II and III
clinical trials. Based on these positive results erenumab was recently approved
in the US for the preventive treatment of migraine in adults and has received a
positive opinion in the EU for the prophylaxis of migraines in adults who have
at least 4 migraine days per month. This article summarizes the milestones in
the development of erenumab leading to this first approval. Background We evaluated the effect of erenumab, a fully human monoclonal
antibody that inhibits the canonical calcitonin gene-related peptide receptor,
on migraine-related disability, impact, and health-related quality of life among
patients with episodic migraine. Methods Patients enrolled in a phase 3,
6-month, double-blind, placebo-controlled study of once-monthly erenumab 70 and
140 mg for migraine prevention (STRIVE) used an eDiary during the baseline and
double-blind treatment phases to complete validated, specific questionnaires,
including the modified (monthly) Migraine Disability Assessment Questionnaire;
Headache Impact Test; and Migraine-Specific Quality of Life Questionnaire-role
function-restrictive (MSQ-RFR), -role function-preventive (MSQ-RFP), and
-emotional function (MSQ-EF). Results A total of 955 patients were randomized to
receive erenumab 70 mg (n = 317), erenumab 140 mg (n = 319), or placebo
(n = 319). Erenumab versus placebo resulted in significantly greater
improvements in all patient-reported outcomes; changes from baseline were
numerically higher with 140 mg erenumab. Improvements occurred rapidly and were
maintained over 6 months of treatment. Between-group differences from placebo
over months 4-6 for the 70- and 140-mg dose groups were, respectively, -2.1 and
-2.8 for modified (monthly) Migraine Disability Assessment Questionnaire, -2.1
and -2.3 for Headache Impact Test, 5.1 and 6.5 for MSQ-RFR, 4.2 and 5.4 for
MSQ-RFP, and 5.2 and 6.7 for MSQ-EF ( p < 0.001 for all). Erenumab also
significantly reduced the proportion of patients with severe and very severe
migraine-related disability and increased the proportion of patients with
clinically meaningful improvements in migraine-related impact and health-related
quality of life. Conclusion Erenumab reduced migraine disability and impact and
improved patients' health-related quality of life, reinforcing its role as a
promising new therapy for migraine prevention. BACKGROUND: A substantial proportion of patients with migraine does not respond
to, or cannot tolerate, oral preventive treatments. Erenumab is a novel
CGRP-receptor antibody with preventive efficacy in migraine. We assessed its
efficacy and tolerability in patients with episodic migraine in whom previous
treatment with two-to-four migraine preventives had been unsuccessful.
METHODS: LIBERTY was a 12-week, double-blind, placebo-controlled randomised
study at 59 sites in 16 countries. Eligible patients were aged 18-65 years and
had a history of episodic migraine with or without aura for at least 12 months,
had migraine for an average of 4-14 days per month during the 3 months before
screening, and had been treated unsuccessfully (in terms of either efficacy or
tolerability, or both) with between two and four preventive treatments. Eligible
participants were randomly assigned (1:1) to receive either erenumab 140 mg (via
two 70 mg injections) or placebo every 4 weeks subcutaneously for 12 weeks.
Randomisation was by interactive response technology and was stratified by
monthly frequency of migraine headache (4-7 vs 8-14 migraine days per month)
during the baseline phase. Cenduit generated the randomisation list and assigned
participants to groups. Participants, investigators, people doing various
assessments, and the study sponsor were masked to treatment assignment. The
primary endpoint was the proportion of patients achieving a 50% or greater
reduction in the mean number of monthly migraine days during weeks 9-12.
Efficacy was measured in the full analysis set, which included all randomly
assigned patients who started their assigned treatment and completed at least
one post-baseline monthly migraine day measurement. Safety and tolerability were
assessed by recording adverse events and by physical examination, assessment of
vital signs, clinical laboratory assessments, and electrocardiography. Safety
was assessed in all randomly assigned patients who received at least one dose of
study drug. This trial is registered with ClinicalTrials.gov, number
NCT03096834. The trial is closed to new participants, but the open-label
extension phase is ongoing.
FINDINGS: Between March 20, 2017, and Oct 27, 2017, 246 participants were
randomly assigned, 121 to the erenumab group and 125 to the placebo group. 95 of
246 (39%) participants had previously unsuccessfully tried two preventive drugs,
93 (38%) had tried three, and 56 (23%) had tried four. At week 12, 36 (30%)
patients in the erenumab had a 50% or greater reduction from baseline in the
mean number of monthly migraine days, compared with 17 (14%) in the placebo
group (odds ratio 2·7 [95% CI 1·4-5·2]; p=0·002). The tolerability and safety
profiles of erenumab and placebo were similar. The most frequent
treatment-emergent adverse event was injection site pain, which occurred in
seven (6%) participants in both groups.
INTERPRETATION: Compared with placebo, erenumab was efficacious in patients with
episodic migraine who previously did not respond to or tolerate between two and
four previous migraine preventive treatments. Erenumab might be an option for
patients with difficult-to-treat migraine who have high unmet needs and few
treatment options.
FUNDING: Novartis Pharma. BACKGROUND: Migraine prevention with erenumab and migraine induction by
calcitonin gene-related peptide (CGRP) both carry notable individual variance.
We wanted to explore a possible association between individual efficacy of
anti-CGRP treatment and susceptibility to migraine induction by CGRP.
METHODS: Thirteen migraine patients, previously enrolled in erenumab anti-CGRP
receptor monoclonal antibody trials, received CGRP in a double-blind,
placebo-controlled, randomized cross-over design to investigate their
susceptibility to migraine induction. A standardized questionnaire was used to
assess the efficacy of previous antibody treatment. The patients were stratified
into groups of high responders and poor responders. Primary outcomes were
incidence of migraine-like attacks and area under the curve of headache
intensity after infusion of CGRP and placebo. All interviews and experiments
were performed in laboratories at the Danish Headache Center, Copenhagen,
Denmark.
RESULTS: Ten high responders and three poor responders were included. CGRP
induced migraine-like attacks in ten (77%) patients, whereof two were poor
responders, compared to none after placebo (p = 0.002). The area under the curve
for headache intensity was greater after CGRP, compared to placebo, at 0-90 min
(p = 0.009), and 2-12 h (p = 0.014). The median peak headache intensity score
was 5 (5-9) after CGRP, compared to 2 (0-4) after placebo (p = 0.004).
CONCLUSIONS: Patients with an excellent effect of erenumab are highly
susceptible to CGRP provocation. If an association is evident, CGRP provocation
could prove a biomarker for predicting antibody treatment efficacy.
TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov with
identifier: NCT03481400 . |
Are recessive coding variants responsible for the majority of undiagnosed nonconsanguineous individuals? | No. It is suggested that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration. | Author information:
(1)Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
[email protected] [email protected].
(2)Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
(3)Great Ormond Street Hospital for Children, National Health Service (NHS)
Foundation Trust, Great Ormond Street Hospital, Great Ormond Street, London WC1N
3JH, UK.
(4)European Molecular Biology Laboratory-European Bioinformatics Institute,
Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
(5)Department of Paediatrics, Cambridge University Hospitals NHS Foundation
Trust, Cambridge, UK.
(6)Division of Cardiovascular Medicine, Radcliffe Department of Medicine,
University of Oxford, Oxford, UK.
(7)Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation
Trust, OPD2, Northern General Hospital, Herries Rd., Sheffield, S5 7AU, UK.
(8)Department of Genetics, Aberdeen Royal Infirmary, Aberdeen, UK.
(9)Wessex Clinical Genetics Service, G Level, Princess Anne Hospital, Coxford
Road, Southampton SO16 5YA, UK.
(10)Cheshire and Merseyside Clinical Genetic Service, Liverpool Women's NHS
Foundation Trust, Crown Street, Liverpool L8 7SS, UK.
(11)Department of Clinical Genetics, City Hospital Campus, Hucknall Road,
Nottingham NG5 1PB, UK.
(12)Institute of Cancer and Genetics, University Hospital of Wales, Cardiff, UK.
(13)Temple Street Children's Hospital, Dublin, Ireland.
(14)Department of Clinical Genetics, Cambridge University Hospitals NHS
Foundation Trust, Cambridge, UK.
(15)Clinical Genetics Unit, Birmingham Women's Hospital, Edgbaston, Birmingham
B15 2TG, UK.
(16)Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western
Bank, Sheffield S10 2TH, UK.
(17)Northern Genetics Service, Newcastle upon Tyne Hospitals, NHS Foundation
Trust, Newcastle upon Tyne, UK.
(18)Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
(19)Department of Clinical Genetics, University Hospitals of Leicester NHS
Trust, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
(20)University of Exeter Medical School, Institute of Biomedical and Clinical
Science, Research, Innovation, Learning and Development (RILD), Royal Devon and
Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
(21)Medical Research Council (MRC) Human Genetics Unit, MRC Institute of
Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General
Hospital, Edinburgh EH4 2XU, UK. |
How can super-enhancers be used in disease diagnosis? | Super-enhancers are clusters of transcriptional enhancers that drive cell-type-specific gene expression and are crucial to cell identity. Many disease-associated sequence variations are enriched in super-enhancer regions of disease-relevant cell types. Thus, super-enhancers can be used as potential biomarkers for disease diagnosis and therapeutics. Current studies have identified super-enhancers in more than 100 cell types and demonstrated their functional importance. | |
List sirtuin inhibitors. | Sirtinol
nicotinamide (NAM)
LC-0296
BZD9L1 | Lysine acetylation is a protein posttranslational modification (PTM) that occurs
on thousands of lysine residues in diverse organisms from bacteria to humans.
Accurate measurement of acetylation stoichiometry on a proteome-wide scale
remains challenging. Most methods employ a comparison of chemically acetylated
peptides to native acetylated peptides, however, the potentially large
differences in abundance between these peptides presents a challenge for
accurate quantification. Stable isotope labeling by amino acids in cell culture
(SILAC)-based mass spectrometry (MS) is one of the most widely used quantitative
proteomic methods. Here we show that serial dilution of SILAC-labeled peptides
(SD-SILAC) can be used to identify accurately quantified peptides and to
estimate the quantification error rate. We applied SD-SILAC to determine
absolute acetylation stoichiometry in exponentially-growing and stationary-phase
wild-type and Sirtuin deacetylase CobB-deficient cells. To further analyze
CobB-regulated sites under conditions of globally increased or decreased
acetylation, we measured stoichiometry in phophotransacetylase (ptaΔ) and
acetate kinase (ackAΔ) mutant strains in the presence and absence of the Sirtuin
inhibitor nicotinamide. We measured acetylation stoichiometry at 3,669 unique
sites and found that the vast majority of acetylation occurred at a low
stoichiometry. Manipulations that cause increased nonenzymatic acetylation by
acetyl-phosphate (AcP), such as stationary-phase arrest and deletion of ackA,
resulted in globally increased acetylation stoichiometry. Comparison to relative
quantification under the same conditions validated our stoichiometry estimates
at hundreds of sites, demonstrating the accuracy of our method. Similar to
Sirtuin deacetylase 3 (SIRT3) in mitochondria, CobB suppressed acetylation to
lower than median stoichiometry in WT, ptaΔ, and ackAΔ cells. Together, our
results provide a detailed view of acetylation stoichiometry in E. coli and
suggest an evolutionarily conserved function of Sirtuin deacetylases in
suppressing low stoichiometry acetylation. Histone deacetylases regulate the acetylation levels of numerous proteins and
play key roles in physiological processes and disease states. In addition to
acetyl groups, deacetylases can remove other acyl modifications on lysines, the
roles and regulation of which are far less understood. A peptide-based
fluorescent probe for single-reagent, real-time detection of deacetylase
activity that can be readily adapted for probing broader lysine deacylation,
including decrotonylation, is reported. Following cleavage of the lysine
modification, the probe undergoes rapid intramolecular imine formation that
results in marked optical changes, thus enabling convenient detection of
deacylase activity with good statistical Z' factors for both absorption and
fluorescence modalities. The peptide-based design offers broader isozyme scope
than that of small-molecule analogues, and is suitable for probing both metal-
and nicotinamide adenine dinucleotide (NAD+ )-dependent deacetylases. With an
effective sirtuin activity assay in hand, it is demonstrated that iron chelation
by Sirtinol, a commonly employed sirtuin inhibitor, results in an enhancement in
the inhibitory activity of the compound that may affect its performance in vivo. The evolutionarily-conserved sirtuin family of histone deacetylases regulates a
multitude of DNA-associated processes. A recent genome-wide screen conducted in
the yeast Saccharomyces cerevisiae identified Yku70/80, which regulate
nonhomologous end-joining (NHEJ) and telomere structure, as being essential for
cell proliferation in the presence of the pan-sirtuin inhibitor nicotinamide
(NAM). Here, we show that sirtuin-dependent deacetylation of both histone H3
lysine 56 and H4 lysine 16 promotes growth of yku70Δ and yku80Δ cells, and that
the NAM sensitivity of these mutants is not caused by defects in DNA
double-strand break repair by NHEJ, but rather by their inability to maintain
normal telomere length. Indeed, our results indicate that in the absence of
sirtuin activity, cells with abnormally short telomeres, e.g., yku70/80Δ or
est1/2Δ mutants, present striking defects in S phase progression. Our data
further suggest that early firing of replication origins at short telomeres
compromises the cellular response to NAM- and genotoxin-induced replicative
stress. Finally, we show that reducing H4K16ac in yku70Δ cells limits activation
of the DNA damage checkpoint kinase Rad53 in response to replicative stress,
which promotes usage of translesion synthesis and S phase progression. Our
results reveal a novel interplay between sirtuin-mediated regulation of
chromatin structure and telomere-regulating factors in promoting timely
completion of S phase upon replicative stress. AIM: This study aims to investigate the mode of action of a novel sirtuin
inhibitor (BZD9L1) and its associated molecular pathways in colorectal cancer
(CRC) cells.
