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Which human disease is experimental autoimmune encephalomyelitis (EAE) model for? | Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS (Multiple Sclerosis). | OBJECTIVES: It has been shown that calcitriol and all-trans retinoic acid (ATRA)
have modulatory effects on the immune system. The present study investigates the
synergistic effects of combination treatment of calcitriol and ATRA in
experimental autoimmune encephalomyelitis (EAE), an animal model of multiple
sclerosis (MS).
METHODS: The mice were allocated to four preventive groups, each consisting of
eight animals, ATRA (250 μg/mouse), calcitriol (100 ng/mouse), combination of
ATRA and calcitriol (125 μg/mouse and 50 ng/mouse) and vehicle groups. EAE was
induced by MOG35-55 peptide in female C57BL/6 mice. Treatments were initiated at
day 1 before immunization and continued every other day throughout the study
until the day 21 post-immunization. Splenocytes were isolated from EAE-induced
mice and the expression of retinoic acid receptor-related orphan receptor gamma
t (ROR-γt), Interleukin-17 (IL-17), transforming growth factor beta (TGF-β), and
forkhead box P3 (FOXP3) genes was measured using real-time polymerase chain
reaction.
RESULTS: The expression of FOXP3 and TGF-β genes in the splenocytes of
combination-treated and calcitriol alone-treated mice was significantly
increased compared to vehicle group (P < 0.05). The expression of ROR-γt and
IL-17 genes in the splenocytes of ATRA, calcitriol and combination- treated mice
was significantly reduced compared to those of vehicle- treated mice (P < 0.05).
The relative expression level of ROR-γt was significantly (P < 0.05) lower in
the combination group than in the mice treated by ATRA or calcitriol alone.
DISCUSSION: This study demonstrated that treatment with combination of
calcitriol and ATRA can be considered as a new strategy for MS prevention and
treatment. |
What is the cause if the rare disease cystinosis? | Cystinosis is a rare autosomal recessive disorder resulting from defective lysosomal transport of cystine due to mutations in the cystinosin lysosomal cystine transporter (CTNS) gene. | Cystinosis is a rare, autosomal recessive disorder leading to defective
transport of cystine out of lysosomes. Subsequent cystine crystal accumulation
can occur in various tissues, including the ocular surface. This review explores
the efficacy of cysteamine hydrochloride eye drops in the treatment of corneal
cystine crystal accumulation and its safety profile. Cystinosis is a rare autosomal recessive disorder resulting from defective
lysosomal transport of cystine due to mutations in the cystinosin lysosomal
cystine transporter (CTNS) gene. The clinical phenotype of nephropathic
cystinosis is characterized by renal tubular Fanconi syndrome and development of
end-stage renal disease during the first decade. Although metabolic acidosis is
the classically prominent finding of the disease, a few cases may present with
hypokalemic metabolic alkalosis mimicking Bartter syndrome. Bartter-like
presentation may lead to delay in diagnosis and initiation of specific treatment
for cystinosis. We report a case of a 6-year-old girl initially presenting with
the features of Bartter syndrome that was diagnosed 2 years later with
nephropathic cystinosis and a novel CTNS mutation. |
Is lithium effective for treatment of amyotrophic lateral sclerosis? | No, lithium is not effective for treatment of amyotrophic lateral sclerosis. | ALS is a devastating neurodegenerative disorder with no effective treatment. In
the present study, we found that daily doses of lithium, leading to plasma
levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human
patients affected by ALS. None of the patients treated with lithium died during
the 15 months of the follow-up, and disease progression was markedly attenuated
when compared with age-, disease duration-, and sex-matched control patients
treated with riluzole for the same amount of time. In a parallel study on a
genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by
lithium, which delayed disease onset and duration and augmented the life span.
These effects were concomitant with activation of autophagy and an increase in
the number of the mitochondria in motor neurons and suppressed reactive
astrogliosis. Again, lithium reduced the slow necrosis characterized by
mitochondrial vacuolization and increased the number of neurons counted in
lamina VII that were severely affected in saline-treated G93A mice. After
lithium administration in G93A mice, the number of these neurons was higher even
when compared with saline-treated WT. All these mechanisms may contribute to the
effects of lithium, and these results offer a promising perspective for the
treatment of human patients affected by ALS. In a pilot clinical study that we recently published we found that lithium
administration slows the progression of Amyotrophic Lateral Sclerosis (ALS) in
human patients. This clinical study was published in addition with basic (in
vitro) and pre-clinical (in vivo) data demonstrating a defect of autophagy as a
final common pathway in the genesis of ALS. In fact, lithium was used as an
autophagy inducer. In detailing the protective effects of lithium we found for
the first time that this drug stimulates the biogenesis of mitochondria in the
central nervous system and, uniquely in the spinal cord, it induces
neuronogenesis and neuronal differentiation. In particular, the effects induced
by lithium can be summarized as follows: (i) the removal of altered mitochondria
and protein aggregates; (ii) the biogenesis of well-structured mitochondria;
(iii) the suppression of glial proliferation; (iv) the differentiation of newly
formed neurons in the spinal cord towards a specific phenotype. In this addendum
we focus on defective autophagy as a "leit motif" in ALS and the old and novel
features of lithium which bridge autophagy activation to concomitant effects
that may be useful for the treatment of a variety of neurodegenerative
disorders. In particular, the biogenesis of mitochondria and the increase of
calbindin D 28K-positive neurons, which are likely to support powerful
neuroprotection towards autophagy failure, mitochondriopathy and neuronal loss
in the spinal cord. Collaborators: D'Amour M, Souchon F, Lefebvre C, Blais L, Cardin E, Allard L,
Quessy G, Limbo A, Cabral K, Spinelli N, Robertson G, Lewis P, Grant IA,
Benstead TJ, Reidy SL, Hebert SL, Bouchard JP, Dionne A, Dupre N, Morel L, Roy
G, Tran TV, Turnbull J, Martin J, Genge A, Lavoie D, Wang JW, Bertone D,
Normandin K, Melanson M, McBride EV, O'Connell C, Worley S, Brophy-LeBlanc S,
Zinman L, McKinley J, Pinto H, Friedman Y, Iazzetta J, Chrichton B, Johnston W,
Kalra S, Sekhon R, Briemberg H, Krieger C, Fabros M, Poirier B, White C, Korngut
L, Mawani S, Munro S, Cameron C, Casey A, Ethans K, Olafson T, Shan RL, Hader W,
Ridley S, Bruce L, Munchinsky J, Dal Bello-Haas V, Shoesmith C, Strong M, Row A,
Findlater K, Verheyden J, Muthukumaran A, Tsimerinov E, Gruendler H, Kaufmann P,
Andrews J, Vecchio D, Heiman-Patterson T, Deboo A, Rojas L, Feldman S, Mazurek
M, Barr C, Deitch J, Bedlack R, Harward-Grace K, Boyette C, Tiryaki E, Bundlie
S, Leviton T, Rohde C, Swanson S, Pascuzzi RM, Kincaid JC, Snook RJ, Bodkin CL,
Guingrich S, Micheels A, Humma KG, Morrison BM, Rothstein J, Kimball RM, Clawson
LL, Riley KM, David WS, Wills AM, Atassi N, Goldenberg AR, Pulley DE, Berndt JL,
Castrillo-Viguera Mdel C, Bellanich M, Jaffa MN, Reilly-Tremblay C, Boylan K,
Kennelly K, Johnston A, DeSaro P, Fuqua P, Wright T, Ward C, Schoenberger S,
Swan A, DeOliveira G, Huser A, Kissel JT, Nash SM, Kolb SJ, Quick AD, Chelnick
SA, King WM, Fudge RP, Reynold J, Bartlett A, Scott K, Simmons Z, Clardy SL,
Brothers A, Schaeffer C, Stephens HE, Heisey H, Mottilla S, Saperstein D, Levine
T, Hank N, Clarke K, Simionescu L, Bradshaw D, Watson ML, Grosso M, Boevin T,
Heitzman D, Spears B, Hand SL, White L, Lomen-Hoerth C, Ahmed F, Kasarskis E,
Vanderpool K, Taylor D, Wells RS, Sitzlar SC, Sharma KR, Koggan D, Valdez S,
Gonzalez G, Perez M, Palomeque M, Weiss E, Tandan R, Singh P, Potter C, Phillips
LH, Burns TM, Solorzano G, Keller K, Warder J, Caress JB, Cartwright MS, Marandi
M, O'Neil C, Pestronk A, Harms M, Florence J, Townsend P, Vehe K, Malkus E,
Jani-Acsadi A, Lewis RA, Masse S, Mariani M, MacDonald JL, Genge A, Turnbull J,
Zinman L, Shoesmith C, Kaufmann P, Rothstein J, Aggarwal S, Cudkowicz M,
Schoenfeld D, Boylan KB, Conwit R, Shefner J, Brown R, Kasarskis E, Aggarwal S,
Cudkowicz M, Simpson E, Jackson KE, Sherman A, Yu H, Lanka V, Schnupp L, Deng J,
Padilla O, Badayan I, Yerramilli-Rao P, Rosenbaum E, Kearney M, Maloutas M,
Zinman I, McKinley J, Pinto H, Shefner J, Watson ML, Tindall K, Money K,
Varghese B, Lew B, Markis K, Hand H, Kaufman P, Andrews J, Vecchio D, Coffey C,
Benatar M, Joyce C, Trivedi M, Wisniewski S, Leventhal C, Russell J. BACKGROUND: Amyotrophic lateral sclerosis is a rapidly progressive
neurodegenerative disorder characterised by loss of motor neurons leading to
severe weakness and death from respiratory failure within 3-5 years. Riluzole
prolongs survival in ALS. A published report has suggested a dramatic effect of
lithium carbonate on survival. 44 patients were studied, with 16 randomly
selected to take LiCO3 and riluzole and 28 allocated to take riluzole alone. In
the group treated with lithium, no patients had died (i.e., 100% survival) at
the end of the study (15 months from entry), compared to 71% surviving in the
riluzole-only group. Although the trial can be criticised on several grounds,
there is a substantial rationale from other laboratory studies that lithium is
worth investigating therapeutically in amyotrophic lateral sclerosis.
METHODS/DESIGN: LiCALS is a multi-centre double-blind randomised parallel group
controlled trial of the efficacy, safety, and tolerability of lithium carbonate
(LiCO3) at doses to achieve stable 'therapeutic' plasma levels (0.4-0.8 mmol/L),
plus standard treatment, versus matched placebo plus standard treatment, in
patients with amyotrophic lateral sclerosis. The study will be based in the UK,
in partnership with the MND Association and DeNDRoN (the Dementias and
Neurodegnerative Diseases Clinical Research Network). 220 patients will be
recruited. All patients will be on the standard treatment for ALS of riluzole
100 mg daily. The primary outcome measure will be death from any cause at 18
months defined from the date of randomisation. Secondary outcome measures will
be changes in three functional rating scales, the ALS Functional Rating
Scale-Revised, The EuroQOL (EQ-5D), and the Hospital Anxiety and Depression
Scale.Eligible patients will have El Escorial Possible, Laboratory-supported
Probable, Probable or Definite amyotrophic lateral sclerosis with disease
duration between 6 months and 36 months (inclusive), vital capacity ≥ 60% of
predicted within 1 month prior to randomisation and age at least18 years.
DISCUSSION: Patient recruitment began in June 2009 and the last patient is
expected to complete the trial protocol in November 2011.
TRIAL REGISTRATION: Current controlled trials ISRCTN83178718. Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative
disorder; riluzole is marginally effective, and as a consequence a large number
of trials are regularly reported. Lithium raised marked enthusiasm based on the
report of a pilot study that suggested very positive results. Two previous
trials were negative, applying a different methodology. The reviewed article
reports the results of a third trial using a historical control group. In this
trial, lithium was detrimental to ALS progression. Two more trials testing
lithium in ALS are in progress. This study is discussed in the context of the
great competitive effort that was derived from the unsupported hope created by a
false-positive preliminary study. BACKGROUND: Preclinical studies have shown that lithium modifies pathological
cascades implicated in certain neurodegenerative disorders, such as Alzheimer's
disease (AD), Huntigton`s disease (HD), multiple system atrophy (MSA) and
amyotrophic lateral sclerosis (ALS). A critical question is whether these
pharmacodynamic properties of lithium translate into neurodegenerative diseases
modifying effects in human subjects.
METHODS: We reviewed all English controlled clinical trials published in PubMed,
PsycINFO, Embase, SCOPUS, ISI-Web with the use of lithium for the treatment of
neurodegenerative disorders between July 2004 and July 2014.
RESULTS: Lithium showed evidence for positive effects on cognitive functions and
biomarkers in amnestic mild cognitive impairment (aMCI, 1 study) and AD (2
studies), even with doses lower than those used for mood stabilisation. Studies
of Li in HD, MSA and CSI did not show benefits of lithium. However, due to
methodological limitations and small sample size, these studies may be
inconclusive. Studies in ALS showed consistently negative results and presented
evidence against the use of lithium for the treatment of this disease.
CONCLUSION: In absence of disease modifying treatments for any neurodegenerative
disorders, the fact that at least 3 studies supported the effect of lithium in
aMCI/AD is noteworthy. Future studies should focus on defining the dose range
necessary for neuroprotective effects to occur. Author information:
(1)From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E.,
F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics
and Research Support (M.J.C.E.), University Medical Centre Utrecht, the
Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdom
Dementia Research Institute Centre (A.R.J., W.S., A.S., C.E.S., A.A.-C.),
Department of Basic and Clinical Neuroscience, King's College London; Sheffield
Institute for Translational Neuroscience (SITraN) (P.J.S.), University of
Sheffield, South Yorkshire; Department of Clinical Neuroscience (P.N.L.),
Trafford Centre for Biomedical Research, Brighton and Sussex Medical School,
Falmer, Brighton; The Walton Centre NHS Trust (C.A.Y.), Liverpool, UK; Istituti
Clinici Scientifici Maugeri IRCSS (G.M.), Milan; Department of Neuroscience
(J.M.), Sant'Agostino-Estense Hospital and University of Modena and Reggio
Emilia, Modena; Department of Neurology (G.B.), Azienda Universitario
Ospedaliera di Cagliari and University of Cagliari; Istituti Clinici Scientifici
Maugeri IRCSS (P.V.), Mistretta, Italy; Rijnstate Ziekenhuis (E.V.), Arnhem, the
Netherlands; Rita Levi Montalcini' Department of Neuroscience (A.C.), ALS
Centre, University of Torino; and Azienda Ospedaliera Città della Salute e della
Scienza (A.C.), Turin, Italy.
(2)From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E.,
F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics
and Research Support (M.J.C.E.), University Medical Centre Utrecht, the
Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdom
Dementia Research Institute Centre (A.R.J., W.S., A.S., C.E.S., A.A.-C.),
Department of Basic and Clinical Neuroscience, King's College London; Sheffield
Institute for Translational Neuroscience (SITraN) (P.J.S.), University of
Sheffield, South Yorkshire; Department of Clinical Neuroscience (P.N.L.),
Trafford Centre for Biomedical Research, Brighton and Sussex Medical School,
Falmer, Brighton; The Walton Centre NHS Trust (C.A.Y.), Liverpool, UK; Istituti
Clinici Scientifici Maugeri IRCSS (G.M.), Milan; Department of Neuroscience
(J.M.), Sant'Agostino-Estense Hospital and University of Modena and Reggio
Emilia, Modena; Department of Neurology (G.B.), Azienda Universitario
Ospedaliera di Cagliari and University of Cagliari; Istituti Clinici Scientifici
Maugeri IRCSS (P.V.), Mistretta, Italy; Rijnstate Ziekenhuis (E.V.), Arnhem, the
Netherlands; Rita Levi Montalcini' Department of Neuroscience (A.C.), ALS
Centre, University of Torino; and Azienda Ospedaliera Città della Salute e della
Scienza (A.C.), Turin, Italy. [email protected]
[email protected]. In this review, we summarize the most important recent developments in the
treatment of amyotrophic lateral sclerosis (ALS). In terms of disease-modifying
treatment options, several drugs such as dexpramipexole, pioglitazone, lithium,
and many others have been tested in large multicenter trials, albeit with
disappointing results. Therefore, riluzole remains the only directly
disease-modifying drug. In addition, we discuss antisense oligonucleotides
(ASOs) as a new and potentially causal treatment option. Progress in symptomatic
treatments has been more important. Nutrition and ventilation are now an
important focus of ALS therapy. Several studies have firmly established that
noninvasive ventilation improves patients' quality of life and prolongs
survival. On the other hand, there is still no consensus regarding best
nutritional management, but big multicenter trials addressing this issue are
currently ongoing. Evidence regarding secondary symptoms like spasticity, muscle
cramps or sialorrhea remains generally scarce, but some new insights will also
be discussed. Growing evidence suggests that multidisciplinary care in
specialized clinics improves survival. Lithium is used as a first line treatment in bipolar disorder. The
neuroprotective effects of lithium in this indication tend to be well known and
are mediated by its action on two enzymes: glycogen synthase kinase-3 and
inositol monophosphatase-1. Preclinical and clinical studies seek to evaluate
the neuroprotective effect of lithium in neurodegenerative disorders. The aims
of this literature review is to gather clinical studies that investigated the
efficacy of lithium in neurodegenerative diseases, using a systematic method
based on PubMed data. Results were found concerning Alzheimer's disease and
related dementias, Huntington's disease, amyotrophic lateral sclerosis and
spino-cerebellar ataxia. Lithium exposure showed a potential neuroprotective
effect in studies on psychiatric populations with a lower prevalence of
Alzheimer's disease in exposed patients. In patients with mild cognitive
impairment, lithium would be associated with clinical improvement and a lower
level of cerebrospinal phosphorylated tau protein. Lithium would allow at least
a partial improvement in symptoms, including suicidal thoughts, in Huntington's
disease. Despite several positive case reports and short studies, further
controlled researches have failed to substantiate any positive effects of
lithium exposure in amyotrophic lateral sclerosis. In spinocerebellar ataxia,
introduction of lithium may be of benefits in terms of improvement of cerebellar
symptoms. Large randomized controlled trials are required to asses the effect of
early exposure lithium in these indications, based on reliable biological
markers of disease. |
Should dacomitinib be used for treatment of glioblastoma patients? | No, dacomitinib has a limited single-agent activity in recurrent glioblastoma with EGFR amplification. | BACKGROUND: We conducted a multicenter, 2-stage, open-label, phase II trial to
assess the efficacy and safety of dacomitinib in adult patients with recurrent
glioblastoma (GB) and epidermal growth factor receptor gene (EGFR) amplification
with or without variant III (EGFRvIII) deletion.
METHODS: Patients with first recurrence were enrolled in 2 cohorts. Cohort A
included patients with EGFR gene amplification without EGFRvIII mutation. Cohort
B included patients with EGFR gene amplification and EGFRvIII mutation.
Dacomitinib was administered (45 mg/day) until disease progression/unacceptable
adverse events (AEs). Primary endpoint was progression-free survival (PFS; RANO
criteria) at 6 months (PFS6).
RESULTS: Thirty patients in Cohort A and 19 in Cohort B were enrolled. Median
age was 59 years (range 39-81), 65.3% were male, and Eastern Cooperative
Oncology Group Performance Status 0/1/2 were 10.2%/65.3%/24.5%, respectively.
PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months
(Cohort A: 2.7 mo; Cohort B: 2.6 mo). Four patients were progression free at 6
months and 3 patients were so at 12 months. Median overall survival was 7.4
months (Cohort A: 7.8 mo; Cohort B: 6.7 mo). The best overall response included
1 complete response and 2 partial responses (4.1%). Stable disease was observed
in 12 patients (24.5%: eight in Cohort A and four in Cohort B). Diarrhea and
rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4
drug-related AEs.
CONCLUSIONS: Dacomitinib has a limited single-agent activity in recurrent GB
with EGFR amplification. The detailed molecular characterization of the 4
patients with response in this trial can be useful to select patients who could
benefit from dacomitinib. |
Which molecular does daratumumab target? | Daratumumab is an anti-CD38 antibody. | Natural killer (NK) cell-based immunotherapy is a promising novel approach to
treat cancer. However, NK cell function has been shown to be potentially
diminished by factors common in the tumor microenvironment (TME). In this study,
we assessed the synergistic potential of antibody-dependent cell-mediated
cytotoxicity (ADCC) and killer immunoglobin-like receptor (KIR)-ligand
mismatched NK cells to potentiate NK cell antitumor reactivity in multiple
myeloma (MM). Hypoxia, lactate, prostaglandin E2 (PGE2) or combinations were
selected to mimic the TME. To investigate this, NK cells from healthy donors
were isolated and NK cell ADCC capacity in response to MM cells was assessed in
flow cytometry-based cytotoxicity and degranulation (CD107a) assays in the
presence of TME factors. Hypoxia, lactate and PGE2 reduced cytotoxicity of NK
cells against myeloma target cells. The addition of daratumumab (anti-CD38
antibody) augmented NK-cell cytotoxicity against target cells expressing high
CD38, but not against CD38 low or negative target cells also in the presence of
TME. Co-staining for inhibitory KIRs and NKG2A demonstrated that daratumumab
enhanced degranulation of all NK cell subsets. Nevertheless, KIR-ligand
mismatched NK cells were slightly better effector cells than KIR-ligand matched
NK cells. In summary, our study shows that combination therapy using strategies
to maximize activating NK cell signaling by triggering ADCC in combination with
an approach to minimize inhibitory signaling through a selection of KIR-ligand
mismatched donors, can help to overcome the NK-suppressive TME. This can serve
as a platform to improve the clinical efficacy of NK cells. |
What is etarfolatide used for? | Etarfolatide in the form of 99mTc-etarfolatide is used as a companion imaging agent | PURPOSE: Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that
binds to the folate receptor (FR), which is expressed on the majority of
epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide
combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The
utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in
selecting patients likely to benefit from vintafolide was also examined.
PATIENTS AND METHODS: Women with recurrent platinum-resistant ovarian cancer who
had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1
ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without
vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide
scanning was optional. The primary objective was to compare progression-free
survival (PFS) between the groups.
RESULTS: The intent-to-treat population comprised 149 patients. Median PFS was
5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively
(hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit
was observed in patients with 100% of lesions positive for FR, with median PFS
of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P
= .013). The group of patients with FR-positive disease (10% to 90%) experienced
some PFS improvement (HR, 0.873), whereas patients with disease that did not
express FR experienced no PFS benefit (HR, 1.806).
CONCLUSION: Vintafolide plus PLD is the first combination to demonstrate an
improvement over standard therapy in a randomized trial of patients with
platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to
benefit from vintafolide. BACKGROUND: This report examines (99m)Tc-etarfolatide imaging to identify the
presence of folate receptor (FR) on tumors of women with recurrent/refractory
ovarian or endometrial cancer and correlates expression with response to
FR-targeted therapy (vintafolide).
PATIENTS AND METHODS: In this phase II, single-arm, multicenter study, patients
with advanced ovarian cancer were imaged with (99m)Tc-etarfolatide before
vintafolide treatment. Up to 10 target lesions (TLs) were selected based on
Response Evaluation Criteria In Solid Tumors criteria using computed tomography
scans. Single-photon emission computed tomography images of TLs were assessed
for (99m)Tc-etarfolatide uptake as either FR positive or negative. Patients were
categorized by percentage of TLs positive and grouped as FR(100%), FR(10%-90%),
and FR(0%). Lesion and patient response were correlated with etarfolatide
uptake.
RESULTS: Forty-nine patients were enrolled; 43 were available for analysis. One
hundred thirty-nine lesions were (99m)Tc-etarfolatide evaluable: 110 FR positive
and 29 FR negative. Lesion disease control rate (DCR = stable or response) was
observed in 56.4% of FR-positive lesions versus 20.7% of FR-negative lesions (P
< 0.001). Patient DCR was 57%, 36%, and 33% in FR(100%), FR(10%-90%), and FR(0%)
patients, respectively. Median overall survival was 14.6, 9.6, and 3.0 months in
FR(100%), FR(10%-90%), and FR(0%) patients, respectively.
CONCLUSIONS: Overall response to FR-targeted therapy and DCR correlate with FR
positivity demonstrated by (99m)Tc-etarfolatide imaging.
CLINICAL TRIAL NUMBER: NCT00507741. Conventional cancer treatment modalities have several limitations including lack
of sufficient efficacy, serious untoward toxicity, as well as innate and
acquired drug resistance. In contrast, targeted imaging agents can identify
patients with receptors overexpressed on the surface of cancer cells, thus
allowing appropriate selection of patients for personalized treatment with a
desirable targeted therapeutic. The folate receptor (FR) has been identified as
a new molecularly targeted entity, which is highly overexpressed on the surface
of a spectrum of solid tumor cells, including ovarian, kidney, lung, brain,
endometrial, colorectal, pancreatic, gastric, prostate, testicular, bladder,
head and neck, breast, and non-small cell lung cancer. Folic acid conjugation is
a novel approach for targeting FR-expressing tissues for personalized treatment.
With the development of FRα-targeted therapies comes a concomitant prerequisite
for reliable methods for the quantification of FRα tissue expression. Therefore,
attaching a radioactive probe to folic acid to target diseased tissue has become
a novel and powerful imaging technique. Currently available diagnostic tools
frequently require invasive surgical biopsy. In contrast, the noninvasive
single-photon emission computed tomography-based companion imaging agent,
(99m)Tc-etarfolatide ((99m)Tc-EC20), is in development for use as a companion
diagnostic with the FRα-targeted folate conjugate, vintafolide (EC145), to
identify patients whose tumors express FRα. Vintafolide is a folic acid
conjugate of Vinca alkaloid (desacetylvinblastine hydrazide) that targets
FRα-expressing tumors, thereby disrupting microtubule polymerization.
(99m)Tc-etarfolatide is taken up by FR-positive tumors and allows for
noninvasive, whole-body monitoring of FRα expression status throughout
treatment. The combination of vintafolide plus etarfolatide has been evaluated
in three Phase 2 studies for the treatment of various solid tumors, including
ovarian, endometrial, peritoneal, and platinum-resistant ovarian cancer, as well
as lung cancer. Patients with FR-positive tumors, as identified by etarfolatide
uptake, have had better clinical outcomes than patients with FR-negative tumors,
indicating the potential of etarfolatide as a companion biomarker for predicting
vintafolide response. Targeted therapies combined with a reliable companion
diagnostic test represent a novel approach toward efficient personalized
medicine for maligt and nonmaligt disorders. Furthermore, the recent
availability of the crystal structures of FRα and FRβ in complex with folates
and antifolates forms a realistic basis for the rational design and
implementation of novel FR-targeted drugs for the treatment of cancer and
inflammatory disorders. OBJECTIVE: Technetium etarfolatide ((99m)Tc-EF) is a radioactive diagnostic
imaging agent that was developed to assess the expression of folate receptors in
tumors. Administering folic acid prior to the administration of (99m)Tc-EF has
been shown to improve SPECT images. Here, we conducted a phase I clinical trial
to assess the safety, pharmacokinetics, and radiation dosimetry of (99m)Tc-EF
injection following pre-administration of folic acid in healthy Japanese male
adults.
METHODS: Six healthy Japanese male adults were enrolled in the study. Folic acid
was intravenously administered, followed 1-3 min later by an intravenous
injection of (99m)Tc-EF (740 MBq ± 20 %). Assessments of subjective symptoms and
objective findings, electrocardiograms, physical examination, and laboratory
tests were performed before and up to 7 days after the injection to assess the
safety of (99m)Tc-EF. Blood and urine collections and whole-body planar imaging
were conducted at various time points up to 24 h after the injection to assess
the pharmacokinetics of (99m)Tc-EF. The internal radiation dosimetry was
calculated based on the pharmacokinetics results using the MIRD method.
RESULTS: Five adverse events were observed in three subjects (50 %) after
administration of the folic acid and (99m)Tc-EF, while these events were mild
and non-serious. Of those five events, three were considered to be related to
the administered agents. The radioactivity in blood rapidly decreased and showed
a biphasic profile. The activity of (99m)Tc-EF at 5 min post injection was
largest in the bone marrow, followed by the liver and kidneys, and had decreased
within 24 h in all organs/tissues without appreciable retention. The
pharmacokinetics results suggested that (99m)Tc-EF was mainly eliminated by
kidney. The results also suggested that when administered at 925 MBq of
(99m)Tc-EF, which is the maximum dose generally used for clinical trials in
other countries, the corresponding effective dose of (99m)Tc-EF is equal to or
less than those determined for the current radioactive diagnostic imaging
agents.
CONCLUSIONS: The results of this study assessing the safety and radiation
dosimetry of (99m)Tc-EF with folic acid pre-administration suggested that folic
acid and (99m)Tc-EF should be appropriate for further studies. No
pharmacokinetics concerns were noted. OBJECTIVE: Through binding to folate receptor-β (FR-β), the new (99m)Tc-EC20
(Etarfolatide) imaging technique detects activated but not resting macrophages
in vivo. The goal of this study was to investigate macrophage-related
inflammation in osteoarthritis (OA).
METHODS: Twenty-five individuals (50 knees) with symptomatic OA of at least one
knee underwent SPECT-CT imaging of both knees and planar imaging of the whole
body after injection of Etarfolatide. Scans and knee radiographs were scored
blinded to clinical information including knee and other joint site pain
severity. Measures of association controlled for age, gender, body mass index
(BMI) and employed repeated measures to adjust for correlation between knees.
DESIGN: Activated macrophages were present in the majority (76%) of knees. The
quantity of knee-related macrophages was significantly associated with knee pain
severity (R = 0.60, P < 0.0001) and radiographic knee OA severity including
joint space narrowing (R = 0.68, P = 0.007), and osteophyte (R = 0.66,
P = 0.001). Macrophages were also localized to joints commonly affected by OA
including hand finger joints (12%), thumb bases (28%), shoulders (26%), great
toes (18%) and ankles (12%). The presence of joint pain at fingers, wrists,
ankles and great toes was significantly positively associated with presence of
activated macrophages at these sites (P < 0.0001-0.04).
CONCLUSIONS: This study provides the first direct in vivo evidence for
macrophage involvement in OA in a substantial proportion of human knees. The
association of quantity of activated macrophages with radiographic knee OA
severity and joint symptoms suggests that drugs targeting macrophages and
macrophage-associated inflammatory pathways may have the potential to be both
symptom and structure modifying. |
What is the function of Plasminogen activator inhibitor 1? | Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of tissue-type plasminogen activator (tPA) and plays a critical role in fibrinolysis. | OBJECTIVES: Plasminogen activator inhibitor-1 (PAI-1), a crucial regulator of
fibrinolysis, is increased in sepsis, but its values in predicting disease
severity or mortality outcomes have been controversial. Therefore, we conducted
a systematic review and meta-analysis of its predictive values in sepsis.
METHODS: PubMed and Embase were searched until August 18, 2017 for studies that
evaluated the relationships between PAI-1 levels and disease severity or
mortality in sepsis.
RESULTS: A total of 112 and 251 entries were retrieved from the databases, of
which 18 studies were included in the final meta-analysis. A total of 4,467
patients (36% male, mean age: 62 years, mean follow-up duration: 36 days) were
analyzed. PAI-1 levels were significantly higher in non-survivors than survivors
[odds ratios (OR): 3.93, 95% confidence interval (CI): 2.31-6.67, P < 0.0001]
and in patients with severe sepsis than in those less severe sepsis (OR: 3.26,
95% CI: 1.37-7.75, P = 0.008).
CONCLUSION: PAI-1 is a significant predictor of disease severity and all-cause
mortality in sepsis. Although the predictive values of PAI-1 reached statistical
significance, the clinical utility of PAI-1 in predicting outcomes will require
carefully designed prospective trials. |
What is the mechanism of action of durvalumab? | Durvalumab is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1, which binds to PD-1 and CD80, but not to PD-L2. It is Immune checkpoint inhibitor used of treating advanced cancer patients, principally antibodies against CTLA-4 and PD-1 or PD-L1. | Anti-programmed cell death-1 and anti-programmed cell death ligand-1 (PD-L1)
monotherapies have shown promising clinical activity in advanced, refractory
non-small-cell lung cancer (NSCLC), but antitumor activity appears to be greater
in patients with PD-L1(+) tumors compared with patients harboring PD-L1(-)
tumors. Combining the anti-PD-L1 antibody durvalumab and the anti-cytotoxic
T-lymphocyte antigen 4 antibody tremelimumab offers the potential for antitumor
activity in patients with advanced NSCLC, regardless of PD-L1 tumor status.