MATERIALS & METHODS: BZD9L1 was tested against metastatic CRC cell lines to
evaluate cytotoxicity, cell cycle and apoptosis, senescence, apoptosis related
genes and protein expressions, as well as effect against major cancer signaling
pathways.
RESULTS & CONCLUSION: BZD9L1 reduced the viability, cell migration and colony
forming ability of both HCT 116 and HT-29 metastatic CRC cell lines through
apoptosis. BZD9L1 regulated major cancer pathways differently in CRC with
different mutation profiles. BZD9L1 exhibited anticancer activities as a
cytotoxic drug in CRC and as a promising therapeutic strategy in CRC treatment. |
Is the NLM medical text indexer (MTI) still useful and relevant? | Yes. The NLM Medical Text Indexer (MTI) is still relevant and useful, and needs to be improved and expanded. The BioASQ Challenge results have shown that more machine learning needs to be incorporated into MTI while still retaining the indexing rules that have earned MTI the indexers' trust over the years. MTI also needs to be expanded through the use of full text, when and where it is available, to provide coverage of indexing terms that are typically only found in the full text. | BACKGROUND: Facing a growing workload and dwindling resources, the US National
Library of Medicine (NLM) created the Indexing Initiative project in 1996. This
cross-library team's mission is to explore indexing methodologies for ensuring
quality and currency of NLM document collections. The NLM Medical Text Indexer
(MTI) is the main product of this project and has been providing automated
indexing recommendations since 2002. After all of this time, the questions arise
whether MTI is still useful and relevant.
METHODS: To answer the question about MTI usefulness, we track a wide variety of
statistics related to how frequently MEDLINE indexers refer to MTI
recommendations, how well MTI performs against human indexing, and how often MTI
is used. To answer the question of MTI relevancy compared to other available
tools, we have participated in the 2013 and 2014 BioASQ Challenges. The BioASQ
Challenges have provided us with an unbiased comparison between the MTI system
and other systems performing the same task.
RESULTS: Indexers have continually increased their use of MTI recommendations
over the years from 15.75% of the articles they index in 2002 to 62.44% in 2014
showing that the indexers find MTI to be increasingly useful. The MTI
performance statistics show significant improvement in Precision (+0.2992) and
F1 (+0.1997) with modest gains in Recall (+0.0454) over the years. MTI
consistency is comparable to the available indexer consistency studies. MTI
performed well in both of the BioASQ Challenges ranking within the top tier
teams.
CONCLUSIONS: Based on our findings, yes, MTI is still relevant and useful, and
needs to be improved and expanded. The BioASQ Challenge results have shown that
we need to incorporate more machine learning into MTI while still retaining the
indexing rules that have earned MTI the indexers' trust over the years. We also
need to expand MTI through the use of full text, when and where it is available,
to provide coverage of indexing terms that are typically only found in the full
text. The role of MTI at NLM is also expanding into new areas, further
reinforcing the idea that MTI is increasingly useful and relevant. |
Has strimvelis been approved by the European Medicines Agency? | Yes, the gene therapy Strimvelis has been approved by the European Medicines Agency. | BACKGROUND: Strimvelis (autologous CD34+ cells transduced to express adenosine
deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the
European Medicines Agency (EMA), indicated as a single treatment for patients
with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched
related bone marrow donor. Existing primary immunodeficiency registries are
tailored to transplantation outcomes and do not capture the breadth of safety
and efficacy endpoints required by the EMA for the long-term monitoring of gene
therapies. Furthermore, for extended monitoring of Strimvelis, the young age of
children treated, small patient numbers, and broad geographic distribution of
patients all increase the risk of loss to follow-up before sufficient data have
been collected. Establishing individual investigator sites would be impractical
and uneconomical owing to the small number of patients from each location
receiving Strimvelis.
RESULTS: An observational registry has been established to monitor the safety
and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years.
To address the potential challenges highlighted above, data will be collected by
a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and
entered into the registry via a central electronic platform. Patients/families
and the patient's local physician will also be able to submit healthcare
information directly to the registry using a uniquely designed electronic
platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded
by GlaxoSmithKline) who will ensure that necessary information is collected and
flows between OSR, the patient/family and the patient's local healthcare
provider.
CONCLUSION: The Strimvelis registry sets a precedent for the safety monitoring
of future gene therapies. A unique, patient-focused design has been implemented
to address the challenges of long-term follow-up of patients treated with gene
therapy for a rare disease. Strategies to ensure data completeness and patient
retention in the registry will help fulfil pharmacovigilance requirements.
Collaboration with partners is being sought to expand from a treatment registry
into a disease registry. Using practical and cost-efficient approaches, the
Strimvelis registry is hoped to encourage further innovation in registry design
within orphan drug development. |
What antibiotic is currently used as the standard of care for Clostridium Difficile infection as of 2018 | fidaxomicin has recently been introduced as a new antibiotic that has been shown to significantly reduce the recurrence of this infection. fidaxomicin is a new antibiotic used to treat clostridium difficile infection (cdi). | Recurrences of Clostridium difficile infections lead to hospital readmissions
and high costs, in addition to the suffering and frustration for the patients.
Fidaxomicin has recently been introduced as a new antibiotic that has been shown
to significantly reduce the recurrence of this infection. Despite this
superiority, its high cost has led to very restrictive policies in its use, as
such that many institutions only use it in patients with multiple recurrences.
While waiting for new predictive clinical tools, we propose the development of
scoring systems that allow the more high-risk patients to be treated earlier. BACKGROUND AND GOALS: Fidaxomicin is a new antibiotic used to treat Clostridium
difficile infection (CDI). Given limited clinical experience with fidaxomicin,
we assessed outcomes in a diverse cohort of patients with CDI treated with
fidaxomicin.
STUDY: All CDI cases treated with fidaxomicin at 3 referral centers over a
4-year period were included. Response was defined as resolution of diarrhea and
recurrence was defined by recurrence of CDI within 8 weeks of the end of
treatment.
RESULTS: Overall, 81 patients (median age 55.9 y; 53% female; 26% with
inflammatory bowel disease) were included. Response occurred in 90%. Responders
had fewer prior CDI episodes [median 1 (range, 0 to 8)] than nonresponders
[median 2.5 (range, 1 to 8)], P=0.01. Response after a first CDI episode was
100%, 96% after 1 prior episode, and 82% after 2 or more, P=0.02. Recurrence
occurred in 19%. Patients without recurrence had fewer prior episodes of CDI
[median 1 (range, 0 to 6)] than patients who recurred [median 2 (range, 1 to
8)], P=0.005. Recurrence after a first episode was 0%, 23% after 1 prior
episode, and 29% after 2 or more, P=0.005. All patients with inflammatory bowel
disease responded either with improvement of symptoms or a negative C. difficile
test; 19% recurred.
CONCLUSIONS: All patients with a first CDI episode treated with fidaxomicin
responded with no recurrences. Patients with prior CDI episodes were less likely
to respond (especially with more than 1 prior episode) and more likely to recur,
suggesting a greater clinical benefit of fidaxomicin earlier in the course of
CDI. |
Which proteins are markers of HPV oncogenic activity? | p16INK4a (p16) tumor-suppressor protein is a biomarker of human papillomavirus (HPV) oncogenic activity that has revealed a high rate of positivity in histological high-gade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 2 (HSIL/CIN2) lesions. | Overexpression of p16(INK4a) has been observed when retinoblastoma protein is
inactivated by high-risk human papillomavirus (HPV) oncoprotein E7. We
investigated overexpression of p16(INK4a) and HPV infection in cervical squamous
neoplasia to evaluate the oncogenic potential among various HPV subtypes. The
high-risk HPV was detected by PCR in 69.8% (37/53), 97.5% (39/40), 91.7%
(44/48), and 100% (16/16) of cervical intraepithelial neoplasia (CIN)1, CIN2,
CIN3, and squamous cell carcinoma (SCC), respectively. The p16(INK4a)
overexpression was investigated immunohistochemically using a
p16(INK4a)-specific monoclonal antibody (clone E6H4). In high-risk HPV positive
cases, 32.4% (12/37) of CIN1, 82.1% (32/39) of CIN2, 93.2% (41/44) of CIN3, and
all (16/16) SCC showed p16(INK4a) overexpression. The incidence of p16(INK4a)
overexpression was significantly different between CIN1 and CIN2, suggesting
that the disorder of cell cycle regulation by HPV frequently occurred from CIN2.
As for CIN1 cases, p16(INK4a) overexpression was observed more frequently in
HPV16 and HPV52 than in HPV51 and HPV35. Using p16(INK4a) as a bio marker of HPV
oncogenic activity, we demonstrate that the level of pRb dysfunction by
high-risk HPV varied from subtypes and was getting more frequent from CIN2. Human papillomavirus (HPV) oncogenic activity is the result of viral oncogene E6
and E7 expression in infected cells. Oncogene expression analysis is, however,
not part of the routine diagnostic evaluation of HPV-associated oropharyngeal
squamous cell carcinoma (OPSCC) since it requires fresh tumor tissue. We
compared the diagnostic accuracy of several methods commonly employed for HPV
characterization in OPSCC with the results of the newly available HPV E6/E7 mRNA
in situ hybridization (ISH) on formalin-fixed, paraffin-embedded biopsy samples,
in order to establish if the latter should be introduced in the diagnostic
routine to increase accuracy when fresh tissue is not available. p16
immunostain, DNA ISH for high-risk HPV genotypes, SPF LiPA amplification and
genotyping, and HPV16 E6 amplification were performed on 41 consecutive OPSCC
samples. Twenty (48.7%) cases were positive by mRNA ISH; sensitivity and
specificity were 100% and 90% for p16, 90% and 100% for DNA ISH, 70% and 76% for
SPF10 LiPA, 90% and 76% for E6 amplification. A diagnostic algorithm considering
p16 immunostain as first step followed by either high-risk HPV DNA ISH or HPV16
E6 amplification in p16-positive cases correctly characterized 90% of
mRNA-positive and all mRNA-negative cases; combining the 3 tests correctly
identified all cases. While no stand-alone test was sufficiently accurate for
classifying HPV-associated OPSCC, the high sensitivity and specificity of the
established combination of p16 immunostain, DNA ISH, and HPV16 DNA amplification
suggests that the introduction of labour- and cost-intensive mRNA ISH, is not
necessary in the diagnostic routine of oropharyngeal tumors. p16INK4a (p16) tumor-suppressor protein is a biomarker of human papillomavirus
(HPV) oncogenic activity that has revealed a high rate of positivity in
histological high-gade squamous intraepithelial lesion/cervical intraepithelial
neoplasia grade 2 (HSIL/CIN2) lesions. However, there is a paucity of data
regarding p16 status as a surrogate marker of HSIL/CIN2 evolution. The aim of
this study was to evaluate the outcome of HSIL/CIN2 patients followed up without
treatment for 12 months according to p16 immunohistochemical staining. Patients
diagnosed with HSIL/CIN2 colposcopy-directed biopsy, were recruited
prospectively between December 2011 and October 2013. p16 staining was performed
in all HSIL/CIN2 diagnostic biopsies. Follow-up was conducted every 4 months by
cytology, colposcopy and biopsy if suspicion of progression and once the 12
months of follow-up completed. Complete regression, partial regression,
persistence, and progression rates of HSIL/CIN2 were defined as a final outcome.
A total of 96 patients were included in the analysis. The rate of spontaneous
regression was 64%, while 28% had persistent disease, and 8% progressed at 12
months of follow-up. p16 was positive in 81 (84%) initial HSIL/CIN2 biopsies.
Regression was observed in all 15 p16 negative cases and in 46 of 81 (57%) p16
positive cases (P=0.001). In conclusion, patients with p16 negative HSIL/CIN2
biopsy had a high rate of regression during first 12 months of follow-up. Status
of p16 staining could be considered for HSIL/CIN2 management. |
Which features are evaluated with the CRAFFT screening test? | The CRAFFT (Car, Relax, Alone, Forget, Friends, Trouble) was developed as a brief screening instrument for adolescents to measure Alcohol and other substance use disorders. | INTRODUCTION: Substance use and abuse and their consequences are a major problem
among adolescents. The screening for problematic alcohol and substance use,
abuse and dependence should be part of the case-taking process for adolescents.
The Problem Oriented Screening Instrument for Teenagers (POSIT) and the Car,
Relax, Alone, Forget, Family/Friends, Trouble questionnaire (CRAFFT) are used to
this end.
POSIT: 17 items corresponding to substance use and abuse (POSITsua); it has been
validated in Spanish.
CRAFFT: six questions; it has not been validated in Argentina.
OBJECTIVE: To assess the validity of a version of the CRAFFT screening test
adapted to Spanish in a group of Argentine adolescents using the POSITsua test
as reference.
POPULATION AND METHODS: The CRAFFTa and the POSITsua tests were administered to
14-20 year-old adolescents. An affirmative answer was scored as 1, and a
negative answer, as 0. An individual was considered to have an increased risk of
problematic use, abuse and dependence if he/she scored >2 in the CRAFFTa and
POSITsua tests.