ARCTIC (NCT02352948) is a global, phase III, randomized, open-label multicenter
study in patients with advanced NSCLC assessing the safety and clinical activity
of durvalumab versus standard of care (SoC; erlotinib, gemcitabine, or
vinorelbine) in patients with PD-L1(+) tumors (≥25% of tumor cells with membrane
staining using VENTANA PD-L1 [SP263] CDx Assay) (Sub-study A) and the
combination of durvalumab + tremelimumab or either agent as monotherapy versus
SoC in patients with PD-L1(-) tumors (Sub-study B). Eligible patients are those
with locally advanced or metastatic NSCLC (Stage IIIB/IV), without epidermal
growth factor receptor tyrosine kinase activating mutations or anaplastic
lymphoma kinase rearrangements, who have received at least 2 prior systemic
regimens, including 1 platinum-based chemotherapy regimen. Co-primary endpoints
are progression-free survival and overall survival. Secondary endpoints include
the proportion of patients alive at 12 months, objective response rate, duration
of response, progression-free survival at 6 and 12 months, safety and
tolerability, pharmacokinetics, immunogenicity, and quality of life. The
exploratory endpoints will assess potential biomarkers of treatment response.
Recruitment started in January 2015 and is ongoing. Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition
and/or reduced vascular endothelial growth factor signaling by vascular
endothelial growth factor receptor inhibition may complement antitumor activity
of immune checkpoint blockade. We hypothesize the programmed death-ligand 1
(PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable
and active in recurrent women's cancers. Patients and Methods This phase I study
tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was
administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either
olaparib tablets twice daily or cediranib on two schedules. The primary end
point was the recommended phase II dose (RP2D). Response rate and
pharmacokinetic analysis were secondary end points. Results Between June 2015
and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4
weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days
off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The
cediranib intermittent schedule (n = 6) was examined because of recurrent grade
2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily
schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight),
diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary
hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus
intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and
fatigue (one of six). Exposure to durvalumab increased cediranib area under the
curve and maximum plasma concentration on the daily, but not intermittent,
schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable
diseases ≥ 4 months (median, 8 months [4 to 14.5 months]) were seen in patients
who received durvalumab plus olaparib, yielding an 83% disease control rate. Six
partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to
≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus
cediranib, for a 50% response rate and a 75% disease control rate. Response to
therapy was independent of PD-L1 expression. Conclusion To our knowledge, this
is the first reported anti-PD-L1 plus olaparib or cediranib combination therapy.
The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib
are tolerable and active. Phase II studies with biomarker evaluation are
ongoing. Intravenous durvalumab (Imfinzi™; AstraZeneca) is a fully human monoclonal
antibody that blocks programmed cell death ligand-1 binding to its receptors
(PD-1 and CD80), resulting in enhanced T-cell responses against cancer cells.
The US FDA has granted durvalumab accelerated approval for the treatment of
patients with locally advanced or metastatic urothelial carcinoma who have
disease progression during or following platinum-containing chemotherapy, or
within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
Durvalumab ± tremelimumab is under phase III clinical trials in urothelial
carcinoma, non-small cell lung cancer, small cell lung cancer and head and neck
squamous cell carcinoma. The drug is also being evaluated in phase I or II
clinical trials in a wide range of solid tumours and haematological
maligcies. This article summarizes the milestones in the development of
durvalumab leading to this first approval for urothelial carcinoma. Immune checkpoint inhibitors (ICI) are now a therapeutic option for advanced
non-small cell lung cancer (NSCLC) patients. ICI, such as the PD-1 inhibitors
nivolumab and pembrolizumab and the PD-L1 inhibitor atezolizumab, have already
been marketed for the treatment of pretreated patients with advanced NSCLC.
Other notable PD-L1 inhibitors under development include avelumab and
durvalumab. Areas covered: This article reviews literature on durvalumab
development, from the preclinical data to the results of phase III clinical
trials, whether published or presented at international scientific conferences.
Ongoing clinical trials were also reviewed. Expert opinion: Early phase trials
of durvalumab monotherapy (and in combination) have demonstrated activity in
advanced NSCLC patients and it has demonstrated a good safety profile. The
authors believe that durvalumab will likely play an important role in future
treatment strategies for NSCLC. The PACIFIC trial assessing durvalumab after
standard chemoradiotherapy for locally advanced NSCLC has already met its
primary endpoint and the potential of durvalumab will be reinforced if phase III
randomized studies of first-line (MYSTIC trial) and second or subsequent (ARCTIC
trial) lines of therapy demonstrate superiority over the current standard of
care. In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab,
durvalumab, and avelumab, were approved by the FDA for the treatment of multiple
advanced cancers. And many other anti-PD-L1 antibodies are under clinical
trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and
avelumab have been determined, revealing details of the antigen-antibody
interactions. However, it is still unknown how atezolizumab and durvalumab
specifically recognize PD-L1, although this is important for investigating novel
binding sites on PD-L1 targeted by other therapeutic antibodies for the design
and improvement of anti-PD-L1 agents. Here, we report the crystal structures of
PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise
epitopes involved and the structural basis for PD-1/PD-L1 blockade by these
antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1
antibodies provides a better understanding of the mechanism of PD-L1 blockade as
well as new insights into the rational design of improved anti-PD-L1
therapeutics. BACKGROUND: Most patients with locally advanced, unresectable, non-small-cell
lung cancer (NSCLC) have disease progression despite definitive
chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3
study compared the anti-programmed death ligand 1 antibody durvalumab as
consolidation therapy with placebo in patients with stage III NSCLC who did not
have disease progression after two or more cycles of platinum-based
chemoradiotherapy.
METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab
(at a dose of 10 mg per kilogram of body weight intravenously) or placebo every
2 weeks for up to 12 months. The study drug was administered 1 to 42 days after
the patients had received chemoradiotherapy. The coprimary end points were
progression-free survival (as assessed by means of blinded independent central
review) and overall survival (unplanned for the interim analysis). Secondary end
points included 12-month and 18-month progression-free survival rates, the
objective response rate, the duration of response, the time to death or distant
metastasis, and safety.
RESULTS: Of 713 patients who underwent randomization, 709 received consolidation
therapy (473 received durvalumab and 236 received placebo). The median
progression-free survival from randomization was 16.8 months (95% confidence
interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to
7.8) with placebo (stratified hazard ratio for disease progression or death,
0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival
rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was
44.2% versus 27.0%. The response rate was higher with durvalumab than with
placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was
longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months).
The median time to death or distant metastasis was longer with durvalumab than
with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events
occurred in 29.9% of the patients who received durvalumab and 26.1% of those who
received placebo; the most common adverse event of grade 3 or 4 was pneumonia
(4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab
group and 9.8% of those in the placebo group discontinued the study drug because
of adverse events.
CONCLUSIONS: Progression-free survival was significantly longer with durvalumab
than with placebo. The secondary end points also favored durvalumab, and safety
was similar between the groups. (Funded by AstraZeneca; PACIFIC
ClinicalTrials.gov number, NCT02125461 .). Immune checkpoint inhibitors (ICIs) are a key component of treating advanced
cancer patients, principally antibodies against CTLA-4 and PD-1 or PD-L1.
Durvalumab (MEDI4736) is a selective, high-affinity, human IgG1 monoclonal
antibody that blocks PD-L1, which binds to PD-1 and CD80, but not to PD-L2.
Single-agent durvalumab showed clinical efficacy and a manageable safety profile
in advanced non-small-cell lung cancer, particularly the ≥25% PD-L1+ population.
Durvalumab is under evaluation in early, locally advanced and advanced disease
as monotherapy and combined with ICIs, targeted therapies, chemotherapy and
radiotherapy. Impressive activity has been recently reported after
chemoradiation in locally advanced patients; promising activity was observed
with other ICI combinations, and potentially with other drugs including
platinum-based chemotherapy. In contrast, early data reveal lower response rates
in EGFR and ALK-positive patients. Clinical trials are currently ongoing to evaluate the utility of antibodies
against programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1),
and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) as monotherapy or
combination therapy in patients with hepatocellular carcinoma (HCC). Results of
combination treatment with the anti-PD-L1 antibody durvalumab and the
anti-CTLA-4 antibody tremelimumab in HCC were presented at the 2017 annual
meeting of the ASCO (American Society of Clinical Oncology). Response rates were
25% in all 40 patients and 40% in the 20 uninfected patients, both of which are
encouraging. Transcatheter arterial chemoembolization and radiofrequency
ablation can activate tumor immunogenicity by releasing tumor-associated antigen
and by inducing the migration of cytotoxic T lymphocytes to small intrahepatic
metastatic nodules. Subsequent administration of anti-PD-1 antibody could
control these small intrahepatic metastatic nodules. In a nonclinical study, the
combination of pembrolizumab and lenvatinib inhibited the cancer
immunosuppressive environments induced by tumor-associated macrophages and
regulatory T cells. This, in turn, decreased the levels of TGF-β and IL-10, the
expression of PD-1, and the inhibition of Tim-3, triggering anticancer immunity
mediated by immunostimulatory cytokines such as IL-12. Studies such as these may
provide insight into the appropriate molecular targeted agents to be used with
immune checkpoint inhibitors. 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. Immunotherapy has revolutionized cancer care in the modern era of oncology.
Research in immunotherapy has led to important advances in the treatment of
melanoma, non-small cell lung cancer and other maligcies using checkpoint
inhibition. Multiple systemic immunotherapies have been approved or are
currently being investigated for the management of urothelial maligcies (1).
Five antibodies targeting the programmed cell death protein 1--programmed cell
death 1 ligand 1 (PD-1--PD-L1) pathway have been approved by the U.S. Food and
Drug Administration (FDA) for the management of various maligcies:
pembrolizumab, nivolumab, atezolizumab, durvalumab and avelumab. Recent
publications illustrate that in specific stages, immunotherapy is more effective
than chemotherapy with a better toxicity profile (1). Currently, the only
FDA-approved indication for the anti-PD-L1 monoclonal antibody durvalumab
(MEDI-4736) is locally advanced or metastatic urothelial carcinoma that has
progressed during or following platinum-based chemotherapy within 12 months of
treatment. This article summarizes the milestones in the development of
durvalumab leading to its approval for urothelial carcinoma. BACKGROUND: Immune checkpoint inhibitors are a new standard of care for patients
with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or
anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical
benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has
not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in
three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour
expression of PD-L1.
METHODS: ATLANTIC is a phase 2, open-label, single-arm trial at 139 study
centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC
with disease progression following at least two previous systemic regimens,
including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if
indicated); were aged 18 years or older; had a WHO performance status score of 0
or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung
cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1
antibody; and any previous grade 3 or worse immune-related adverse event while
receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC
with at least 25%, or less than 25%, of tumour cells with PD-L1 expression.
Patients in cohorts 2 and 3 had EGFR-/ALK- NSCLC; cohort 2 included patients
with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and
cohort 3 included patients with at least 90% of tumour cells with PD-L1
expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via
intravenous infusion, for up to 12 months. Retreatment was allowed for patients
who benefited but then progressed after completing 12 months. The primary
endpoint was the proportion of patients with increased tumour expression of
PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour
cells in cohort 3) who achieved an objective response, assessed in patients who
were evaluable for response per independent central review according to RECIST
version 1.1. Safety was assessed in all patients who received at least one dose
of durvalumab and for whom any post-dose data were available. The trial is
ongoing, but is no longer open to accrual, and is registered with
ClinicalTrials.gov, number NCT02087423.
FINDINGS: Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and
received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among
patients with at least 25% of tumour cells expressing PD-L1 who were evaluable
for objective response per independent central review, an objective response was
achieved in 9 (12·2%, 95% CI 5·7-21·8) of 74 patients in cohort 1 and 24 (16·4%,
10·8-23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2-43·3) of 68
patients achieved an objective response. Grade 3 or 4 treatment-related adverse
events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in
cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most
common treatment-related grade 3 or 4 adverse events were pneumonitis (four
patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three
[1%]), infusion-related reaction (three [1%]), elevated aspartate
aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two
[<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events
occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort
1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most
common serious adverse events overall were pneumonitis (five patients [1%]),
fatigue (three [1%]), and infusion-related reaction (three [1%]).
Immune-mediated events were manageable with standard treatment guidelines.
INTERPRETATION: In patients with advanced and heavily pretreated NSCLC, the
clinical activity and safety profile of durvalumab was consistent with that of
other anti-PD-1 and anti-PD-L1 agents. Responses were recorded in all cohorts;
the proportion of patients with EGFR-/ALK- NSCLC (cohorts 2 and 3) achieving a
response was higher than the proportion with EGFR+/ALK+ NSCLC (cohort 1)
achieving a response. The clinical activity of durvalumab in patients with EGFR+
NSCLC with ≥25% of tumour cells expressing PD-L1 was encouraging, and further
investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted.
FUNDING: AstraZeneca. BACKGROUND: Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed
good activity when used alone in patients with mesothelioma, but did not improve
the overall survival of patients who failed on first-line or second-line
chemotherapy compared with placebo in the DETERMINE study. We aimed to
investigate the efficacy and safety of first-line or second-line tremelimumab
combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with
maligt mesothelioma.
METHODS: In this open-label, non-randomised, phase 2 trial, patients with
unresectable pleural or peritoneal mesothelioma received intravenous
tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4
weeks for four doses, followed by maintece intravenous durvalumab at the same
dose and schedule for nine doses. The primary endpoint was the proportion of
patients with an immune-related objective response according to the
immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST;
for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal
mesothelioma). The primary analysis was done by intention to treat, whereas the
safety analysis included patients who received at least one dose of study drug.
This trial is registered with the European Clinical Trials Database, number
2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but
no longer recruiting patients.
FINDINGS: From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were
enrolled and received at least one dose each of tremelimumab and durvalumab.
Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%)
of 40 patients had an immune-related objective response (all partial responses;
confirmed in ten patients), with a median response duration of 16·1 months (IQR
11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%)
had disease control. Median immune-related progression-free survival was 8·0
months (95% CI 6·7-9·3), median progression-free survival was 5·7 months
(1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline
tumour PD-L1 expression did not correlate with the proportion of patients who
had an immune-related objective response or immune-related disease control, with
immune-related progression-free survival, or with overall survival. 30 (75%)
patients experienced treatment-related adverse events of any grade, of whom
seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related
toxicity was generally manageable and reversible with protocol guidelines.
INTERPRETATION: The combination of tremelimumab and durvalumab appeared active,
with a good safety profile in patients with mesothelioma, warranting further
exploration.
FUNDING: Network Italiano per la Bioterapia dei Tumori Foundation, Associazione
Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori. In non-small cell lung cancer (NSCLC), immunotherapy is one of today's most
important and ground-breaking systemic treatments, mainly represented by
antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and
programmed death protein 1 or ligand 1 (PD-1/PD-L1). Durvalumab (MEDI4736) is a
high-affinity human IgG1 monoclonal antibody that binds to PD-1 and CD80,
blocking PD-L1, but not PD-L2. Areas covered: In advanced NSCLC patients,
durvalumab has demonstrated activity and acceptable tolerability, particularly
with ≥25% PD-L1 tumor expression in the EGFR and ALK wild-type population.
However, preliminary data have shown lower efficacy in EGFR mutant and
ALK-positive patients. The results from the recent PACIFIC study in locally
advanced patients have placed durvalumab as standard of care in consolidation
after chemoradiation, leading to Food and Drug Administration (FDA) approval.
Expert commentary: Early data suggest promising activity for durvalumab with the
CTLA-4 inhibitor tremelimumab, regardless of PD-L1 expression, and potentially
in combination with other drugs such as platinum-doublet chemotherapy. However,
treatment-related toxicity associated with the combinations is an important
aspect of the benefit-risk evaluation in the decision-making process. Results of
ongoing phase III trials will provide illuminating data to confirm the place of
durvalumab in the management of NSCLC patients. PURPOSE OF REVIEW: Despite aggressive treatment based on definitive
chemoradiotherapy, 5-year overall survival in unresectable stage III nonsmall
cell lung cancer remains poor (15-20%). The novel immunotherapy based on immune
checkpoint inhibitors (ICIs) presents as the therapeutic 'Holly Grail' in lung
cancer treatment.
RECENT FINDINGS: Preclinical models provide evidence of
immunotherapy-radiotherapy (IM-RT) synergy. The exposure to ionizing radiation
turns tumor in an in-situ vaccine, primes the innate immune system, increases
immunotherapy efficacy by overcoming the immunosuppressive microenvironment of
immune-resistant tumors and promotes a systemic, out-of-field antitumor
T-cell-mediated response called abscopal effect. The immunomodulatory and
abscopal effects of radiotherapy can be further enhanced by combining with
systemic immunotherapies. The phase III START trial proved that liposomal
vaccine - tecemotide (L-BLP25) administered as maintece therapy after
concurrent chemoradiotherapy (CRT) in LA-NSCLC prolongs survival. In the phase
III PACIFIC trial consolidation with durvalumab, an anti-PDL-1 antibody, was
associated with survival benefit in patients diagnosed with LA-NSCLC who
responded to concurrent chemoradiotherapy.
SUMMARY: PACIFIC trial results are expected to definitely establish durvalumab
as standard consolidation strategy in LA-NSCLC. Many clinical trials are ongoing
in the field of immunoradiotherapy in LA-NSCLC to define the optimal conditions
for this therapeutic combination. |
Which tool has been developed for GPU-accelerated alignment of bisulfite-treated DNA sequences? | The alignment of bisulfite-treated DNA sequences (BS-seq reads) to a large genome involves a significant computational burden beyond that required to align non-bisulfite-treated reads. In the analysis of BS-seq data, this can present an important performance bottleneck that can be mitigated by appropriate algorithmic and software-engineering improvements. One strategy is to modify the read-alignment algorithms by integrating the logic related to BS-seq alignment, with the goal of making the software implementation amenable to optimizations that lead to higher speed and greater sensitivity than might otherwise be attainable. This strategy was evaluated using Arioc, a short-read aligner that uses GPU (general-purpose graphics processing unit) hardware to accelerate computationally-expensive programming logic. | MOTIVATION: The alignment of bisulfite-treated DNA sequences (BS-seq reads) to a
large genome involves a significant computational burden beyond that required to
align non-bisulfite-treated reads. In the analysis of BS-seq data, this can
present an important performance bottleneck that can be mitigated by appropriate
algorithmic and software-engineering improvements. One strategy is to modify the
read-alignment algorithms by integrating the logic related to BS-seq alignment,
with the goal of making the software implementation amenable to optimizations
that lead to higher speed and greater sensitivity than might otherwise be
attainable.
RESULTS: We evaluated this strategy using Arioc, a short-read aligner that uses
GPU (general-purpose graphics processing unit) hardware to accelerate
computationally-expensive programming logic. We integrated the BS-seq
computational logic into both GPU and CPU code throughout the Arioc
implementation. We then carried out a read-by-read comparison of Arioc's
reported alignments with the alignments reported by well-known CPU-based BS-seq
read aligners. With simulated reads, Arioc's accuracy is equal to or better than
the other read aligners we evaluated. With human sequencing reads, Arioc's
throughput is at least 10 times faster than existing BS-seq aligners across a
wide range of sensitivity settings.
AVAILABILITY AND IMPLEMENTATION: The Arioc software is available for download at
https://github.com/RWilton/Arioc. It is released under a BSD open-source
license.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online. |
Which disease is gemtuzumab ozogamicin used for? | Gemtuzumab ozogamicin is used for the treatment of acute myeloid leukemia | Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-drug conjugate for the
treatment of acute myeloid leukemia (AML). Although GO shows a narrow
therapeutic window in early clinical studies, recent reports detailing a
modified dosing regimen of GO can be safely combined with induction
chemotherapy, and the combination provides significant survival benefits in AML
patients. Here we tested whether the survival benefits seen with the combination
arise from the enhanced reduction of chemoresidual disease and leukemic
initiating cells (LICs). Herein, we use cell line and patient-derived xenograft
(PDX) AML models to evaluate the combination of GO with daunorubicin and
cytarabine (DA) induction chemotherapy on AML blast growth and animal survival.
DA chemotherapy and GO as separate treatments reduced AML burden but left
significant chemoresidual disease in multiple AML models. The combination of GO
and DA chemotherapy eliminated nearly all AML burden and extended overall
survival. In two small subsets of AML models, chemoresidual disease following DA
chemotherapy displayed hallmark markers of leukemic LICs (CLL1 and CD34). In
vivo, the two chemoresistant subpopulations (CLL1+/CD117- and CD34+/CD38+)
showed higher ability to self-renewal than their counterpart subpopulations,
respectively. CD33 was coexpressed in these functional LIC subpopulations. We
demonstrate that the GO and DA induction chemotherapy combination more
effectively eliminates LICs in AML PDX models than either single agent alone.
These data suggest that the survival benefit seen by the combination of GO and
induction chemotherapy, nonclinically and clinically, may be attributed to the
enhanced reduction of LICs. |
What is GeneWeaver used for? | GeneWeaver: a web-based system for integrative functional genomics. | High-throughput genome technologies have produced a wealth of data on the
association of genes and gene products to biological functions. Investigators
have discovered value in combining their experimental results with published
genome-wide association studies, quantitative trait locus, microarray,
RNA-sequencing and mutant phenotyping studies to identify gene-function
associations across diverse experiments, species, conditions, behaviors or
biological processes. These experimental results are typically derived from
disparate data repositories, publication supplements or reconstructions from
primary data stores. This leaves bench biologists with the complex and
unscalable task of integrating data by identifying and gathering relevant
studies, reanalyzing primary data, unifying gene identifiers and applying ad hoc
computational analysis to the integrated set. The freely available GeneWeaver
(http://www.GeneWeaver.org) powered by the Ontological Discovery Environment is
a curated repository of genomic experimental results with an accompanying tool
set for dynamic integration of these data sets, enabling users to interactively
address questions about sets of biological functions and their relations to sets
of genes. Thus, large numbers of independently published genomic results can be
organized into new conceptual frameworks driven by the underlying, inferred
biological relationships rather than a pre-existing semantic framework. An
empirical 'ontology' is discovered from the aggregate of experimental knowledge
around user-defined areas of biological inquiry. BACKGROUND: Integrating and analyzing heterogeneous genome-scale data is a huge
algorithmic challenge for modern systems biology. Bipartite graphs can be useful
for representing relationships across pairs of disparate data types, with the
interpretation of these relationships accomplished through an enumeration of
maximal bicliques. Most previously-known techniques are generally ill-suited to
this foundational task, because they are relatively inefficient and without
effective scaling. In this paper, a powerful new algorithm is described that
produces all maximal bicliques in a bipartite graph. Unlike most previous
approaches, the new method neither places undue restrictions on its input nor
inflates the problem size. Efficiency is achieved through an innovative
exploitation of bipartite graph structure, and through computational reductions
that rapidly eliminate non-maximal candidates from the search space. An
iterative selection of vertices for consideration based on non-decreasing common
neighborhood sizes boosts efficiency and leads to more balanced recursion trees.
RESULTS: The new technique is implemented and compared to previously published
approaches from graph theory and data mining. Formal time and space bounds are
derived. Experiments are performed on both random graphs and graphs constructed
from functional genomics data. It is shown that the new method substantially
outperforms the best previous alternatives.
CONCLUSIONS: The new method is streamlined, efficient, and particularly
well-suited to the study of huge and diverse biological data. A robust
implementation has been incorporated into GeneWeaver, an online tool for
integrating and analyzing functional genomics experiments, available at
http://geneweaver.org. The enormous increase in scalability it provides empowers
users to study complex and previously unassailable gene-set associations between
genes and their biological functions in a hierarchical fashion and on a
genome-wide scale. This practical computational resource is adaptable to almost
any applications environment in which bipartite graphs can be used to model
relationships between pairs of heterogeneous entities. Extensive genetic and genomic studies of the relationship between alcohol
drinking preference and withdrawal severity have been performed using animal
models. Data from multiple such publications and public data resources have been
incorporated in the GeneWeaver database with >60,000 gene sets including 285
alcohol withdrawal and preference-related gene sets. Among these are evidence
for positional candidates regulating these behaviors in overlapping quantitative
trait loci (QTL) mapped in distinct mouse populations. Combinatorial integration
of functional genomics experimental results revealed a single QTL positional
candidate gene in one of the loci common to both preference and withdrawal.
Functional validation studies in Ap3m2 knockout mice confirmed these
relationships. Genetic validation involves confirming the existence of
segregating polymorphisms that could account for the phenotypic effect. By
exploiting recent advances in mouse genotyping, sequence, epigenetics, and
phylogeny resources, we confirmed that Ap3m2 resides in an appropriately
segregating genomic region. We have demonstrated genetic and alcohol-induced
regulation of Ap3m2 expression. Although sequence analysis revealed no
polymorphisms in the Ap3m2-coding region that could account for all phenotypic
differences, there are several upstream SNPs that could. We have identified one
of these to be an H3K4me3 site that exhibits strain differences in methylation.
Thus, by making cross-species functional genomics readily computable we
identified a common QTL candidate for two related bio-behavioral processes via
functional evidence and demonstrate sufficiency of the genetic locus as a source
of variation underlying two traits. The GeneWeaver bipartite data model provides an efficient means to evaluate
shared molecular components from sets derived across diverse species, disease
states and biological processes. In order to adapt this model for examining
related molecular components and biological networks, such as pathway or gene
network data, we have developed a means to leverage the bipartite data structure
to extract and analyze shared edges. Using the Pathway Commons database we
demonstrate the ability to rapidly identify shared connected components among a
diverse set of pathways. In addition, we illustrate how results from maximal
bipartite discovery can be decomposed into hierarchical relationships, allowing
shared pathway components to be mapped through various parent-child
relationships to help visualization and discovery of emergent kernel driven
relationships. Interrogating common relationships among biological networks and
conventional GeneWeaver gene lists will increase functional specificity and
reliability of the shared biological components. This approach enables
self-organization of biological processes through shared biological networks. A persistent challenge lies in the interpretation of consensus and discord from
functional genomics experimentation. Harmonizing and analyzing this data will
enable investigators to discover relations of many genes to many diseases, and
from many phenotypes and experimental paradigms to many diseases through their
genomic substrates. The GeneWeaver.org system provides a platform for
cross-species integration and interrogation of heterogeneous curated and
experimentally derived functional genomics data. GeneWeaver enables researchers
to store, share, analyze, and compare results of their own genome-wide
functional genomics experiments in an environment containing rich companion data
obtained from major curated repositories, including the Mouse Genome Database
and other model organism databases, along with derived data from highly
specialized resources, publications, and user submissions. The data, largely
consisting of gene sets and putative biological networks, are mapped onto one
another through gene identifiers and homology across species. A versatile suite
of interactive tools enables investigators to perform a variety of set analysis
operations to find consilience among these often noisy experimental results.
Fast algorithms enable real-time analysis of large queries. Specific
applications include prioritizing candidate genes for quantitative trait loci,
identifying biologically valid mouse models and phenotypic assays for human
disease, finding the common biological substrates of related diseases,
classifying experiments and the biological concepts they represent from
empirical data, and applying patterns of genomic evidence to implicate novel
genes in disease. These results illustrate an alternative to strict emphasis on
replicability, whereby researchers classify experimental results to identify the
conditions that lead to their similarity. The GeneWeaver data and analytics website (www.geneweaver.org) is a publically
available resource for storing, curating and analyzing sets of genes from
heterogeneous data sources. The system enables discovery of relationships among
genes, variants, traits, drugs, environments, anatomical structures and diseases
implicitly found through gene set intersections. Since the previous review in
the 2012 Nucleic Acids Research Database issue, GeneWeaver's underlying
analytics platform has been enhanced, its number and variety of publically
available gene set data sources has been increased, and its advanced search
mechanisms have been expanded. In addition, its interface has been redesigned to
take advantage of flexible web services, programmatic data access, and a refined
data model for handling gene network data in addition to its original emphasis
on gene set data. By enumerating the common and distinct biological molecules
associated with all subsets of curated or user submitted groups of gene sets and
gene networks, GeneWeaver empowers users with the ability to construct data
driven descriptions of shared and unique biological processes, diseases and
traits within and across species. The abundance of existing functional genomics studies permits an integrative
approach to interpreting and resolving the results of diverse systems genetics
studies. However, a major challenge lies in assembling and harmonizing
heterogeneous data sets across species for facile comparison to the positional
candidate genes and coexpression networks that come from systems genetic
studies. GeneWeaver is an online database and suite of tools at
www.geneweaver.org that allows for fast aggregation and analysis of gene
set-centric data. GeneWeaver contains curated experimental data together with
resource-level data such as GO annotations, MP annotations, and KEGG pathways,
along with persistent stores of user entered data sets. These can be entered
directly into GeneWeaver or transferred from widely used resources such as
GeneNetwork.org. Data are analyzed using statistical tools and advanced graph
algorithms to discover new relations, prioritize candidate genes, and generate
function hypotheses. Here we use GeneWeaver to find genes common to multiple
gene sets, prioritize candidate genes from a quantitative trait locus, and
characterize a set of differentially expressed genes. Coupling a large
multispecies repository curated and empirical functional genomics data to fast
computational tools allows for the rapid integrative analysis of heterogeneous
data for interpreting and extrapolating systems genetics results. |
Are there ultraconserved regions in the budding yeast (Saccharomyces cerevisiae)? | Yes. In addition to some fundamental biological functions, ultraconserved regions play an important role in the adaptation of Saccharomyces cerevisiae to the acidic environment. | MOTIVATION: In the evolution of species, a kind of special sequences, termed
ultraconserved sequences (UCSs), have been inherited without any change, which
strongly suggests those sequences should be crucial for the species to survive
or adapt to the environment. However, the UCSs are still regarded as mysterious
genetic sequences so far. Here, we present a systematic study of ultraconserved
genomic regions in the budding yeast based on the publicly available genome
sequences, in order to reveal their relationship with the adaptability or
fitness advantages of the budding yeast.
RESULTS: Our results indicate that, in addition to some fundamental biological
functions, the UCSs play an important role in the adaptation of Saccharomyces
cerevisiae to the acidic environment, which is backed up by the previous
observation. Besides that, we also find the highly unchanged genes are enriched
in some other pathways, such as the nutrient-sensitive signaling pathway. To
facilitate the investigation of unique UCSs, the UCSC Genome Browser was
utilized to visualize the chromosomal position and related annotations of UCSs
in S.cerevisiae genome.
AVAILABILITY AND IMPLEMENTATION: For more details on UCSs, please refer to the
Supplementary information online, and the custom code is available on request.
CONTACT: [email protected].
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online. |
Which disease can be classified with the Awaji Criteria? | Awaji Criteria are used for amyotrophic lateral sclerosis. | The Awaji Commission recently proposed a modification of the electrodiagnostic
criteria for ALS. We assessed whether the Awaji recommendations improve the
sensitivity of the early diagnosis of ALS. In a retrospective study we reviewed
clinical and neurophysiological data for 213 patients who visited our motor
neuron disease outpatient clinic between October 2006 and December 2008. Using
the El Escorial criteria, 51 patients were diagnosed with definite or probable
ALS, 14 with probable laboratory-supported ALS, and 28 with possible ALS. An
alternative diagnosis was present in 120 patients. Applying the Awaji
recommendations, 66 patients were diagnosed with either definite or probable
ALS, and 27 with possible ALS. Of the 14 patients diagnosed with probable
laboratory-supported ALS, eight switched to probable ALS and six to possible ALS
using the Awaji recommendations; none of the patients with an ALS mimic was
diagnosed with ALS according to the Awaji recommendations. In conclusion, the
new criteria for ALS do not result in a loss of specificity and can potentially
improve the sensitivity by 16%. However, this diagnostic improvement appears
eliminated if patients with probable laboratory-supported ALS - due to UMN signs
in one region - should be categorized as possible ALS. OBJECTIVE: The diagnosis of amyotrophic lateral sclerosis (ALS) includes
demonstration of lower motor neuron (LMN) and upper motor neuron (UMN)
involvement of bulbar and spinal muscles. Electromyography (EMG) is essential to
confirm LMN affection in weak muscles, and to demonstrate changes in clinically
non-involved muscles. The aim of the study was to determine the relative
importance of ongoing (active) denervation, fasciculations, chronic partial
denervation with reinnervation at weak effort and loss of motor units at maximal
voluntary contraction (MVC) in ALS.