RESULTS: Two hundred and eighty-six adolescents were included; 52% were female;
mean age: 16.6 years old. The CRAFFTa score was >2 for 29%, while the POSIT
score was >2 for 37%. CRAFFTa sensitivity: 59%; specificity: 88%. CRAFFTa
positive predictive value: 0.74; negative predictive value: 0.78. The area under
the curve was 0.73. In the linear regression, the R for the six CRAFFT questions
was 0.60. Gender and age did not modify results. Cronbach's alpha was 0.64.
CONCLUSION: CRAFFTa sensitivity was 59%, and its specificity was 88%, compared
to the POSITsua test as a screening tool for problematic alcohol and substance
use, abuse and dependence among Argentine adolescents. BACKGROUND: Adolescent substance use is an important public health problem in
New Mexico and the United States. The New Mexico Department of Health
school-based health centers (SBHCs) universally administer a validated screen,
the CRAFFT (Car, Relax, Alone, Forget, Friends, Trouble), for adolescent
substance use concerns; however, quality assurance efforts revealed that SBHC
providers needed more information at the point of screening to initiate brief
interventions for students with positive CRAFFT screens. The CHISPA (Cocaine,
Heroin, IV drugs, Synthetic pot, Pot, Alcohol) was developed to gather specific
information on recent substance use experience to guide brief interventions.
This paper describes the development and initial reliability and validity of
data obtained using the CHISPA instrument.
METHODS: In 2015, 99 high school-aged SBHC users in Albuquerque, New Mexico,
completed the CRAFFT and CHISPA twice over 2 weeks using standard test-retest
methods. Using the CHISPA, students reported for the prior 3 months substances
used, frequency of use, and signs of addiction or acute danger (adverse events).
RESULTS: Retest reliability for the CRAFFT score was 0.82. CHISPA retest
reliabilities were 0.75 for alcohol use; 0.91 for having used any substances;
0.92 for number of substances used; 0.81 for frequency of substance use; and
0.79 for number of adverse events. CRAFFT scores correlated with CHISPA measures
of number of substances used at 0.62; with frequency of substance use at 0.58;
and with number of adverse events at 0.64.
CONCLUSIONS: CHISPA measures show preliminary evidence of reliability and
validity. SBHC providers and other providers in primary care settings who use
the CRAFFT screen may benefit from using the CHISPA to define recent substance
use experience to guide brief interventions for adolescents with substance use
concerns. The CHISPA instrument is currently being tested in electronic form in
selected SBHCs in the state of New Mexico. Substance-related disorders (SRD) are common psychiatric morbidities among
adolescents within youth correctional systems. Identification and treatment of
SRDs is critical for successful reformation and reintegration. Lack of simple,
structured, valid, brief screening instruments that can be easily administered
and scored by lay workers militates against screening for SRDs. We present the
results of the reliability and concurrent validity of the CRAFFT (acronym for
Car, Relax, Alone, Forget, Friends, and Trouble) substance abuse screening
instrument among residents of youth correctional facilities in Lagos, Nigeria.
Adolescents who screened positive on CRAFFT were further assessed with the
Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) to determine
whether they met diagnostic criteria for SRDs. The mean CRAFFT scores for all
the adolescents (n = 178) was 0.66 (SD ± 1.45). A total of 23 (12.9%) had CRAFFT
scores of >1.00. The CRAFFT instrument has good internal consistency (Cronbach's
α = 0.85) and 2-week test reliability (Spearman correlation = 0.979; p < .001).
At a cutoff point of >1.00, CRAFFT had the best sensitivity and specificity
(area under the curve = 0.889; 95% confidence interval 0.765-1.000) among the
participants. As validated, the CRAFFT is a reliable instrument for screening
for SRDs in incarcerated youth. |
Describe the bartender algorithm | Barcode sequencing (bar-seq) is a high-throughput, and cost effective method to assay large numbers of cell lineages or genotypes in complex cell pools. Because of its advantages, applications for bar-seq are quickly growing-from using neutral random barcodes to study the evolution of microbes or cancer, to using pseudo-barcodes, such as shRNAs or sgRNAs to simultaneously screen large numbers of cell perturbations. Bartender is an accurate clustering algorithm to detect barcodes and their abundances from raw next-generation sequencing data. It comprises a set of simple-to-use command line tools that can be performed on a laptop at comparable run times to existing methods. Bartender is available at no charge for non-commercial use at https://github.com/LaoZZZZZ/bartender-1.1 | |
Which was the first gene therapy to receive marketing authorization in the European Union? | The first gene therapy to receive marketing authorization in the European Union was Glybera (alipogene tiparvovec). | |
Is treatment with Bacillus Calmette Guerin used for bladder cancer? | Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. | It has been established that the urothelial mucin layer functions as a bacterial
anti-adherence factor. Intravesical Bacillus Calmette-Guerin is used to treat
patients with superficial bladder cancer. The proposed mechanism of action of
Bacillus Calmette-Guerin is adherence to the urothelium with induction of an
immunologic and/or inflammatory response. The current study was designed to
determine if rabbit bladder mucin removal results in increased Bacillus
Calmette-Guerin urothelial adherence. PAS and colloidal iron stains were used to
demonstrate that intravesical instillation of 50% acetone renders rabbit bladder
urothelium mucin deficient. The urothelium remains mucin deficient at two hours,
but by 24 hours the mucin layer has been regenerated. Two hours following
intravesical 3H-labeled Escherichia coli administration, bacterial adherence was
29-fold greater in mucin deficient than mucin intact rabbits (p = 0.05). By 12
hours, the difference in adherence was not significant. Two hours following
intravesical administration of 3H-labeled Bacillus Calmette Guerin, mucosal
adherence was 21-fold greater in mucin deficient compared to mucin intact
rabbits (p = 0.002). After mucin removal, Bacillus Calmette Guerin urothelial
adherence was significantly increased. The significant increase in Bacillus
Calmette Guerin adherence after mucin removal may be clinically exploitable. Intravesical administration of bacillus Calmette-Guerin has been shown to be
highly effective treatment of superficial bladder cancer. Complications from
bacillus Calmette-Guerin therapy are usually minor but serious and even fatal
reactions can occur. Five recent cases illustrate the gravity of bacillus
Calmette-Guerin sepsis. One man with severe debility and the organic brain
syndrome died acutely with a fever of 40 C. Two men had frank sepsis that
progressed to multiorgan failure and death. Sepsis progressed despite the use of
isoniazid, rifampin and streptomycin. Two men who had equally progressive sepsis
with intravesical bacillus Calmette-Guerin survived with the use of cycloserine
for the first 72 hours of treatment. Triple antituberculous antibiotics,
including cycloserine, may be lifesaving. Sepsis resulted from intravenous
absorption through inflamed or disrupted urothelium. Bacillus Calmette-Guerin
treatment should not be administered in the presence of severe cystitis or after
grossly traumatic catheterization. Bacillus Calmette-Guerin immunotherapy has been found by a number of
investigators to be effective in the treatment and prevention of superficial
bladder cancer. While the optimal protocol for bacillus Calmette-Guerin remains
to be determined, experience with 92 randomized and 30 nonrandomized (high risk)
patients followed for up to 5 years provides information that may improve future
protocols. Side effects of bacillus Calmette-Guerin are observed to increase
with increasing frequency and duration of treatment. The protection from tumor
recurrence has persisted: only 6 of 30 patients (20 per cent) treated with
bacillus Calmette-Guerin have had recurrent tumor compared to 14 of 27 controls
(52 per cent, p equals 0.008, chi-square test), and mean time to recurrence
increased from 24 to 48 months (p less than 0.005, Savage). Skin test reactivity
to purified protein derivative is particularly useful in predicting response to
bacillus Calmette-Guerin immunotherapy. Currently, 60 patients have been
randomized to receive bacillus Calmette-Guerin immunotherapy and only 1 of 22
patients (4.5 per cent) in whom the purified protein derivative skin test
results converted from negative to positive has had recurrent tumor, compared to
12 recurrences (32 per cent) in patients whose skin tests were positive before
treatment or failed to convert following treatment (p equals 0.014, chi-square).
Seven recurrences (33 per cent) developed in 21 patients whose skin tests
remained negative (p equals 0.015) and 5 recurrences (29 per cent) developed in
17 patients whose tests previously were positive (p equals 0.068, Fisher's test,
not significant). The benefit of percutaneous bacillus Calmette-Guerin is
suggested by the observations that the recurrence rate in patients treated with
intravesical bacillus Calmette-Guerin alone is 40 per cent, and all 7 patients
whose purified protein derivative skin tests were negative continued to have
negative results when percutaneous bacillus Calmette-Guerin was omitted (p
equals 0.003). Among high risk patients a marked decrease in or complete
prevention of recurrent tumor was observed in 82 per cent of 22 patients treated
previously with chemotherapy and 11 of 14 (78 per cent) with carcinoma in situ
have had a complete response. We treated 40 patients with superficial bladder cancer via intravesical bacillus
Calmette-Guerin for 1) prophylaxis against tumor recurrence, 2) residual
carcinoma or 3) flat carcinoma in situ. A single course of intravesical bacillus
Calmette-Guerin therapy was successful in 6 of 11 patients (55 per cent) treated
for residual carcinoma and 6 of 12 (50 per cent) treated for carcinoma in situ.
Of 17 patients receiving a single course of bacillus Calmette-Guerin for
prophylaxis 11 remained free of tumor during short-term followup. A second
course of therapy was administered to failures in each treatment category, which
resulted in favorable responses in 5 of 6 patients treated for prophylaxis, 2 of
5 treated for residual tumor and 3 of 6 treated for carcinoma in situ. Over-all
complete responses were achieved in 16 of 17 patients (94 per cent) treated for
prophylaxis, 8 of 11 (73 per cent) for residual carcinoma and 8 of 12 (66 per
cent) for carcinoma in situ, with a mean followup from the final treatment of
9.3, 12.3 and 7.9 months, respectively. Favorable results occurred more
frequently among patients who exhibited a granulomatous inflammatory response in
the bladder and delayed hypersensitivity skin test response to purified protein
derivative. Marked variability in viability of bacillus Calmette-Guerin
organisms was observed among different lots of bacillus Calmette-Guerin, and a
direct relationship was observed between bacillus Calmette-Guerin vaccine
viability and therapeutic efficacy. Most patients who failed initial therapy
with a low viability lot of bacillus Calmette-Guerin responded favorably to
re-treatment with a higher viability lot. The results suggest that the level of
viability of each lot of bacillus Calmette-Guerin vaccine should be verified
before clinical use. Despite effective treatment of existing tumors, patients with bladder cancer
remain at risk of developing new tumors. Effective immunotherapy may lower that
risk. To test this hypothesis, mice that had survived transitional cell
carcinoma (MBT2) transplantation with the aid of bacillus Calmette-Guerin
immunotherapy were randomized and tested for long term protective immunity
against bladder carcinoma. Fifty-one tumor-free mice that had survived tumor
challenge 10 to 15 months previously were randomized into 3 groups to receive
intradermal tumor .noculation and intraperitoneal levamisole, intralesional Tice
strain bacillus Calmette-Guerin, or intralesional saline. Fifteen previously
unchallenged animals also received tumor and intralesional saline. All 3 groups
of survivors had less tumor growth (p less than 0.01) than nonsurviving
controls. Even among survivors, additional bacillus Calmette-Guerin
immunization, but not levamisole treatment, significantly inhibited tumor growth
(p less than 0.01). A 2nd experiment compared 22 nonimmune mice, 21 mice
preimmunized intravenously with 300 micrograms of bacillus Calmette-Guerin cell
walls, and 18 mice that had survived MBT2 by 8 months after live bacillus
Calmette-Guerin treatment. Nonimmune and survivor groups were randomly
subdivided into saline or treatment groups. Cell wall-preimmunized mice were
divided into matching groups according to footpad response to purified protein
derivative. The cell-wall preimmunized and nonimmune mice received the
immunostimulant P3+Re-glycolipid or the carrier solution alone. The group of
survivors received either intralesional saline or live bacillus Calmette-Guerin.
Both bacillus Calmette-Guerin and saline-treated groups had significantly less
tumor growth (p less than 0.001) than nonsurviving controls. Animals treated
with P3-Re-glycolipid (with or without preimmunization with cell wall) did not
differ from nonsurviving control. Footpad response to purified protein
derivative did not correlate with tumor growth in these mice. Our results
suggest that intralesional bacillus Calmette-Guerin immunotherapy can afford
long term protection from transplanted bladder cancer, and that live bacillus
Calmette-Guerin is superior to levamisole and P3 + Re-glycolipid + bacillus
Calmette-Guerin cell walls in the treatment of bladder cancer. A randomized controlled prospective evaluation of intravesical and percutaneous
bacillus Calmette-Guerin immunotherapy was done in 57 patients with transitional
cell carcinoma of the bladder. In addition, 9 patients at high risk for tumor
recurrence were treated with bacillus Calmette-Guerin produced a self-limited
cystitis and 1 complication (hydronephrosis) of immunotherapy was observed. Of
the 57 randomized patients 54 were followed for 3 to 30 months. Tumor recurrence
was documented in 13 of 26 controls (50 per cent) and only 6 of 28 patients (21
per cent) treated with bacillus Calmette-Guerin (p equals 0.027, chi-square).
The interval free of disease was prolonged significantly with bacillus
Calmette-Guerin treatment (p equals 0.014, generalized Wilcoxon test).