METHODS: EMG was carried out in weak and non-weak muscles in 220 patients
suspected of ALS using concentric needle electrodes. Denervation activity and
fasciculations in 966 muscles was quantified, the mean durations and amplitudes
of motor unit potentials (MUPs) were compared to controls in 745 muscles, and
the amplitudes and recruitment patterns at maximal voluntary effort were
measured in 939 muscles. Twenty-five percent of patients had clinical
involvement of 1 region, 42% of 2 regions and 33% of 3 regions. Clinically 65%
had UMN involvement. Eighty-six percent of the patients had died on follow-up.
RESULTS: Denervation activity occurred in 72% of weak muscles but in only 45% of
non-weak muscles. Fasciculations occurred in 56% of weak muscles and in 65% of
non-weak muscles. MUPs showed reinnervation in 87-91% of weak and non-weak
muscles and in 44% of muscles neurogenic MUPs occurred in the absence of
denervation activity. In patients with clinical involvement of 1 region,
combined EMG criteria increased the number of affected regions in 93%, and in
40% of patients with clinical involvement of 2 regions EMG increased the number
of involved regions.
CONCLUSIONS: Quantitative EMG confirmed widespread LMN involvement in patients
with early ALS including clinically non-involved regions. These findings suggest
that the maintece of force is due to compensatory reinnervation in early
disease and that this capacity may decline at later stages of ALS.
SIGNIFICANCE: These findings support a recent consensus report (the Awaji
criteria) that EMG should have equivalent weight to clinical manifestations to
indicate LMN involvement. The findings strongly indicate that spontaneous
activity is insufficient to show LMN involvement in non-affected muscles at
early stages of disease, and that analysis of MUPs are needed to document the
distribution of LMN involvement. Amyotrophic lateral sclerosis (ALS) remains a clinical diagnosis without
validated biomarkers. To increase diagnostic sensitivity, an expert group
modified the Airlie House diagnostic criteria and formulated new recommendations
at a meeting on Awaji Island. Our retrospective analysis of patients referred
over a 6-month period to the electromyography (EMG) laboratory for suspected
motor neuron disease (MND) showed a higher agreement of the Awaji modifications
than the Airlie House criteria with the clinical diagnosis of ALS. OBJECTIVE: Early and accurate diagnosis of amyotrophic lateral sclerosis (ALS)
is important for patient care and for entry in clinical trials. Retrospective
studies suggest that the use of the Awaji algorithm for the diagnosis of ALS is
more sensitive for early diagnosis than the currently used revised El Escorial
criteria.
METHODS: We prospectively compared the revised El Escorial criteria with the
Awaji algorithm in patients seen with suspected ALS at the University Hospitals
Leuven between January 2008 and April 2010.
RESULTS: Out of 200 patients referred for the diagnosis of ALS, 66% and 85%
could be categorized to definite or probable ALS at first presentation according
to the revised El Escorial and the Awaji algorithm, respectively (p < 5.6 ×
10(-17) ). This corresponds to a >50% reduction of patients not eligible for
clinical trial entry. Application of the Awaji algorithm made the diagnosis of
ALS more likely by at least 1 diagnostic category in 25.7% of patients and
identified at least 1 additional region with electrodiagnostic signs of ongoing
lower motor neuron loss in 46.4% of electrodiagnostic investigations.
Application of the Awaji algorithm did not result in a single false-positive
diagnosis of ALS in this study.
INTERPRETATION: Our data demonstrate that the Awaji algorithm is significantly
more sensitive compared to the revised El Escorial criteria, without resulting
in false-positive diagnoses of ALS. It should therefore be used in clinical
trials. OBJECTIVE: To assess whether Awaji criteria improve the sensitivity of diagnosis
for amyotrophic lateral sclerosis (ALS). In Awaji ALS criteria, fasciculation
potentials are regarded as evidence of acute denervation in the presence of
chronic neurogenic changes on needle electromyography.
METHODS: We reviewed clinical and neurophysiological data of 113 consecutive
patients who were suspected as suffering ALS. The six muscles (trapezius,
biceps, first dorsal interosseous, T10-paraspinalis, vastus lateralis, and
tibialis anterior muscles) were examined by EMG, focusing on the presence of
fasciculation potentials. The sensitivity of revised El Escorial (R-EEC) and
Awaji criteria was compared.
RESULTS: Probable or definite ALS was diagnosed in 61% of the patients by R-EEC
and 71% by Awaji criteria. By applying Awaji criteria; (1) 17 of the 44 patients
categorized as possible ALS by R-EEC reached to probable/definite ALS, 11 of
whom had bulbar onset, (2) in 48 patients with bulbar onset, the proportion of
probable/definite ALS increased from 59% to 82%, (3) in 62 patients with limb
onset, the proportion of probable/definite ALS was 61% (63% by R-EEC).
CONCLUSIONS: Awaji criteria improve the sensitivity of ALS diagnosis in patients
with bulbar onset, but not in those with limb onset.
SIGNIFICANCE: Accepting fasciculation potentials as evidence of acute
denervation increases the diagnostic sensitivity of ALS, particularly in
patients with bulbar onset, and contributes to early diagnosis. OBJECTIVES: To study the utility of muscle ultrasound (US) for detection of
fasciculations and its contribution to diagnosis in amyotrophic lateral
sclerosis (ALS). Fasciculations are characteristic features of ALS, and US can
detect them easily and reliably. New diagnostic criteria for ALS, the Awaji
algorithm, reintroduced fasciculations as evidence of acute denervation
equivalent to that of fibrillations and positive sharp waves.
METHODS: In 81 consecutive patients with sporadic ALS, we prospectively
performed needle EMG and US in 6 muscles (tongue, biceps brachii, first dorsalis
interosseous, paraspinalis, vastus lateralis, and tibialis anterior), and
diagnostic category were determined by revised El Escorial criteria and Awaji
criteria.
RESULTS: Fasciculations were much more frequently detected by US than by EMG in
the tongue (60% vs 0%), biceps brachii (88% vs 60%), and tibialis anterior
muscles (83% vs 45%). The proportion of the patients with definite or probable
ALS was 48% by revised El Escorial criteria and 79% by Awaji criteria using US.
CONCLUSIONS: Muscle US is a practical and efficient tool to detect
fasciculations, particularly in the tongue. A combination of US and EMG
substantially increases the diagnostic sensitivity of ALS. OBJECTIVE: To estimate the potential diagnostic added value of the Awaji
criteria for diagnosis of a myotrophiclateral sclerosis (ALS), which have been
compared with the previously accepted gold standard the revised El Escorial
criteria in several studies.
DATA SOURCES: MEDLINE and Web of Science (until October2011).
STUDY SELECTION: We searched for studies testing the diagnostic accuracy of the
Awaji criteria vs the revised El Escorial criteria in patients referred with
suspected ALS.
DATA EXTRACTION: Evaluation and data extraction of identified studies were done
independently. The Quality Assessment of Diagnostic Accuracy Studies list was
used to assess study quality. We determined the proportion of patients
classified as having probable/definite ALS and derived indices of diagnostic
performance(sensitivity, specificity, and diagnostic odds ratio). Quantitative
data synthesis was accomplished through random-effects meta-analysis, and
heterogeneity was assessed with the I2 test.
DATA SYNTHESIS: Eight studies were included (3 prospective and 5 retrospective)
enrolling 1187 patients. Application of Awaji criteria led to a 23% (95% CI, 12%
to 33%; I2=84%) increase in the proportion of patients classified as having
probable/definite ALS. Diagnostic performance of the Awaji criteria was higher
than the revised El Escorial criteria (pooled sensitivity: 81.1% [95%CI, 72.2%
to 90.0%; I2=91%] vs 62.2% [95% CI, 49.4%to 75.1%; I2=93%]; pooled diagnostic
odds ratio, 35.8[95% CI, 15.2 to 84.7; I2=3%] vs 8.7 [95% CI, 2.2 to
35.6;I2=50%]). Diagnostic accuracy of Awaji criteria was higher in bulbar- than
in limb-onset cases.
CONCLUSION: The Awaji criteria have a significant clinical impact allowing
earlier diagnosis and clinical trial entry in ALS. Amyotrophic lateral sclerosis is the most common motor neuron disorder in
adults. Although the diagnosis appears obvious in theory, clinical practice
shows the contrary as diagnosis is delayed in many patients; the average time
between symptom onset and diagnosis can reach 12 months. The delay can be
explained by the variability of the clinical presentation and by the absence of
diagnostic markers. In order to standardize diagnosis for enrollment in clinical
research, diagnostic criteria for ALS were created and revisited during the last
20 years. In 2006, the Awaji criteria for the diagnosis of ALS were proposed,
adding two major points to the diagnostic criteria: electromyography is
considered equivalent to clinical examination for the identification of LMN
signs and fasciculation potentials resume their prominent place in the
diagnosis. Comparisons of the accuracy of the revisited El Escorial and Awaji
criteria support improved diagnostic sensitivity without any effect on
specificity with the new classification. The only weakness of the new
classification involves patients with UMN signs in one region and LMN in two
regions; these patients were previously classified as laboratory-supported
probable ALS and currently as possible ALS, a lower level of diagnostic
certainty. In all other instances the accuracy appears to be improved by the
Awaji criteria. Nevertheless, there is a body of evidence suggesting the need
for a revision of these new criteria, giving more weight to clinical and
complementary findings of UMN involvement. The need to diagnose and treat ALS
quickly could be facilitated by the inclusion of complementary investigations
that detect UMN signs. OBJECTIVES: ALS may be diagnosed although affection of other organs suggests
another pathogenetic back-ground.
CASE REPORT: In a 72yo non-smoking male progressive gait disturbance with
recurrent falls since 2y was initially attributed to axonal polyneuropathy.
Additionally, he had arterial hypertension, diabetes, hyperlipidemia,
hyperuricemia, hyper-CK-emia, hepatopathy, atrial fibrillation, recurrent
heart-failure, pulmonary hypertension, mitral insufficiency, and restrictive
cardiomyopathy. Possible causes of polyneuropathy were diabetes, long-standing
alcoholism, folate-deficiency, or hereditary disease. Later the patient was
re-diagnosed as ALS despite absence of upper motor-neuron or bulbar signs, the
presence of multiple risk factors for polyneuropathy, of stocking-type sensory
disturbances, and of cardiac abnormalities, which could explain dyspnea.
Misdiagnosing polyneuropathy as ALS stigmatized the patient and prevented him
from further diagnostic work-up for cardiac disease and adequate treatment for
heart-failure. Though the diagnosis of ALS was withdrawn, he was put on comfort
care and opiates were given when dyspnea acutely deteriorated to death without
further cardiac or pulmonary investigations or specific cardiac treatment.
CONCLUSIONS: ALS should be diagnosed only if the Awaji-shima criteria are
fulfilled and if all differential diagnoses were profoundly excluded.
Respiratory insufficiency should not be attributed to bulbar involvement in ALS
as long as cardiac, pulmonary, or myopathic causes were excluded. The Awaji criteria, recently introduced to increase diagnosis sensitivity in
amyotrophic lateral sclerosis (ALS), equate the diagnostic significance of
neurogenic electrophysiological changes to clinical signs of lower motor neuron
dysfunction. They also increase the electrophysiological significance of
fasciculation potentials (FPs). The aim of our study was to analyse whether the
new parameters improve diagnostic sensitivity in ALS patients primarily
diagnosed with the El Escorial criteria. Medical and electrophysiological
records of 135 consecutive patients with ALS and 25 patients with progressive
muscular atrophy (PMA) who underwent electrophysiological examination of at
least three anatomical regions were analysed retrospectively. Results showed
that implementation of the Awaji criteria increased the level of ALS diagnosis
sensitivity in 5.9% of cases - 1.5% due to the new role of FPs potentials and
4.4% because of equalization of clinical and EMG findings. In 4% of patients the
ALS diagnosis was, however, changed from laboratory-supported probable ALS to
possible ALS. In conclusion, our study confirms that Awaji modifications are
able to improve the diagnostic certainty in a few ALS cases. Although the new
approach to FPs markedly increases the number of involved muscles, it only
slightly raises the number of involved regions. BACKGROUND AND PURPOSE: The diagnosis of amyotrophic lateral sclerosis (ALS)
relies on identification of a combination of upper and lower motor neuron signs.
In order to improve the diagnostic sensitivity for ALS, Awaji criteria were
developed, in part to better incorporate neurophysiological measures, although
assessment of upper motor neuron dysfunction remained clinically based. Given
that cortical hyperexcitability appears to be an early feature in ALS, the
present study assessed the diagnostic utility of a threshold tracking
transcranial magnetic stimulation technique as an aid to the research-based
Awaji criteria in establishing an earlier diagnosis of ALS.
METHODS: Prospective studies were undertaken on a cohort of 82 patients with
suspected ALS and results were compared with 34 healthy controls.
RESULTS: Short-interval intracortical inhibition (SICI) was significantly
reduced in ALS patients (P < 0.0001), with a comparable reduction evident in the
Awaji groups (SICIAWAJI POSSIBLE 1.3% ± 1.3%; SICIAWAJI PROBABLE/DEFINITE
1.4% ±1.7%). Central motor conduction time was significantly prolonged
(P < 0.001), whereas the motor evoked potential amplitude (P < 0.05) and
intracortical facilitation (P < 0.05) were increased. The frequency of
transcranial magnetic stimulation abnormalities was similar across Awaji
subgroups, and addition of transcranial magnetic stimulation abnormalities as a
diagnostic category enabled reclassification of 88% of Awaji possible patients
to Awaji probable/definite.
CONCLUSIONS: Cortical excitability studies potentially facilitate an earlier
diagnosis of ALS when combined with clinical and conventional neurophysiological
findings, albeit in a research setting. INTRODUCTION: Recently, some authors have claimed that the Awaji criteria (AC)
are not always more sensitive than the revised El Escorial criteria (rEEC) in
amyotrophic lateral sclerosis (ALS).
METHODS: A meta-analysis examined 2 prospective and 7 retrospective studies,
which included 1,121 ALS patients, to compare AC and rEEC for early diagnosis of
ALS.
RESULTS: AC led to an 11% greater likelihood of being classified into the
categories "clinically definite" or "clinically probable", while if confined to
the "clinically probable - laboratory supported (LS)" category, this effect was
40% higher with the rEEC (95% cnfidence interval, 3-82%; I2=98%). Specifically,
AC downgraded 20% of the rEEC "clinically probable - LS" category to the AC
"clinically possible".
CONCLUSIONS: Despite overall superiority of AC, this meta-analysis shows that it
is not always more sensitive than rEEC. These results are related to the
requirement for 2 upper motor neuron signs in the AC "clinically probable"
category. BACKGROUND: Diagnosis of amyotrophic lateral sclerosis (ALS) remains
problematic, with substantial diagnostic delays. We assessed the sensitivity and
specificity of a threshold tracking transcranial magnetic stimulation (TMS)
technique, which might allow early detection of upper motor neuron dysfunction,
for the diagnosis of the disorder.
METHODS: We did a prospective study of patients referred to three neuromuscular
centres in Sydney, Australia, in accordance with the Standards for Reporting of
Diagnostic Accuracy. Participants had definite, probable, or possible ALS, as
defined by the Awaji criteria; or pure motor disorder with clinical features of
upper and lower motor neuron dysfunction in at least one body region,
progressing over a 6 month follow-up period; or muscle wasting and weakness for
at least 6 months. All patients underwent threshold tracking TMS at recruitment
(index test), with application of the reference standard, the Awaji criteria, to
differentiate patients with ALS from those with non-ALS disorders. The
investigators who did the index test were masked to the results of the reference
test and all other investigations. The primary outcome measures were the
sensitivity and specificity of TMS in differentiating ALS from non-ALS
disorders; these measures were derived from receiver operator curve analysis.
FINDINGS: Between Jan 1, 2010, and March 1, 2014, we screened 333 patients; 281
met our inclusion criteria. We eventually diagnosed 209 patients with ALS and 68
with non-ALS disorders; the diagnosis of four patients was inconclusive. The
threshold tracking TMS technique differentiated ALS from non-ALS disorders with
a sensitivity of 73·21% (95% CI 66·66-79·08) and specificity of 80·88%
(69·53-89·40) at an early stage in the disease. All patients tolerated the study
well, and we did not record any adverse events from performance of the index
test.
INTERPRETATION: The threshold tracking TMS technique reliably distinguishes ALS
from non-ALS disorders and, if these findings are replicated in larger studies,
could represent a useful diagnostic investigation when combined with the Awaji
criteria to prove upper motor neuron dysfunction at early stages of ALS.
FUNDING: Motor Neuron Disease Research Institute of Australia, National Health
and Medical Research Council of Australia, and Pfizer. INTRODUCTION: The contribution of cranial and thoracic region electromyography
(EMG) to diagnostic criteria for amyotrophic lateral sclerosis (ALS) has not
been evaluated.
METHODS: Clinical and EMG data from each craniospinal region were
retrospectively assessed in 470 patients; 214 had ALS. Changes to diagnostic
classification in Awaji-Shima and revised El Escorial criteria after withdrawal
of cranial/thoracic EMG data were ascertained.
RESULTS: Sensitivity for lower motor neuron involvement in ALS was highest in
the cervical/lumbar regions; specificity was highest in cranial/thoracic
regions. Cranial EMG contributed to definite/probable Awaji-Shima categorization
in 1.4% of patients. Thoracic EMG made no contribution. For revised El Escorial
criteria, cranial and thoracic data reclassified 1% and 5% of patients,
respectively.
CONCLUSION: Cranial EMG data make small contributions to both criteria, whereas
thoracic data contribute only to the revised El Escorial criteria. However,
cranial and thoracic region abnormalities are specific in ALS. Consideration
should be given to allowing greater diagnostic contribution from thoracic EMG.
Muscle Nerve 54: 378-385, 2016. Author information:
(1)Western Clinical School, University of Sydney, Sydney, Australia.
(2)School of Public Health, University of Sydney, Sydney, Australia.
(3)Hospital of Santa Maria and Instituto de Medicina Molecular and Faculty of
Medicine, University of Lisbon, Lisbon, Portugal.
(4)Hospital of Santa Maria and Instituto de Medicina Molecular and Faculty of
Medicine, University of Lisbon, Lisbon, Portugal; The Royal London Hospital and
Queen Mary School of Medicine, University of London, London, UK.
(5)Neurology Department, University Hospitals Leuven, Leuven, Belgium.
(6)Neurology Department, University Hospitals Leuven, Leuven, Belgium; KU Leuven
- University of Leuven, Department of Neurosciences, VIB - Vesalius Research
Center, Experimental Neurology - Laboratory of Neurobiology, Leuven, Belgium.
(7)Department of Neurology, and Neurodegenerative Diseases Research Group,
Medical University of Warsaw, Warsaw, Poland.
(8)Department of Neurology, Teikyo University School of Medicine, Tokyo, Japan.
(9)Department of Neurology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
(10)Department of Neurology, Graduate School of Medical Science, Kyoto
Prefectural University of Medicine, Kyoto, Japan.
(11)Brain and Mind Center, University of Sydney, Sydney, Australia.
(12)Western Clinical School, University of Sydney, Sydney, Australia. Electronic
address: [email protected]. OBJECTIVE: To assess the sensitivity and specificity of the Awaji and revised El
Escorial diagnostic criteria (rEEC) in amyotrophic lateral sclerosis (ALS).
METHODS: We conducted a large prospective multicenter study, recruiting 416
patients (253 male, 163 female) between January 1, 2012, and August 31, 2015, to
compare the diagnostic accuracy of Awaji and rEEC in accordance with standards
of reporting of diagnostic accuracy criteria.
RESULTS: The sensitivity of the Awaji criteria (57%, 50.0%-63.3%) was higher
when compared to rEEC (45%, 38.7%-51.7%, p < 0.001), translating to a 12% gain
in sensitivity. The specificity of the both criteria were identical, 99.5%,
indicating the number needed to test in order to diagnose one extra case of ALS
was 1.8 (1.5-2) for Awaji criteria and 2.4 (2-2.6) for rEEC. The Awaji criteria
exhibited a higher sensitivity across subgroups, including bulbar (p < 0.001)
and limb-onset (p < 0.001) patients. The inclusion of the possible diagnostic
category as a positive finding enhanced sensitivity of the Awaji criteria and
rEEC, particularly in early stages of ALS, while maintaining specificity.
CONCLUSION: The present study established a higher sensitivity of Awaji criteria
when compared to rEEC, with diagnostic benefits evident in bulbar and limb-onset
disease. Inclusion of possible as a positive finding enhanced sensitivity of
both criteria, while maintaining specificity, and should be considered in
clinical practice and future therapeutic trials.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the Awaji
criteria have a higher sensitivity and the same specificity as the rEEC in
identifying patients with ALS. OBJECTIVES: The accurate and early diagnosis of amyotrophic lateral sclerosis
(ALS) is important for extending the life expectancy of patients. However,
previous studies that have assessed the diagnostic sensitivities of the Awaji
criteria (AC) and the revised El Escorial criteria (rEEC) in patients with ALS
have been inconsistent, most of them were consensual regarding the advantage of
Awaji over conventional criteria. Our study sought to compare the roles of AC
and rEEC in the diagnosis of ALS.
METHODS: Data from a total of 294 consecutive patients with ALS were collected
between January 2014 and August 2015 in the Peking Union Medical College
Hospital. The clinical and electrophysiological records of 247 patients were
eventually analyzed. The primary outcome measures were the sensitivities of the
AC and rEEC for the diagnosis of ALS.
RESULTS: The sensitivity of probable or definite ALS as diagnosed with the AC
(78%) was greater than that of the rEEC (36%, P <0.001). Following the
application of the AC, 103 of the 147 patients categorized as probable
ALS-laboratory supported from the rEEC were upgraded to probable or definite
ALS, and 44 were downgraded to possible ALS.
CONCLUSIONS: Our data demonstrated that the AC exhibited greater diagnostic
sensitivity than the rEEC in a Chinese ALS population. The use of the AC should
be considered in clinical practice. OBJECTIVE: To investigate the frequency of anxiety and depression and their
association with clinical features of amyotrophic lateral sclerosis.
METHODS: This is a cross-sectional and descriptive study including a consecutive
series of patients with sporadic amyotrophic lateral sclerosis according to
Awaji's criteria. Patients underwent clinical and psychiatric assessment
(anxiety and depression symptoms).
RESULTS: We included 76 patients. The men/women ratio was 1.6:1. Participants'
mean age at disease onset was 55 years (SD±12.1). Sixty-six patients (86.8%)
were able to complete psychiatric evaluation. Clinically significant anxiety was
found in 23 patients (34.8%) while clinically significant depression was found
in 24 patients (36.4%). When we compared patients with and without depression a
significant difference was seen only in the frequency of anxiety symptoms
(p<0.001). We did further analysis comparing subgroups of patients classified
according to the presence or not of anxiety and or depression, without any
significant difference regarding sex, age at onset, initial form, disease
duration or functional measures. A positive correlation between anxiety and
depressive symptoms was found (p<0.001).
CONCLUSION: Anxiety and depressive symptoms were highly correlated and frequent
in patients with amyotrophic lateral sclerosis. In addition, anxiety and
depression were not associated with disease duration and presentation, sex, age
at onset, and functional score.
OBJETIVO: Investigar a frequência de ansiedade e depressão e sua associação com
aspectos clínicos da esclerose lateral amiotrófica.
MÉTODOS: Estudo transversal e descritivo de uma série consecutiva de pacientes
com esclerose lateral amiotrófica esporádica conforme os critérios de Awaji. Os
pacientes foram submetidos à avaliação clínica e psiquiátrica (sintomas
depressivos e ansiosos).
RESULTADOS: Foram incluídos 76 pacientes. A relação homem/mulher foi de 1,6:1. A
média de idade de início dos sintomas foi de 55 anos (DP±12,1). Foram capazes de
completar a avaliação psiquiátrica 66 (86,8%) pacientes. Ansiedade clinicamente
significativa foi encontrada em 23 pacientes (34,8%), enquanto depressão
clinicamente significativa foi encontrada em 24 pacientes (36,4%). Ao comparar
os pacientes com e sem depressão, houve diferença significativa apenas na
frequência de sintomas de ansiedade (p<0,001). Posteriormente, foram comparados
subgrupos de pacientes categorizados em relação à presença ou não de ansiedade
e/ou depressão, sem diferença significativa em relação a sexo, idade de início
dos sintomas, forma inicial, duração da doença ou na escala funcional. Foi
encontrada correlação positiva entre os sintomas de ansiedade e depressão
(p<0,001).
CONCLUSÃO: Sintomas de ansiedade e depressão são frequentes em pacientes com
esclerose lateral amiotrófica e estiveram altamente correlacionados. Ansiedade e
depressão não foram associadas com duração da doença, forma inicial, sexo, idade
de início dos sintomas e pontuação na escala funcional. Neuronal and/or axonal hyperactivity and hyperexcitability is an important
feature of motor neuron diseases. It results clinically in cramps and
fasciculations. It is not specific to motor neuron diseases, and can occur in
healthy subjects, as well as in various pathologies of the peripheral nervous
system, including nerve hyperexcitability syndromes. Hyperexcitability plays an
important and debated role in the pathophysiology of motor neuron diseases,
especially in amyotrophic lateral sclerosis (ALS). The mechanisms causing
hyperexcitability are not yet clearly identified. While most studies favor a
distal axonal origin site of fasciculations, some of the fasciculations could be
of cortical origin. The consequences of hyperexcitability are also discussed,
whether it is rather protective or deleterious in the disease course.
Fasciculations are depicted both clinically and using electromyogram, and more
recently the interest of ultrasound has been highlighted. The importance of
fasciculation potentials in the diagnosis of ALS led to changes in
electrophysiological criteria at Awaji consensus conference. The contribution of
these modifications to ALS diagnosis has been the subject of several studies. In
clinical practice, it is necessary to distinguish fasciculations potentials of
motor neuron disease from benign fasciculations. In most studies of
fasciculation potentials in ALS, the presence of complex fasciculation
potentials appears to be relevant for the diagnosis and the prognosis of the
disease. OBJECTIVE: To assess the added prognostic value of the aggregated clinical and
electrodiagnostic data, which define a given diagnostic category according to
the Awaji or revised El Escorial criteria at time of diagnosis in patients with
amyotrophic lateral sclerosis (ALS).
METHODS: Clinical signs and electrodiagnostic test results were collected at
time of diagnosis in 396 patients with ALS between January 2009 and January
2016. Significant predictors of prognosis were identified using a univariate
model, and later combined in a multivariate Cox regression model.
RESULTS: Known factors associated with reduced survival included older age at
onset, shorter diagnostic delay, higher ALSFRS-R slope and presence of C9orf72
mutation (all p < 0.05). Diagnostic category according to Awaji (p < 0.0001) or
to revised El Escorial (p = 0.0177) criteria, definite ALS according to Awaji
(p < 0.0001) or to revised El Escorial (p = 0.0343) and number of regions with
LMN involvement (p < 0.0001) were all associated with shorter survival.
DISCUSSION: Clinical and electrodiagnostic data at time of diagnosis provide
additional prognostic information compared to other known prognostic factors.
Diagnostic category according to Awaji and the extensiveness of LMN involvement
contain the most additional value. |
Endolymphatic hydrops is associated with Meniere’s disease. Please provide a summary of endoymphatic hydrops including the symptoms and affected body part. | Endolymphatic hydrops is a disorder of the inner ear. It consists of an excessive build-up of the endolymph fluid, which fills the hearing and balance structures of the inner ear. The symptoms of endolymphatic hydrops include the feeling of pressure or fullness in the ears, hearing loss, tinnitus (ringing in the ears) and balance problems. | CONCLUSION: All definite Meniere's disease (MD) had endolymphatic hydrops (EH)
at least in the cochlea or the vestibule. Symptoms of MD may appear after
formation of EH. It is assumed that the probability of immediate progression to
bilateral MD from unilateral MD is very low in patients without EH on the
non-affected side.
OBJECTIVE: To evaluate the EH on both sides in patients with unilateral and
bilateral MD, and to investigate factors with progression to bilateral MD
including the degree of EH, hearing level, and the duration of MD.
PATIENTS AND METHODS: The study included 29 patients with unilateral definite MD
and 12 patients with bilateral definite MD. The endolymphatic space size was
visualized by using 3-Tesla magnetic resoce imaging.
RESULTS: All patients with unilateral and bilateral MD had significant or mild
EH at least in the cochlea or the vestibule on the affected side. On the
non-affected side, EH was not observed at all in eight patients, but
asymptomatic EH was observed in the cochlea in 14 patients and in the vestibule
in 16 patients. There was no relationship between the EH on the non-affected
side and the duration of MD. Ménière's disease is associated with hydrops of the inner ear endolymphatic
space, and histopathologically, the cochlea and vestibule are usually involved.
We used gadolinium-enhanced magnetic resoce imaging and measured cervical and
ocular vestibular evoked myogenic potentials and the gain in the utricular
induced linear vestibulo-ocular reflex to test the hypothesis that vestibular
hydrops in Ménière's disease patients is associated with otolith organ
dysfunction. We evaluated 21 patients diagnosed with unilateral definitive
Ménière's disease using gadolinium magnetic resoce imaging to detect
endolymphatic hydrops in the cochlea and vestibule. Cervical and ocular
vestibular evoked myogenic potentials and the gain in utricular induced linear
vestibulo-ocular reflex during eccentric rotation were measured to assess
otolith organ function. For eccentric rotation, patients were rotated while
displaced from the axis of rotation, while linear acceleration stimulated the
utricle and induced the vestibulo-ocular reflex. Magnetic resoce imaging
revealed vestibular hydrops in 14 of 20 patients (70%). Among the 14 patients,
ten (71%) had abnormal cervical and three (21%) had abnormal ocular vestibular
evoked myogenic potentials. Four patients (4/21, 19%) had abnormal linear
vestibulo-ocular reflexes, three of whom also had abnormal ocular vestibular
evoked myogenic potentials. Overall, 16 of 17 patients had normal linear
vestibulo-ocular reflexes and normal ocular vestibular evoked myogenic
potentials. Vestibular endolymphatic hydrops in Ménière's disease patients
caused otolith organ dysfunction, mainly in the saccule. The number of Ménière's
disease patients with abnormal ocular vestibular evoked myogenic potentials was
low (19%), and they also had abnormal utricular induced linear vestibulo-ocular
reflexes. OBJECTIVES: Endolymphatic hydrops (EH) can be studied in patients by MRI. With
the semi-quantitative grading system, previous imaging studies showed
discrepancies in the occurrence and grading of EH in patients with Meniere's
disease (MD). Here, we compared the inversion of the saccule to utricle area
ratio (SURI) with the semi-quantitative method of grading conventionally used to
diagnose MD.
METHODS: Imaging was carried out on a 3-T MRI scanner. We performed 3D-FLAIR
sequences 4 h after a single intravenous dose of contrast agent. Two
radiologists independently studied the morphology of the inner ear structures in
the healthy subjects and MD patients. Each subject was then graded on the basis
of the EH semi-quantitative analysis and on saccular morphology using axial and
sagittal reference slices in the vestibule plane.
RESULTS: Thirty healthy subjects and 30 MD patients had MRI scans. Using the
semi-quantitative method, we found no significant difference in the number of
subjects with EH between the two groups. SURI was found in 15 out of 30 MD
patients and in none of the 30 healthy subjects. In three MD patients the
saccule was not visible.
CONCLUSION: SURI is currently the most specific criterion for imaging diagnosis
of MD.
KEY POINTS: • Half of MD patients presented with inversion of the saccule to
utricle ratio. • Saccular analysis is crucial when assessing patients with
Meniere's disease. • In some patients, the saccule is not visible, suggestive of
intra-labyrinthine fistulae. |
Where does gemtuzumab ozogamicin bind? | Gemtuzumab ozogamicin binds to CD33 | |
Where, in what US state, was there a measles outbreak in an Amish community | The measles outbreak started an Amish community in Ohio | Measles outbreaks in the United States continue to occur in subpopulations with
sufficient numbers of undervaccinated individuals, with a 2014 outbreak in Amish
communities in Ohio pushing the annual cases to the highest national number
reported in the last 20 years. We adapted an individual-based model developed to
explore potential poliovirus transmission in the North American Amish to
characterize a 1988 measles outbreak in the Pennsylvania Amish and the 2014
outbreak in the Ohio Amish. We explored the impact of the 2014 outbreak response
compared to no or partial response. Measles can spread very rapidly in an
underimmunized subpopulation like the North American Amish, with the potential
for national spread within a year or so in the absence of outbreak response.
Vaccination efforts significantly reduced the transmission of measles and the
expected number of cases. Until global eradication, measles importations will
continue to pose a threat to clusters of underimmunized individuals in the
United States. Aggressive outbreak response efforts in Ohio probably prevented
widespread transmission of measles within the entire North American Amish. BACKGROUND: Although measles was eliminated in the United States in 2000,
importations of the virus continue to cause outbreaks. We describe the
epidemiologic features of an outbreak of measles that originated from two
unvaccinated Amish men in whom measles was incubating at the time of their
return to the United States from the Philippines and explore the effect of
public health responses on limiting the spread of measles.
METHODS: We performed descriptive analyses of data on demographic
characteristics, clinical and laboratory evaluations, and vaccination coverage.
RESULTS: From March 24, 2014, through July 23, 2014, a total of 383
outbreak-related cases of measles were reported in nine counties in Ohio. The
median age of case patients was 15 years (range, <1 to 53); a total of 178 of
the case patients (46%) were female, and 340 (89%) were unvaccinated.
Transmission took place primarily within households (68% of cases). The virus
strain was genotype D9, which was circulating in the Philippines at the time of
the reporting period. Measles-mumps-rubella (MMR) vaccination coverage with at
least a single dose was estimated to be 14% in affected Amish households and
more than 88% in the general (non-Amish) Ohio community. Containment efforts
included isolation of case patients, quarantine of susceptible persons, and
administration of the MMR vaccine to more than 10,000 persons. The spread of
measles was limited almost exclusively to the Amish community (accounting for
99% of case patients) and affected only approximately 1% of the estimated 32,630
Amish persons in the settlement.
CONCLUSIONS: The key epidemiologic features of a measles outbreak in the Amish
community in Ohio were transmission primarily within households, the small
proportion of Amish people affected, and the large number of people in the Amish
community who sought vaccination. As a result of targeted containment efforts,
and high baseline coverage in the general community, there was limited spread
beyond the Amish community. (Funded by the Ohio Department of Health and the
Centers for Disease Control and Prevention.). |
Is there any role for HUWE1 in MYC signalling? | Yes. HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation. | Cancer genome sequencing projects have identified hundreds of genetic
alterations, often at low frequencies, raising questions as to their functional
relevance. One exemplar gene is HUWE1, which has been found to be mutated in
numerous studies. However, due to the large size of this gene and a lack of
functional analysis of identified mutations, their significance to
carcinogenesis is unclear. To determine the importance of HUWE1, we chose to
examine its function in colorectal cancer, where it is mutated in up to 15 per
cent of tumours. Modelling of identified mutations showed that they inactivate
the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly
accelerated tumourigenic in mice carrying loss of the intestinal tumour
suppressor gene Apc, with a dramatic increase in tumour initiation.
Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage
accumulation leading to loss of the second copy of Apc The increased levels of
DNA damage sensitised Huwe1-deficient tumours to DNA-damaging agents and to
deletion of the anti-apoptotic protein MCL1. Taken together, these data identify
HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and
suggest a potential vulnerability of HUWE1-mutated tumours to DNA-damaging
agents and inhibitors of anti-apoptotic proteins. |
List MHC-I-associated inflammatory disorders. | ankylosing spondylitis
birdshot chorioretinopathy
Behçet's disease
psoriasis | Birdshot chorioretinopathy is a rare ocular inflammation whose genetic
association with HLA-A*29:02 is the highest between a disease and a major
histocompatibility complex (MHC) molecule. It belongs to a group of
MHC-I-associated inflammatory disorders, also including ankylosing spondylitis,
psoriasis, and Behçet's disease, for which endoplasmic reticulum aminopeptidases
(ERAP) 1 and/or 2 have been identified as genetic risk factors. Since both
enzymes are involved in the processing of MHC-I ligands, it seems reasonable
that common peptide-mediated mechanisms may underlie the pathogenesis of these
diseases. In this study, comparative immunopeptidomics was used to characterize
>5000 A*29:02 ligands and quantify the effects of ERAP1 polymorphism and
expression on the A*29:02 peptidome in human cells. The peptides predomit in
an active ERAP1 context showed a higher frequency of nonamers and bulkier amino
acid side chains at multiple positions, compared with the peptides predomit
in a less active ERAP1 background. Thus, ERAP1 polymorphism has a large
influence, shaping the A*29:02 peptidome through length-dependent and
length-independent effects. These changes resulted in increased affinity and
hydrophobicity of A*29:02 ligands in an active ERAP1 context. The results reveal
the nature of the functional interaction between A*29:02 and ERAP1 and suggest
that this enzyme may affect the susceptibility to birdshot chorioretinopathy by
altering the A*29:02 peptidome. The complexity of these alterations is such that
not only peptide presentation but also other potentially pathogenic features
could be affected. |
What is the predicted function for TMEM132 family? | The TMEM132 family proteins are strongly predicted to have a cellular adhesion function, connecting the extracellular medium with the intracellular actin cytoskeleton. | |
What type of topoisomerase inhibitor is gepotidacin? | Gepotidacin is a type IIA topoisomerase inhibitor. | Gepotidacin, a novel triazaacenaphthylene antibacterial agent, is the first in a
new class of type IIA topoisomerase inhibitors with activity against many
biothreat and conventional pathogens, including Neisseria gonorrhoeae To assist
ongoing clinical studies of gepotidacin to treat gonorrhea, a multilaboratory
quality assurance investigation determined the reference organism (N.
gonorrhoeae ATCC 49226) quality control MIC range to be 0.25 to 1 μg/ml (88.8%
of gepotidacin MIC results at the 0.5 μg/ml mode). |
What is the mechanism of action of Alpelisib? | Alpelisib is selective inhibitor of Phosphatidylinositol 3-Kinase α (PI3Kα). It is used for treatment of cancer. | The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors,
including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective
inhibitor alpelisib (BYL719), currently in clinical development by Novartis
Oncology, may therefore be effective as anticancer agents. Early clinical
studies with PI3K inhibitors have demonstrated preliminary antitumor activity
and acceptable safety profiles. However, a number of uswered questions
regarding PI3K inhibition in cancer remain, including: what is the best approach
for different tumor types, and which biomarkers will accurately identify the
patient populations most likely to benefit from specific PI3K inhibitors? This
review summarizes the strategies being employed by Novartis Oncology to help
maximize the benefits of clinical studies with buparlisib and alpelisib,
including stratification according to PI3K pathway activation status, selective
enrollment/target enrichment (where patients with PI3K pathway-activated tumors
are specifically recruited), nonselective enrollment with mandatory tissue
collection, and enrollment of patients who have progressed on previous targeted
agents, such as mTOR inhibitors or endocrine therapy. An overview of
Novartis-sponsored and Novartis-supported trials that are utilizing these
approaches in a range of cancer types, including breast cancer, head and neck
squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and
glioblastoma multiforme, is also described. Author information:
(1)The Netherlands Cancer Institute, Amsterdam, the Netherlands.
(2)Vall d'Hebron University Hospital and Institute of Oncology (VHIO),
Universitat Autònoma de Barcelona, Barcelona, Spain.
(3)Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
(4)Princess Margaret Cancer Centre, Toronto, Canada.
(5)West German Cancer Center, University Hospital Essen, University
Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), partner
site University Hospital Essen, Essen, Germany.
(6)National Cancer Center Hospital East, Chiba, Japan.
(7)Institut Claudius Regaud, Toulouse, France.
(8)National Cancer Center Hospital, Tokyo, Japan.
(9)University Medical Center Utrecht, Utrecht, the Netherlands.
(10)Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
(11)Massachusetts General Hospital, Boston, Massachusetts.
(12)Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
(13)Memorial Sloan-Kettering Cancer Center, New York, New York.
(14)Keck School of Medicine at the University of Southern California, Los
Angeles, California.
(15)UCLA Medical Center, Santa Monica, California.
(16)Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
(17)Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
(18)Array BioPharma Inc., Boulder, Colorado.
(19)Novartis Pharma AG, Basel, Switzerland.
(20)The Netherlands Cancer Institute, Amsterdam, the Netherlands.
[email protected].
(21)Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University,
Utrecht, the Netherlands. Tamoxifen is the standard first-line hormonal therapy for premenopausal women
with estrogen receptor (ER)-positive metastatic breast cancer (BC). One of the
crucial mechanisms underlying hormonal therapy resistance is the collateral
activation of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We explored
whether PI3K inhibitors, buparlisib and alpelisib, enhance the efficacy of
tamoxifen against ER-positive BC cells. We have observed a synergism between
alpelisib or buparlisib and tamoxifen in the treatment for ER-positive BC cell
lines harboring different PI3K alterations. Immunoblotting analysis showed
alpelisib, buparlisib, or either drug in combination with tamoxifen
downregulated the PI3K downstream targets in the MCF-7 and ZR75-1 cells. In the
MCF-7 cells transfected with a constitutive active (myristoylated) AKT1
construct or mutant ER, the synergistic effect between alpelisib and tamoxifen
was markedly attenuated, indicating that synergism depends on AKT inhibition or
normally functioning ER. Combining alpelisib or buparlisib with tamoxifen also
attenuated MCF-7 tumor growth in Balb/c nude mice. Our data suggest that
additional PI3K blockade might be effective in enhancing the therapeutic effect
of tamoxifen in ER-positive BC and support the rationale combination in clinical
trials. Purpose: We describe herein a novel P447_L455 deletion in the C2 domain of
PIK3CA in a patient with an ER+ breast cancer with an excellent response to the
PI3Kα inhibitor alpelisib. Although PIK3CA deletions are relatively rare, a
significant portion of deletions cluster within amino acids 446-460 of the C2
domain, suggesting these residues are critical for p110α function.Experimental
Design: A computational structural model of PIK3CAdelP447-L455 in complex with
the p85 regulatory subunit and MCF10A cells expressing PIK3CAdelP447-L455 and
PIK3CAH450_P458del were used to understand the phenotype of C2 domain
deletions.Results: Computational modeling revealed specific favorable
inter-residue contacts that would be lost as a result of the deletion,
predicting a significant decrease in binding energy. Coimmunoprecipitation
experiments showed reduced binding of the C2 deletion mutants with p85 compared
with wild-type p110α. The MCF10A cells expressing PIK3CA C2 deletions exhibited
growth factor-independent growth, an invasive phenotype, and higher
phosphorylation of AKT, ERK, and S6 compared with parental MCF10A cells. All
these changes were ablated by alpelisib treatment.Conclusions: C2 domain
deletions in PIK3CA generate PI3K dependence and should be considered biomarkers
of sensitivity to PI3K inhibitors. Clin Cancer Res; 24(6); 1426-35. ©2017 AACR. Purpose We report the first-in-human phase Ia study to our knowledge (
ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated
dose and assessing safety and preliminary efficacy of single-agent alpelisib
(BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor.
Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered
advanced solid tumors received once-daily or twice-daily oral alpelisib on a
continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered
solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal
growth factor receptor 2-negative breast cancer received alpelisib 400 mg once
daily. Results One hundred thirty-four patients received treatment. Alpelisib
maximum tolerated doses were established as 400 mg once daily and 150 mg twice
daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting
toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and
hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events
included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%),
diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed;
half-life was 7.6 hours at 400 mg once daily with minimal accumulation.
Objective tumor responses were observed at doses ≥ 270 mg once daily; overall
response rate was 6.0% (n = 8; one patient with endometrial cancer had a
complete response, and seven patients with cervical, breast, endometrial, colon,
and rectal cancers had partial responses). Stable disease was achieved in 70
(52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease
control rate (complete and partial responses and stable disease) was 58.2%. In
patients with estrogen receptor-positive/human epidermal growth factor receptor
2-negative breast cancer, median progression-free survival was 5.5 months.
Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS
(22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a
tolerable safety profile and encouraging preliminary activity in patients with
PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα
inhibition in combination with other agents for the treatment of PIK3CA-mutant
tumors. Although inhibition of phosphoinositide 3-kinase (PI3K) is an emerging strategy
in cancer therapy, we and others have reported that this action can also
contribute to drug-induced QT prolongation and arrhythmias by increasing cardiac
late sodium current (INaL). Previous studies in mice implicate the PI3K-α
isoform in arrhythmia susceptibility. Here, we have determined the effects of
new anticancer drugs targeting specific PI3K isoforms on INaL and action
potentials (APs) in mouse cardiomyocytes and Chinese hamster ovary cells (CHO).
Chronic exposure (10-100 nM; 5-48 hours) to PI3K-α-specific subunit inhibitors
BYL710 (alpelisib) and A66 and a pan-PI3K inhibitor (BKM120) increased INaL in
SCN5A-transfected CHO cells and mouse cardiomyocytes. The specific inhibitors
(10-100 nM for 5 hours) markedly prolonged APs and generated triggered activity
in mouse cardiomyocytes (9/12) but not in controls (0/6), and BKM120 caused
similar effects (3/6). The inclusion of water-soluble PIP3, a downstream
effector of the PI3K signaling pathway, in the pipette solution reversed these
arrhythmogenic effects. By contrast, inhibition of PI3K-β, -γ, and -δ isoforms
did not alter INaL or APs. We conclude that inhibition of cardiac PI3K-α is
arrhythmogenic by increasing INaL and this effect is not seen with inhibition of
other PI3K isoforms. These results highlight a mechanism underlying potential
cardiotoxicity of PI3K-α inhibitors. Ribociclib is a specific cyclin dependent kinase (Cdk) 4/6 inhibitor that
induces G1 arrest by blocking the formation of cyclin D1-Cdk4/6 complex and
inhibiting retinoblastoma (RB) phosphorylation. Cyclin D1 is overexpressed in
over 90% of nasopharyngeal carcinoma (NPC) and CCND1 gene activation plays a
critical role in NPC pathogenesis. This study evaluated the preclinical
activities of ribociclib in NPC cell lines and patient derived xenograft (PDX)
models. Over 95% cell growth inhibition was observed at 96 hours after
ribociclib treatment. (IC50 concentrations: HK1 = 1.42 ± 0.23 µM;
HK1-LMP1 = 2.18 ± 0.70 µM and C666-1 = 8.26 ± 0.92 µM). HK1 and C666-1 cells
were chosen for analysis of ribociclib on kinase signaling, apoptosis and cell
cycle. Treatment with ribociclib for 48 hours consistently showed a
dose-dependent reduction in phosphorylated and total RB expression and G1 cycle
arrest was only observed. Combining ribociclib with the alpha-specific PI3K
inhibitor alpelisib showed a synergistic effect in two NPC PDX models in nude
mice. The co-treatment induced a significant reduction in tumor volume in both
xeno-666 and xeno-2117 compared with ribociclib treatment alone and control
(p < 0.01). In summary, ribociclib is active in NPC models and the effect on
growth inhibition was augmented when combined with alpelisib. This study
supports the clinical evaluation of ribociclib in NPC. Phosphatidylinositol 3-kinase (PI3K) pathway activation is associated with
resistance to paclitaxel in solid tumors. We assessed the safety and activity of
alpelisib, an oral, selective PI3K p110α inhibitor, plus paclitaxel in patients
with advanced solid tumors. This Phase Ib, multicenter, open-label, dose-finding
study, with a planned dose-expansion phase of alpelisib once daily (QD) plus
fixed-dose paclitaxel, recruited patients with advanced solid tumors. For the
dose-finding phase, the primary objective was determination of maximum tolerated
and/or recommended Phase II dose of alpelisib plus paclitaxel, and the secondary
objectives included the assessment of safety for this combination. From March
2014 to August 2016, 19 patients with advanced solid tumors were treated with
alpelisib QD (300 mg, n=6; 250 mg, n=4; 150 mg, n=9) plus paclitaxel (80 mg/m2,
per standard of care). During dose finding, five of 12 (41.7%) evaluable
patients for MTD determination experienced dose-limiting toxicities: alpelisib
300 mg, Grade 2 hyperglycemia (n=1); alpelisib 250 mg, Grade 2 hyperglycemia
(n=1), Grade 4 hyperglycemia and Grade 3 acute kidney injury (n=1); and
alpelisib 150 mg, Grade 2 hyperglycemia (n=1) and Grade 4 leukopenia (n=1). The
MTD of alpelisib when administered with paclitaxel was 150 mg QD. Most frequent
all-grade AEs were diarrhea (73.7%; Grade 3/4 10.5%) and hyperglycemia (57.9%;
Grade 3/4 31.6%). The planned dose-expansion phase was not initiated. Alpelisib
plus paclitaxel has a challenging safety profile in patients with advanced solid
tumors. This study was closed following the completion of the dose-finding
phase.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02051751. |
What is the normal function p53? | Wild-type p53 can suppress tumour development by multiple pathways. | P53 tumor suppressor gene mutations occur in the majority of human cancers and
contribute to tumor development, progression and therapy resistance. Direct
functional restoration of p53 as a transcription factor has been difficult to
achieve in the clinic. We performed a functional screen using a
bioluminescence-based transcriptional read-out to identify small molecules that
restore the p53 pathway in mutant p53-bearing cancer cells. We identified CB002,
as a candidate that restores p53 function in mutant p53-expressing colorectal
cancer cells and without toxicity to normal human fibroblasts. Cells exposed to
CB002 show increased expression of endogenous p53 target genes NOXA, DR5, and
p21 and cell death which occurs by 16 hours, as measured by cleaved caspases or
PARP. Stable knockdown of NOXA completely abrogates PARP cleavage and reduces
sub-G1 content, implicating NOXA as the key mediator of cell death induction by
CB002. Moreover, CB002 decreases the stability of mutant p53 in RXF393 cancer
cells and an exogenously expressed R175H p53 mutant in HCT116 p53-null cells.
R175H p53 expression was rescued by addition of proteasome inhibitor MG132 to
CB002, suggesting a role for ubiquitin-mediated degradation of the mutant
protein. In summary, CB002, a p53 pathway-restoring compound that targets mutant
p53 for degradation and induces tumor cell death through NOXA, may be further
developed as a cancer therapeutic. The three p53 family members, p53, p63 and p73, are structurally similar and
share many biochemical activities. Yet, along with their common fundamental role
in protecting genomic fidelity, each has acquired distinct functions related to
diverse cell autonomous and non-autonomous processes. Similar to the p53 family,
the Hippo signaling pathway impacts a multitude of cellular processes, spanning
from cell cycle and metabolism to development and tumor suppression. The core
Hippo module consists of the tumor-suppressive MST-LATS kinases and oncogenic
transcriptional co-effectors YAP and TAZ. A wealth of accumulated data suggests
a complex and delicate regulatory network connecting the p53 and Hippo pathways,
in a highly context-specific manner. This generates multiple layers of
interaction, ranging from interdependent and collaborative signaling to apparent
antagonistic activity. Furthermore, genetic and epigenetic alterations can
disrupt this homeostatic network, paving the way to genomic instability and
cancer. This strengthens the need to better understand the nuances that control
the molecular function of each component and the cross-talk between the
different components. Here, we review interactions between the p53 and Hippo
pathways within a subset of physiological contexts, focusing on normal stem
cells and development, as well as regulation of apoptosis, senescence and
metabolism in transformed cells. The tumour suppressor gene TP53 is the most frequently mutated gene in cancer.
Wild-type p53 can suppress tumour development by multiple pathways. However,
mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour
cell death and rapid tumour progression. The high frequency of TP53 mutation in
tumours has prompted efforts to restore normal function of mutant p53 and
thereby trigger tumour cell death and tumour elimination. Small molecules that
can reactivate missense-mutant p53 protein have been identified by different
strategies, and two compounds are being tested in clinical trials. Novel
approaches for targeting TP53 nonsense mutations are also underway. This Review
discusses recent progress in pharmacological reactivation of mutant p53 and
highlights problems and promises with these strategies. |
What is eravacycline? | Finafloxacin is a fluoroquinolone antimicrobial agent that exhibits optimum efficacy in slightly acidic environments. It is being developed to treat serious bacterial infections associated with an acidic environment, including urinary tract infections, complicated urinary tract infections, pyelonephritis and Helicobacter pylori infections, while it has already received approval for the treatment of acute otitis externa. | |
What is PEGylation? | Attachment of a chain of poly(ethylene glycol) (PEG) to a therapeutic protein, a process widely known as PEGylation, can lead to several beneficial effects. It has the potential to significantly delay aggregation of the protein by steric shielding, a frequently encountered issue in the development of protein drugs. Moreover, it can modify the pharmacokinetic profile of the PEGylated protein by delaying renal excretion, leading to a longer half-life (t1/2) of the drug. By steric hindrance, it can also inhibit interactions between the protein drug and proteases as well as the host immune system, thereby inhibiting inactivation of the PEGylated protein and also attenuating its immunogenicity. | Attachment of a chain of poly(ethylene glycol) (PEG) to a therapeutic protein, a
process widely known as PEGylation, can lead to several beneficial effects. It
has the potential to significantly delay aggregation of the protein by steric
shielding, a frequently encountered issue in the development of protein drugs.
Moreover, it can modify the pharmacokinetic profile of the PEGylated protein by
delaying renal excretion, leading to a longer half-life (t1/2) of the drug. By
steric hindrance, it can also inhibit interactions between the protein drug and
proteases as well as the host immune system, thereby inhibiting inactivation of
the PEGylated protein and also attenuating its immunogenicity. Unfortunately,
the effect of steric hindrance also applies to protein drug-target interaction,
leading to a (partial) loss of efficacy. In order to avoid this undesirable
effect, several efforts have been made to link PEG to a protein in a noncovalent
way, providing the protein with several of the beneficial effects of PEGylation
while also taking advantage of its native affinity to its target. |
What is the 3D tomography imaging technique for diagnosis of eye disease? | Currently, eye care professionals use optical coherence tomography (OCT) scans to help diagnose eye conditions. | Glaucoma is a chronic neurodegenerative disease characterized by loss of retinal
ganglion cells, resulting in distinctive changes in the optic nerve head (ONH)
and retinal nerve fiber layer (RNFL). Important advances in technology for
non-invasive imaging of the eye have been made providing quantitative tools to
measure structural changes in ONH topography, a crucial step in diagnosing and
monitoring glaucoma. 3D spectral domain optical coherence tomography (SD-OCT),
an optical imaging technique, has been commonly used to discriminate
glaucomatous from healthy subjects. In this paper, we present a new approach for
locating the Bruch's membrane opening BMO and then estimating the optic disc
size and rim area of 3D Spectralis SD-OCT images. To deal with the overlapping
of the Bruch's membrane BM layer and the border tissue of Elschnig due to the
poor image resolution, we propose the use of image deconvolution approach to
separate these layers. To estimate the optic disc size and rim area, we propose
the use of a new regression method based on the artificial neural network
principal component analysis (ANN-PCA), which allows us to model irregularity in
the BMO estimation due to scan shifts and/or poor image quality. The diagnostic
accuracy of rim area, and rim to disc area ratio is compared to the diagnostic
accuracy of global RNFL thickness measurements provided by two commercially
available SD-OCT devices using receiver operating characteristic curve analyses. Glaucoma is an ocular disease characterized by distinctive changes in the optic
nerve head (ONH) and visual field. Glaucoma can strike without symptoms and
causes blindness if it remains without treatment. Therefore, early disease
detection is important so that treatment can be initiated and blindness
prevented. In this context, important advances in technology for non-invasive
imaging of the eye have been made providing quantitative tools to measure
structural changes in ONH topography, an essential element for glaucoma
detection and monitoring. 3D spectral domain optical coherence tomography
(SD-OCT), an optical imaging technique, has been commonly used to discriminate
glaucomatous from healthy subjects. In this paper, we present a new framework
for detection of glaucoma progression using 3D SD-OCT images. In contrast to
previous works that the retinal nerve fiber layer (RNFL) thickness measurement
provided by commercially available spectral-domain optical coherence tomograph,
we consider the whole 3D volume for change detection. To integrate a priori
knowledge and in particular the spatial voxel dependency in the change detection
map, we propose the use of the Markov Random Field to handle a such dependency.
To accommodate the presence of false positive detection, the estimated change
detection map is then used to classify a 3D SDOCT image into the
"non-progressing" and "progressing" glaucoma classes, based on a fuzzy logic
classifier. We compared the diagnostic performance of the proposed framework to
existing methods of progression detection. PURPOSE: To compare the effect of elevated intraocular pressure (IOP) on retinal
capillary filling in elderly vs adult rats using optical coherence tomography
angiography (OCTA).
METHODS: The IOP of elderly (24-month-old, N=12) and adult (6-8month-old, N=10)
Brown Norway rats was elevated in 10mmHg increments from 10 to 100mmHg. At each
IOP level, 3D OCT data were captured using an optical microangiography (OMAG)
scanning protocol and then post-processed to obtain both structural and vascular
images. Mean arterial blood pressure (MAP), respiratory rate, pulse and blood
oxygen saturation were monitored non-invasively throughout each experiment.
Ocular perfusion pressure (OPP) was calculated as the difference between MAP for
each animal and IOP at each level. The capillary filling index (CFI), defined as
the ratio of area occupied by functional capillary vessels to the total scan
area but excluding relatively large vessels of >30μm, was calculated at each IOP
level and analyzed using the OCTA angiograms. Relative CFI vs IOP was plotted
for the group means. CFI vs OPP was plotted for every animal in each group and
data from all animals were combined in a CFI vs OPP scatter plot comparing the
two groups.
RESULTS: The MAP in adult animals was 108±5mmHg (mean±SD), whereas this value in
the elderly was 99±5mmHg. All other physiologic parameters for both age groups
were uniform and stable. In elderly animals, significant reduction of the CFI
was first noted at IOP 40mmHg, as opposed to 60mmHg in adult animals. Individual
assessment of CFI as a function of OPP for adult animals revealed a consistent
plateau until OPP reached between 40 and 60mmHg. Elderly individuals
demonstrated greater variability, with many showing a beginning of gradual
deterioration of CFI at an OPP as high as 80mmHg. Overall comparison of CFI vs
OPP between the two groups was not statistically significant.
CONCLUSIONS: Compared to adults, some, but not all, elderly animals demonstrate
a more rapid deterioration of CFI vs OPP. This suggests a reduced autoregulatory
capacity that may contribute to increased glaucoma susceptibility in some older
individuals. This variability must be considered when studying the relationship
between IOP, ocular perfusion and glaucoma in elderly animal models. PURPOSE: To evaluate the ability of new Swept source (SS) optical coherence
tomography (OCT) technology to detect changes in retinal and choroidal thickness
in patients with Parkinson's disease (PD).
DESIGN: Observational case-control cross sectional study, developed from January
to May 2016.
METHODS: In total, 50 eyes from 50 patients diagnosed with PD and 54 eyes of 54
healthy controls underwent retinal and choroidal assessment using SS DRI Triton
OCT (Topcon), using the 3D Wide protocol. Total macular thickness and
peripapillary data (retinal, ganglion cell layer [GCL+, GCL++] and retinal nerve
fiber layer [RNFL] thickness) were analyzed. Macular and peripapillary choroidal
thickness was evaluated (Figure 1).
RESULTS: Significant peripapillary retinal thinning was observed in PD patients
in total average (p = 0.017), in the nasal (p = 0.038) and temporal (p = 0.004)
quadrants and in superotemporal (p = 0.004), nasal (p = 0.039), inferotemporal
(p = 0.019), and temporal (p = 0.003) sectors. RNFL and GCL ++ thickness showed
a significant reduction in the inferotemporal sector (p = 0.026 and 0.009,
respectively). No differences were observed in macular retinal thickness between
controls and patients. Choroidal thickness was found to have increased in all
sectors in PD patients compared with controls, both in the macular (inner nasal,
p = 0.015; inner inferior, p = 0.030; outer nasal, p = 0.012; outer inferior,
p = 0.049) and the peripapillary area (total thickness, p = 0.011; nasal,
p = 0.025; inferior, p = 0.007; temporal, p = 0.003; inferotemporal, p = 0.003;
inferonasal, p = 0.016) Conclusion: New SS technology for OCT devices detects
retinal thinning in PD patients, providing increased depth analysis of the
choroid in these patients. The choroid in PD may present increased thickness
compared to healthy individuals; however, more studies and histological analysis
are needed to corroborate our findings. BACKGROUND This study analyzed the macular 3D-OCT images of Vogt-Koyanagi-Harada
disease (VKH) in uveitis, explored the characteristics of 3D-OCT images of the
macular region of VKH, and assessed which characteristics contribute most to VKH
diagnosis. MATERIAL AND METHODS The 3D-OCT examination of 25 cases of VKH was
performed on the macular area, and the image characteristics were analyzed.
RESULTS Our study included a total of 50 eyes from 25 cases of VKH patients, 10
males and 15 females, aged 17 to 64 years, mean (39.44±11.60) years old.
According to OCT B-scan images, 49 (98%) eyes had ERD, 49 (98%) eyes had nerve
retinal edema, 36 (72%) eyes had endometrium-like structure (including cysts), 5
(10%) eyes had RPE folds, 35 (70%) eyes had changes in the internal septum, 49
(98%) eyes had RPE monolayer structure outside the ERD region. In ILM-RPE
thickness, 49 (98%) eyes had retinal irregular thickening and 31 (62%) eyes had
radial stripe changes. In ILM contour figure, 50 eyes (100%) showed exceptional
uplift, 5 (10%) eyes had small focal uplift for PED on the RPE surface, and 48
(96%) eyes had wavy ups and downs. CONCLUSIONS In OCT B-scan imaging, the ERT,
retinal edema of the retina, and the RPE monolayer structure outside the range
are most likely to occur in VKH. The ILM-RPE thickness chart in 3D
reconstruction showed irregular thickening of the retina. The ILM contour graph
showed abnormal uplift, and RPE surface wavy ups and downs in VKH most likely to
occur. |
Which was the first mutant IDH2 inhibitor to be approved for patients with acute myeloid leukemia? | Enasidenib was the first mutant IDH2 inhibitor to be approved for the treatment of refractory and relapsed acute myeloid leukemia. | BACKGROUND: Acute myeloid leukemia is the collective name for different types of
leukemias of myeloid origin affecting blood and bone marrow. The overproduction
of immature myeloblasts (white blood cells) is the characteristic feature of
AML, thus flooding the bone marrow and reducing its capacity to produce normal
blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly
known as AG-221 which is being marketed under the name Idhifa to treat R/R AML
with IDH2 mutation. The present review depicts the broad profile of enasidenib
including various aspects of chemistry, preclinical, clinical studies,
pharmacokinetics, mode of action and toxicity studies.
METHODS: Various reports and research articles have been referred to summarize
different aspects related to chemistry and pharmacokinetics of enasidenib.
Clinical data was collected from various recently published clinical reports
including clinical trial outcomes.
RESULT: The various findings of enasidenib revealed that it has been designed to
allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also
presented good safety and efficacy profile along with 9.3 months overall
survival rates of patients in which disease has relapsed. The drug is still
under study either in combination or solely to treat hematological maligcies.
Molecular modeling studies revealed that enasidenib binds to its target through
hydrophobic interaction and hydrogen bonding inside the binding pocket.
Enasidenib is found to be associated with certain adverse effects like elevated
bilirubin level, diarrhea, differentiation syndrome, decreased potassium and
calcium levels, etc.
CONCLUSION: Enasidenib or AG-221was introduced by FDA as an anticancer agent
which was developed as a first in class, a selective allosteric inhibitor of the
tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial
of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%.