Importantly, a simple purified protein derivative skin test distinguished those
patients who responded to bacillus Calmette-Guerin immunotherapy from those who
did not. Only 1 of 17 treated patients (6 per cent) whose purified protein
derivative test converted from negative to positive had tumor recurrence
compared to 5 recurrences (38 per cent) among the 13 patients whose test
remained negative or had been positive before treatment (p equals 0.022,
chi-square). Bacillus Calmette-Guerin was given to 10 patients with stage B
transitional cell carcinoma who were not candidates for cystectomy and 7 are
free of disease. Of 5 patients with carcinoma in situ 3 remain free of tumor
after bacillus Calmette-Guerin treatment and 5 of 6 who had multiple recurrences
after intravesical chemotherapy responded favorably to bacillus Calmette-Guerin
immunotherapy. Local immunotherapy with bacillus Calmette-Guerin (BCG) is an effective and
frequently used treatment for superficial bladder cancer. Serious side effects
are infrequent but can affect every organ system. We describe a 53 year- old man
with a disseminated bacillus Calmette-Guerin (BCG) infection after intravescical
instillation for bladder carcinoma. Recent literature is reviewed for this rare
complication. PURPOSE: We assessed the safety and efficacy of intravesical bacillus
Calmette-Guerin instillations in steroid treated and immunocompromised patients.
MATERIALS AND METHODS: We retrospectively reviewed the charts of 697 patients
treated with bacillus Calmette-Guerin instillations at our institution from 1991
to 2004. In 24 patients (3.5%) an underlying comorbidity directly affecting the
immune system was diagnosed before bacillus Calmette-Guerin administration or
steroids were administered at least 6 weeks before and at the time of bacillus
Calmette-Guerin instillations. The immunosuppressive effect of steroids was
assessed by the percent of lymphocytes. End points were the bacillus
Calmette-Guerin response at 6 months, defined as normal cystoscopy, cytology and
biopsy when available, and treatment related toxicity.
RESULTS: Four patients (17%) had active lymphoma or chronic lymphocytic leukemia
during bacillus Calmette-Guerin administration and 21 (88%) had a concurrent
condition for which oral steroids (11), inhaled steroids (14) or oral and
inhaled steroids (4) were administered. Patients treated with oral steroids had
a lower percent of lymphocytes than patients treated with inhaled steroids and
15 age matched patients with high risk superficial bladder cancer and no steroid
treatment (12.3% vs 17.5% and 18.6%, respectively). The overall bacillus
Calmette-Guerin response rate at 6 months was 58%. Ten of the 24 patients had
disease recurrence and 3 had disease progression at a median followup of 63.5
months (IQR 19.5, 89). One patient treated with oral steroids had self-limited
febrile disease and worsening of myalgia 48 hours after his third bacillus
Calmette-Guerin cycle. No other systemic adverse event following bacillus
Calmette-Guerin therapy was recorded and all patients completed scheduled
treatments.
CONCLUSIONS: Intravesical bacillus Calmette-Guerin is a viable therapeutic
option in patients with high risk superficial bladder cancer and concomitant
lymphoma or chronic lymphocytic leukemia, treatment with low dose oral steroids
or treatment with inhaled steroids. The bacillus Calmette-Guerin response rate
at 6 months and the side effects profile associated with bacillus
Calmette-Guerin therapy in these patients were comparable to those in patients
with no evidence of immunosuppression. Further studies are warranted to assess
the safety and efficacy of bacillus Calmette-Guerin instillations in critically
immunocompromised patients. PURPOSE: We review how the bacillus Calmette-Guerin vaccine evolved to become
standard therapy for superficial bladder cancer.
MATERIALS AND METHODS: We reviewed the historical literature describing the
origin of the bacillus Calmette-Guerin vaccine as an anticancer agent and its
singular success as the most effective immunotherapy used against a human
neoplasm.
RESULTS: The association between tuberculosis and cancer, and the demonstration
that bacillus Calmette-Guerin invoked immunological reactivity, inhibiting tumor
growth in experimental animal models, led to clinical trials showing that
intravesical bacillus Calmette-Guerin eradicated and prevented recurrence of
superficial bladder tumors.
CONCLUSIONS: For the last 3 decades bacillus Calmette-Guerin therapy has
remained the most effective local therapy for superficial bladder cancer, an
outstanding example of successful translational medicine in urology. Among the many immunological events associated with successful intravesical
bacillus Calmette Guerin (BCG) immunotherapy of bladder cancer is the induction
of a wide range of cytokines including the T helper 2 (T(H)2) designated
cytokines Interleukin-6 (IL-6) and IL-10, but not IL-4, in the urine of the
patients. The aim of this work was to determine if this treatment resulted in
the production of IL-5, a classical T(H)2 cytokine. Following treatment using
ELISA this cytokine was detected in the urine of all patients examined
confirming that intravesical BCG therapy does not induce in bladder cancer
patients solely a T(H)1 response but rather T(H)1/2 or T(H)0 like response. Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for
progression of non-muscle invasive bladder cancer. We aimed to monitor changes
at the proteome level to identify putative protein biomarkers associated with
the response of urothelial precancerous lesions to intravesical BCG treatment.
The rats were divided into three groups (n = 10/group): control, non-treated,
and BCG-treated groups. The non-treated and BCG-treated groups received
N-methyl-N-nitrosourea intravesically. BCG Tice-strain was instilled into
bladder in BCG-treated group. At the endpoint of experiment, all surviving rat
bladders were collected and equally divided into two portions vertically from
dome to neck. Half of each bladder was assessed immunohistopathologically and
the other half was used for 2D-based comparative proteomic analysis.
Differentially expressed proteins were validated by Western blot analysis.
Precancerous lesions of bladder cancer were more common in non-treated group
(77.8%) than in BCG-treated group (50%) and the control group (0%). Greater than
twofold changes occurred in the expression of a number of proteins. Among them,
Rab-GDIβ, aldehyde dehydrogenase 2 (ALDH2) and 14-3-3 zeta/delta were important
since they were previously reported to be associated with cancer and their
expression levels were found to be lower in BCG-treated group in comparison to
the non-treated group. ALDH2 and 14-3-3 zeta/delta were also found to be highly
expressed in the non-treated group compared to the control group. The
down-regulation of these proteins and Rab-GDIβ was achieved with BCG; this
result indicates that they may be used as putative biomarkers for monitoring
changes in bladder carcinogenesis in response to BCG immunotherapy. PURPOSE: The identification of factors predicting the outcome of stage T1
high-grade bladder cancer (BC) is a major clinical issue.
METHODS: We performed immunohistochemistry to assess the role of human epidermal
growth factor receptor-2 (HER-2) and microsatellite instability (MSI) factors
MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in predicting recurrence and
progression of T1 high-grade BCs having undergone transurethral resection of
bladder tumor (TURBT) alone or TURBT + intravesical instillations of bacillus
Calmette-Guerin (BCG).
RESULTS: HER-2 overexpression was a significant predictor of disease-free
survival (DFS) in the overall as well as in the two patients' population; as for
progression-free survival (PFS), it was significant in the overall but not in
the two patients' population. MLH1 was an independent predictor of PFS only in
patients treated with BCG and MSH2 failed to predict DFS and PFS in all
populations. Most importantly, the higher the number of altered markers the
lowers the DFS and PFS. In multivariate Cox proportional-hazards regression
analysis, the number of altered molecular markers and BCG treatment were
significant predictors (p = 0.0004 and 0.0283, respectively) of DFS, whereas the
number of altered molecular markers was the only significant predictor
(p = 0.0054) of PFS.
CONCLUSIONS: Altered expression of the proto-oncogene HER-2 and the two
molecular markers of genetic instability MLH1 and MSH2 predicted T1 high-grade
BC outcome with the higher the number of altered markers the lower the DFS and
PFS. These findings provide grounds for further testing them in predicting the
outcome of this challenging disease. OBJECTIVES: To evaluate the efficacy and safety of a tailored endovesical
immunotherapy protocol with biweekly BCG for elderly Patients with high risk non
muscle invasive bladder cancer (HG-NMIBC).
MATERIALS AND METHODS: We retrospectively evaluated data from 200 patients older
than 80 years newly diagnosed with HG-NMIBC: 100 (group 1) with multiple
comorbidities (WHO PS 2-3, ASA score ≥3, Charlson Comorbidity index ≥3,
GFR<60 mL/min) were treated with BCG induction course administered biweekly; 100
(group 2) with statistically significant better conditions were treated with
standard weekly BCG therapy. After the induction treatment disease-free patients
underwent to at least one year of BCG maintece therapy. Endpoints were:
initial response to BCG, cancer-free survival and rate of progression at
2 years, rate of complications.
RESULTS: No statistically significant differences were found in terms of initial
response to BCG (69% in Group 1 vs 71% in Group 2, P = 0.75), cancer free
survival (57% vs 55% respectively, P = 0.77) and rate of progression (20% vs 14%
respectively, P = 0.26) at 2 years. The difference in the rate of overall
complications was statistically significant (15% in Group 1 vs 27% in Group 2,
P = 0.03), in the rate of severe complications was not statistically significant
(5% in Group 1 vs 7% in Group 2, P = 0.61).
CONCLUSION: A tailored regimen of BCG administration is possible and safe in
frail elderly patients, limiting side effects and risk of undertreatment but
maintaining oncological outcomes. Preliminary results in a small patients group
are promising but larger randomized studies are needed to confirm our data. |
List lymphocytes that are analyzed by a flow cytometer. | Quantitation of lymphocyte subsets (B cells, T cells, CD4 and CD8 T cells and NK cells) classically relies on quantitation of lymphocytes and immunophenotyping by flow cytometry. | AIMS: Thermal ablation can evoke an immune response, which may have effects on
the prognosis of patients with hepatocellular carcinoma (HCC). Our aim is to
investigate the changes of circulating T-cell subsets after microwave ablation
(MWA) and to explore the risk factors of tumor recurrence in patients with
hepatitis B virus (HBV)-related HCC.
METHODS: Thirty patients with HBV-related HCC were enrolled in this study. The
blood samples were collected both before and after MWA (24 h, 72 h, and 1 month
after MWA). The distributions of Th17 cells, regulatory Treg-cells, CD4+
T-cells, CD8+ T-cells, and CD3+ T-cells were determined by flow cytometer. The
potential-related factors of tumor recurrence were analyzed by logistic
regression.
RESULTS: The levels of circulating T-cell subsets, except for Th17 cells, were
relatively stable after MWA. The frequency of Th17 cells increased from 3.98% ±
2.40% before treatment to 5.53% ±3.27% 24 h after treatment. Eight of 30
patients had a tumor recurrence. The results of logistic regression suggested
that among 11 candidates, only the level of Th17 cells was the risk factor of
tumor recurrence. To remove the interference from other factors, seven patients
with tumor(s) >3 cm or alpha-fetoprotein >400 ng/mL were excluded in another
parallel logistic regression. The results of such regression clearly
demonstrated that circulating Th17 cells is indeed a related factor of tumor
recurrence.
CONCLUSIONS: Thermal ablation may evoke a transitional immune response by
increasing the frequency of Th17 cells. Patients with high levels of baseline
circulating Th17 cells, instead of the transient elevation of Th17 cells induced
by MWA, are at the risk of tumor recurrence. Age and gender-related variability of main lymphocyte subsets (T, B and NK cell
absolute counts and percentages from Ly; T4, T8 and DN cell absolute counts and
percentages from lymphocytes and from T cells; T4:T8 and T:B ratios) was studied
in a large cohort of pediatric patients (2 days - 17 years) at yearly intervals.
4128 6-color TBNK tests performed on BD FACSCanto II flow cytometer were
assessed; patients with immune deficiencies and tumors were not included. The
study revealed significant age and gender-related changes in all subsets.
Absolute counts of T, B, T4 cells dropped from neonates to adolescents, decrease
of T8 and NK cells was milder; relative count of T cells increased with age and
that of B cells decreased; T4:T8 ratio went down and T:B ratio grew. Total T, T4
cells and T4:T8 ratio were significantly higher in girls, while T8, NK and DN
cells - in boys; significantly higher relative and absolute B cell counts in
boys appeared in adolescence. We compared our results with reference values for
healthy children (Tosato et al., 2015), there was a good concordance, except for
DN cells. Advantages of using patient cohort instead of healthy children as
reference, possibilities for adjusting age and gender-specific reference ranges
and potential international data pooling are discussed. This article is
protected by copyright. All rights reserved. |
List two drugs that are included in the Akynzeo pill? | Akynzeo is an oral fixed combination of netupitant and palonosetron that is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). | Ledipasvir/sofosbuvir (Harvoni) for hepatitis C virus genotype 1 infection;
dulaglutide (Trulicity) for glycemic control in type-2 diabetes;
netupitant/palonosetron (Akynzeo) for prevention of nausea and vomiting related
to chemotherapy; and naloxegol (Movantik) for opioid-induced constipation in
patients with chronic noncancer pain. An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo(®)) is
available for use in the prevention of acute and delayed chemotherapy-induced
nausea and vomiting (CINV). Netupitant is a highly selective neurokinin-1
receptor antagonist and palonosetron is a serotonin 5-HT3 receptor antagonist
with a distinct pharmacological profile. Complete response rates during the
delayed, acute and overall phases were significantly higher with single-dose
netupitant 300 mg plus palonosetron 0.5 mg than with single-dose palonosetron
0.5 mg in cycle 1 of cisplatin-based highly emetogenic chemotherapy (HEC) in a
phase II trial and with single-dose netupitant/palonosetron 300/0.5 mg than with
single-dose palonosetron 0.5 mg in cycle 1 of anthracycline-cyclophosphamide
(AC) moderately emetogenic chemotherapy (MEC) in a phase III trial; the greater
efficacy of netupitant/palonosetron was maintained over repeated cycles of AC
MEC in the phase III trial. In another phase III trial, netupitant/palonosetron
300/0.5 mg was effective over repeated cycles of non-AC MEC or HEC.