Phase III trial on the Enasidenib is still under process along with another
trial to test its potency against other cell lines. Edasidenib is associated
with certain adverse effects, which can be reduced by investigators by designing
its newer derivatives on the basis of SAR studies. Hence, it may come in the
light as a potent lead entity for anticancer treatment in the coming years. |
What part of the body is affected by Meniere's disease? | The inner ear is the body part that is associated with Meniere's disease. | Meniere's disease is a disease of the inner ear characterized by a triad of
symptoms: vestibular symptoms, auditory symptoms, and pressure. The pathologic
correlate of Meniere's disease is endolymphatic hydrops and the etiopathogenesis
involves a deficiency in the absorption of endolymph. The pathophysiology of the
symptoms is still disputed: membranous ruptures, pressure and mechanical
displacement of the end organs, or obstruction followed by an abrupt clearance
of the endolymphatic duct. The course of the disease may be progressive or
nonprogressive and, in addition to the typical presentation of Meniere's
disease, two variations of the disorder have been identified: cochlear Meniere's
disease, and vestibular Meniere's disease. It can be further broken into two
subsets: Meniere's syndrome, with a known and well-established cause, and
Meniere's disease, in which the cause seems to be idiopathic. It is likely that
there are racial (genetic) as well as environmental factors that influence
differences in incidence among countries and among various sections of
countries. The disease is much more common in adults, with an average age of
onset in the fourth decade, the symptoms beginning usually between ages 20 and
60 years. Meniere's disease is (grossly) equally common in each sex, and right
and left ears are affected with fairly equal frequency. The diagnosis of
Meniere's disease is by exclusion, and a careful history is the most important
guide to a correct diagnosis. Its medical treatment is largely empiric. Surgery
can be considered when, even after medical therapy, the disease progresses and
the symptoms become intractable. Surgery may be either conservative or
destructive. Bilaterality must be considered when deciding the best surgical
option for a patient with Meniere's disease. It is the authors' opinion that
endolymphatic sac surgery is an extension of conservative treatment. CONCLUSION: Blockage of the endolymphatic duct is a significant finding in
Meniere's disease. The position of the utriculo-endolymphatic valve (UEV) and
blockage of the ductus reuniens in the temporal bones were not found to be
directly indicative of Meniere's disease.
OBJECTIVE: Comparison of blockage of the longitudinal flow of endolymph between
ears affected by Meniere's disease and normal ears.
METHODS: We examined 21 temporal bones from 13 subjects who had Meniere's
disease and 21 normal temporal bones from 12 controls.
RESULTS: The endolymphatic duct was blocked in five (23%) ears affected by
Meniere's disease (p = 0.016). The utricular duct was blocked in 16 (76%) ears
affected by Meniere's disease and 11 (52%) normal ears (p = 0.112). The saccular
duct was blocked in 6 (28%) of ears affected by Meniere's disease and 16 (76%)
normal ears (p = 0.001). The ductus reuniens was blocked in 10 (47%) ears
affected by Meniere's disease and 10 (47%) normal ears (p = 1.000). Meniere's disease is an inner ear disease, characterized by recurrent rotatory
vertigo, sensorineural hearing loss and tinnitus. There are some with frequent
vertigo attacks, progressive hearing loss and persistent annoying tinnitus even
through the continuous standard medical treatments. These cases are thought to
account for 10%-20% of all cases of Meniere's disease. In this review article,
we would like to demonstrate the evidences for surgical treatments according to
the previous papers, and consider the next therapeutic strategies including
surgical options according to the international guidelines. OBJECTIVE: Ménière's Disease (MD) is a chronic, non-life threatening inner ear
disease, with attacks of disabling vertigo, progressive hearing loss, and
tinnitus as the major symptoms. All three symptoms, separately or in
combination, cause great distress and have a considerable impact on the quality
of life of the patients. The aims of this study were to develop a
disease-specific quality of life survey for patients with MD and to analyze the
relationships between the audiovestibular findings and the survey.
MATERIALS AND METHODS: Following Ear-Nose-Throat examination and audiovestibular
tests, the Dokuz Eylül University Meniere's Disease Disability Scale (DEU-MDDS)
and Turkish version of the Dizziness Handicap Inventory (DHI-T) were
administered to 93 patients with definite MD. Reliability and validity analyses
of the scale were performed.
RESULTS: There were 45 (48.4%) male and 48 (51.6%) female patients and the mean
age was 48.9±12.1 years. Cronbach's alpha was 0.92 and intraclass correlation
coefficients of the DEU-MMDS were significant (p<0.001). Results of the Goodness
of Fit Statistics showed that the expression levels of the items were high and
the correlation coefficients of each item with the scale were sufficient. There
was a statistically significant correlation between DHI-T scores and MDDS.
DEU-MDDS was not related to the vestibular tests, age or gender (p>0.05).
CONCLUSION: The MDDS is a valid and reliable scale as a disease-specific quality
of life questionnaire for patients with MD. |
Which two drugs are included in the MAVYRET pill? | MAVYRET pill includes glecaprevir and pibrentasvir. It is used for treatment of hepatitis C infection. | |
Describe the 4D-CHAINS algorithm | 4D-CHAINS/autoNOE-Rosetta is a complete pipeline for NOE-driven structure determination of medium- to larger-sized proteins. The 4D-CHAINS algorithm analyzes two 4D spectra recorded using a single, fully protonated protein sample in an iterative ansatz where common NOEs between different spin systems supplement conventional through-bond connectivities to establish assignments of sidechain and backbone resonances at high levels of completeness and with a minimum error rate. The 4D-CHAINS assignments are then used to guide automated assignment of long-range NOEs and structure refinement in autoNOE-Rosetta. | Automated methods for NMR structure determination of proteins are continuously
becoming more robust. However, current methods addressing larger, more complex
targets rely on analyzing 6-10 complementary spectra, suggesting the need for
alternative approaches. Here, we describe 4D-CHAINS/autoNOE-Rosetta, a complete
pipeline for NOE-driven structure determination of medium- to larger-sized
proteins. The 4D-CHAINS algorithm analyzes two 4D spectra recorded using a
single, fully protonated protein sample in an iterative ansatz where common NOEs
between different spin systems supplement conventional through-bond
connectivities to establish assignments of sidechain and backbone resoces at
high levels of completeness and with a minimum error rate. The 4D-CHAINS
assignments are then used to guide automated assignment of long-range NOEs and
structure refinement in autoNOE-Rosetta. Our results on four targets ranging in
size from 15.5 to 27.3 kDa illustrate that the structures of proteins can be
determined accurately and in an unsupervised manner in a matter of days. |
What is an organoid? | Organoids are a three-dimensional in vitro culture platform constructed from self-organizing stem cells. They can almost accurately recapitulate tumor heterogeneity and microenvironment "in a dish," which surpass established cell lines and are not as expensive and time-consuming as PDTXs. As an intermediate model, tumor organoids are also used to study the fundamental issues of tumorigenesis and metastasis. They are specifically applied for drug testing and stored as "living biobanks." | Author information:
(1)Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China.
(2)Department of Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji
University School of Medicine, Shanghai 200433, PR China.
(3)Department of Neurosurgery, General Hospital of Ji Military Command, Ji
250031, PR China.
(4)Institute of Neuroscience, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai 200031, PR China. Electronic address:
[email protected].
(5)Department of Gynecology Oncology, The Tumor Hospital, Harbin Medical
University, Harbin, 150086, PR China. Electronic address:
[email protected].
(6)Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center
for Intelligent Diagnosis and Treatment Instrument, Department of Instrument
Science and Engineering, Key Laboratory for Thin Film and Microfabrication
Technology of Ministry of Education, School of Electronic Information and
Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR
China; National Center for Translational Medicine, Collaborative Innovational
Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, PR
China; Shaanxi Key Laboratory of Brain Disorders and School of Basic Medical
Sciences, Xi'an Medical University, Xi'an 710021, PR China. Electronic address:
[email protected]. The introduction of stem cell-based technologies for the derivation of
three-dimensional retinal tissues, the so-called retinal organoids, offers many
new possibilities for vision research: Organoids facilitate studies on retinal
development and in vitro retinal disease modeling, as well as being valuable for
drug testing. Further, retinal organoids also provide an unlimited cell source
for cell replacement therapies. Here, we describe our protocol for efficiently
differentiating large, stratified retinal organoids from mouse embryonic stem
cells: unbiased manual dissection of the developing retinal organoid at an early
stage into three evenly sized neuroepithelial portions (trisection step) doubles
the yield of high-quality organoids. We also describe some useful applications
of the protocol, e.g., generation of rod- or cone-enriched retinal organoids,
AAV transfection, and cell birth dating. In addition, we provide details of how
to process retinal organoids for single organoid gene expression analysis,
immunohistochemistry, and electron microscopy. |
Do raspberries improve postprandial glucose and acute and chronic inflammation in adults with type 2 Diabetes? | yes, raspberries improve postprandial glucose and acute and chronic inflammation in adults with type 2 Diabetes. | |
Are Mesenchymal stem cells (MSC) multipotent cells? | Yes, Mesenchymal stem cells (MSC) are multipotent cells. | |
Which two drugs are included in the Entresto pill? | Entresto includes Sacubitril and Valsartan. | Sacubitril/valsartan (Entresto) for chronic heart failure; brexpiprazole
(Rexulti) for major depressive disorder and schizophrenia; and
lumacaftor/ivacaftor (Orkambi) for cystic fibrosis involving specific CFTR
mutations. ▼ Sacubitril valsartan (Entresto-Novartis) is a new oral drug licensed for the
treatment of symptomatic chronic heart failure in adults with reduced ejection
fraction.(1) It is described as an angiotensin receptor neprilysin inhibitor and
contains the neprilysin inhibitor, sacubitril and the angiotensin II receptor
antagonist, valsartan.(1-3) Here, we review the evidence for sacubitril
valsartan and consider its place in the management of heart failure. In this article, we consider the new drugs approved for the European market in
2015. We present a summary of the new mechanisms of action introduced and
highlight three new mechanisms of action with a potentially high future impact:
PCSK9 inhibition (alirocumab (Praluent®) and evolocumab (Repatha®)) for
hypercholesterolaemia, neprilysin inhibition (sacubitril in combination with
valsartan (Entresto®)) for heart failure, and interleukin-5 inhibition
(mepolizumab (Nucala®)) for asthma. A 63-year-old woman previously stable on a regimen of atorvastatin 40 mg daily,
carvedilol 25 mg twice daily, digoxin 0.125 mg daily, furosemide 40 mg daily,
spironolactone 25 mg daily, rivaroxaban 15 mg daily, and enalapril 20 mg twice
daily for heart failure developed rhabdomyolysis 26 days after enalapril was
stopped and sacubitril/valsartan (Entresto™) started. The patient received
sacubitril/valsartan at 24/26 mg twice daily for heart failure; however, after
26 days she developed muscle and skin pain. Investigations revealed elevated
creatine kinase and liver function tests, and rhabdomyolysis with raised
transaminases was diagnosed. Sacubitril/valsartan and atorvastatin were
discontinued and the patient was hydrated. She returned to baseline in 23 days
and has not had any reoccurrence of rhabdomyolysis and elevated transaminases
for 46 days. A Naranjo assessment score of 5 was obtained, indicating a probable
relationship between the patient's rhabdomyolysis and her use of
sacubitril/valsartan. The Drug Interaction Probability Scale score was 3,
consistent with a possible interaction as a cause for the reaction, with
sacubitril/valsartan as the precipitant drug and atorvastatin as the object
drug. Heart failure (HF) is one of the leading causes of morbidity, mortality, and
health care expenditures in the US and worldwide. For three decades, the pillars
of treatment of HF with reduced ejection fraction (HFrEF) were medications that
targeted the sympathetic nervous system (SNS) and the
renin-angiotensin-aldosterone system (RAAS). Prior attempts to augment the
natriuretic peptide system (NPS) for the management of HF failed either due to
lack of significant clinical benefit or due to the unacceptable side effect
profile. This review article will discuss the NPS, the failure of early drugs
which targeted the NPS as therapies for HF, and the sequence of events which led
to the development of sacubitril plus valsartan (Entresto; LCZ696; Novartis).
LCZ696 has been shown to be superior to the standard of care available for
treatment of HFrEF in several substantial hard endpoints including heart failure
hospitalizations, cardiovascular mortality, and all-cause mortality. Entresto was recommanded by major guidelines as the frontline therapy for heart
failure with reduced ejection fraction since its clinical benefit was proved by
the PARADIGM-HF trial. Angiotensin converting enzyme inhibitors are the
cornerstone of the treatment of HF. Varying incidences of first-dose hypotension
have been reported and recognized as a potential limiting factor for
prescribing. According to previous reports, the onset of hypotension mostly
occur 3-5 hours after the first dose. However, the pattern of entresto-related
hypotension has not been reported. We present a case of HF, who had delay onset
(about 8 to 18 hours) and prolonged (3 to 6 days) first-dose hypotension.
Further investigation is required to illustrate this phenomenon. Vasoplegia occurs in up to 16% of patients who undergo heart transplantation
(HT) and is associated with significant morbidity and mortality. We present a
case of a 61-year-old man with ischemic cardiomyopathy receiving
sacubitril/valsartan (Entresto; Novartis, Cambridge, MA) who developed profound
hypotension after HT. He was treated with intravenous methylene blue and
high-dose vasopressors, but developed acute kidney injury requiring dialysis and
a prolonged stay in the intensive care unit. This case supports a potent
vasodilatory effect of sacubitril/valsartan, and if confirmed by other studies,
might warrant consideration for withholding treatment while awaiting HT,
particularly in patients with risk factors for vasoplegia. Heart Failure (HF) is one of the main healthcare burdens in the United States
and in the world. Many drugs are approved and used in practice for management of
this condition; including beta blockers, diuretics, aldosterone antagonists,
Angiotensin Converting Enzyme Inhibitors (ACEI's), and Angiotensin Receptor
Blockers (ARBs). Recently, the Food and Drug Administration (FDA) approved a
drug with brand name Entresto (Sacubitril/Valsartan or LCZ696), an angiotensin
receptor neprilysin inhibitor for the use in Heart Failure with Reduced Ejection
Fraction (HFrEF) patients instead of ACEI's and ARBs. The drug works through
angiotensin receptor blockage via valsartan as well as neprilysin inhibition
with sacubitril. This represented a new milestone in managing heart failure
patients and provided yet another therapy in our armamentarium. This article
reviews the stages that led to the development of this drug, the failure of its
preceding agents, the lessons we have learnt, and the current trials of Entresto
for new indications. BACKGROUND: The effects of sacubitril/valsartan (S/V) on the
renin-angiotensin-aldosterone system (RAAS) in dogs with cardiomegaly secondary
to myxomatous mitral valve disease (MMVD) are currently unknown.
OBJECTIVES: To determine the pharmacodynamic effects of S/V on the RAAS,
natriuretic peptide concentrations, systolic arterial pressure (SAP), tests of
renal function, and serum electrolyte concentrations in dogs with cardiomegaly
secondary to MMVD.
ANIMALS: Thirteen client-owned dogs weighing 4-15 kg with American College of
Veterinary Internal Medicine (ACVIM) Stage B2 MMVD.
METHODS: Prospective, randomized, double-blind, placebo-controlled pilot study
of S/V in dogs with ACVIM Stage B2 MMVD.
RESULTS: Thirteen dogs were recruited: S/V (n = 7) and placebo (n = 6). The
median percentage increase in urinary aldosterone to creatinine ratio (UAldo :
C) between day 0 and day 30 was significantly lower in the S/V group (12%;
P = .032) as compared with the placebo group (195%). The median percentage
decrease of NT-proBNP concentration from day 0 to day 30 was not statistically
different between groups (P = .68). No statistical differences were seen in
echocardiographic, thoracic radiographic, SAP, or serum biochemical test results
measured at any time point between groups. No adverse events were observed for
dogs in either group.
CONCLUSION AND CLINICAL IMPORTANCE: Sacubitril/valsartan may provide a new
pharmaceutical method to effectively inhibit the RAAS in dogs with ACVIM Stage
B2 MMVD. |
Is there a deep-learning algorithm for protein solubility prediction? | Yes. DeepSol is a novel deep learning-based protein solubility predictor. It is a convolutional neural network that exploits k-mer structure and additional sequence and structural features extracted from the protein sequence. | MOTIVATION: Protein solubility plays a vital role in pharmaceutical research and
production yield. For a given protein, the extent of its solubility can
represent the quality of its function, and is ultimately defined by its
sequence. Thus, it is imperative to develop novel, highly accurate in silico
sequence-based protein solubility predictors. In this work we propose, DeepSol,
a novel Deep Learning-based protein solubility predictor. The backbone of our
framework is a convolutional neural network that exploits k-mer structure and
additional sequence and structural features extracted from the protein sequence.
RESULTS: DeepSol outperformed all known sequence-based state-of-the-art
solubility prediction methods and attained an accuracy of 0.77 and Matthew's
correlation coefficient of 0.55. The superior prediction accuracy of DeepSol
allows to screen for sequences with enhanced production capacity and can more
reliably predict solubility of novel proteins.
AVAILABILITY AND IMPLEMENTATION: DeepSol's best performing models and results
are publicly deposited at https://doi.org/10.5281/zenodo.1162886 (Khurana and
Mall, 2018).
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online. |
Have machine learning methods been used to predict the severity of major depressive disorder(MDD)? | Machine-learning (ML) models developed from self-reports can be used to predict persistence and severity of major depressive disorder(MDD) | Quantitative abnormalities of brain structure in patients with major depressive
disorder have been reported at a group level for decades. However, these
structural differences appear subtle in comparison with conventional
radiologically defined abnormalities, with considerable inter-subject
variability. Consequently, it has not been possible to readily identify scans
from patients with major depressive disorder at an individual level. Recently,
machine learning techniques such as relevance vector machines and support vector
machines have been applied to predictive classification of individual scans with
variable success. Here we describe a novel hybrid method, which combines machine
learning with feature selection and characterization, with the latter aimed at
maximizing the accuracy of machine learning prediction. The method was tested
using a multi-centre dataset of T(1)-weighted 'structural' scans. A total of 62
patients with major depressive disorder and matched controls were recruited from
referred secondary care clinical populations in Aberdeen and Edinburgh, UK. The
generalization ability and predictive accuracy of the classifiers was tested
using data left out of the training process. High prediction accuracy was
achieved (~90%). While feature selection was important for maximizing high
predictive accuracy with machine learning, feature characterization contributed
only a modest improvement to relevance vector machine-based prediction (~5%).
Notably, while the only information provided for training the classifiers was
T(1)-weighted scans plus a categorical label (major depressive disorder versus
controls), both relevance vector machine and support vector machine 'weighting
factors' (used for making predictions) correlated strongly with subjective
ratings of illness severity. These results indicate that machine learning
techniques have the potential to inform clinical practice and research, as they
can make accurate predictions about brain scan data from individual subjects.
Furthermore, machine learning weighting factors may reflect an objective
biomarker of major depressive disorder illness severity, based on abnormalities
of brain structure. Author information:
(1)Department of Psychiatry,University of Groningen, University Medical Center
Groningen,The Netherlands.
(2)Department of Biostatistics,Harvard School of Public Health,Boston, MA,USA.
(3)Department of Psychiatry,MGH Clinical Trials Network and Institute,Depression
Clinical and Research Program, Massachusetts General Hospital, Boston, MA,USA.
(4)Department of Health Care Policy,Harvard Medical School,Boston, MA,USA.
(5)Depression Clinical and Research Program and the Bipolar Clinic and Research
Program,Massachusetts General Hospital and Harvard Medical School,Boston,
MA,USA.
(6)Johnson & Johnson Pharmaceutical Research and Development,Titusville, NJ,USA.
(7)IMIM-Hospital del Mar Research Institute, Parc de Salut Mar,Pompeu Fabra
University (UPF), andCIBER en Epidemiología y Salud Pública (CIBERESP),
Barcelona,Spain.
(8)Department of Psychiatry and Behavioral Science, Stony Brook School of
Medicine,State University of New York at Stony Brook,Stony Brook, NY,USA.
(9)Psychology Research Institute,University of Ulster,Londonderry,UK.
(10)National School of Public Health,Management and Professional Development,
Bucharest,Romania.
(11)Department of Public Health,Yamagata University School of Medicine,Japan.
(12)University College Hospital,Ibadan,Nigeria.
(13)Shenzhen Institute of Mental Health and Shenzhen Kangning Hospital,Guangdong
Province,People's Republic of China.
(14)Institute of Mental Health, Peking University,Beijing,People's Republic of
China.
(15)Department of Psychiatry and Clinical Psychology,St George Hospital
University Medical Center,Department of Psychiatry and Clinical Psychology,
Faculty of Medicine, Balamand University Medical School, andInstitute for
Development Research Advocacy and Applied Care (IDRAAC), Beirut,Lebanon.
(16)Research and Planning,Mental Health Services,Ministry of Health,
Jerusalem,Israel.
(17)National Institute of Psychiatry,Calzada Mexico Xochimilco, Mexico
City,Mexico.
(18)Universidad Colegio Mayor de Cundinamarca,Bogota,Colombia.
(19)Department of Psychological Medicine,University of Otago,Dunedin,New
Zealand.
(20)Mental Health Center-Duhok,Kurdistan Region,Iraq.
(21)Department of Social Medicine,Federal University of Espirito
Santo,Vitoria,Brazil.
(22)Department of Mental Health,Universidade Nova de Lisboa,Lisbon,Portugal.
(23)National Center of Public Health and Analyses,Department of Mental Health,
Sofia,Bulgaria. OBJECTIVE: We aimed to integrate neural data and an advanced machine learning
technique to predict individual major depressive disorder (MDD) patient
severity.
METHODS: MEG data was acquired from 22 MDD patients and 22 healthy controls (HC)
resting awake with eyes closed. Individual power spectra were calculated by a
Fourier transform. Sources were reconstructed via beamforming technique.
Bayesian linear regression was applied to predict depression severity based on
the spatial distribution of oscillatory power.
RESULTS: In MDD patients, decreased theta (4-8 Hz) and alpha (8-14 Hz) power was
observed in fronto-central and posterior areas respectively, whereas increased
beta (14-30 Hz) power was observed in fronto-central regions. In particular,
posterior alpha power was negatively related to depression severity. The
Bayesian linear regression model showed significant depression severity
prediction performance based on the spatial distribution of both alpha (r=0.68,
p=0.0005) and beta power (r=0.56, p=0.007) respectively.
CONCLUSIONS: Our findings point to a specific alteration of oscillatory brain
activity in MDD patients during rest as characterized from MEG data in terms of
spectral and spatial distribution.
SIGNIFICANCE: The proposed model yielded a quantitative and objective estimation
for the depression severity, which in turn has a potential for diagnosis and
monitoring of the recovery process. BACKGROUND: Growing evidence documents the potential of machine learning for
developing brain based diagnostic methods for major depressive disorder (MDD).
As symptom severity may influence brain activity, we investigated whether the
severity of MDD affected the accuracies of machine learned MDD-vs-Control
diagnostic classifiers.
METHODS: Forty-five medication-free patients with DSM-IV defined MDD and 19
healthy controls participated in the study. Based on depression severity as
determined by the Hamilton Rating Scale for Depression (HRSD), MDD patients were
sorted into three groups: mild to moderate depression (HRSD 14-19), severe
depression (HRSD 20-23), and very severe depression (HRSD ≥ 24). We collected
functional magnetic resoce imaging (fMRI) data during both resting-state and
an emotional-face matching task. Patients in each of the three severity groups
were compared against controls in separate analyses, using either the
resting-state or task-based fMRI data. We use each of these six datasets with
linear support vector machine (SVM) binary classifiers for identifying
individuals as patients or controls.
RESULTS: The resting-state fMRI data showed statistically significant
classification accuracy only for the very severe depression group (accuracy 66%,
p = 0.012 corrected), while mild to moderate (accuracy 58%, p = 1.0 corrected)
and severe depression (accuracy 52%, p = 1.0 corrected) were only at chance.
With task-based fMRI data, the automated classifier performed at chance in all
three severity groups.
CONCLUSIONS: Binary linear SVM classifiers achieved significant classification
of very severe depression with resting-state fMRI, but the contribution of brain
measurements may have limited potential in differentiating patients with less
severe depression from healthy controls. OBJECTIVE: A growing literature indicates that unipolar depression and bipolar
depression are associated with alterations in grey matter volume. However, it is
unclear to what degree these patterns of morphometric change reflect symptom
dimensions. Here, we aimed to predict depressive symptoms and hypomanic symptoms
based on patterns of grey matter volume using machine learning.
METHOD: We used machine learning methods combined with voxel-based morphometry
to predict depressive and self-reported hypomanic symptoms from grey matter
volume in a sample of 47 individuals with unmedicated unipolar and bipolar
depression.
RESULTS: We were able to predict depressive severity from grey matter volume in
the anteroventral bilateral insula in both unipolar depression and bipolar
depression. Self-reported hypomanic symptoms did not predict grey matter loss
with a significant degree of accuracy.
DISCUSSION: The results of this study suggest that patterns of grey matter
volume alteration in the insula are associated with depressive symptom severity
across unipolar and bipolar depression. Studies using other modalities and
exploring other brain regions with a larger sample are warranted to identify
other systems that may be associated with depressive and hypomanic symptoms
across affective disorders. INTRODUCTION: The heterogeneity of symptoms and complex etiology of depression
pose a significant challenge to the personalization of treatment. Meanwhile, the
current application of generic treatment approaches to patients with vastly
differing biological and clinical profiles is far from optimal. Here, we conduct
a meta-review to identify predictors of response to antidepressant therapy in
order to select robust input features for machine learning models of treatment
response. These machine learning models will allow us to learn associations
between patient features and treatment response which have predictive value at
the individual patient level; this learning can be optimized by selecting
high-quality input features for the model. While current research is difficult
to directly apply to the clinic, machine learning models built using knowledge
gleaned from current research may become useful clinical tools.
METHODS: The EMBASE and MEDLINE/PubMed online databases were searched from
January 1996 to August 2017, using a combination of MeSH terms and keywords to
identify relevant literature reviews. We identified a total of 1909 articles,
wherein 199 articles met our inclusion criteria.
RESULTS: An array of genetic, immune, endocrine, neuroimaging, sociodemographic,
and symptom-based predictors of treatment response were extracted, varying
widely in clinical utility.
LIMITATIONS: Due to heterogeneous sample sizes, effect sizes, publication
biases, and methodological disparities across reviews, we could not accurately
assess the strength and directionality of every predictor.
CONCLUSION: Notwithstanding our cautious interpretation of the results, we have
identified a multitude of predictors that can be used to formulate a priori
hypotheses regarding the input features for a computational model. We highlight
the importance of large-scale research initiatives and clinically accessible
biomarkers, as well as the need for replication studies of current findings. In
addition, we provide recommendations for future improvement and standardization
of research efforts in this field. |
What is known about the gut bacteria and depression. | Evidence indicates that major depression is accompanied by increased translocation of gut commensal Gram-negative bacteria (leaky gut) and consequent activation of oxidative and nitrosative (O&NS) pathways.
Major depressive disorder (MDD) is a highly prevalent and debilitating mental illness, which is associated with disorder of gut microbiota. | The human gut is a composite anaerobic environment with a large, diverse and
dynamic enteric microbiota, represented by more than 100 trillion
microorganisms, including at least 1000 distinct species. The discovery that a
different microbial composition can influence behavior and cognition, and in
turn the nervous system can indirectly influence enteric microbiota composition,
has significantly contributed to establish the well-accepted concept of
gut-brain axis. This hypothesis is supported by several evidence showing mutual
mechanisms, which involve the vague nerve, the immune system, the
hypothalamic-pituitaryadrenal (HPA) axis modulation and the bacteria-derived
metabolites. Many studies have focused on delineating a role for this axis in
health and disease, ranging from stress-related disorders such as depression,
anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disorders, such
as autism, and to neurodegenerative diseases, such as Parkinson Disease,
Alzheimer's Disease etc. Based on this background, and considering the relevance
of alteration of the symbiotic state between host and microbiota, this review
focuses on the role and the involvement of bioactive lipids, such as the
N-acylethanolamine (NAE) family whose main members are
N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and
oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate,
belonging to a large group of bioactive lipids able to modulate peripheral and
central pathologic processes. Their effective role has been studied in
inflammation, acute and chronic pain, obesity and central nervous system
diseases. A possible correlation has been shown between these lipids and gut
microbiota through different mechanisms. Indeed, systemic administration of
specific bacteria can reduce abdominal pain through the involvement of
cannabinoid receptor 1 in the rat; on the other hand, PEA reduces inflammation
markers in a murine model of inflammatory bowel disease (IBD), and butyrate,
producted by gut microbiota, is effective in reducing inflammation and pain in
irritable bowel syndrome and IBD animal models. In this review, we underline the
relationship among inflammation, pain, microbiota and the different lipids,
focusing on a possible involvement of NAEs and SCFAs in the gut-brain axis and
their role in the central nervous system diseases. Evidence indicates that major depression is accompanied by increased
translocation of gut commensal Gram-negative bacteria (leaky gut) and consequent
activation of oxidative and nitrosative (O&NS) pathways. This present study
examined the associations among chronic apical periodontitis (CAP), root canal
endotoxin levels (lipopolysaccharides, LPS), O&NS pathways, depressive symptoms,
and quality of life. Measurements included advanced oxidation protein products
(AOPP), nitric oxide metabolites (NOx), lipid peroxides (LOOH), -sulfhydryl (SH)
groups, total radical trapping antioxidant parameter (TRAP), and paraoxonase
(PON)1 activity in participants with CAP, with and without depression, as well
as healthy controls (no depression, no CAP). Root canal LPS levels were
positively associated with CAP, clinical depression, severity of depression (as
measured with the Hamilton Depression Rating Scale (HDRS) and the Beck
Depression Inventory) and O&NS biomarkers, especially NOx and TRAP. CAP-related
depression was accompanied by increased levels of NOx, LOOH, AOPP, and TRAP. In
CAP participants, there was a strong correlation (r = 0.734, p < 0.001) between
root canal LPS and the HDRS score. There were significant and positive
associations between CAP or root canal endotoxin with the vegetative and
physio-somatic symptoms of the HDRS as well as a significant inverse association
between root canal endotoxin and quality of life with strong effects on
psychological, environmental, and social domains. It is concluded that increased
root canal LPS accompanying CAP may cause depression and a lowered quality of
life, which may be partly explained by activated O&NS pathways, especially NOx
thereby enhancing hypernitrosylation and thus neuroprogressive processes. Dental
health and "leaky teeth" may be intimately linked to the etiology and course of
depression, while significantly impacting quality of life. The complex bidirectional communication between the gut and the brain is finely
orchestrated by different systems, including the endocrine, immune, autonomic,
and enteric nervous systems. Moreover, increasing evidence supports the role of
the microbiome and microbiota-derived molecules in regulating such interactions;
however, the mechanisms underpinning such effects are only beginning to be
resolved. Microbiota-gut peptide interactions are poised to be of great
significance in the regulation of gut-brain signaling. Given the emerging role
of the gut-brain axis in a variety of brain disorders, such as anxiety and
depression, it is important to understand the contribution of bidirectional
interactions between peptide hormones released from the gut and intestinal
bacteria in the context of this axis. Indeed, the gastrointestinal tract is the
largest endocrine organ in mammals, secreting dozens of different signaling
molecules, including peptides. Gut peptides in the systemic circulation can bind
cognate receptors on immune cells and vagus nerve terminals thereby enabling
indirect gut-brain communication. Gut peptide concentrations are not only
modulated by enteric microbiota signals, but also vary according to the
composition of the intestinal microbiota. In this review, we will discuss the
gut microbiota as a regulator of anxiety and depression, and explore the role of
gut-derived peptides as signaling molecules in microbiome-gut-brain
communication. Here, we summarize the potential interactions of the microbiota
with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY,
pancreatic polypeptide, cholecystokinin, glucagon-like peptide,
corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain
signaling. Together, gut peptides are important regulators of
microbiota-gut-brain signaling in health and stress-related psychiatric
illnesses. Major depressive disorder (MDD) is a highly prevalent and debilitating mental
illness, which is associated with disorder of gut microbiota. However, few
studies focusing on detection of the signatures of bacteria in feces of MDD
patients using proteomics approach have been carried out. Here, a comparative
metaproteomics analysis on the basis of an isobaric tag for relative and
absolute quantification coupled with tandem mass spectrometry was carried out to
explore the signature of gut microbiota in patients with MDD. Ten patients (age:
18-56 years, five women) who had MDD and a score over 20 on the Hamilton's
Depression Scale and 10 healthy controls (age: 24-65 years, five women) group
matched for sex, age, and BMI were enrolled. As a result, 279 significantly
differentiated bacterial proteins (P<0.05) were detected and used for further
bioinformatic analysis. According to phylogenetic analysis, statistically
significant differences were observed for four phyla: Bacteroidetes,
Proteobacteria, Firmicutes, Actinobacteria (P<0.05, for each). Abundances of 16
bacterial families were significantly different between the MDD and healthy
controls (P<0.05). Furthermore, Cluster of Orthologous Groups analysis and Kyoto
Encyclopedia of Genes and Genomes pathway analysis showed that disordered
metabolic pathways of bacterial proteins were mainly involved in glucose
metabolism and amino acid metabolism. In conclusion, fecal microbiota signatures
were altered significantly in MDD patients. Our findings provide a novel insight
into the potential connection between gut microbiota and depression. |
Can midostaurin inhibit angiogenesis? | Yes, midostaurin can inhibit angiogenesis through the inhibition of ithe vascular endothelial growth factor receptor. | |
For which indications has midostaurin received FDA and EMA approval? | Midostaurin was approved by the Food and Drug Administration (FDA) and the European Medical Agency (EMA) for acute myeloid leukemia with activating FLT3 mutations in combination with intensive induction and consolidation therapy as well as aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN) or mast cell leukemia (MCL). | Midostaurin (PKC412, Rydapt®) is an oral multiple tyrosine kinase inhibitor.
Main targets are the kinase domain receptor, vascular endothelial-, platelet
derived-, and fibroblast growth factor receptor, stem cell factor receptor
c-KIT, as well as mutated and wild-type FLT3 kinases. Midostaurin was approved
by the Food and Drug Administration (FDA) and the European Medical Agency (EMA)
for acute myeloid leukemia with activating FLT3 mutations in combination with
intensive induction and consolidation therapy as well as aggressive systemic
mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm
(SM-AHN) or mast cell leukemia (MCL). Several clinical trials are active or are
planned to further investigate the role of midostaurin in myeloid maligcies
and mastocytosis. |
Does Groucho related gene 5 (GRG5) have a role only in late development? | Groucho related gene 5 (GRG5) has been described as a multifunctional protein that has been implicated in late embryonic and postnatal mouse development. By both loss and gain of function approaches ablation of GRG5 has been shown to deregulate the Embryonic Stem Cell (ESC) pluripotent state whereas its overexpression leads to enhanced self-renewal and acquisition of cancer cell-like properties. The malignant characteristics of teratomas generated by ESCs that overexpress GRG5 reveal its pro-oncogenic potential. | Groucho related gene 5 (GRG5) is a multifunctional protein that has been
implicated in late embryonic and postnatal mouse development. Here, we describe
a previously unknown role of GRG5 in early developmental stages by analyzing its
function in stem cell fate decisions. By both loss and gain of function
approaches we demonstrate that ablation of GRG5 deregulates the Embryonic Stem
Cell (ESC) pluripotent state whereas its overexpression leads to enhanced
self-renewal and acquisition of cancer cell-like properties. The maligt
characteristics of teratomas generated by ESCs that overexpress GRG5 reveal its
pro-oncogenic potential. Furthermore, transcriptomic analysis and cell
differentiation approaches underline GRG5 as a multifaceted signaling regulator
that represses mesendodermal-related genes. When ESCs exit pluripotency, GRG5
promotes neuroectodermal specification via Wnt and BMP signaling suppression.
Moreover, GRG5 promotes the neuronal reprogramming of fibroblasts and maintains
the self-renewal of Neural Stem Cells (NSCs) by sustaining the activity of
Notch/Hes and Stat3 signaling pathways. In summary, our results demonstrate that
GRG5 has pleiotropic roles in stem cell biology functioning as a stemness factor
and a neural fate specifier. |
Which drugs are included in the Orkambi pill? | Orkambi pill includes lumacaftor combined with ivacaftor. It is approved for treatment of cystic fibrosis with F508del-CFTR mutation. | Sacubitril/valsartan (Entresto) for chronic heart failure; brexpiprazole
(Rexulti) for major depressive disorder and schizophrenia; and
lumacaftor/ivacaftor (Orkambi) for cystic fibrosis involving specific CFTR
mutations. ORKAMBI (ivacaftor-lumacaftor [LUMA]) and KALYDECO (ivacaftor; IVA) are two new
breakthrough cystic fibrosis (CF) drugs that directly modulate the activity and
trafficking of the defective CFTR underlying the CF disease state. Currently, no
therapeutic drug monitoring assays exist for these very expensive, albeit,
important drugs. In this study, for the first time HPLC and LC-MS methods were
developed and validated for rapid detection and quantification of IVA and its
major metabolites hydroxymethyl-IVA M1 (active) and IVA-carboxylate M6
(inactive); and LUMA in the plasma and sputum of CF patients. With a mobile
phase consisting of acetonitrile/water:0.1% formic acid (60:40v/v) at a flow
rate of 1mL/min, a linear correlation was observed over a concentration range
from 0.01 to 10μg/mL in human plasma (IVA R2>0.999, IVA M1 R2>0.9961, IVA M6
R2>0.9898, LUMA R2>0.9954). The assay was successfully utilized to quantify the
concentration of LUMA, IVA, M1 and M6 in the plasma and sputum of CF patients
undergoing therapy with KALYDECO (IVA 150mg/q12h) or ORKAMBI (200mg/q12h
LUMA-125mg/q12h IVA). The KALYDECO patient exhibited an IVA plasma concentration
of 0.97μg/mL at 2.5h post dosage. M1 and M6 plasma concentrations were 0.50μg/mL
and 0.16μg/mL, respectively. Surprisingly, the ORKAMBI patient displayed very
low plasma concentrations of IVA (0.06μg/mL) and M1 (0.07μg/mL). The M6
concentrations (0.15μg/mL) were comparable to those of the KALYDECO patient.
However, we observed a relatively high plasma concentration of LUMA (4.42μg/mL).
This reliable and novel method offers a simple and sensitive approach for
therapeutic drug monitoring of KALYDECO and ORKAMBI in plasma and sputum. The
introduction of the assay into the clinical setting will facilitate
pharmacokinetics/pharmacodynamic analysis and assist clinicians to develop more
cost effective and efficacious dosage regimens for these breakthrough CF drugs. Cystic fibrosis (CF) is a life-limiting disease caused by defective or deficient
cystic fibrosis transmembrane conductance regulator (CFTR) activity. The recent
US Food and Drug Administration (FDA) approval of lumacaftor combined with
ivacaftor (Orkambi) targets patients with the F508del-CFTR. The question
remains: Is this breakthrough combination therapy the "magic-bullet" cure for
the vast majority of patients with CF? This review covers the contemporary
clinical and scientific knowledge-base for lumacaftor/ivacaftor and highlights
the emerging issues from recent conflicting literature reports. Lisinopril oral solution (Qbrelis) for the treatment of hypertension, heart
failure, and acute myocardial infarction; etanercept-szzs (Erelzi) for multiple
autoimmune disorders; and lumacaftor/ivacaftor (Orkambi) for cystic fibrosis. Ivacaftor is currently used for the treatment of cystic fibrosis as both
monotherapy (Kalydeco; Vertex Pharmaceuticals, Boston, MA) and combination
therapy with lumacaftor (Orkambi; Vertex Pharmaceuticals). Each therapy targets
specific patient populations: Kalydeco treats patients carrying one of nine
gating mutations in the cystic fibrosis transmembrane conductance regulator
(CFTR) protein, whereas Orkambi treats patients homozygous for the F508del CFTR
mutation. In this study, we explored the pharmacological and metabolic effects
of precision deuteration chemistry on ivacaftor by synthesizing two novel
deuterated ivacaftor analogs, CTP-656 (d9-ivacaftor) and d18-ivacaftor.
Ivacaftor is administered twice daily and is extensively converted in humans to
major metabolites M1 and M6; therefore, the corresponding deuterated metabolites
were also prepared. Both CTP-656 and d18-ivacaftor showed in vitro pharmacologic
potency similar to that in ivacaftor, and the deuterated M1 and M6 metabolites
showed pharmacology equivalent to that in the corresponding metabolites of
ivacaftor, which is consistent with the findings of previous studies of
deuterated compounds. However, CTP-656 exhibited markedly enhanced stability
when tested in vitro. The deuterium isotope effects for CTP-656 metabolism (DV =
3.8, DV/K = 2.2) were notably large for a cytochrome P450-mediated oxidation.
The pharmacokinetic (PK) profile of CTP-656 and d18-ivacaftor were assessed in
six healthy volunteers in a single-dose crossover study, which provided the
basis for advancing CTP-656 in development. The overall PK profile, including
the 15.9-hour half-life for CTP-656, suggests that CTP-656 may be dosed once
daily, thereby enhancing patient adherence. Together, these data continue to
validate deuterium substitution as a viable approach for creating novel
therapeutic agents with properties potentially differentiated from existing
drugs. Cystic fibrosis (CF) is a disease caused by a mutation in the cystic fibrosis
transmembrane conductance regulator protein in the epithelial membrane, and
affects at least 30,000 people in the USA. There are between 900 and 1000 new
cases diagnosed every year. Traditionally, CF has been treated symptomatically
with pancreatic enzymes, bronchodilators, hypertonic saline, and pulmozyme. In
July 2015, the US Food and Drug Administration approved Orkambi
(lumacaftor/ivacaftor), a combination drug that works on reversing the effects
of the defective cystic fibrosis transmembrane conductance regulator protein.
Orkambi and mucolytics decrease the viscosity of mucous secretions, leading to
an accumulation of hypoviscous fluid in the alveoli, resulting in dyspnea. This
presentation can be mistaken for an infective exacerbation. We present a case in
which a young female with CF recently started on Orkambi therapy presented to
her primary care physician with dyspnea and increased respiratory secretions and
was admitted to the hospital for 2 weeks of intravenous and inhaled antibiotic
therapy for a presumed CF exacerbation. We highlight this case to bring
awareness and educate patients and clinicians of the side-effect profile of
Orkambi therapy with an intent to avoid unnecessary hospitalizations, inpatient
antibiotics, and other costly medical services. Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000
people worldwide. Approximately 73% of patients are homozygous for the F508del
cystic fibrosis transmembrane conductance regulator [CFTR] mutation.
Traditionally treatment has only included supportive care. Therefore, there is a
need for safe and effective novel therapies targeting the underlying molecular
defects seen with CF. Areas covered: In 2016, the Food and Drug Administration
and the European Commission approved LUM/IVA (Orkambi), a CFTR modulator that
includes both a CFTR corrector and potentiator, for CF patients homozygous for
the F508del CFTR mutation. This article reviews the pharmacologic features,
clinical efficacy, and safety of LUM/IVA and summarize the available
pre-clinical and clinical data of LUM/IVA use. Expert commentary: LUM/IVA showed
modest, but significant improvements from baseline in percent predicted FEV1
(ppFEV1) as well as a reduction in pulmonary exacerbations by 35% It was shown
to be safe for short- and long-term use. Currently, LUM/IVA is the only oral
agent in its class available and represents a milestone the development of
therapies for the management of CF. Nonetheless, pharmacoeconomic data are
necessary to justify its high cost before is use becomes standard of care. Cystic fibrosis (CF), the most common lethal genetic disease in Caucasians, is
characterized by chronic bacterial lung infection and excessive inflammation,
which lead to progressive loss of lung function and premature death. Although
ivacaftor (VX-770) alone and ivacaftor in combination with lumacaftor (VX-809)
improve lung function in CF patients with the Gly551Asp and del508Phe mutations,
respectively, the effects of these drugs on the function of human CF macrophages
are unknown. Thus studies were conducted to examine the effects of lumacaftor
alone and lumacaftor in combination with ivacaftor (i.e., ORKAMBI) on the
ability of human CF ( del508Phe/ del508Phe) monocyte-derived macrophages (MDMs)
to phagocytose and kill Pseudomonas aeruginosa. Lumacaftor alone restored the
ability of CF MDMs to phagocytose and kill P. aeruginosa to levels observed in
MDMs obtained from non-CF (WT-CFTR) donors. This effect contrasts with the
partial (~15%) correction of del508Phe Cl- secretion of airway epithelial cells
by lumacaftor. Ivacaftor reduced the ability of lumacaftor to stimulate
phagocytosis and killing of P. aeruginosa. Lumacaftor had no effect on P.
aeruginosa-stimulated cytokine secretion by CF MDMs. Ivacaftor (5 µM) alone and
ivacaftor in combination with lumacaftor reduced secretion of several
proinflammatory cytokines. The clinical efficacy of ORKAMBI may be related in
part to the ability of lumacaftor to stimulate phagocytosis and killing of P.
aeruginosa by macrophages. Deletion of phenylalanine at position 508 (F508del) in cystic fibrosis
transmembrane conductance regulator (CFTR) is the most common cystic fibrosis
(CF)-causing mutation. Recently, ORKAMBI, a combination therapy that includes a
corrector of the processing defect of F508del-CFTR (lumacaftor or VX-809) and a
potentiator of channel activity (ivacaftor or VX-770), was approved for CF
patients homozygous for this mutation. However, clinical studies revealed that
the effect of ORKAMBI on lung function is modest and it was proposed that this
modest effect relates to a negative impact of VX-770 on the stability of
F508del-CFTR. In the current studies, we showed that this negative effect of
VX-770 at 10 μM correlated with its inhibitory effect on VX-809-mediated
correction of the interface between the second membrane spanning domain and the
first nucleotide binding domain bearing F508del. Interestingly, we found that
VX-770 exerted a similar negative effect on the stability of other membrane
localized solute carriers (SLC26A3, SLC26A9, and SLC6A14), suggesting that this
negative effect is not specific for F508del-CFTR. We determined that the
relative destabilizing effect of a panel of VX-770 derivatives on F508del-CFTR
correlated with their predicted lipophilicity. Polarized total internal
reflection fluorescence microscopy on a supported lipid bilayer model shows that
VX-770, and not its less lipophilic derivative, increased the fluidity of and
reorganized the membrane. In summary, our findings show that there is a
potential for nonspecific effects of VX-770 on the lipid bilayer and suggest
that this effect may account for its destabilizing effect on VX-809- rescued
F508del-CFTR. |
List available R packages for processing NanoString data | NanoStringNorm and NanoStringNormCNV. | SUMMARY: The NanoString System is a well-established technology for measuring
RNA and DNA abundance. Although it can estimate copy number variation,
relatively few tools support analysis of these data. To address this gap, we
created NanoStringNormCNV, an R package for pre-processing and copy number
variant calling from NanoString data. This package implements algorithms for
pre-processing, quality-control, normalization and copy number variation
detection. A series of reporting and data visualization methods support
exploratory analyses. To demonstrate its utility, we apply it to a new dataset
of 96 genes profiled on 41 prostate tumour and 24 matched normal samples.
AVAILABILITY AND IMPLEMENTATION: NanoStringNormCNV is implemented in R and is
freely available at
http://labs.oicr.on.ca/boutros-lab/software/ostringnormcnv.
CONTACT: [email protected].
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online. |
Which disease is PGT121 used for? | The broadly neutrilizing antibody PGT121 is being tested against HIV-1. | |
What is the mechanism of action of anlotinib? | Anlotinib is a receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR1, VEGFR2/KDR, and VEGFR3), stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFβ), and fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3). It is used for treatment of cancer. | BACKGROUND: Anlotinib is a novel multi-target tyrosine kinase inhibitor that is
designed to primarily inhibit VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret. We
aimed to evaluate the safety, pharmacokinetics, and antitumor activity of
anlotinib in patients with advanced refractory solid tumors.
METHODS: Anlotinib (5-16 mg) was orally administered in patients with solid
tumor once a day on two schedules: (1) four consecutive weeks (4/0) or (2)
2-week on/1-week off (2/1). Pharmacokinetic sampling was performed in all
patients. Twenty-one patients were further enrolled in an expanded cohort study
on the recommended dose and schedule. Preliminary tumor response was also
assessed.
RESULTS: On the 4/0 schedule, dose-limiting toxicity (DLT) was grade 3
hypertension at 10 mg. On the 2/1 schedule, DLT was grade 3 hypertension and
grade 3 fatigue at 16 mg. Pharmacokinetic assessment indicated that anlotinib
had long elimination half-lives and significant accumulation during multiple
oral doses. The 2/1 schedule was selected, with 12 mg once daily as the maximum
tolerated dose for the expanding study. Twenty of the 21 patients (with colon
adenocarcinoma, non-small cell lung cancer, renal clear cell cancer, medullary
thyroid carcinoma, and soft tissue sarcoma) were assessable for antitumor
activity of anlotinib: 3 patients had partial response, 14 patients had stable
disease including 12 tumor burden shrinkage, and 3 had disease progression. The
main serious adverse effects were hypertension, triglyceride elevation,
hand-foot skin reaction, and lipase elevation.
CONCLUSIONS: At the dose of 12 mg once daily at the 2/1 schedule, anlotinib
displayed manageable toxicity, long circulation, and broad-spectrum antitumor
potential, justifying the conduct of further studies. BACKGROUND: Anlotinib (AL3818) is a novel multitarget tyrosine kinase inhibitor,
inhibiting tumour angiogenesis and proliferative signalling. The objective of
this study was to assess the safety and efficacy of third-line anlotinib for
patients with refractory advanced non-small-cell lung cancer (RA-NSCLC).
METHODS: Eligible patients were randomised 1 : 1 to receive anlotinib (12 mg per
day, per os; days 1-14; 21 days per cycle) or a placebo. The primary end point
was progression-free survival (PFS).
RESULTS: A total of 117 eligible patients enrolled from 13 clinical centres in
China were analysed in the full analysis set. No patients received immune
check-point inhibitors and epidermal growth factor receptor status was unknown
in 60.7% of the population. PFS was better with anlotinib compared with the
placebo (4.8 vs 1.2 months; hazard ratio (HR)=0.32; 95% confidence interval
(CI), 0.20-0.51; P<0.0001), as well as overall response rate (ORR) (10.0%; 95%
CI, 2.4-17.6% vs 0%; 95% CI, 0-6.27%; P=0.028). The median overall survival (OS)
was 9.3 months (95% CI, 6.8-15.1) for the anlotinib group and 6.3 months (95%
CI, 4.3-10.5) for the placebo group (HR=0.78; 95% CI, 0.51-1.18; P=0.2316).
Adverse events were more frequent in the anlotinib than the placebo group. The
percentage of grade 3-4 treatment-related adverse events was 21.67% in the
anlotinib group.
CONCLUSIONS: Anlotinib as a third-line treatment provided significant PFS
benefits to patients with RA-NSCLC when compared with the placebo, and the
toxicity profiles showed good tolerance. Abrogating tumor angiogenesis by inhibiting vascular endothelial growth factor
receptor-2 (VEGFR2) has been established as a therapeutic strategy for treating
cancer. However, because of their low selectivity, most small molecule
inhibitors of VEGFR2 tyrosine kinase show unexpected adverse effects and limited
anticancer efficacy. In the present study, we detailed the pharmacological
properties of anlotinib, a highly potent and selective VEGFR2 inhibitor, in
preclinical models. Anlotinib occupied the ATP-binding pocket of VEGFR2 tyrosine
kinase and showed high selectivity and inhibitory potency (IC50 <1 nmol/L) for
VEGFR2 relative to other tyrosine kinases. Concordant with this activity,
anlotinib inhibited VEGF-induced signaling and cell proliferation in HUVEC with
picomolar IC50 values. However, micromolar concentrations of anlotinib were
required to inhibit tumor cell proliferation directly in vitro. Anlotinib
significantly inhibited HUVEC migration and tube formation; it also inhibited
microvessel growth from explants of rat aorta in vitro and decreased vascular
density in tumor tissue in vivo. Compared with the well-known tyrosine kinase
inhibitor sunitinib, once-daily oral dose of anlotinib showed broader and
stronger in vivo antitumor efficacy and, in some models, caused tumor regression
in nude mice. Collectively, these results indicate that anlotinib is a
well-tolerated, orally active VEGFR2 inhibitor that targets angiogenesis in
tumor growth, and support ongoing clinical evaluation of anlotinib for a variety
of maligcies. In recent years, the number of advanced non-small cell lung cancer (NSCLC)
patients has gradually increased, and the treatment methods have also been
significantly increased. However, there are no standard treatment plans at home
and abroad for third-line and above patients who are refractory to targeted
therapy epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)
or chemotherapy. The clinical treatment effect is also not satisfactory.
Anlotinib is a novel TKI targeting the vascular endothelial growth factor
receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived
growth factor receptor (PDGFR) and c-Kit. ALTER0303 trail, phase III study has
demonstrated that Anlotinib significantly prolonged overall survival (OS) and
progression-free survival (PFS) in advanced NSCLC patients as 3rd line
treatment.Here we report a case of advanced lung adenocarcinoma harboring KRAS
mutation treated with Anlotinib.
. Jiangsu Chia-Tai Tianqing Pharmaceutical and Advenchen Laboratories are
co-developing anlotinib (Focus V®) for the treatment of advanced cancer.
Anlotinib is an oral small molecule inhibitor of multiple receptor tyrosine
kinases, with a broad spectrum of inhibitory effects on tumour angiogenesis and
growth. Anlotinib is approved in China for the treatment of patients with
locally advanced or metastatic non-small cell lung cancer (NSCLC) who have
undergone progression or recurrence after ≥ 2 lines of systemic chemotherapy.
Anlotinib is also undergoing phase II and/or III clinical development for
various sarcomas and carcinomas in China, USA and Italy. This article summarizes
the milestones in the development of anlotinib leading to this first approval
for NSCLC. OBJECTIVES: Anlotinib is a novel multi-target tyrosine Kinase inhibitor that
inhibits VEGFR2/3, FGFR1-4, PDGFD α/β, c-Kit and Ret. In the phase III
ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib
significantly improved overall survival versus placebo in advanced
non-small-cell lung cancer (NSCLC) patients who had received at least two
previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma
kinase targeted therapy regimens. This study assessed quality of life (QoL) in
these patients.
METHODS: Patients were randomized (2:1) to anlotinib or placebo up to
progression or intolerable toxicity. The QoL were assessed using the European
Organization for Research and Treatment of Cancer (EORTC) Quality of Life
Questionnaire Core 30 (QLQ-C30) and the associated EORTC Quality of Life Lung
Cancer Specific Module (QLQ-LC13) at baseline, end of cycle 1, end of every two
cycles, and at the final visit. The analyses were conducted in the first 6
cycles. Differences in scores of 10 points or more between two arms or from
baseline were considered clinically meaningful.
RESULTS: A total of 437 patients were assigned to anlotinib (n = 294) and
placebo (n = 143). The completion rates of the QoL questionnaires were from
69.9% to 97.0%. Mean scores of QLQ-C30 and QLQ-LC13 subscales were similar in
the anlotinib and placebo arms at baseline. Compared to placebo, anlotinib
improved role functioning, social functioning, dyspnea, insomnia, constipation
and ficial problems. Only sore mouth or tongue symptom was worse in the
anlotinib arm than in the placebo arm.
CONCLUSIONS: Anlotinib improved quality of life versus placebo in advanced NSCLC
patients who had received at least two previous chemotherapies. The QoL analyses
provided evidence that anlotinib should be a choice for the third-line treatment
or beyond in advanced NSCLC. IMPORTANCE: Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor
angiogenesis and proliferative signaling. A phase 2 trial showed anlotinib to
improve progression-free survival with a potential benefit of overall survival,
leading to the phase 3 trial to confirm the drug's efficacy in advanced
non-small cell lung cancer (NSCLC).
OBJECTIVE: To investigate the efficacy of anlotinib on overall survival of
patients with advanced NSCLC progressing after second-line or further treatment.
DESIGN, SETTING, AND PARTICIPANTS: The ALTER 0303 trial was a multicenter,
double-blind, phase 3 randomized clinical trial designed to evaluate the
efficacy and safety of anlotinib in patients with advanced NSCLC. Patients from
31 grade-A tertiary hospitals in China were enrolled between March 1, 2015, and
August 31, 2016. Those aged 18 to 75 years who had histologically or
cytologically confirmed NSCLC were eligible (n = 606), and those who had
centrally located squamous cell carcinoma with cavitary features or brain
metastases that were uncontrolled or controlled for less than 2 months were
excluded. Patients (n = 440) were randomly assigned in a 2-to-1 ratio to receive
either 12 mg/d of anlotinib or a matched placebo. All cases were treated with
study drugs at least once in accordance with the intention-to-treat principle.
MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. The
secondary end points were progression-free survival, objective response rate,
disease control rate, quality of life, and safety.
RESULTS: In total, 439 patients were randomized, 296 to the anlotinib group (106
[36.1%] were female and 188 [64.0%] were male, with a mean [SD] age of 57.9
[9.1] years) and 143 to the placebo group (46 [32.2%] were female and 97 [67.8%]
were male, with a mean [SD] age of 56.8 [9.1] years). Overall survival was
significantly longer in the anlotinib group (median, 9.6 months; 95% CI,
8.2-10.6) than the placebo group (median, 6.3 months; 95% CI, 5.0-8.1), with a
hazard ratio (HR) of 0.68 (95% CI, 0.54-0.87; P = .002). A substantial increase
in progression-free survival was noted in the anlotinib group compared with the
placebo group (median, 5.4 months [95% CI, 4.4-5.6] vs 1.4 months [95% CI,
1.1-1.5]; HR, 0.25 [95% CI, 0.19-0.31]; P < .001). Considerable improvement in
objective response rate and disease control rate was observed in the anlotinib
group over the placebo group. The most common grade 3 or higher adverse events
in the anlotinib arm were hypertension and hyponatremia.
CONCLUSIONS AND RELEVANCE: Among the Chinese patients in this trial, anlotinib
appears to lead to prolonged overall survival and progression-free survival.
This finding suggests that anlotinib is well tolerated and is a potential
third-line or further therapy for patients with advanced NSCLC.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02388919. Anlotinib is a new, orally administered tyrosine kinase inhibitor that targets
vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor
receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit.
Compared to the effect of placebo, it improved both progression-free survival
(PFS) and overall survival (OS) in a phase III trial in patients with advanced
non-small-cell lung cancer (NSCLC), despite progression of the cancer after two
lines of prior treatments. Recently, the China Food and Drug Administration
(CFDA) approved single agent anlotinib as a third-line treatment for patients
with advanced NSCLC. Moreover, a randomized phase IIB trial demonstrated that
anlotinib significantly prolonged the median PFS in patients with advanced soft
tissue sarcoma (STS). Anlotinib also showed promising efficacy in patients with
advanced medullary thyroid carcinoma and metastatic renal cell carcinoma (mRCC).
The tolerability profile of anlotinib is similar to that of other tyrosine
kinase inhibitors that target VEGFR and other tyrosine kinase-mediated pathways;
however, anlotinib has a significantly lower incidence of grade 3 or higher side
effects compared to that of sunitinib. We review the rationale, clinical
evidence, and future perspectives of anlotinib for the treatment of multiple
cancers. |
Describe Canvas SPW | Whole genome sequencing is becoming a diagnostics of choice for the identification of rare inherited and de novo copy number variants in families with various pediatric and late-onset genetic diseases. Joint variant calling in pedigrees is hampered by the complexity of consensus breakpoint alignment across samples within an arbitrary pedigree structure. Canvas SPW is a tool developed for the identification of inherited and de novo copy number variants from pedigree sequencing data. Canvas SPW supports a number of family structures and provides a wide range of scoring and filtering options to automate and streamline identification of de novo variants. The tool is available for download from https://github.com/Illumina/canvas. | MOTIVATION: Whole genome sequencing is becoming a diagnostics of choice for the
identification of rare inherited and de novo copy number variants in families
with various pediatric and late-onset genetic diseases. However, joint variant
calling in pedigrees is hampered by the complexity of consensus breakpoint
alignment across samples within an arbitrary pedigree structure.
RESULTS: We have developed a new tool, Canvas SPW, for the identification of
inherited and de novo copy number variants from pedigree sequencing data. Canvas
SPW supports a number of family structures and provides a wide range of scoring
and filtering options to automate and streamline identification of de novo
variants.
AVAILABILITY AND IMPLEMENTATION: Canvas SPW is available for download from
https://github.com/Illumina/canvas.
CONTACT: [email protected].
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online. |
List phagosomal markers. | Rab7
LAMP1
Cathepsin D
Rab9
V-ATPase
CD63 | The acid sphingomyelinase (ASMase) localizes to the lumen of endosomes,
phagosomes and lysosomes as well as to the outer leaflet of the plasma membrane
and hydrolyses sphingomyelin to ceramide and phosphorylcholine. Using the
facultative intracellular bacterium Listeria monocytogenes, we show that
maturation of phagosomes into phagolysosomes is severely impaired in macrophages
genetically deficient for ASMase. Unlike in wild-type macrophages, phagosomes
containing L. monocytogenes in ASMase(-/-) macrophages remained positive for the
late phagosomal markers mannose-6-phosphate receptor (M6PR) and Rab7 for at
least 2 h and, correspondingly, showed delayed acquisition of lysosomal markers
like lysosome associated membrane protein 1 (Lamp1). The transfer of lysosomal
fluid phase markers into phagosomes containing L. monocytogenes was severely
impaired in ASMase(-/-) macrophages and decreased with increasing size of the
cargo. Moreover, phagosomes containing L. monocytogenes from ASMase(-/-) cells
acquired significantly less listeriocidal proteases cathepsin D, B and L. The
results of this study suggest that ASMase is required for the proper fusion of
late phagosomes with lysosomes, which is crucial for efficient transfer of
lysosomal antibacterial hydrolases into phagosomes. Promastigote form of Leishmania, an intracellular pathogen, delays phagosome
maturation and resides inside macrophages. But till date limited study has been
done to manipulate the phagosomal machinery of macrophages to restrict
Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a
respiratory burst and enhanced production of pro-inflammatory mediators. The
augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and
p44/42 MAPK. In our study, these activated macrophages are found to induce
phagosome maturation when infected with pathogenic Leishmania donovani.
Increased co-localization of carboxyfluorescein succinimidyl ester labeled
pathogenic L. donovani with Lysosome was found. Moreover, increased
co-localization was observed between pathogenic L. donovani and late phagosomal
markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9,
and V-ATPase which indicate phagosome maturation. It was also observed that
inhibition of V-type ATPase caused significant hindrance in attenuated
Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK
is the key player in acidification and maturation of phagosome in attenuated
Leishmania strain pre-exposed macrophages. To our knowledge, this study for the
first time reported an approach to induce phagosome maturation in L. donovani
infected macrophages which could potentiate short-term prophylactic response in
future. Phagolysosomal trafficking is an important innate defense pathway that clears
microbes by delivering them to lysosomes, the degradative compartment of the
cell. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis,
subverts this host defense mechanism by arresting maturation of the phagosome.
The ability of Mtb to arrest its delivery to the lysosome can be demonstrated by
the prolonged co-localization of bacteria containing phagosomes/vacuole with
early phagosomal markers [such as, Ras-related proteins in the brain 5 (Rab5)
and Transferrin receptor (TfR)], and a failure to acquire late phagosomal and
lysosomal markers (such as Rab7 and LAMP1) (Deretic and Fratti, 1999, Mehra et
al., 2013). Here, a protocol is outlined for infection of macrophages with
mycobacterial species like pathogenic Mtb, vaccine strain Mycobacterium bovis-
bacillus Calmatte- Guérin (BCG) and rapidly dividing non-pathogenic
Mycobacterium smegmatis (Msmeg), followed by indirect-immunofluorescence
microscopy to visualize host vacuolar markers. Thereafter, automated
quantification of degree of co-localization between mycobacteria and host
vacuolar markers like TfR and LAMP1 is done by processing the binary images of
bacteria using mathematical tools. This results in quantification of the mean
fluorescence intensity (MFI) of these host markers directly around the
bacteria/bacterial clusters with increased sensitivity relative to when done
manually. By manipulating host or pathogen, this assay can be used to evaluate
host or bacterial determits of intracellular trafficking. The basic method
can be applied to studying trafficking of other bacteria or particles like
beads, although the kinetics of infection and phagosome maturation will depend
upon the phagocytic cargo. The mathematical analysis tools are available in many
standard imaging analysis programs. However, any adaption for similar analysis
should be confirmed by the individual user with their imaging and analysis
platform. Histophilus somni is capable of intracellular survival within professional
phagocytic cells, but the mechanism of survival is not understood. The Fic motif
within the direct repeat (DR1)/DR2 domains of the IbpA fibrillary network
protein of H. somni is cytotoxic to epithelial and phagocytic cells, which may
interfere with the bactericidal activity of these cells. To determine the
contribution of IbpA and Fic to resistance to host defenses, H. somni strains
and mutants that lacked all or a region of ibpA (including the DR1/DR2 regions)
were tested for survival in bovine monocytic cells and for serum susceptibility.