Netupitant/palonosetron was well tolerated, with no cardiac safety concerns. The
convenience of administering netupitant/palonosetron as a single dose in a fixed
combination has the potential to improve adherence to CINV prevention
guidelines. In conclusion, netupitant/palonosetron is an important option to
consider in the prevention of acute and delayed CINV in patients receiving MEC
or HEC. Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca2+)-dependent
release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.)
from the gastrointestinal enterochromaffin cells and/or the brainstem.
Intracellular Ca2+ signaling is triggered by activation of diverse emetic
receptors (including tachykininergic NK1, serotonergic 5-HT3, dopaminergic D2,
cholinergic M1, or histaminergic H1), whose activation in vomit-competent
species can evoke emesis. Other emetogens such as cisplatin, rotavirus NSP4
protein and bacterial toxins can also induce intracellular Ca2+ elevation.
Netupitant is a highly selective neurokinin NK1 receptor (NK1R) antagonist and
palonosetron is a selective second-generation serotonin 5-HT3 receptor (5-HT3R)
antagonist with a distinct pharmacological profile. An oral fixed combination of
netupitant/palonosetron (NEPA; Akynzeo(®)) with >85% antiemetic efficacy is
available for use in the prevention of acute and delayed chemotherapy-induced
nausea and vomiting (CINV). Cannabinoid CB1 receptor agonists possess
broad-spectrum antiemetic activity since they prevent vomiting caused by a
variety of emetic stimuli including the chemotherapeutic agent cisplatin, 5-HT3R
agonists, and D2R agonists. Our findings demonstrate that application of the
L-type Ca2+ channel (LTCC) agonist FPL 64176 and the intracellular Ca2+
mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca2+-ATPase
inhibitor) cause vomiting in the least shrew. On the other hand, blockade of
LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide
broad-spectrum antiemetic efficacy against diverse agents that specifically
activate emetogenic receptors such as 5-HT3, NK1, D2, and M1 receptors, but can
also potentiate the antiemetic efficacy of palonosetron against the non-specific
emetogen, cisplatin. In this review, we will provide an overview of Ca2+
involvement in the emetic process; discuss the relationship between Ca2+
signaling and the prevailing therapeutics in control of vomiting; highlight the
evidence for Ca2+-signaling blockers/inhibitors in suppressing emetic behavior
in the least shrew model of emesis as well as in the clinical setting; and also
draw attention to the clinical benefits of Ca2+-signaling blockers/inhibitors in
the treatment of nausea and vomiting. BACKGROUND: Prevention of chemotherapy-induced nausea and vomiting (CINV) can be
improved with guideline-consistent use of antiemetics. However, adherence to
antiemetic guidelines remains often insufficient. Therefore, new strategies that
improve adherence are needed.
OBJECTIVES: To review the latest antiemetic guideline recommendations and
provide an update on the use of NEPA, a fixed combination antiemetic composed of
the neurokinin-1 receptor antagonist (RA) netupitant and the
5-hydroxytryptamine-3 RA palonosetron (Akynzeo®).
METHODS: Analysis of the literature was performed, including guidelines,
published literature, congress data on NEPA, and relevant articles on CINV.
FINDINGS: Nurses are in a unique position to promote guideline-consistent
antiemetic prophylaxis and are central in the education of patients and
caregivers. Thus, nurses’ continuous education on antiemetic treatments is key
for the prevention and management of CINV. NEPA offers a simplified antiemetic
therapy with the potential to increase guideline adherence. |
Describe CapSim | CapSim is a software package for simulation of targeted capture sequencing. Given a genome sequence and a set of probes, CapSim simulates the fragmentation, the dynamics of probe hybridization and the sequencing of the captured fragments on Illumina and PacBio sequencing platforms. The simulated data can be used for evaluating the performance of the analysis pipeline, as well as the efficiency of the probe design. Parameters of the various stages in the sequencing process can also be evaluated in order to optimize the experiments.Availability and implementation: CapSim is publicly available under BSD license at https://github.com/Devika1/capsim. | |
Which company produces Glybera? | Glybera is a product of Chiesi Pharma. | |
What is the mode of action of Tetrocarcin-A? | The anti-tumor antibiotic, tetrocarcin A, directly induces apoptosis of human breast cancer cells. | PURPOSE: Bcl-2, an inhibitor of apoptosis frequently shows elevated expression
in human tumors, thus resulting in resistance to radiation therapy. Therefore,
inhibiting Bcl-2 function may enhance the radiosensitivity of tumor cells.
Tetrocarcin A (TC-A) and bcl-2 antisense oligonucleotides exhibit antitumor
activity by inhibiting Bcl-2 function and transcription, respectively. We
investigated whether these antitumor agents would enhance the cytotoxic effects
of radiation in tumor cells overexpressing Bcl-2.
METHODS AND MATERIALS: We used HeLa/bcl-2 cells, a stable Bcl-2-expressing cell
line derived from wild-type HeLa (HeLa/wt) cells. Cells were incubated with TC-A
and bcl-2 antisense oligonucleotides for 24 h after irradiation, and cell
viability was then determined. Apoptotic cells were quantified by flow
cytometric assay.
RESULTS: The HeLa/bcl-2 cells were more resistant to radiation than HeLa/wt
cells. At concentrations that are not inherently cytotoxic, both TC-A and bcl-2
antisense oligonucleotides increased the cytotoxic effects of radiation in
HeLa/bcl-2 cells, but not in HeLa/wt cells. However, in HeLa/bcl-2 cells,
additional treatment with TC-A in combination with radiation did not
significantly increase apoptosis.
CONCLUSIONS: The present results suggest that TC-A and bcl-2 antisense
oligonucleotides reduce radioresistance of tumor cells overexpressing Bcl-2.
Therefore, a combination of radiotherapy and Bcl-2 inhibitors may prove to be a
useful therapeutic approach for treating tumors that overexpress Bcl-2. A survival kinase, Akt, is a downstream factor in the
phosphatidylinositide-3'-kinase-dependent pathway, which mediates many
biological responses including glucose uptake, protein synthesis and the
regulation of proliferation and apoptosis, which is assumed to contribute to
acquisition of maligt properties of human cancers. Here we find that an
anti-tumor antibiotic, tetrocarcin A, directly induces apoptosis of human breast
cancer cells. The apoptosis is accompanied by the activation of a proteolytic
cascade of caspases including caspase-3 and -9, and concomitantly decreases
phosphorylation of Akt, PDK1, and PTEN, a tumor suppressor that regulates the
activity of Akt through the dephosphorylation of polyphosphoinositides.
Tetrocarcin A affected neither expression of Akt, PDK1, or PTEN, nor did it
affect the expression of Bcl family members including Bcl-2, Bcl-X(L), and Bax.
These results suggest that tetrocarcin A could be a potent chemotherapeutic
agent for human breast cancer targeting the phosphatidylinositide-3'-kinase/Akt
signaling pathway. Overexpression of the tight junction protein Junctional Adhesion Molecule-A
(JAM-A) has been linked to aggressive disease in breast and other cancers, but
JAM-targeting drugs remain elusive. Screening of a natural compound library
identified the antibiotic Tetrocarcin-A as a novel downregulator of JAM-A and
human epidermal growth factor receptor-2 (HER2) protein expression in breast
cancer cells. Lysosomal inhibition partially rescued the downregulation of JAM-A
and HER2 caused by Tetrocarcin-A, and attenuated its cytotoxic activity.
Tetrocarcin-A treatment or JAM-A silencing reduced AKT and ERK phosphorylation,
inhibited c-FOS phosphorylation at Threonine-232 (its transcriptional regulation
site), inhibited nuclear localization of c-FOS, and downregulated expression of
the inhibitor of apoptosis proteins (IAP). This was accompanied by
Tetrocarcin-A-induced caspase-dependent apoptosis. To begin evaluating the
potential clinical relevance of our findings, we extended our studies to other
models. Encouragingly, Tetrocarcin-A downregulated JAM-A expression and caused
cytotoxicity in primary breast cells and lung cancer stem cells, and inhibited
the growth of xenografts in a semi-in vivo model involving invasion across the
chicken egg chorioallantoic membrane. Taken together, our data suggest that
Tetrocarcin-A warrants future evaluation as a novel cancer therapeutic by virtue
of its ability to downregulate JAM-A expression, reduce tumorigenic signaling
and induce apoptosis. |
List some substances important for proper nervous system function that gut microbes produce. | serotonin
gamma-aminobutyric acid
short-chain fatty acids
neurotransmitters | The gut microbiome is being more widely recognized for its association with
positive health outcomes, including those distant to the gastrointestinal
system. This has given the ability to maintain and restore microbial homeostasis
a new significance. Prebiotic compounds are appealing for this purpose as they
are generally food-grade substances only degraded by microbes, such as
bifidobacteria and lactobacilli, from which beneficial short-chain fatty acids
are produced. Saccharides such as inulin and other fructo-oligosaccharides,
galactooligosaccharides, and polydextrose have been widely used to improve
gastrointestinal outcomes, but they appear to also influence distant sites. This
review examined the effects of prebiotics on bone strength, neural and cognitive
processes, immune functioning, skin, and serum lipid profile. The mode of action
is in part affected by intestinal permeability and by fermentation products
reaching target cells. As the types of prebiotics available diversify, so too
will our understanding of the range of microbes able to degrade them, and the
extent to which body sites can be impacted by their consumption. |
Safinamide is approved for treatment of which disease? | Safinamide is a monoamine-oxidase B (MAO-B) inhibitor licensed as add-on therapy for people with idiopathic Parkinson's disease who are experiencing motor fluctuations with levodopa. | Safinamide (Xadago(®)) is an oral α-aminoamide derivative developed by Newron
for the treatment of Parkinson's disease (PD). The drug has both dopaminergic
properties (highly selective and reversible inhibition of monoamine oxidase-B)
and non-dopaminergic properties (selective sodium channel blockade and calcium
channel modulation, with consequent inhibition of excessive glutamate release).
Safinamide is approved in the EU, Iceland, Lichtenstein and Norway, as an add-on
therapy to stable-dose levodopa, alone or in combination with other PD therapies
in mid- to late-stage fluctuating PD patients; regulatory submissions have also
been filed in the USA and Switzerland for its use in this indication. Additional
submissions have been made in the USA, Iceland, Lichtenstein, Norway and
Switzerland for early-stage PD. Safinamide has also undergone phase II
investigation in PD patients with drug-induced dyskinesia (France, Germany,
Austria, Canada and South Africa) or cognitive impairment (USA and Spain). This
article summarizes the milestones in the development of safinamide leading to
its first approval for PD. BACKGROUND: Pain, a frequent non-motor symptom in Parkinson's Disease (PD),
significantly impacts on quality of life. Safinamide is a new drug with
dopaminergic and non-dopaminergic properties, approved in Europe as adjunct
therapy to levodopa for the treatment of fluctuating PD patients. Results from
two 24-month, double-blind, placebo-controlled studies demonstrated that
safinamide has positive effects on both motor functions and quality of life in
PD patients.
OBJECTIVE: To investigate the effects of safinamide on pain management in PD
patients with motor fluctuations using pooled data from studies 016 and SETTLE.
METHODS: This post-hoc analysis evaluated the reduction of concomitant pain
treatments and the changes in the scores of the items related to pain of the
Parkinson's Disease Quality of Life Questionnaire (PDQ-39). A path analysis was
performed in order to examine direct and indirect associations between
safinamide and PDQ-39 pain-related items assessed after 6-months of treatment.
RESULTS: The percentage of patients with no pain treatments at the end of the
trials was significantly lower in the safinamide group compared to the placebo
group. Safinamide 100 mg/day significantly reduced on average the individual use
of pain treatments by ≈24% and significantly improved two out of three PDQ-39
pain-related items of the "Bodily discomfort" domain.Path analysis showed that
the direct effect of safinamide on pain accounted for about 80% of the total
effect.
CONCLUSIONS: These results suggest that safinamide may have a positive effect on
pain, one of the most underestimated non-motor symptoms. Prospective studies are
warranted to investigate this potential benefit. Safinamide (Xadago®) is an orally active, selective, reversible monoamine
oxidase-B inhibitor with both dopaminergic and non-dopaminergic (glutamatergic)
properties. In the EU, safinamide is approved for the treatment of mid- to
late-stage fluctuating Parkinson's disease (PD) as add-on therapy to a stable
dose of levodopa alone or in combination with other PD medications. Safinamide
50-100 mg/day administered as a fixed or flexible dose significantly increased
daily 'on' time without dyskinesia (primary endpoint) in patients with mid- to
late-stage PD with motor fluctuations in 24-week, placebo-controlled clinical
trials. Other outcomes, including motor function, overall clinical status and
health-related quality of life, were also generally improved with safinamide.