An H. somni mutant lacking IbpA, but not the DR1/DR2 region within ibpA, was
more susceptible to killing by antiserum than the parent, indicating that the
entire protein was associated with serum resistance. H. somni strains expressing
IbpA replicated in bovine monocytes for at least 72 h and were toxic for these
cells. Virulent strain 2336 mutants lacking the entire ibpA gene or both DR1 and
DR2 were not toxic to the monocytes but still survived within the monocytes for
at least 72 h. Monitoring of intracellular trafficking of H. somni with
monoclonal antibodies to phagosomal markers indicated that the early phagosomal
marker early endosome antigen 1 colocalized with all isolates tested, but only
strains that could survive intracellularly did not colocalize with the late
lysosomal marker lysosome-associated membrane protein 2 and prevented the
acidification of phagosomes. These results indicated that virulent isolates of
H. somni were capable of surviving within phagocytic cells through interference
in phagosome-lysosome maturation. Therefore, H. somni may be considered a
permissive intracellular pathogen. |
List bacterial families for which delafloxacin has been shown to be effective. | Delafloxacin has been shown to be effective against multiple gram-positive and gram-negative bacteria, including Strepotococcus pneumoniae, Haemophilus influenzae, Moraxella atarrhalis, Staphylococcus aureus, Klebsiella pneumoniae and more. | Delafloxacin is a broad-spectrum anionic fluoroquinolone under development for
the treatment of bacterial pneumonia. The goal of the study was to determine the
pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection
model for Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella
pneumoniae Four isolates of each species were utilized for in vivo studies: for
S. aureus, one methicillin-susceptible and three methicillin-resistant isolates;
S. pneumoniae, two penicillin-susceptible and two penicillin-resistant isolates;
K. pneumoniae, one wild-type and three extended-spectrum
beta-lactamase-producing isolates. MICs were determined using CLSI methods. A
neutropenic murine lung infection model was utilized for all treatment studies,
and drug dosing was by the subcutaneous route. Single-dose plasma
pharmacokinetics was determined in the mouse model after administration of 2.5,
10, 40, and 160 mg/kg. For in vivo studies, 4-fold-increasing doses of
delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to
infected mice. Treatment outcome was measured by determining organism burden in
the lung (CFU counts) at the end of each experiment (24 h). The Hill equation
for maximum effect (Emax) was used to model the dose-response data. The
magnitude of the PK/PD index, the area under the concentration-time curve over
24 h in the steady state divided by the MIC (AUC/MIC), associated with net
stasis and 1-log kill endpoints was determined in the lung model for all
isolates. MICs ranged from 0.004 to 1 mg/liter. Single-dose PK parameter ranges
include the following: for maximum concentration of drug in serum (Cmax), 2 to
70.7 mg/liter; AUC from 0 h to infinity (AUC0-∞), 2.8 to 152 mg · h/liter;
half-life (t1/2), 0.7 to 1 h. At the start of therapy mice had 6.3 ± 0.09 log10
CFU/lung. In control mice the organism burden increased 2.1 ± 0.44 log10
CFU/lung over the study period. There was a relatively steep dose-response
relationship observed with escalating doses of delafloxacin. Maximal organism
reductions ranged from 2 log10 to more than 4 log10 The median free-drug AUC/MIC
magnitude associated with net stasis for each species group was 1.45, 0.56, and
40.3 for S. aureus, S. pneumoniae, and K. pneumoniae, respectively. AUC/MIC
targets for the 1-log kill endpoint were 2- to 5-fold higher. Delafloxacin
demonstrated in vitro and in vivo potency against a diverse group of pathogens,
including those with phenotypic drug resistance to other classes. These results
have potential relevance for clinical dose selection and evaluation of
susceptibility breakpoints for delafloxacin for the treatment of lower
respiratory tract infections involving these pathogens. Delafloxacin, an investigational anionic fluoroquinolone, is active against a
broad range of Gram-positive and Gram-negative bacteria. In this study, 200
Streptococcus pneumoniae (plus 30 levofloxacin-resistant isolates), 200
Haemophilus influenzae, and 100 Moraxella catarrhalis isolates selected
primarily from the United States (2014) were tested against delafloxacin and
comparator agents. Delafloxacin was the most potent agent tested. MIC50 and
MIC90 values against all S. pneumoniae isolates were 0.008 and 0.015 μg/ml.
Delafloxacin susceptibility was not affected by β-lactamase status against H.
influenzae and M. catarrhalis. |
What is the cause of Sandhoff disease? | Sandhoff disease (SD) is a genetic disorder caused by a mutation of the β-subunit gene β-hexosaminidase B (HexB) in humans, which results in the massive accumulation of the ganglioside GM2 and related glycosphingolipids in the nervous system. | Approximately 70 lysosomal storage diseases are currently known, resulting from
mutations in genes encoding lysosomal enzymes and membrane proteins. Defects in
lysosomal enzymes that hydrolyze sphingolipids have been relatively well
studied. Gaucher disease is caused by the loss of activity of
glucocerebrosidase, leading to accumulation of glucosylceramide. Gaucher disease
exhibits a number of subtypes, with types 2 and 3 showing significant
neuropathology. Sandhoff disease results from the defective activity of
β-hexosaminidase, leading to accumulation of ganglioside GM2. Niemann-Pick type
C disease is primarily caused by the loss of activity of the lysosomal membrane
protein, NPC1, leading to storage of cholesterol and sphingosine. All three
disorders display significant neuropathology, accompanied by neuroinflammation.
It is commonly assumed that neuroinflammation is the result of infiltration of
monocyte-derived macrophages into the brain; for instance, cells resembling
lipid-engorged macrophages ('Gaucher cells') have been observed in the brain of
Gaucher disease patients. We now review the evidence that inflammatory
macrophages are recruited into the brain in these diseases and then go on to
provide some experimental data that, at least in the three mouse models tested,
monocyte-derived macrophages do not appear to infiltrate the brain. Resident
microglia, which are phenotypically distinct from infiltrating macrophages, are
the only myeloid population present in significant numbers within the brain
parenchyma in these authentic mouse models, even during the late symptomatic
stages of disease when there is substantial neuroinflammation. OPEN SCIENCE
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Special Issue "Lysosomal Storage Disorders". Sandhoff disease (SD) results from mutations in the HEXB gene, subsequent
deficiency of N-acetyl-β-hexosaminidase (Hex) and accumulation of GM2
gangliosides. SD leads to progressive neurodegeneration and early death.
However, there is a lack of established SD biomarkers, while the pathogenesis
etiology remains to be elucidated. To identify potential biomarkers and unveil
the pathogenic mechanisms, metabolomics analysis with reverse phase liquid
chromatography (RPLC) was conducted. A total of 177, 112 and 119 metabolites
were found to be significantly dysregulated in mouse liver, mouse brain and
human hippocampus samples, respectively (p < .05, ID score > 0.5). Principal
component analysis (PCA) analysis of the metabolites showed clear separation of
metabolomics profiles between normal and diseased individuals. Among these
metabolites, dipeptides, amino acids and derivatives were elevated, indicating a
robust protein catabolism. Through pathway enrichment analysis, we also found
alterations in metabolites associated with neurotransmission, lipid metabolism,
oxidative stress and inflammation. In addition, N-acetylgalactosamine
4-sulphate, key component of glycosaminoglycans (GAG) was significantly
elevated, which was also confirmed by biochemical assays. Collectively, these
results indicated major shifts of energy utilization and profound metabolic
impairments, contributing to the pathogenesis mechanisms of SD. Global
metabolomics profiling may provide an innovative tool for better understanding
the disease mechanisms, and identifying potential diagnostic biomarkers for SD. |
Are there tools for reviewing variant calls? | Yes. Tools such as the Variant InsPector and Expert Rating tool (VIPER) have been developed that speed up the manual inspection of variant calls by integrating the Integrative Genomics Viewer into a web application. Analysts can then quickly iterate through variants, apply filters and make decisions based on the generated images and variant metadata. VIPER was successfully employed in analyses with manual inspection of more than 10 000 calls. | |
Name one CCR4 targeted drug. | Mogamulizumab is an anti-CCR4 monoclonal antibody. | BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) causes the debilitating
neuroinflammatory disease HTLV-1-associated myelopathy-tropical spastic
paraparesis (HAM-TSP) as well as adult T-cell leukemia-lymphoma (ATLL). In
patients with HAM-TSP, HTLV-1 infects mainly CCR4+ T cells and induces
functional changes, ultimately causing chronic spinal cord inflammation. We
evaluated mogamulizumab, a humanized anti-CCR4 monoclonal antibody that targets
infected cells, in patients with HAM-TSP.
METHODS: In this uncontrolled, phase 1-2a study, we assessed the safety,
pharmacokinetics, and efficacy of mogamulizumab in patients with
glucocorticoid-refractory HAM-TSP. In the phase 1 dose-escalation study, 21
patients received a single infusion of mogamulizumab (at doses of 0.003 mg per
kilogram of body weight, 0.01 mg per kilogram, 0.03 mg per kilogram, 0.1 mg per
kilogram, or 0.3 mg per kilogram) and were observed for 85 days. Of those
patients, 19 continued on to the phase 2a study and received infusions, over a
period of 24 weeks, of 0.003 mg per kilogram, 0.01 mg per kilogram, or 0.03 mg
per kilogram at 8-week intervals or infusions of 0.1 mg per kilogram or 0.3 mg
per kilogram at 12-week intervals.
RESULTS: The side effects of mogamulizumab did not limit administration up to
the maximum dose (0.3 mg per kilogram). The most frequent side effects were
grade 1 or 2 rash (in 48% of the patients) and lymphopenia and leukopenia (each
in 33%). The dose-dependent reduction in the proviral load in peripheral-blood
mononuclear cells (decrease by day 15 of 64.9%; 95% confidence interval [CI],
51.7 to 78.1) and inflammatory markers in cerebrospinal fluid (decrease by day
29 of 37.3% [95% CI, 24.8 to 49.8] in the CXCL10 level and of 21.0% [95% CI,
10.7 to 31.4] in the neopterin level) was maintained with additional infusions
throughout the phase 2a study. A reduction in spasticity was noted in 79% of the
patients and a decrease in motor disability in 32%.
CONCLUSIONS: Mogamulizumab decreased the number of HTLV-1-infected cells and the
levels of inflammatory markers. Rash was the chief side effect. The effect of
mogamulizumab on clinical HAM-TSP needs to be clarified in future studies.
(Funded by the Japan Agency for Medical Research and Development and the
Ministry of Health, Labor, and Welfare; UMIN trial number, UMIN000012655 .). |
What is the mechanism of action of cemiplimab? | Cemiplimab is human programmed death receptor-1 (PD-1) monoclonal antibody that binds to PD-1 and blocks its interaction with programmed death ligands 1 (PD-L1) and 2 (PD-L2). It is approved to treat patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for surgery or radiation. | Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target in
several maligcies, including cervical cancer. Chemotherapy doublets combined
with the fully humanized monoclonal antibody, bevacizumab, now constitute
first-line therapy for women struggling with recurrent/metastatic cervical
carcinoma. Regulatory approval for this indication was based on the phase III
randomized trial, GOG 240, which demonstrated a statistically significant and
clinically meaningful improvement in overall survival when bevacizumab was added
to chemotherapy: 17.0 vs 13.3 months; HR 0.71; 98% CI, 0.54-0.95; p = .004.
Incorporation of bevacizumab resulted in significant improvements in
progression-free survival and response. These benefits were not accompanied by
deterioration in quality of life. GOG 240 identified vaginal fistula as a new
adverse event associated with bevacizumab use. All fistulas occurred in women
who had received prior pelvic radiotherapy, and none resulted in emergency
surgery, sepsis, or death. Final protocol-specified analysis demonstrated
continued separation of the survival curves favoring VEGF inhibition: 16.8 vs
13.3 months; HR 0.77; 95% CI, 0.62-9.95; p = .007. Post-progression survival was
not significantly different between the arms in GOG 240. Moving forward,
immunotherapy has now entered the clinical trial arena to address the high unmet
clinical need for effective and tolerable second line therapies in this patient
population. Targeting the programmed cell death 1/programmed death ligand 1
(PD-1/PD-L1) pathway using checkpoint inhibitors to break immunologic tolerance
is promising. The immunologic landscape involving human papillomavirus-positive
head and neck carcinoma and cutaneous squamous cell carcinoma can be informative
when considering feasibility of checkpoint blockade in advanced cervical cancer.
Phase II studies using anti-PD-1 molecules, nivolumab and pembrolizumab are
ongoing, and GOG 3016, the first phase III randomized trial of a checkpoint
inhibitor (cemiplimab) in cervical cancer, recently activated. Important
considerations in attempts to inhibit the inhibitors include pseudoprogression
and post-progression survival, abscopal effects, and immune-related adverse
events, including endocrinopathies. 1. Cemiplimab (LIBTAYO®; cemiplimab-rwlc), a human programmed death receptor-1
(PD-1) monoclonal antibody that binds to PD-1 and blocks its interaction with
programmed death ligands 1 (PD-L1) and 2 (PD-L2), is being developed by
Regeneron Pharmaceuticals and Sanofi Genzyme. The drug is being investigated as
a treatment for various cancers and in September 2018 received approval in the
USA for the treatment of patients with metastatic cutaneous squamous cell
carcinoma or locally advanced cutaneous squamous cell carcinoma who are not
candidates for curative surgery or curative radiation. This article summarizes
the milestones in the development of cemiplimab leading to this first global
approval for the treatment of advanced cutaneous squamous cell carcinoma. |
Which algorithm has been developed for finding conserved non-coding elements (CNEs) in genomes? | CNEFinder is a tool for identifying CNEs between two given DNA sequences with user-defined criteria. | MOTIVATION: Conserved non-coding elements (CNEs) represent an enigmatic class of
genomic elements which, despite being extremely conserved across evolution, do
not encode for proteins. Their functions are still largely unknown. Thus, there
exists a need to systematically investigate their roles in genomes. Towards this
direction, identifying sets of CNEs in a wide range of organisms is an important
first step. Currently, there are no tools published in the literature for
systematically identifying CNEs in genomes.
RESULTS: We fill this gap by presenting CNEFinder; a tool for identifying CNEs
between two given DNA sequences with user-defined criteria. The results
presented here show the tool's ability of identifying CNEs accurately and
efficiently. CNEFinder is based on a k-mer technique for computing maximal exact
matches. The tool thus does not require or compute whole-genome alignments or
indexes, such as the suffix array or the Burrows Wheeler Transform (BWT), which
makes it flexible to use on a wide scale.
AVAILABILITY AND IMPLEMENTATION: Free software under the terms of the GNU GPL
(https://github.com/lorrainea/CNEFinder). |
What causes Bathing suit Ichthyosis(BSI)? | Bathing suit ichthyosis (BSI) is a rare variant of autosomal recessive congenital ichthyosis (ARCI) due to transglutaminase-1 gene (TGM1) mutations leading to a temperature sensitive phenotype. | Bathing suit ichthyosis (BSI) is a striking and unique clinical form of
autosomal recessive congenital ichthyosis characterized by pronounced scaling on
the bathing suit areas but sparing of the extremities and the central face. Here
we report on a series of 10 BSI patients. Our genetic, ultrastructural and
biochemical investigations show that BSI is caused by transglutaminase-1
(TGase-1) deficiency. Altogether, we identified 13 mutations in TGM1-among them
seven novel missense mutations and one novel nonsense mutation. Structural
modeling for the Tyr276Asn mutation reveals that the residue is buried in the
hydrophobic interior of the enzyme and that the hydroxyl side chain of Tyr276 is
exposed to solvent in a cavity of the enzyme. Cryosections of healthy skin areas
demonstrated an almost normal TGase activity, in contrast to the affected BSI
skin, which only showed a cytoplasmic and clearly reduced TGase-1 activity. The
distribution of TGase-1 substrates in the epidermis of affected skin
corresponded to the situation in TGase-1 deficiency. Interestingly, the
expression of TGase-3 and cathepsin D was reduced. Digital thermography
validated a striking correlation between warmer body areas and presence of
scaling in patients suggesting a decisive influence of the skin temperature. In
situ TGase testing in skin of BSI patients demonstrated a marked decrease of
enzyme activity when the temperature was increased from 25 to 37 degrees C. We
conclude that BSI is caused by TGase-1 deficiency and suggest that it is a
temperature-sensitive phenotype. Bathing suit ichthyosis (BSI) is a rare variant of autosomal recessive lamellar
ichthyosis due to transglutaminase-1 (TGase-1) gene mutations leading to a
temperature sensitive phenotype. It is characterized by dark-grey or brownish
scaling restricted to the 'bathing suit' areas, whereas the extremities and
central face are almost completely spared. We report a 2-year-old African girl
with BSI with ultrastructural and biochemical demonstration of TGase-1
deficiency over the affected skin. TGase-1 gene analysis disclosed the
homozygous p.R315L mutation, which may lead to a temperature sensitive
dysfunction of the enzyme. BACKGROUND: Bathing suit ichthyosis (BSI) is an uncommon phenotype classified as
a minor variant of autosomal recessive congenital ichthyosis (ARCI).
OBJECTIVES: We report a case of BSI in a 3-year-old Tunisian girl with a novel
mutation of the transglutaminase 1 gene (TGM1).
CASE REPORT: This infant had been born with a collodion membrane encasing her
entire body. From the age of three months, brownish scaling was noted on the
bathing suit area. Histology showed orthohyperkeratosis with acanthosis of the
epidermis. The granular layer was normal, and the superficial dermis was mildly
inflammatory, confirming a diagnosis of proliferating ichthyosis. Molecular
analysis in the patient and her parents revealed the mutation I304F of TGM1.
Treatment with emollients and keratolytics partially improved the patient's skin
condition.
CONCLUSIONS: Bathing suit ichthyosis is an uncommon phenotype unique in its
topography, which involves the trunk but spares the face and extremities.
Previous studies using molecular analysis have shown that BSI is caused mainly
by mutations in TGM1. Twenty missense mutations have been reported in BSI. Of
these 20 missense mutations, nine occurred only in patients with the BSI
phenotype and 11 were common to BSI and other types of ARCI. Until recently,
there has been no genotype-phenotype correlation. Therefore, the same mutation
of the transglutaminase 1 could result in either generalized ARCI or BSI. The
present case demonstrates this phenotype in a White Tunisian patient with a
novel mutation of TGM1 (I304F) not previously reported in BSI. |
What type of data does the UK biobank resource contain? | The UK Biobank contains deep phenotyping and genomic data. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. | Author information:
(1)Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
(2)Procter & Gamble, Brussels, Belgium.
(3)Department of Statistics, University of Oxford, Oxford, UK.
(4)Melbourne Integrative Genomics and the Schools of Mathematics and Statistics,
and BioSciences, The University of Melbourne, Parkville, Victoria, Australia.
(5)Murdoch Children's Research Institute, Parkville, Victoria, Australia.
(6)Department of Genetic Medicine and Development, University of Geneva, Geneva,
Switzerland.
(7)Swiss Institute of Bioinformatics, University of Geneva, Geneva, Switzerland.
(8)Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva,
Switzerland.
(9)Illumina Ltd, Chesterford Research Park, Little Chesterford, Essex, UK.
(10)Nuffield Department of Clinical Neurosciences, Division of Clinical
Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK.
(11)UK Biobank, Adswood, Stockport, Cheshire, UK.
(12)Big Data Institute, Li Ka Shing Centre for Health Information and Discovery,
University of Oxford, Oxford, UK.
(13)Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
[email protected].
(14)Department of Statistics, University of Oxford, Oxford, UK.
[email protected]. |
Has ivosidenib been FDA approved for use against acute myeloid leukemia? | The FDA approved ivosidenib for patients with IDH1-mutant relapsed/refractory acute myeloid leukemia. | 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. |
Which two surgical methods were compared in the RAZOR trial? | The RAZOR trial compared open radical cystectomy vs. robot-assisted radical cystectomy in patients with bladder cancer. | The purpose of the RAZOR (randomized open vs robotic cystectomy) study is to
compare open radical cystectomy (ORC) vs robot-assisted RC (RARC), pelvic lymph
node dissection (PLND) and urinary diversion for oncological outcomes,
complications and health-related quality of life (HRQL) measures with a primary
endpoint of 2-year progression-free survival (PFS). RAZOR is a
multi-institutional, randomized, non-inferior, phase III trial that will enrol
at least 320 patients with T1-T4, N0-N1, M0 bladder cancer with ≈160 patients in
both the RARC and ORC arms at 15 participating institutions. Data will be
collected prospectively at each institution for cancer outcomes, complications
of surgery and HRQL measures, and then submitted to trial data management
services Cancer Research and Biostatistics (CRAB) for final analyses. To date,
306 patients have been randomized and accrual to the RAZOR trial is expected to
conclude in 2014. In this study, we report the RAZOR trial experimental design,
objectives, data safety, and monitoring, and accrual update. The RAZOR trial is
a landmark study in urological oncology, randomizing T1-T4, N0-N1, M0 patients
with bladder cancer to ORC vs RARC, PLND and urinary diversion. RAZOR is a
multi-institutional, non-inferiority trial evaluating cancer outcomes, surgical
complications and HRQL measures of ORC vs RARC with a primary endpoint of 2-year
PFS. Full data from the RAZOR trial are not expected until 2016-2017. |
Are Copy Number Variants (CNVs) depleted in regions of low mappability? | No. Low-mappability regions are approximately 5 times more likely to harbor germline CNVs, in stark contrast to the nearly uniform distribution observed for somatic CNVs in 95 cancer genomes. | |
List potential reasons regarding why potentially important genes are ignored | Differences in attention can be explained, to a large extent, exclusively from a small set of identifiable chemical, physical, and biological properties of genes. Together with knowledge about homologous genes from model organisms, these features accurately predict the number of publications on individual human genes, the year of their first report, the levels of funding awarded by the National Institutes of Health (NIH), and the development of drugs against disease-associated genes. | Biomedical research has been previously reported to primarily focus on a
minority of all known genes. Here, we demonstrate that these differences in
attention can be explained, to a large extent, exclusively from a small set of
identifiable chemical, physical, and biological properties of genes. Together
with knowledge about homologous genes from model organisms, these features allow
us to accurately predict the number of publications on individual human genes,
the year of their first report, the levels of funding awarded by the National
Institutes of Health (NIH), and the development of drugs against
disease-associated genes. By explicitly identifying the reasons for
gene-specific bias and performing a meta-analysis of existing computational and
experimental knowledge bases, we describe gene-specific strategies for the
identification of important but hitherto ignored genes that can open novel
directions for future investigation. |
Which random forest method has been developed for detecting Copy Numbers Variants (CNVs)? | CNV-RF Is a Random Forest-Based Copy Number Variation Detection Method Using Next-Generation Sequencing. | Simultaneous detection of small copy number variations (CNVs) (<0.5 kb) and
single-nucleotide variants in clinically significant genes is of great interest
for clinical laboratories. The analytical variability in next-generation
sequencing (NGS) and artifacts in coverage data because of issues with
mappability along with lack of robust bioinformatics tools for CNV detection
have limited the utility of targeted NGS data to identify CNVs. We describe the
development and implementation of a bioinformatics algorithm, copy number
variation-random forest (CNV-RF), that incorporates a machine learning component
to identify CNVs from targeted NGS data. Using CNV-RF, we identified 12 of 13
deletions in samples with known CNVs, two cases with duplications, and
identified novel deletions in 22 additional cases. Furthermore, no CNVs were
identified among 60 genes in 14 cases with normal copy number and no CNVs were
identified in another 104 patients with clinical suspicion of CNVs. All positive
deletions and duplications were confirmed using a quantitative PCR method.
CNV-RF also detected heterozygous deletions and duplications with a specificity
of 50% across 4813 genes. The ability of CNV-RF to detect clinically relevant
CNVs with a high degree of sensitivity along with confirmation using a low-cost
quantitative PCR method provides a framework for providing comprehensive
NGS-based CNV/single-nucleotide variant detection in a clinical molecular
diagnostics laboratory. |
What is the indication for Truvada? | Truvada is used for HIV pre-exposure prophylaxis (PrEP) in high risk individuals | Chronic hepatitis B affects 5-10% of HIV patients in Western countries.
Lamivudine should no longer be used as a single anti-HBV agent in HIV-HBV
co-infected patients, given its limited antiviral potency and high risk of
selection of resistance, which further results in wide cross-resistance to all
other nucleoside analogues. Recent reports of transmission of
lamivudine-resistant HBV in HIV patients are of especial concern, and large
surveillance studies suggest that it may occur in up to 10% of new HBV
infections in Western countries. Another worrisome aspect of the selection of
lamivudine-resistant HBV is the potential for selection of vaccine escape
mutants. Currently, tenofovir must be viewed as the drug of choice in HIV-HBV
co-infected patients in whom antiretroviral therapy is advised. Its
co-formulation with emtricitabine (Truvada) is particularly convenient for
treating both HIV and HBV in co-infected individuals. While pegIFN-alpha
monotherapy for 1 year may be considered for HIV-HBV coinfected individuals with
good spontaneous HIV control (elevated CD4 cell count, low plasma HIV-RNA), and
certain HBV features (genotype A, HBeAg+, low serum HBV-DNA and elevated ALT),
it is clear that very few coinfected patients fulfill these criteria. In
HBeAg-negative HIV patients, adefovir may be an option but the relatively low
antiviral potency of this drug discourages its wide use. Given its potential
anti-HIV activity, both entecavir and telbivudine must only be prescribed with
antiretroviral agents. Lack of information about potential pharmacodynamic
interactions between entecavir and abacavir (both are guanosine analogues) or
between telbivudine and zidovudine or stavudine (all are thymidine analogues)
further discourages their concomitant use. At this time, most experts agree that
early introduction of anti-HBV active HAART is the best strategy for the
treatment of chronic hepatitis B in HIV patients, and Truvada must be part of
the triple regimen. Daily preexposure prophylaxis (PrEP) with Truvada (emtricitabine [FTC] and
tenofovir disoproxil fumarate [TDF]) is a novel HIV prevention strategy recently
found to reduce HIV incidence among men who have sex with men. We used a macaque
model of HIV transmission to investigate if Truvada maintains prophylactic
efficacy against an FTC-resistant isolate containing the M184V mutation. Five
macaques received a dose of Truvada 3 days before exposing them rectally to the
simian/human immunodeficiency virus mutant SHIV162p3(M184V), followed by a
second dose 2 h after exposure. Five untreated animals were used as controls.
Virus exposures were done weekly for up to 14 weeks. Despite the high
(>100-fold) level of FTC resistance conferred by M184V, all five treated animals
were protected from infection, while the five untreated macaques were infected
(P = 0.0008). Our results show that Truvada maintains high prophylactic efficacy
against an FTC-resistant isolate. Increased susceptibility to tenofovir due to
M184V and other factors, including residual antiviral activity by FTC and/or
reduced virus fitness due to M184V, may all have contributed to the observed
protection. Twenty years after its original discovery, tenofovir has acquired a crucial
position in the fight against human immunodeficiency virus (HIV). First,
tenofovir disoproxil fumarate (TDF) is not only efficacious against, and has
been licensed for the treatment of HIV (AIDS), but also HBV (hepatitis B).
Second, for the treatment of HIV infections, TDF can be used in combination with
other anti-HIV drugs, such as emtricitabine (combination termed Truvada(®)) and
Truvada can be further combined with efavirenz, rilpivirine, elvitegravir,
atazanavir, or darunavir, as a single once-daily oral pill. Third, Truvada can
be used prophylactically to prevent transmission of HIV infection. And fourth,
to prevent sexual HIV transmission, tenofovir could also be used topically
(i.e., as a vaginal gel). In the United States, an estimated 48,100 new human immunodeficiency virus (HIV)
infections occurred in 2009. Of these, 27% were in heterosexual men and women
who did not inject drugs, and 64% were in men who have sex with men (MSM),
including 3% in MSM who inject drugs. In January 2011, following publication of
evidence of safety and efficacy of daily oral tenofovir disoproxil fumarate 300
mg (TDF)/emtricitabine 200 mg (FTC) (Truvada, Gilead Sciences) as antiretroviral
preexposure prophylaxis (PrEP) to reduce the risk for HIV acquisition among MSM
in the iPrEx trial, CDC issued interim guidance to make available information
and important initial cautions on the use of PrEP in this population. Those
recommendations remain valid for MSM, including MSM who also have sex with
women. Since January 2011, data from studies of PrEP among heterosexual men and
women have become available, and on July 16, 2012, the Food and Drug
Administration (FDA) approved a label indication for reduction of risk for
sexual acquisition of HIV infection among adults, including both heterosexuals
and MSM. This interim guidance includes consideration of the new information and
addresses pregcy and safety issues for heterosexually active adults at very
high risk for sexual HIV acquisition that were not discussed in the previous
interim guidance for the use of PrEP in MSM. BACKGROUND: Daily pre-exposure prophylaxis (PrEP) with Truvada (a combination of
emtricitabine (FTC) and tenofovir (TFV) disoproxil fumarate (TDF)) is a novel
HIV prevention strategy recently found to prevent HIV transmission in men who
have sex with men and heterosexual couples. We previously showed that a
coitally-dependent Truvada regimen protected macaques against rectal SHIV
transmission. Here we examined FTC and tenofovir TFV exposure in vaginal tissues
after oral dosing and assessed if peri-coital Truvada also protects macaques
against vaginal SHIV infection.
METHODS: The pharmacokinetic profile of emtricitabine (FTC) and tenofovir (TFV)
was evaluated at first dose. FTC and TFV levels were measured in blood plasma,
rectal, and vaginal secretions. Intracellular concentrations of FTC-triphosphate
(FTC-TP) and TFV-diphosphate (TFV-DP) were measured in PBMCs, rectal tissues,
and vaginal tissues. Efficacy of Truvada in preventing vaginal SHIV infection
was assessed using a repeat-exposure vaginal SHIV transmission model consisting
of weekly exposures to low doses of SHIV162p3. Six pigtail macaques with normal
menstrual cycles received Truvada 24 h before and 2 h after each weekly virus
exposure and six received placebo. Infection was monitored by serology and PCR
amplification of SHIV RNA and DNA.
RESULTS: As in humans, the concentration of FTC was higher than the
concentration of TFV in vaginal secretions. Also as in humans, TFV levels in
vaginal secretions were lower than in rectal secretions. Intracellular TFV-DP
concentrations were also lower in vaginal tissues than in rectal tissues.
Despite the low vaginal TFV exposure, all six treated macaques were protected
from infection after 18 exposures or 4 full menstrual cycles. In contrast, all 6
control animals were infected.
CONCLUSIONS: We modeled a peri-coital regimen with two doses of Truvada and
showed that it fully protected macaques from repeated SHIV exposures. Our
results open the possibility for simplified PrEP regimens to prevent vaginal HIV
transmission in women. Antiretroviral preexposure prophylaxis (PrEP; emtricitabine and tenofovir
disoproxil fumarate [Truvada]) prevents HIV without penalizing sexual pleasure,
and may even enhance pleasure (e.g., by reducing HIV-related anxiety). However,
concern about sexual risk behavior increasing with PrEP use (risk compensation)
and corresponding stereotypes of promiscuity may undermine PrEP's preventive
potential. In this commentary, we review literature on sexual behavior change
accompanying PrEP use, discuss risk compensation concerns and the "Truvada
whore" stereotype as PrEP barriers, question the appropriateness of restricting
PrEP access because of risk compensation, and consider sexual pleasure as a
benefit of PrEP, an acceptable motive for seeking PrEP, and a core element of
health. It is essential for science to trump stereotypes and sex-negative
messaging in guiding decision-making affecting PrEP access and uptake. INTRODUCTION: The FEM-PrEP trial was a pre-exposure prophylaxis clinical trial
to test the safety and efficacy of Truvada (tenofovir disoproxil fumarate and
emtricitabine) in the prevention of human immunodeficiency virus infection.