Furthermore, in an 18-month extension of one study, although dyskinesia (primary
endpoint) was not significantly improved with safinamide relative to placebo,
treatment benefits in other outcomes were generally sustained over 24 months of
treatment. Safinamide was generally well tolerated in clinical trials;
dyskinesia was the most common adverse event. Although further studies are
needed, including comparative and long-term studies, current evidence indicates
that safinamide extends the treatment options available for use as add-on
therapy to levodopa and other PD medications in patients with mid- to late-stage
PD experiencing motor fluctuations. Safinamide has been recently approved as an add-on to levodopa therapy for
Parkinson disease. In addition to inhibiting monoamine oxidase type B, it blocks
sodium channels and modulates glutamate (Glu) release in vitro. Since this
property might contribute to the therapeutic action of the drug, we undertook
the present study to investigate whether safinamide inhibits Glu release also in
vivo and whether this effect is consistent across different brain areas and is
selective for glutamatergic neurons. To this aim, in vivo microdialysis was used
to monitor the spontaneous and veratridine-induced Glu and GABA release in the
hippocampus and basal ganglia of naive, awake rats. Brain levels of safinamide
were measured as well. To shed light on the mechanisms underlying the effect of
safinamide, sodium currents were measured by patch-clamp recording in rat
cortical neurons. Safinamide maximally inhibited the veratridine-induced Glu and
GABA release in hippocampus at 15 mg/kg, which reached free brain concentrations
of 1.89-1.37 µM. This dose attenuated veratridine-stimulated Glu (but not GABA)
release in subthalamic nucleus, globus pallidus, and substantia nigra
reticulata, but not in striatum. Safinamide was ineffective on spontaneous
neurotransmitter release. In vitro, safinamide inhibited sodium channels,
showing a greater affinity at depolarized (IC50 = 8 µM) than at resting (IC50 =
262 µM) potentials. We conclude that safinamide inhibits in vivo Glu release
from stimulated nerve terminals, likely via blockade of sodium channels at
subpopulations of neurons with specific firing patterns. These data are
consistent with the anticonvulsant and antiparkinsonian actions of safinamide
and provide support for the nondopaminergic mechanism of its action. In this retrospective study, we evaluated both efficacy and effectiveness of
safinamide 50 and 100 mg in the treatment of motor fluctuations and disabling
dyskinesias in a cohort of patients with idiopathic Parkinson's disease (PD).
Ninety-one PD patients were evaluated during the first year of commercialization
of the drug, both prior to starting safinamide and at the last available
follow-up. Evaluations were based on the Unified Parkinson's Disease Scale part
III (UPDRS III), Hoehn & Yahr (HY), Unified Dyskinesia Rating Scale (UDysRS)
walking and balance item 9 score, daily time spent in OFF and in ON with
disabling dyskinesias (1 week diary), mean daily dose of levodopa (LD),
dopamine-agonists (DA), catechol-O-methyl transferase inhibitor (COMT-I),
monoamine oxidase B inhibitor (MAOB-I), and their LD equivalent dose (LEDD).
Eight patients withdrew safinamide within the first month for minor side
effects. At the follow-up evaluation, after a mean time with safinamide of
7.5 months ± 3.4, all patients showed a significant improvement of all the scale
scores, except for HY, and of the daily dosages of the drugs and the LEDD. The
same results were shown by PD patients treated with safinamide 50 mg and
patients who started safinamide without switching from a previous MAOBI. PD
patients with safinamide 100 mg and patients who started safinamide switching
from a previous MAOBI significantly improved in time spent in OFF and LEDD. In
conclusion, safinamide is safe and effective in improving motor complications in
patients with idiopathic PD and can be considered a useful levodopa sparing
strategy. Heterogeneous expression of neurotransmitter deficits results from onset and
progression of Parkinson's disease. Intervals, characterized by reappearance of
motor and associated certain nonmotor symptoms, determine the end of good
tolerability and efficacy of oral levodopa therapy. These "OFF" states result
from levodopa pharmacokinetics and disease progression-related deterioration of
the central buffering capacity for fluctuations of dopamine levels. This review
discusses safinamide as an add-on therapeutic agent in orally levodopa-treated
patients with "OFF" phenomena. Safinamide provided beneficial effects on "OFF"
symptoms in pivotal trials with doses of 50 or 100 mg once daily. Safinamide
reversibly inhibits mono-amine oxidase B and declines abnormal glutamate release
by modulation of potassium- and sodium ion channels. An ideal candidate for
combination with safinamide is opicapone. This inhibitor of peripheral
catechol-O-methyltransferase supports continuous brain delivery of levodopa and,
thus, the continuous dopaminergic stimulation concept. Both compounds with their
once-daily application and good tolerability may complement each other by
reduction of necessary oral levodopa intakes and "OFF" times. Thus, a promising,
future option will be combination of safinamide and opicapone in one
formulation. It will reduce adherence issues and may complement levodopa
treatment. It will probably cause less nausea and edema than a dopamine
agonist/levodopa regimen. ▼ Safinamide (Xadago - Zambon S.p.A) is a monoamine-oxidase B (MAO-B) inhibitor
licensed as add-on therapy for people with idiopathic Parkinson's disease who
are experiencing motor fluctuations with levodopa.1 Currently there is no cure
for Parkinson's disease and drugs are used to reduce motor symptoms and improve
daily activities.2,3 Here, we review the evidence for this MAO-B inhibitor. Safinamide (Xadago) is a novel dual-mechanism drug that has been approved in the
European Union and United States as add-on treatment to levodopa in Parkinson's
disease therapy. In addition to its selective and reversible monoamine oxidase B
inhibition, safinamide through use-dependent sodium channel blockade reduces
overactive glutamatergic transmission in basal ganglia, which is believed to
contribute to motor symptoms and complications including levodopa-induced
dyskinesia (LID). The present study investigated the effects of safinamide on
the development of LID in 6-hydroxydopamine (6-OHDA)-lesioned rats, evaluating
behavioral, molecular, and neurochemical parameters associated with LID
appearance. 6-OHDA-lesioned rats were treated with saline, levodopa (6 mg/kg),
or levodopa plus safinamide (15 mg/kg) for 21 days. Abnormal involuntary
movements, motor performance, molecular composition of the striatal
glutamatergic synapse, glutamate, and GABA release were analyzed. In the
striatum, safinamide prevented the rearrangement of the subunit composition of
N-methyl-d-aspartate receptors and the levodopa-induced increase of glutamate
release associated with dyskinesia without affecting the levodopa-stimulated
motor performance and dyskinesia. Overall, these findings suggest that the
striatal glutamate-modulating component of safinamide's activity may contribute
to its clinical effects, where its long-term use as levodopa add-on therapy
significantly improves motor function and "on" time without troublesome
dyskinesia. |
What is the tradename of apixaban? | The tradename of apixaban is Eliquis. | The direct factor Xa inhibitor apixaban (Eliquis(®)) has predictable
pharmacodynamics and pharmacokinetics and does not require routine
anticoagulation monitoring. This article reviews the efficacy and tolerability
of oral apixaban to reduce the risk of stroke or systemic embolism in patients
with nonvalvular atrial fibrillation (AF). In the ARISTOTLE (Apixaban for
Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation)
trial in patients with AF and at least one additional risk factor for stroke,
apixaban recipients were significantly less likely than warfarin recipients to
experience stroke or systemic embolism, major bleeding or death; the beneficial
effects of treatment with apixaban versus warfarin were generally maintained
across various patient subgroups. Apixaban recipients also had a significantly
lower risk of intracranial haemorrhage than warfarin recipients. In the AVERROES
(Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation
Patients who have Failed or are Unsuitable for Vitamin K Antagonist Therapy)
trial in patients with AF and at least one additional risk factor for stroke for
whom vitamin K antagonist therapy was unsuitable, apixaban was associated with a
significantly lower risk of stroke or systemic embolism than aspirin, without an
increase in the risk of major bleeding. In conclusion, although longer-term
efficacy and safety data are needed, apixaban is an important new option for use
in patients with nonvalvular AF to reduce the risk of stroke or systemic
embolism. |
Under which environment does SELANSI run? | SELANSI (SEmi-LAgrangian SImulation of GRNs) is a software toolbox for the simulation of stochastic multidimensional gene regulatory networks. SELANSI exploits intrinsic structural properties of gene regulatory networks to accurately approximate the corresponding Chemical Master Equation with a partial integral differential equation that is solved by a semi-lagrangian method with high efficiency. SELANSI runs under the MATLAB environment, and is available under GPLv3 license at https://sites.google.com/view/selansi. | MOTIVATION: Gene regulation is inherently stochastic. In many applications
concerning Systems and Synthetic Biology such as the reverse engineering and the
de novo design of genetic circuits, stochastic effects (yet potentially crucial)
are often neglected due to the high computational cost of stochastic
simulations. With advances in these fields there is an increasing need of tools
providing accurate approximations of the stochastic dynamics of gene regulatory
networks (GRNs) with reduced computational effort.
RESULTS: This work presents SELANSI (SEmi-LAgrangian SImulation of GRNs), a
software toolbox for the simulation of stochastic multidimensional gene
regulatory networks. SELANSI exploits intrinsic structural properties of gene
regulatory networks to accurately approximate the corresponding Chemical Master
Equation with a partial integral differential equation that is solved by a
semi-lagrangian method with high efficiency. Networks under consideration might
involve multiple genes with self and cross regulations, in which genes can be
regulated by different transcription factors. Moreover, the validity of the
method is not restricted to a particular type of kinetics. The tool offers total
flexibility regarding network topology, kinetics and parameterization, as well
as simulation options.
AVAILABILITY AND IMPLEMENTATION: SELANSI runs under the MATLAB environment, and
is available under GPLv3 license at https://sites.google.com/view/selansi.
CONTACT: [email protected]. |
Is eculizumab used for treatment of myasthenia gravis? | Yes, eculizumab is used for treatment of myasthenia gravis. | INTRODUCTION: Complement activation at the neuromuscular junction is a primary
cause of acetylcholine receptor loss and failure of neuromuscular transmission
in myasthenia gravis (MG). Eculizumab, a humanized monoclonal antibody, blocks
the formation of terminal complement complex by specifically preventing the
enzymatic cleavage of complement 5 (C5).
METHODS: This study was a randomized, double-blind, placebo-controlled,
crossover trial involving 14 patients with severe, refractory generalized MG
(gMG).
RESULTS: Six of 7 patients treated with eculizumab for 16 weeks (86%) achieved
the primary endpoint of a 3-point reduction in the quantitative myasthenia
gravis (QMG) score. Examining both treatment periods, the overall change in mean
QMG total score was significantly different between eculizumab and placebo (P =
0.0144). After assessing data obtained from all visits, the overall change in
mean QMG total score from baseline was found to be significantly different
between eculizumab and placebo (P < 0.0001). Eculizumab was well tolerated.
CONCLUSION: The data suggest that eculizumab may have a role in treating severe,
refractory MG. PURPOSE OF REVIEW: Myasthenic disorders are a well characterized group of
diseases of the neuromuscular junction. Their pathogenesis is diverse, including
genetic and autoimmune mechanisms. We review recent findings on risk factors,
pathogenesis and treatment of autoimmune myasthenia gravis.
RECENT FINDINGS: Better knowledge of congenital myasthenia has led to the
development of efficient diagnostic algorithms that have therapeutic
implications. New epidemiological and genetic risk factors have been identified
and are considered to play a role in the development of myasthenia gravis. The
study of the role of innate immunity in myasthenia gravis has identified
relevant pathways to explain myasthenia gravis causes. The description of the
pathogenic role of IgG4 anti-MuSK antibodies has revealed heterogeneous immune
mechanisms that should lead to more specific therapies. Rituximab seems to be
particularly effective in MuSK myasthenia gravis, and eculizumab arises as an
option in refractory AChR myasthenia gravis. Therapeutic algorithms need to be
tailored to each myasthenia subtype.
SUMMARY: Increasing knowledge about the environmental and genetic risk factors
and basic immunopathogenesis of myasthenia gravis, including the role of innate
immunity, regulatory T cell impairment and autoantibody heterogeneity, is
providing a rationale for treatment with new biological agents. Current
immunotherapies in myasthenia gravis undoubtedly provide benefits, but also
cause side-effects. Controlled trials are, therefore, needed to confirm initial
results from pilot studies. Generalized myasthenia gravis (gMG) is a rare autoimmune disorder characterized
by skeletal muscle weakness caused by disrupted neurotransmission at the
neuromuscular junction (NMJ). Approximately 74-88% of patients with gMG have
acetylcholine receptor (AChR) autoantibodies. Complement plays an important role
in innate and antibody-mediated immunity, and activation and amplification of
complement results in the formation of membrane attack complexes (MACs),
lipophilic proteins that damage cell membranes. The role of complement in gMG
has been demonstrated in animal models and patients. Studies in animals lacking
specific complement proteins have confirmed that MAC formation is required to
induce experimental autoimmune MG (EAMG) and NMJ damage. Complement inhibition
in EAMG models can prevent disease induction and reverse its progression.
Patients with anti-AChR+ MG have autoantibodies and MACs present at NMJs.
Damaged NMJs are associated with more severe disease, fewer AChRs, and MACs in
synaptic debris. Current MG therapies do not target complement directly.
Eculizumab is a humanized monoclonal antibody that inhibits cleavage of
complement protein C5, preventing MAC formation. Eculizumab treatment improved
symptoms compared with placebo in a phase II study in patients with refractory
gMG. Direct complement inhibition could preserve NMJ physiology and muscle
function in patients with anti-AChR+ gMG. The humanized monoclonal antibody eculizumab (Soliris®) is a complement
inhibitor indicated for use in anti-acetylcholine receptor (AChR)
antibody-positive adults with generalized myasthenia gravis (gMG) in the USA,
refractory gMG in the EU, or gMG with symptoms that are difficult to control
with high-dose IVIg therapy or PLEX in Japan. It is the first complement
inhibitor to be approved for use in these patients. In the well-designed,
26-week REGAIN study in patients with anti-AChR-positive refractory gMG,
although a statistically significant benefit of eculizumab over placebo in the
prespecified primary endpoint analysis (change from baseline in MG-activities of
daily living (ADL) score assessed by worst-rank ANCOVA) was not formally
demonstrated, preplanned and post hoc sensitivity analyses of this outcome, as
well as other secondary outcomes supported the efficacy of eculizumab. Overall,
patients receiving eculizumab experienced significant improvements in the ADL,
muscle strength and health-related quality of life (HR-QOL) parameters relative
to patients receiving placebo. Moreover, an ongoing extension of REGAIN showed
that treatment benefits with eculizumab were sustained during continued therapy
for at least 52 weeks. Eculizumab was generally well tolerated in these studies,
with a tolerability profile similar to that reported previously in other
indications. Although several questions remain, such as duration of treatment,
cost effectiveness and long-term efficacy and tolerability, current evidence
indicates that eculizumab is a valuable emerging therapy for patients with
refractory gMG. With specialized care, patients with myasthenia gravis can have very good
outcomes. The mainstays of treatment are acetylcholinesterase inhibitors, and
immunosuppressive and immunomodulatory therapies. There is good evidence
thymectomy is beneficial in thymomatous and nonthymomatous disease. Nearly all
of the drugs used for MG are considered "off-label." The 2 exceptions are
acetylcholinesterase inhibitors and complement inhibition with eculizumab, which
was recently approved by the US Food and Drug Administration for myasthenia
gravis. This article reviews the evidence base and provides a framework for the
treatment of myasthenia gravis, highlighting recent additions to the literature. |
What is the name of the Cas13 based diagnostic test for the Zika and dengue viruses? | The Cas13-based platform that can detect Zika and dengue viruses is called SHERLOCK (specific high-sensitivity enzymatic reporter unlocking). | Author information:
(1)Broad Institute of the Massachusetts Institute of Technology (MIT) and
Harvard, Cambridge, MA 02142, USA. [email protected]
[email protected] [email protected].
(2)Center for Systems Biology, Department of Organismal and Evolutionary
Biology, Harvard University, Cambridge, MA 02138, USA.
(3)Ph.D. Program in Virology, Division of Medical Sciences, Harvard Medical
School, Boston, MA 02115, USA.
(4)Broad Institute of the Massachusetts Institute of Technology (MIT) and
Harvard, Cambridge, MA 02142, USA.
(5)Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
(6)McGovern Institute for Brain Research, MIT, Cambridge, MA 02139, USA.
(7)Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA.
(8)Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
(9)Department of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA.
(10)Department of Electrical Engineering and Computer Science, MIT, Cambridge,
MA 02139, USA.
(11)Institute for Medical Engineering and Science, MIT, Cambridge, MA 02139,
USA.
(12)Department of Biological Sciences, Florida Gulf Coast University, Fort
Myers, FL 33965, USA.
(13)Centro de Investigaciones Genética, Instituto de Investigacion en
Microbiologia, Universidad Nacional Autónoma de Honduras, Tegucigalpa, Honduras.
(14)Department of Immunology and Infectious Disease, Harvard School of Public
Health, Boston, MA 02115, USA.
(15)Araraquara Laboratory of Public Health, School of Pharmaceutical Sciences,
São Paulo State University, São Paulo, Brazil.
(16)Laboratorio de Pesquisas em Virologia, Faculdade de Medicina de Sao Jose do
Rio Preto, São Paulo, Brazil.
(17)Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029,
USA.
(18)Department of Microbiology and Immunobiology, Harvard Medical School,
Boston, MA 02115, USA.
(19)Howard Hughes Medical Institute (HHMI), Chevy Chase, MD 20815, USA. |
What are CRISPR-Cas12a proteins? | CRISPR-Cas12a (Cpf1) proteins are RNA-guided enzymes that bind and cut DNA as components of bacterial adaptive immune systems. Like CRISPR-Cas9, Cas12a has been harnessed for genome editing on the basis of its ability to generate targeted, double-stranded DNA breaks. RNA-guided DNA binding unleashes indiscriminate single-stranded DNA (ssDNA) cleavage activity by Cas12a that completely degrades ssDNA molecules | CRISPR-Cas12a (Cpf1) proteins are RNA-guided enzymes that bind and cut DNA as
components of bacterial adaptive immune systems. Like CRISPR-Cas9, Cas12a has
been harnessed for genome editing on the basis of its ability to generate
targeted, double-stranded DNA breaks. Here we show that RNA-guided DNA binding
unleashes indiscriminate single-stranded DNA (ssDNA) cleavage activity by Cas12a
that completely degrades ssDNA molecules. We find that target-activated,
nonspecific single-stranded deoxyribonuclease (ssDNase) cleavage is also a
property of other type V CRISPR-Cas12 enzymes. By combining Cas12a ssDNase
activation with isothermal amplification, we create a method termed DNA
endonuclease-targeted CRISPR trans reporter (DETECTR), which achieves attomolar
sensitivity for DNA detection. DETECTR enables rapid and specific detection of
human papillomavirus in patient samples, thereby providing a simple platform for
molecular diagnostics. |
What type of drug is apixaban? | Apixaban is an anticoagulant. | |
Can cardiospheres be produced from skin fibroblasts? | Yes, induced cardiospheres (iCS) can be produced by somatic reprogramming of mouse fibroblasts using a panel of pluripotent transcription factors and cardiotrophic growth factors. | |
What the chromsomal location of the gene that is deleted in Potocki-Shaffer syndrome? | In Potocki-Shaffer syndrome (PSS), the full phenotypic spectrum is manifested when deletions are at least 2.1 Mb in size at 11p11.2 | We report a family with inherited Potocki-Shaffer syndrome. The phenotypically
normal mother has an interstitial deletion of 11(p11.12p11.2) with neocentric
marker chromosome formation. The marker chromosome contains the deleted material
on 11p11.2 and is likely a ring. The patient inherited a maternal deleted
chromosome 11 but not the marker chromosome, thus resulting in an unbalanced
karyotype along with the phenotype of Potocki-Shaffer syndrome. The deleted
region in our case-11p11.12p11.2-is a newly reported site of constitutional
neocentromere formation. This is also the first report describing deletion of
11p11.12-p11.2 and neocentromere formation resulting in inherited
Potocki-Shaffer syndrome. WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities and mental
retardation) and Potocki-Shaffer syndrome are rare contiguous gene deletion
syndromes caused by deletions of the 11p14-p12 chromosome region.We present a
patient with mental retardation, unilateral cataract, bilateral ptosis, genital
abnormalities, seizures and a dysmorphic face. Cytogenetic analysis showed a
deletion on 11p that was further characterized using FISH and MLPA analyses. The
deletion (11p13-p12) located in the area between the deletions associated with
the WAGR and Potocki-Shaffer syndromes had a maximum size of 8.5 Mb and
encompasses 44 genes. Deletion of WT1 explains the genital abnormalities
observed. As PAX6 was intact the cataract observed cannot be explained by a
deletion of this gene. Seizures have been described in Potocki-Shaffer syndrome
while mental retardation has been described in both WAGR and Potocki-Shaffer
syndrome. Characterization of this patient contributes further to elucidate the
function of the genes in the 11p14-p12 chromosome region. Potocki-Shaffer syndrome is a rare contiguous gene deletion syndrome due to
haploinsufficiency of the 11p11.2p12 region and is characterized by craniofacial
abnormalities, developmental delay, intellectual disability, multiple exostoses,
and biparietal foramina. In this study, six patients with the Potocki-Shaffer
syndrome were identified and evaluated using a multidisciplinary protocol that
included assessments by a geneticist, ophthalmologist, otolaryngologist,
orthopedist, nephrologist, audiologist, and neuropsychologist. Diagnostic
studies included skeletal survey, magnetic resoce imaging of the brain, renal
ultrasound, complete blood count, comprehensive metabolic panel, thyroid
studies, and urinalysis. Using array comparative genomic hybridization, we
further characterized the deletion in five of these patients. The results of
these evaluations were combined with a comprehensive review of reported cases.
Our data highlight the characteristic facial features, biparietal foramina,
moderate-to-severe developmental delay and intellectual disability, myopia and
strabismus, and multiple exostoses seen with this disorder. We also identify for
the first time an association of Potocki-Shaffer syndrome with sensorineural
hearing loss and autistic behaviors. Finally, we provide recommendations for the
health maintece of patients with Potocki-Shaffer syndrome. We describe the case of an adult patient affected by multiple exostoses, severe
mental retardation, epilepsy and facial dysmorphisms with a deletion of ∼2.3 Mb
on chromosome 11p11.21, correlated to Potocki-Shaffer syndrome (PSS). PSS is a
rare contiguous gene deletion syndrome, mainly characterized by multiple
exostoses and bilateral parietal foramina. Mental retardation and craniofacial
dysmorphisms have often been reported, too. Although the patient showed many
signs of PSS since early childhood, the diagnosis was suggested only when we
examined her at adult age. This case highlights how frequently rare diseases
remain undiagnosed till adulthood and is an excellent example of the need for a
timely and correct diagnosis. Potocki-Shaffer syndrome (PSS) is a rare disorder caused by haploinsufficiency
of genes located on the proximal short arm of chromosome 11 (11p11.2p12).
Classic features include biparietal foramina, multiple exostoses, profound
hypotonia, dysmorphic features, and developmental delay/intellectual disability.
Fewer than 40 individuals with PSS have been reported, with variable clinical
presentations due in part to disparity in deletion sizes. We report on a boy who
presented for initial evaluation at age 13 months because of a history of
developmental delay, hypotonia, subtle dysmorphic features, and neurobehavioral
abnormalities. SNP microarray analysis identified a 137 kb deletion at 11p11.2,
which maps within the classically defined PSS interval. This deletion results in
haploinsufficiency for all or portions of six OMIM genes: SLC35C1, CRY2,
MAPK8IP1, PEX16, GYLTL1B, and PHF21A. Recently, translocations interrupting
PHF21A have been associated with intellectual disability and craniofacial
anomalies similar to those seen in PSS. The identification of this small
deletion in a child with developmental delay and hypotonia provides further
evidence for the genetic basis of developmental disability and identifies a
critical region sufficient to cause hypotonia in this syndrome. Additionally,
this case illustrates the utility of high resolution genomic approaches in
correlating clinical phenotypes with specific genes in contiguous gene deletion
syndromes. Potocki-Shaffer syndrome is a contiguous gene deletion syndrome involving
11p11.2p12 and characterized by multiple exostoses, biparietal foramina,
genitourinary anomalies in males, central nervous system abnormalities,
intellectual disability, and craniofacial abnormalities. Current literature
implicates haploinsufficiency of three genes (ALX4, EXT2, and PHF21A) in causing
some of the cardinal features of PSS. We report a patient with multiple
exostoses, biparietal foramina, and history of mild developmental delay.
Cognitive and behavioral testing supported formal diagnoses of anxiety, verbal
dyspraxia, articulation disorder, and coordination disorder, without
intellectual disability. His facial features, though distinctive, were not
typical of those observed in PSS. As the chromosomal deletion does not encompass
PHF21A, this case lends further support that haploinsufficiency of PHF21A
contributes to the intellectual disability and craniofacial abnormalities in PSS
and that there are other genes in the region which likely contribute to the
behavioral phenotype in this syndrome. © 2017 Wiley Periodicals, Inc. |
List 3 enterotoxins produced by Clostridium difficile. | Toxin A (TcdA), toxin B (TcdB), and binary toxin (CDT) produced by Clostridium difficile (CD) | The action of toxins A, B, and C from Clostridium difficile was studied in the
small intestine and colon of rats. All three caused fluid accumulation in the
small intestine, maximal secretion being induced by 1 micrograms of toxin A, 20
micrograms of B, and 15 micrograms of C. Both toxins A and C caused shedding of
epithelial cells from the villi without visible damage to crypt cells; toxin A
caused further extensive necrosis and bleeding. Toxin B caused secretion without
visible damage to the epithelial cells, though this activity was unstable and
decreased significantly after one week of storage. In the colon, toxin A caused
secretion and shedding of surface epithelial cells without damage to crypt
cells, toxin C caused only a weak secretion, and toxin B had no effect at all.
In terms of immunohistochemistry, it was found that toxin A bound to the
enterocytes at the tips of the villi but not to goblet and crypt cells. The
complex expression or interaction of the toxins produced by Cl difficile may
explain the broad spectrum of disease (diarrhoea, colitis, and pseudomembranous
colitis) associated with this micro-organism. The exotoxins toxin A (TcdA) and toxin B (TcdB) are produced by the bacterial
pathogen Clostridium difficile and are responsible for the pathology associated
with C. difficile infection (CDI). The antitoxin antibodies actoxumab and
bezlotoxumab bind to and neutralize TcdA and TcdB, respectively. Bezlotoxumab
was recently approved by the FDA for reducing the recurrence of CDI. We have
previously shown that a single molecule of bezlotoxumab binds to two distinct
epitopes within the TcdB combined repetitive oligopeptide (CROP) domain,
preventing toxin binding to host cells. In this study, we characterize the
binding of actoxumab to TcdA and examine its mechanism of toxin neutralization.
Using a combination of approaches including a number of biophysical techniques,
we show that there are two distinct actoxumab binding sites within the CROP
domain of TcdA centered on identical amino acid sequences at residues 2162-2189
and 2410-2437. Actoxumab binding caused the aggregation of TcdA especially at
higher antibody:toxin concentration ratios. Actoxumab prevented the association
of TcdA with target cells demonstrating that actoxumab neutralizes toxin
activity by inhibiting the first step of the intoxication cascade. This
mechanism of neutralization is similar to that observed with bezlotoxumab and
TcdB. Comparisons of the putative TcdA epitope sequences across several C.
difficile ribotypes and homologous repeat sequences within TcdA suggest a
structural basis for observed differences in actoxumab binding and/or
neutralization potency. These data provide a mechanistic basis for the
protective effects of the antibody in vitro and in vivo, including in various
preclinical models of CDI. Clostridium difficile is a gram-positive intestine bacterium that causes a
severe diarrhea and could eventually be lethal. The main virulence factor is
related to the release of two major exotoxins, toxin A (TcdA) and toxin B
(TcdB). Recent C. difficile-associated disease (CDAD) outbreaks have been caused
by hypervirulent strains which secrete an additional binary toxin (CDTa/CDTb).
Vaccination against these toxins is considered the best way to combat the CDAD.
Recently, a novel tetravalent C. difficile vaccine candidate containing all four
toxins produced from a baculovirus expression system has been developed. A dose
assay to release this tetravalent C. difficile vaccine was developed using
tandem ion-exchange HPLC chromatography. A sequential weak cation exchange
(carboxyl group) and weak anion exchange (tertiary amine group) columns were
employed. The four C. difficile vaccine antigen pIs range from 4.4 to 8.6. The
final optimized separation employs salt gradient elution at two different pHs.
The standard analytical parameters such as LOD, LOQ, linearity, accuracy,
precision and repeatability were evaluated for this method and it was deemed
acceptable as a quantitative assay for vaccine release. Furthermore, the
developed method was utilized for monitoring the stability of the tetravalent C.
difficile vaccine in final container. PURPOSE OF THE REVIEW: Review tests available for detection of Clostridium
difficile (C. Diff) induced disease, including when such tests should be done in
children and how they should be interpreted.
RECENT FINDINGS: Multiple tests are available for detecting disease due to C.
diff. These include colonoscopy and stool analysis. Colonoscopy with biopsy is
the most sensitive test for detecting the presence of colitis. The toxins
produced by the C. diff. (toxin A, toxin B, and binary toxin) are the agents
that cause injury and disease. Only toxin producing C. diff. Strains will cause
disease. Binary toxin by itself is not thought to produce disease. Binary toxin
causes disease in humans when present with toxin A and B producing bacteria, and
has been implicated with fulmit life threatening disease. Stool analyses vary
in sensitivity and specificity depending on the assay used. The presence of
toxin producing strains of C diff. in the stool does not equate with disease.
The presence of a toxin-producing bacteria or toxins (A or B) only equates with
disease if diarrhea or a diseased colon (toxic megacolon, ileus, and sepsis) is
present. Nucleic acid amplification testing (NAAT), when used in the stool from
patients with diarrhea, appears to be the most efficient study to detect the
gene that encodes for toxin A and B and thus to diagnose C. diff.-induced
disease. Infants have a high carriage rate of C. diff. and are believed not to
develop disease from it or its toxins. Infants should not be tested for C.
difficile. The NAAT is most specific when done on patients with diarrhea with
liquid stools. Testing for C. difficile should only be done on patients with
diarrhea. One can assume that a patient who has no diarrhea and is not ill does
not have C. diff.-induced disease. Treatment should be limited to patients with
diarrhea who test positive for C. diff. toxin (A or B) or toxin-producing
bacteria. Direct testing for binary toxin is not commercially available. Binary
toxin is only thought to cause disease in humans when C. diff. toxin (A and
B)-producing bacteria are present. |
Which tissue secretes vaspin? | Visceral adipose tissue-derived serine protease inhibitor (Vaspin) is an adipocytokine that has been shown to exert anti-inflammatory effects and inhibits apoptosis under diabetic conditions. | Vaspin expression is increased in white adipose tissue (WAT) of diet-induced
obese mice and rats and is supposed to compensate HFD-induced inflammatory
processes and insulin resistance in adipose tissue by counteracting
pro-inflammatory gene expression in obesity. Multiple studies have also
demonstrated strong anti-inflammatory effects in vascular and skin cells. Here,
we used vaspin treated 3T3-L1 murine adipocytes as well as 3T3-L1 cells with
stable vaspin expression to investigate the effect of exogenous and endogenous
vaspin on inflammatory processes and insulin signaling in adipocytes. Our stably
transfected cells secreted significant amounts of vaspin which was in the
physiological range of ∼0.5 ng/ml in cell supernatants. Adipocyte
differentiation was not affected by vaspin as expression of adipogenic marker
genes as well as lipid accumulation after full differentiation was similar to
control cells. We found that IL-1β induced expression and secretion of
pro-inflammatory cytokines, such as IL-6, MCP1 and TNFα was significantly
blunted in vaspin expressing 3T3-L1 cells. Treatment of 3T3-L1 cells with
exogenous vaspin resulted in reduced cytokine-induced activation of the
intracellular and pro-inflammatory NFκB signaling cascades (IKKα/β, IκB and
NFκB). Moreover, endogenous vaspin positively affected insulin signaling by
increasing insulin-stimulated phosphorylation of the key mediator protein kinase
B (AKT). Together, we demonstrate anti-inflammatory effects of vaspin in 3T3-L1
adipocytes as well as increased insulin signaling by endogenous expression or
exogenous treatment. The results provide evidence for potent anti-inflammatory
action of vaspin not only in vascular cells but also in adipose tissue. |
List adipokines. | adiponectin
leptin
resistin | BACKGROUND: Adipose tissue is an important endocrine organ that secretes a
number of adipokines, like Resistin (RETN); it's an adipocytes-secreted cytokine
and has been proposed as a link between obesity and diabetes. Many resistin gene
polymorphisms were described and their implication in obesity was controversial.
This study was to investigate the prevalence of single nucleotide polymorphisms
(SNPs) in RETN gene 420C/G; 44G/A; 62G/A; 394C/G and 299 G/A and their
association with Resistin level and obesity in Tunisian volunteers.
METHODS: We recruited 169 nonobese (mean age=42.16-14.26 years; mean body mass
index [BMI]=24.51-3.69 kg/m2 ) and 160 obese (mean age=47.86-11.17 years; mean
BMI=36-4.78 kg/m2 ). Genotyping was performed using polymerase chain
reaction-restriction fragment length polymorphism. Anthropometric parameters,
lipid levels, Glycemia and insulinemia were measured, BMI was calculated and
insulinresistance was evaluated with the homeostasis model assessment insulin
resistance (HOMA-IR) and resistin level was measured by ELISA. Statistical
analyses were performed by SPSS19.0.
RESULTS: After adjustment for confounding parameters; the Odds Ratio (OR) of
obesity associated with mutated genotypes at 420C/G compared with normal
genotype was as: OR=2.17; 95% CI [1.28-3.68], P=.004. The serum Resistin levels
present no significant association with all RETN polymorphisms and it was
significantly associated with BMI (P=.047). In our haplotype analysis, one
haplotype seems to be protective and one other seems to be the highest risk to
obesity.
CONCLUSION: The 420 C/G Polymorphism were associated with obesity and Leptin
concentration in our population. The aim of this study was to investigate the plasma adipokine responses to
high-intensity interval training (HIT) in overweight/obese women. Twelve women
(age 21.7 ± 3.8 years) completed a 19 days of HIT comprising six session of 4-6
repeats of a Wingate test (0.065 kg load/kg). Plasma adipokine levels were
measured before exercise, and at 5 and 90 min after exercise on the first and
the last training days. Adiponectin was higher at 5 min than 90 min
post-exercise (11.7 ± 7.3 and 10.5 ± 5.8 ng/ml; p = .01) in the first exercise
day. Leptin decreased 5 min after exercise (23.6 ± 13.2 vs. baseline
27.8 ± 14.4 ng/ml; p < .01) and remained depressed following 90 min (p < .01).
The changes in adiponectin and leptin concentrations were similar on the first
and last exercise days. No consistent effect was found on resistin
concentration. Future studies are required to disclose the functional
consequences of these alterations in plasma adipokine levels. Care of premature infants often requires parental and caregiver separation,
particularly during hypoxic and hypothermic episodes. We have established a
neonatal rat model of human prematurity involving maternal-neonatal separation
and hypoxia with spontaneous hypothermia prevented by external heat. Adults
previously exposed to these neonatal stressors show a sex difference in the
insulin and glucose response to arginine stimulation suggesting a state of
insulin resistance. The current study used this cohort of adult rats to evaluate
insulin resistance [homeostatic model assessment of insulin resistance
(HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and
testosterone. The major findings were that daily maternal-neonatal separation
led to an increase in body weight and HOMA-IR in adult male and female rats and
increased plasma leptin in adult male rats only; neither prior neonatal hypoxia
(without or with body temperature control) nor neonatal hypothermia altered
subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in
plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia;
male-female differences in resistin were lost in the adults that were exposed to
hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily
hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone
in adult male rats. We conclude that neonatal stressors result in subsequent
adult sex-dependent increases in insulin resistance and adipokines and that our
rat model of prematurity with hypoxia without hypothermia alters adult
testosterone dynamics. |
List features of the DOOR syndrome. | DOOR syndrome is a rare multisystem genetic disorder, consisting of deafness (sensorineural), onychodystrophy, osteodystrophy, and mental retardation. | The acronym DOOR was first used by Cantwell in 1975 to describe a syndrome
comprising sensorineural deafness, osteodystrophy, onychodystrophy, and mental
retardation. To date, 16 cases of the syndrome have been documented in the
literature. We present two sisters who died in early infancy with the clinical
features of DOOR syndrome, both of whom in addition had cardiac defects and
urinary tract abnormalities. Both infants had the classical clinical features of
sensorineural deafness, seizures, hypoplastic nails, finger-like thumbs, and the
characteristic facies of the syndrome. Autopsy in each case revealed the
additional findings of a membranous ventricular septal defect and a septum
secundum atrial septal defect. The first child had left-sided hydronephrosis and
hydroureter, and the second sibling had bilateral hydronephrosis, hydroureter,
and dilatation of the bladder. Congenital heart disease and renal abnormalities
have not to our knowledge been previously described in association with the DOOR
syndrome. Four patients from three families with the clinical features of DOOR syndrome
(onycho-osteodystrophy, dystrophic thumbs, sensorineural deafness, and increased
urinary levels of 2-oxoglutarate) are the subjects of this report. Our report
deals with the autosomal recessive form of the disease, wherein the activity of
2-oxoglutarate decarboxylase (E1(0)) in fibroblasts and white blood cells of the
patients is decreased. The activity of E1(0) in all patients' fibroblasts and
white blood cells was significantly lower compared to the controls. This study
demonstrates for the first time that E1(0) deficiency is an important
biochemical marker for the autosomal recessive form of DOOR syndrome. Authors highlight the difficulties of syndrome identification through reporting
the first case of DOOR syndrome in Hungary (the 28th case worldwide). The
awareness and appropriate weighing of the importance of vestigial nails
(onychodystrophy) was crucial for the correct diagnosis. Based on the normal
level of 2-oxoglutarate excretion, the patient can be categorized as type 2.
This is associated with better survival, which does not mean a substantial
difference in quality of life. Although, prenatal diagnosis is not possible at
present, knowledge of the enzyme defect and detection of the reduced activity of
the 2-oxoglutarate dehydrogenase E1 component may provide an opportunity. If
parents opt to have another child, a 25% risk is to be taken into account. DOOR syndrome (deafness, onychodystrophy, osteodystrophy, and mental
retardation) is a rarely described disorder with less than 35 reports in the
literature. The hallmarks of the syndrome, represented in the DOOR acronym,
include sensorineural hearing loss, hypoplastic or absent nails on the hands and
feet, small or absent distal phalanges of the hands and feet, and mental
retardation. The purpose of our communication is to report on an additional
patient with DOOR syndrome, delineate common as well as less frequent
manifestations of DOOR syndrome, bring attention to the under appreciated facial
features in DOOR syndrome, document the natural history of this disorder, and
propose a suggested workup of those suspected of DOOR syndrome. DOOR syndrome is
associated with characteristic, coarse facial features with large nose with wide
nasal bridge, bulbous tip and anteverted nares, a long prominent philtrum and
downturned corners of the mouth. The natural history is one of a deteriorative
course, with progressive neurological manifestations including sensorineural
deafness, seizures from infancy, optic atrophy, and a peripheral polyneuropathy.
The majority of patients with DOOR syndrome have elevated levels of
2-oxoglutarate in the urine and plasma. In this report, we present a newborn
with manifestations consistent with DOOR syndrome and a progressive clinical
course. A comprehensive literature review reveals 32 patients with DOOR
syndrome. In conclusion, DOOR syndrome is a neurometabolic disorder with
recognizable facial features and a progressive natural history. We present the case of a 9-year-old boy with DOOR syndrome recognized in the
first year of his life because of a delayed development of speech. The diagnosis
was based on characteristic abnormalities, including congenital deafness, nail
and bone abnormalities, and mild mental retardation. We report the anaesthetic management of a 48-year-old male patient with
Deafness, Onycho-Osteodystrophy and mental Retardation syndrome, epilepsy and
cerebral palsy who had two dental procedures under anaesthetic care. For the
first short examination sedoanalgesia was employed and the second, longer,
procedure was performed under general anaesthesia. His airway management was
moderately difficult and the postoperative period was complicated by partial
seizures involving the upper extremity and a short period of decreased oxygen
saturation. The potential anaesthetic implications of Deafness,
Onycho-Osteodystrophy and mental Retardation syndrome are highlighted. |