Because Truvada can suppress hepatitis B virus replication, and withdrawal of
Truvada can cause hepatic flares in patients with chronic hepatitis B,
pre-enrollment screening included serological screening for hepatitis B virus
markers. Women with chronic infections were not enrolled in the trial. Women
found to be unprotected against hepatitis B were enrolled and offered three
doses of hepatitis B vaccine. Reinfection and reactivation of previously
resolved hepatitis B virus infections have been documented in immunosuppressed
individuals but not in healthy individuals. We present the case of a participant
enrolled in the FEM-PrEP clinical trial with baseline evidence of immunity
against hepatitis B virus who subsequently developed acute hepatitis B.
CASE PRESENTATION: A 21-year-old Black non-pregt woman was enrolled in the
FEM-PrEP trial. She was human immunodeficiency virus-negative and a serological
test for hepatitis B virus was negative. She had evidence of low levels of
protection against hepatitis B virus and normal liver function. She had no
hepatitis B vaccination history, thus it was concluded that she had
post-infection immunity. At week 36 she presented with severely elevated liver
enzyme levels that, upon further investigation, were a result of acute hepatitis
B virus infection. The infection followed an asymptomatic course until full
recovery of her liver enzymes a few weeks later. At study unblinding, the
participant was found to be on the Truvada arm. Retrospective plasma drug level
testing found low levels of study drugs from week 4. The participant remained
human immunodeficiency virus-negative throughout the study.
CONCLUSION: Hepatitis B virus infection reactivation or reinfection is a rare
phenomenon in healthy individuals. However, reactivations have been reported in
patients being treated for chronic hepatitis B with the drugs contained in
Truvada, after treatment had been withdrawn. This participant may have
reactivated after stopping Truvada, or she may have reactivated spontaneously
owing to relatively low levels of protective antibodies against hepatitis B.
Alternatively, she may have been reinfected. Clinicians should be aware that
hepatitis B virus reactivation or reinfection may cause elevated transaminases
even in the presence of low baseline immunity. To achieve the 90-90-90 goals set by UNAIDS, the number of new HIV infections
needs to decrease to approximately 500,000 by 2020. One of the 'five pillars' to
achieve this goal is pre-exposure prophylaxis (PrEP). Truvada
(emtricitabine-tenofovir) is currently the only medication approved for PrEP.
Despite its advantages, Truvada is costly and requires individuals to adhere to
the once-daily regimen. To improve PrEP, many next-generation regimen, including
long-acting formulations, are currently investigated. However, pre-clinical
testing may not guide candidate selection, since it often fails to translate
into clinical efficacy. On the other hand, quantifying prophylactic efficacy in
the clinic is ethically problematic and requires to conduct long (years) and
large (N>1000 individuals) trials, precluding systematic evaluation of
candidates and deployment strategies. To prioritize- and help design PrEP
regimen, tools are urgently needed that integrate pharmacological-, viral- and
host factors determining prophylactic efficacy. Integrating the aforementioned
factors, we developed an efficient and exact stochastic simulation approach to
predict prophylactic efficacy, as an example for dolutegravir (DTG). Combining
the population pharmacokinetics of DTG with the stochastic framework, we
predicted that plasma concentrations of 145.18 and 722.23nM prevent 50- and 90%
sexual transmissions respectively. We then predicted the reduction in HIV
infection when DTG was used in PrEP, PrEP 'on demand' and post-exposure
prophylaxis (PEP) before/after virus exposure. Once daily PrEP with 50mg oral
DTG prevented 99-100% infections, and 85% of infections when 50% of dosing
events were missed. PrEP 'on demand' prevented 79-84% infections and PEP >80%
when initiated within 6 hours after virus exposure and continued for as long as
possible. While the simulation framework can easily be adapted to other PrEP
candidates, our simulations indicated that oral 50mg DTG is non-inferior to
Truvada. Moreover, the predicted 90% preventive concentrations can guide release
kinetics of currently developed DTG o-formulations. |
Is Adar3 involved in learning and memory? | Yes. Adar3 is involved in learning and memory in mice. Mice lacking exon 3 of Adar3 (which encodes two double stranded RNA binding domains) have increased levels of anxiety and deficits in hippocampus-dependent short- and long-term memory formation. RNA sequencing revealed a dysregulation of genes involved in synaptic function in the hippocampi of Adar3-deficient mice. | |
List STING agonists. | CDN 3'3'-cGAMP
dimethylxanthenone-4-acetic acid
α-Mangostin | Author information:
(1)Biomedical Engineering, Johns Hopkins University School of Medicine,
Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins
University School of Medicine, Baltimore, MD, USA; Institute for
Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD,
USA.
(2)Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University
School of Medicine, Baltimore, MD, USA.
(3)Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University
School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer
Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA;
Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
(4)Biomedical Engineering, Johns Hopkins University School of Medicine,
Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins
University School of Medicine, Baltimore, MD, USA; Institute for
Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD,
USA; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins
University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive
Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA;
Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;
Materials Science and Engineering, Johns Hopkins University School of Medicine,
Baltimore, MD, USA; Chemical and Biomolecular Engineering, Johns Hopkins
University School of Medicine, Baltimore, MD, USA; Ophthalmology, Johns Hopkins
University School of Medicine, Baltimore, MD, USA; Neurosurgery, Johns Hopkins
University School of Medicine, Baltimore, MD, USA. Electronic address:
[email protected].
(5)Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University
School of Medicine, Baltimore, MD, USA; Otolaryngology / Head & Neck Surgery,
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN, USA. Electronic address: [email protected]. Most FDA-approved adjuvants for infectious agents boost humoral but not cellular
immunity, and have poorly-understood mechanisms. Stimulator of interferon genes
(STING, also known as MITA, MPYS, or ERIS) is an exciting adjuvant target due to
its role in cyclic dinucleotide (CDN)-driven anti-viral immunity; however, a
major hindrance is STING's cytosolic localization which requires intracellular
delivery of its agonists. As a result, STING agonists administered in a soluble
form have elicited suboptimal immune responses. Delivery of STING agonists via
particle platforms has proven a more successful strategy, but the opportunity
for improved formulations and bioactivity remains. In this study we evaluated
the adjuvant activity of the potent STING agonist, CDN 3'3'-cGAMP (cGAMP),
encapsulated in acid-sensitive acetalated dextran (Ace-DEX) polymeric
microparticles (MPs) which passively target antigen-presenting cells for
intracellular release. This formulation was superior to all particle delivery
systems evaluated and maintained its bioactivity following a sterilizing dose of
gamma irradiation. Compared to soluble cGAMP, the Ace-DEX cGAMP MPs enhanced
type-I interferon responses nearly 1000-fold in vitro and 50-fold in vivo,
caused up to a 104-fold boost in antibody titers, increased Th1-associated
responses, and expanded germinal center B cells and memory T cells. Furthermore,
the encapsulated cGAMP elicited no observable toxicity in animals and achieved
protective immunity against a lethal influenza challenge seven months
post-immunization when using CDN adjuvant doses up to 100-fold lower than
previous reports. For these reasons, Ace-DEX MP-encapsulated cGAMP represents a
potent vaccine adjuvant of humoral and cellular immunity. Sjögren syndrome (SS), a chronic autoimmune disorder causing dry mouth,
adversely affects the overall oral health in patients. Activation of innate
immune responses and excessive production of type I interferons (IFNs) play a
critical role in the pathogenesis of this disorder. Recognition of nucleic acids
by cytosolic nucleic acid sensors is a major trigger for the induction of type I
IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of
interferon genes (STING) protein, and activation of STING causes increased
expression of type I IFNs. The role of STING activation in SS is not known. In
this study, to investigate whether the cytosolic DNA sensing pathway influences
SS development, female C57BL/6 mice were injected with a STING agonist,
dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for
gene expression and inflammatory cell infiltration. SG function was evaluated by
measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and
autoantibodies. Primary SG cells were used to study the expression and
activation of STING. Our data show that systemic DMXAA treatment rapidly induced
the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also
elevated in circulation. In contrast, increased Ifng gene expression was
domitly detected in the SGs. The type I innate lymphoid cells present within
the SGs were the major source of IFN-γ, and their numbers increased
significantly within 3 d of treatment. STING expression in SGs was mainly
observed in ductal and interstitial cells. In primary SG cells, DMXAA activated
STING and induced IFN-β production. The DMXAA-treated mice developed
autoantibodies, sialoadenitis, and glandular hypofunction. Our study
demonstrates that activation of the STING pathway holds the potential to
initiate SS. Thus, apart from viral infections, conditions that cause cellular
perturbations and accumulation of host DNA within the cytosol should also be
considered as possible triggers for SS. The xanthone derivate 5',6'-dimethylxanthenone-4-acetic acid (DMXAA, also known
as ASA404 or vadimezan) is a potent agonist of murine STING (stimulator of
interferon genes), but cannot activate human STING. Herein we report that
α-mangostin, which bears the xanthone skeleton, is an agonist of human STING,
but activates murine STING to a lesser extent. Biochemical and cell-based assays
indicate that α-mangostin binds to and activates human STING, leading to
activation of the downstream interferon regulatory factor (IRF) pathway and
production of type I interferons. Furthermore, our studies show that α-mangostin
has the potential to repolarize human monocyte-derived M2 macrophages to the M1
phenotype. The agonist effect of α-mangostin in the STING pathway might account
for its antitumor and antiviral activities. |
List drugs that were tested in the CheckMate 214 trial. | CheckMate 214 clinical trial compared Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. | BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients
with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared
nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell
advanced renal-cell carcinoma.
METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab
(3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram)
intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per
kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks
(6-week cycle). The coprimary end points were overall survival (alpha level,
0.04), objective response rate (alpha level, 0.001), and progression-free
survival (alpha level, 0.009) among patients with intermediate or poor
prognostic risk.
RESULTS: A total of 1096 patients were assigned to receive nivolumab plus
ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422,
respectively, had intermediate or poor risk. At a median follow-up of 25.2
months in intermediate- and poor-risk patients, the 18-month overall survival
rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus
ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall
survival was not reached with nivolumab plus ipilimumab versus 26.0 months with
sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate
was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%.
The median progression-free survival was 11.6 months and 8.4 months,
respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not
significant per the prespecified 0.009 threshold). Treatment-related adverse
events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab
group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events
occurred in 250 patients (46%) and 335 patients (63%), respectively.
Treatment-related adverse events leading to discontinuation occurred in 22% and
12% of the patients in the respective groups.
CONCLUSIONS: Overall survival and objective response rates were significantly
higher with nivolumab plus ipilimumab than with sunitinib among intermediate-
and poor-risk patients with previously untreated advanced renal-cell carcinoma.
(Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214
ClinicalTrials.gov number, NCT02231749 .). Immune modulatory treatment regimens, led by immune checkpoint inhibitors, have
transformed the treatment of clear-cell renal cell carcinoma. First-in-class,
the PD-1 inhibitor nivolumab improved overall survival in advanced renal cell
carcinoma following prior anti-angiogenic therapy, an important shift in the
management of clear-cell renal cell carcinoma. Further improvements of long-term
outcomes will be driven by combinations in the first-line setting, including
PD-1/PD-L1 associated with antiangiogenic therapies, or PD1/PD-L1 inhibitors
with other immune checkpoint inhibitors such as anti-CTLA-4, anti-LAG-3 or TIM-3
targeted therapies. The first two randomized Phase 3 trials assessing these
combinations have now challenged sunitinib in first-line setting. First, the
CheckMate 214 trial demonstrated an objective response rate and overall survival
benefit for the combination of nivolumab plus ipilimumab in the intermediate-
and poor-risk patients. Second, the IMMotion 151 study demonstrated a
progression-free survival benefit for the atezolizumab plus bevacizumab
combination by investigator assessment. Further Phase 3 trials are awaited with
tyrosine kinase and immune checkpoint inhibitor combinations. Clinical trials of
immune checkpoint inhibitors are also actively investigated in the localized
adjuvant or neoadjuvant setting. Nevertheless, the search for biomarkers along
with new clinical trial designs will be crucial to better select the patients
that may derive the greatest benefit from these advances. The continuing
improvement of antitumor immunity comprehension and the emergence of new immune
modulatory treatments will deeply change the management of renal cell carcinoma
for the years to come. Nivolumab is a programmed death 1 (PD-1) inhibitor currently approved as
second-line treatment for advanced renal cell carcinomas (RCC) after failure of
standard antiangiogenic treatment. Motzer et al. have recently published in the
New England Journal of Medicine the findings of CheckMate 214 trial, using
nivolumab and ipilimumab, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor,
versus sunitinib in previously untreated advanced RCC. The combination
demonstrated a higher 18-month overall survival rate of 75% versus 60%, and a
higher objective response rate of 42% versus 27%, for the combination in favor
over sunitinib monotherapy. These results herald the rapidly changing role of
immune checkpoint inhibitor therapy as first-line treatment for metastatic RCC. |
Mutations in which gene have been found in patients with the CLAPO syndrome? | CLAPO syndrome is a rare vascular disorder characterized by capillary malformation of the lower lip, lymphatic malformation predominant on the face and neck, asymmetry, and partial/generalized overgrowth. In a cohort of 13 patients with CLAPO, five activating mutations have been identified in the PIK3CA gene in affected tissues from 6 of the 9 patients studied. | Author information:
(1)Vascular Malformations Section, Institute of Medical and Molecular Genetics,
INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
(2)Bioinformatics Section, Institute of Medical and Molecular Genetics,
INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
(3)CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras,
ISCIII, Madrid, Spain.
(4)Clinical Genetics Section, Institute of Medical and Molecular Genetics,
INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
(5)Structural and Functional Genomics Section, Institute of Medical and
Molecular Genetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
(6)Department of Genetics, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain.
(7)Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid,
Spain.
(8)Vascular Anomalies Center, Plastic Surgery, Hospital Universitario La Paz,
Madrid, Spain. [email protected].
(9)Vascular Malformations Section, Institute of Medical and Molecular Genetics,
INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
[email protected].
(10)CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras,
ISCIII, Madrid, Spain. [email protected]. |
What is CamurWeb? | CamurWeb is a classification software and a large knowledge base for gene expression data of cancer. It is a web-based software that is able to extract multiple and equivalent classification models in form of logic formulas ("if then" rules) and to create a knowledge base of these rules that can be queried and analyzed. The method is based on an iterative classification procedure and an adaptive feature elimination technique that enables the computation of many rule-based models related to the cancer under study. CamurWeb includes a user friendly interface for running the software, querying the results, and managing the performed experiments. | BACKGROUND: The high growth of Next Generation Sequencing data currently demands
new knowledge extraction methods. In particular, the RNA sequencing gene
expression experimental technique stands out for case-control studies on cancer,
which can be addressed with supervised machine learning techniques able to
extract human interpretable models composed of genes, and their relation to the
investigated disease. State of the art rule-based classifiers are designed to
extract a single classification model, possibly composed of few relevant genes.
Conversely, we aim to create a large knowledge base composed of many rule-based
models, and thus determine which genes could be potentially involved in the
analyzed tumor. This comprehensive and open access knowledge base is required to
disseminate novel insights about cancer.
RESULTS: We propose CamurWeb, a new method and web-based software that is able
to extract multiple and equivalent classification models in form of logic
formulas ("if then" rules) and to create a knowledge base of these rules that
can be queried and analyzed. The method is based on an iterative classification
procedure and an adaptive feature elimination technique that enables the
computation of many rule-based models related to the cancer under study.
Additionally, CamurWeb includes a user friendly interface for running the
software, querying the results, and managing the performed experiments. The user
can create her profile, upload her gene expression data, run the classification
analyses, and interpret the results with predefined queries. In order to
validate the software we apply it to all public available RNA sequencing
datasets from The Cancer Genome Atlas database obtaining a large open access
knowledge base about cancer. CamurWeb is available at
http://bioinformatics.iasi.cnr.it/camurweb .
CONCLUSIONS: The experiments prove the validity of CamurWeb, obtaining many
classification models and thus several genes that are associated to 21 different
cancer types. Finally, the comprehensive knowledge base about cancer and the
software tool are released online; interested researchers have free access to
them for further studies and to design biological experiments in cancer
research. |
Describe SLIC-CAGE | SLIC-CAGE is a Super-Low Input Carrier-CAGE approach to capture 5' ends of RNA polymerase II transcripts from as little as 5-10 ng of total RNA. This dramatic increase in sensitivity is achieved by specially designed, selectively degradable carrier RNA. SLIC-CAGE can generate data for genome-wide promoterome with 1000-fold less material than required by existing CAGE methods. | |
There is no drug available to prevent HIV infection, Pre-exposure prophylaxis (PrEP), yes or no? | Pre-exposure prophylaxis (PrEP) with the drug combination Truvada can substantially decrease HIV transmission in individuals at risk. | Pre-exposure prophylaxis (PrEP) is an experimental approach to HIV prevention
and consists of antiretroviral drugs to be taken before potential HIV exposure
in order to reduce the risk of HIV infection and continued during periods of
risk. An effective PrEP could provide an additional safety net to sexually
active persons at risk, when combined with other prevention strategies. Women
represent nearly 60% of adults infected with HIV and PrEP can be a
female-controlled prevention method for women who are unable to negotiate condom
use. Two antiretroviral nucleoside analog HIV-1 reverse transcriptase inhibitor
drugs are currently under trial as PrEP drugs, namely
tenofovirdisoproxilfumarate (TDF) alone and TDF in combination with emricitabine
(FTC), to be taken as daily single dose oral drugs. There are 11 ongoing trials
of ARV-based prevention in different at risk populations across the world. The
iPrex trial showed that daily use of oral TDF/FTC by MSM resulted in 44%
reduction in the incidence of HIV. This led to publication of interim guidance
by CDC to use of PrEP by health providers for MSM. Few other trials are Bangkok
Tenofovir Study, Partners PrEP Study, FEM-PrEP study, and VOICE (MTN-003) study.
Future trials are being formulated for intermittent PrEP (iPrEP) where drugs are
taken before and after sex, "stand-in dose" iPrEP, vaginal or rectal PrEP, etc.
There are various issues/concerns with PrEP such as ADRs and resistance to
TDF/FTC, adherence to drugs, acceptability, sexual disinhibition, use of PrEP as
first line of defense for HIV without other prevention strategies, and cost. The
PrEP has a potential to address unmet need in public health if delivered as a
part of comprehensive toolkit of prevention services, including risk-reduction,
correct and consistent use of condoms, and diagnosis and treatment of sexually
transmitted infections. Despite significant efforts, the rate of new HIV infections worldwide remains
unacceptably high, highlighting the need for new HIV prevention strategies. HIV
pre-exposure prophylaxis (PrEP) is a new approach that involves the ongoing use
of antiretroviral medications by HIV-negative individuals to reduce the risk of
HIV infection. The use of daily tenofovir/emtricitabine as oral PrEP was found
to be effective in multiple placebo-controlled clinical trials and approved by
the United States Food and Drug Administration. In addition, the Centers for
Disease Control and Prevention in the United States and the World Health
Organization have both released guidelines recommending the offer of oral PrEP
to high-risk populations. The scale-up of PrEP is underway, but several
implementation questions remain uswered. Demonstration projects and
open-label extensions of placebo-controlled trials are ongoing and hope to
contribute to our understanding of PrEP use and delivery outside the randomized
controlled trial setting. Evidence is beginning to emerge from these open-label
studies and will be critical for guiding PrEP scale-up. Outside of such studies,
PrEP uptake has been slow and several client- and provider-related barriers are
limiting uptake. Maximizing the public health impact of PrEP will require
rollout to be combined with interventions to promote uptake, support adherence,
and prevent increases in risk behavior. Additional PrEP strategies are currently
under investigation in placebo-controlled clinical trials and may be available
in the future. Author information:
(1)Department of Genitourinary Medicine and Infectious Disease, Guys and St
Thomas' NHS Trust, London, UK. [email protected].
(2)Department of Sexual Health and HIV, Kings College Hospital, London, UK.
(3)Department of Genitourinary Medicine and Infectious Disease, Guys and St
Thomas' NHS Trust, London, UK.
(4)Nuffield Department of Medicine, University of Oxford, Oxford, UK.
(5)Oxford NIHR Biomedical Research Centre, Oxford, UK.
(6)Oxford Martin School, Oxford, UK.
(7)Department of Molecular and Clinical Pharmacology, University of Liverpool,
Liverpool, UK.
(8)Department of Infectious Diseases, Kings College London, London, UK.
(9)Department of Infectious Diseases, Imperial College, London, UK. INTRODUCTION: Use of pre-exposure prophylaxis (PrEP) among people who inject
drugs (PWID) has been shown to be effective in preventing HIV transmission. We
examined correlates of the willingness to use PrEP among community-recruited
older PWID in Washington, DC.
METHODS: PWID were recruited using respondent-driven sampling (RDS) and
completed a behavioral interview for the National HIV Behavioral Surveillance
system in 2012. Participants reported on willingness to use PrEP and how it
might affect their drug use and sexual behaviors. We reported RDS-weighted
proportions and multivariable correlates of being willing to use PrEP.
RESULTS: Among 304 participants, 69% were male, and the majority was aged ≥50
and black. Only 13.4% had ever heard of using anti-HIV medication to prevent
HIV; none had ever used PrEP or knew anyone who used it in the past year.
Forty-seven percent were very likely and 24% were somewhat likely to take PrEP
if it were available without cost; 13% agreed they would not need to
sterilize/clean needles or use condoms if taking PrEP. Correlates of being very
likely to use PrEP included being younger (<50years), sharing cookers, cotton or
water in the past year, and believing they would no longer need to use clean
needles.
CONCLUSION: Nearly half of PWID reported being very willing to use PrEP if it
were available without cost. Younger PWID and those at higher risk of sharing
cookers, cotton or water were more willing to use PrEP, suggesting a focus on
these groups to explore PrEP use among PWID. HIV pre-exposure prophylaxis (PrEP) is the use of one or more antiretroviral
medications (in combination) to prevent HIV infection. The most commonly used
PrEP medication (Truvada® , Gilead Sciences, Inc.) acts by inhibiting HIV-1
reverse transcriptase. If someone who is using PrEP unknowingly becomes HIV
infected (termed 'PrEP breakthrough infection'), there may be suppressed viral
replication resulting in a virus level undetectable by the most sensitive HIV
NAT. Failure to seroconvert and seroreversion (loss of previously detectable HIV
antibodies) have also both been observed with 2nd, 3rd and 4th generation
screening immunoassays, as well as Western blot assays. If such a person was
tested in the course of donating blood, the results may therefore be difficult
to interpret. The index of suspicion for possible PrEP 'interference' should be
highest in the context of concomitant low-level positive or 'greyzone'
reactivity on HIV NAT and serological tests, which is an unusual pattern in
acutely HIV-infected blood donors. Another possibility is detectable HIV RNA
with negative HIV serology (i.e. a potential 'NAT yield' case) but without
subsequent HIV seroconversion (or disappearance of HIV RNA). Excluding
antiretroviral therapy or PrEP use by the donor in such circumstances would be
important. The current rarity of PrEP breakthrough infection indicates that any
potential safety risk is likely very small. However, considering the increasing
use of PrEP we feel it is prudent for those interpreting HIV donor screening
test results to consider the potential for PrEP interference. OBJECTIVES: The National Health Service in England (NHS England) does not
provide pre-exposure prophylaxis (PrEP) against HIV, forcing people to purchase
generic versions on the internet. However, there are concerns about the
authenticity of medicines purchased online. We established an innovative service
offering plasma tenofovir (TFV) and emcitrabine (FTC) therapeutic drug
monitoring for people buying generic PrEP online, to ensure that drug
concentrations in vivo were consistent with those of propriety brands and
previously published data.
METHODS: TFV/FTC concentrations were measured by ultra-performance liquid
chromatography ultraviolet detection. Evaluation of renal function and testing
for HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) were also carried
out, at baseline and every 3-6 months, with risk reduction advice.
RESULTS: A total of 293 individuals presented having purchased PrEP on the
internet: 85% were white, 84% were taking daily PrEP, and 16% were event-driven.
Most were on generic TFV disoproxil fumarate (TDF)/FTC from Cipla Ltd. Median
(range) TFV and FTC plasma concentrations were 104 (21-597) ng/mL and 140
(17-1876) ng/mL, respectively. All concentrations were above our established
plasma TFV and FTC targets, based on previously published data. Renal function
was normal in all evaluable individuals and no new cases of HIV, HBV or HCV
infection were seen.
CONCLUSIONS: In a population at high risk of HIV acquisition, who cannot yet
access PrEP on the NHS, concentrations of TFV and FTC in generic formulations
purchased over the internet were similar to (or slightly higher than) those
measured in phase I studies with the original formulation from Gilead
(Truvada™), which has demonstrated high levels of protection against HIV
infection in previous PrEP clinical trials. PURPOSE OF REVIEW: The antiviral agent tenofovir is highly effective for the
treatment of HIV and hepatitis B virus infections, and the older prodrug
tenofovir disoproxil fumarate (TDF) is also a component of daily preexposure
prophylaxis (PrEP) to reduce the risk of HIV infection in high-risk populations.
Although TDF is well tolerated, the potential for kidney and bone toxicity has
important implications for public health given the large number of individuals
exposed to TDF worldwide. This review summarizes the recent literature on kidney
and bone health in individuals treated with TDF and the newer prodrug tenofovir
alafenamide (TAF).
RECENT FINDINGS: Risk factors for TDF toxicity appear to be similar in patients
treated for HIV or hepatitis B virus and in HIV-uninfected PrEP users, although
drug-drug interactions are a more important concern in HIV-positive individuals.
The risk of toxicity appears to be lower with TAF, but further studies are
needed to confirm the safety of long-term use and to evaluate the efficacy of
TAF-based PrEP.
SUMMARY: Nephrologists should be aware of the potential kidney and bone toxicity
of TDF, as well as unique situations in which the newer prodrug TAF may
contribute to kidney injury. |
Burosumab is used for treatment of which disease? | Burosumab is a fully human IgG1 monoclonal antibody directed at fibroblast growth factor 23 (FGF23), is indicated for the treatment of X-linked hypophosphatemia (XLH), a condition associated with excessive FGF23 production. | Phosphate plays essential roles in many biological processes, and the serum
phosphate level is tightly controlled. Chronic hypophosphatemia causes impaired
mineralization of the bone matrix and results in rickets and osteomalacia.
Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates
phosphate metabolism. FGF23 excess induces hypophosphatemia via impaired
phosphate reabsorption in the renal proximal tubules and decreased phosphate
absorption in the intestines. There are several types of genetic and acquired
FGF23-related hypophosphatemic diseases. Among these diseases, X-linked
hypophosphatemia (XLH), which is caused by inactivating mutations in the
phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene, is the most
prevalent form of genetic FGF23-related hypophosphatemic rickets. Another
clinically relevant form of FGF23-related hypophosphatemic disease is
tumor-induced osteomalacia (TIO), a paraneoplastic syndrome associated with
FGF23-producing tumors. A combination of active vitamin D and phosphate salts is
the current medical therapy used to treat patients with XLH and inoperative TIO.
However, this therapy has certain efficacy- and safety-associated limitations.
Several measures to inhibit FGF23 activity have been considered as possible new
treatments for FGF23-related hypophosphatemic diseases. In particular, a
humanized monoclonal antibody for FGF23 (burosumab) is a promising treatment in
patients with XLH and TIO. This review will focus on the phosphate metabolism
and the pathogenesis and treatment of FGF23-related hypophosphatemic diseases. Author information:
(1)(1) Department of Paediatrics, Klatovy Hospital, Klatovy, Czech Republic.
(2)(2) Department of Paediatrics, Pardubice Hospital, Pardubice, Czech Republic.
(3)(3) Department of Paediatrics, Faculty of Medicine and Faculty Hospital in
Hradec Kralove, Charles University, Hradec Kralove, Czech Republic. Burosumab (Crysvita®; Kyowa Hakko Kirin Co., Ltd. and Ultragenyx Pharmaceutical
Inc.) is a fully human monoclonal antibody directed at fibroblast growth factor
23 (FGF23). Excessive FGF23 production has been implicated in various
hypophosphataemic diseases. Inhibition of FGF23 by burosumab results in
increased renal phosphate reabsorption and increased serum levels of phosphorus
and active vitamin D. In February 2018, the EMA granted subcutaneous burosumab
conditional marketing authorization for the treatment of X-linked
hypophosphataemia (XLH) with radiographic evidence of bone disease in children
one year of age and older and adolescents with growing skeletons. In April 2018,
the US FDA approved burosumab for the treatment of XLH in adults and children
one year of age and older. Multinational phase III trials of burosumab are
currently underway in adult and paediatric patients with XLH. Burosumab is also
being evaluated in the phase II setting in adults with tumour-induced
osteomalacia and epidermal nevus syndrome in the USA, as well as in Japan and
Korea. This article summarizes the milestones in the development of burosumab
leading to its first global approval in the EU for XLH in paediatric patients. BACKGROUND: X-linked hypophosphatemia is characterized by increased secretion of
fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and
consequently rickets, osteomalacia, and skeletal deformities. We investigated
burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked
hypophosphatemia.
METHODS: In an open-label, phase 2 trial, we randomly assigned 52 children with
X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab
either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum
phosphorus level at the low end of the normal range. The primary end point was
the change from baseline to weeks 40 and 64 in the Thacher rickets severity
total score (ranging from 0 to 10, with higher scores indicating greater disease
severity). In addition, the Radiographic Global Impression of Change was used to
evaluate rachitic changes from baseline to week 40 and to week 64. Additional
end points were changes in pharmacodynamic markers, linear growth, physical
ability, and patient-reported outcomes and the incidence of adverse events.
RESULTS: The mean Thacher rickets severity total score decreased from 1.9 at
baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to
1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these
improvements persisted at week 64. The mean serum phosphorus level increased
after the first dose in both groups, and more than half the patients in both
groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to
2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained
through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption
increased from baseline in both groups, with an overall mean increase of 0.98 mg
per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was
0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per
kilogram with every-4-week dosing. Across both groups, the mean serum alkaline
phosphatase level decreased from 459 U per liter at baseline to 369 U per liter
at week 64. The mean standing-height z score increased in both groups, with
greater improvement seen at all time points with every-2-week dosing (an
increase from baseline of 0.19 at week 64) than with every-4-week dosing (an
increase from baseline of 0.12 at week 64). Physical ability improved and pain
decreased. Nearly all the adverse events were mild or moderate in severity.
CONCLUSIONS: In children with X-linked hypophosphatemia, treatment with
burosumab improved renal tubular phosphate reabsorption, serum phosphorus
levels, linear growth, and physical function and reduced pain and the severity
of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin;
ClinicalTrials.gov number, NCT02163577 ; EudraCT number, 2014-000406-35 ). Burosumab-twza (Crysvita) for a rare inherited form of rickets; ibalizumab-uiyk
(Trogarzo) for human immunodeficiency virus type 1 infection; and
tildrakizumab-asmn (Ilumya) for adults with moderate-to-severe plaque psoriasis. In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the
PHEX gene cause excess circulating levels of fibroblast growth factor 23
(FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia.
Adults with XLH present with chronic musculoskeletal pain and stiffness, short
stature, lower limb deformities, fractures, and pseudofractures due to
osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy.
Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to
correct hypophosphatemia. This report summarizes results from a double-blind,
placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH.
Participants with hypophosphatemia and pain were assigned 1:1 to burosumab
1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were
comparable at baseline. Across midpoints of dosing intervals, 94.1% of
burosumab-treated participants attained mean serum phosphate concentration above
the lower limit of normal compared with 7.6% of those receiving placebo (p <
0.001). Burosumab significantly reduced the Western Ontario and the McMaster
Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with
placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24;
p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48;
p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not
achieve statistical significance after Hochberg multiplicity adjustment. At week
24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully
healed; the odds of healed fracture in the burosumab group was 16.8-fold greater
than that in the placebo group (p < 0.001). Biochemical markers of bone
formation and resorption increased significantly from baseline with burosumab
treatment compared with placebo. The safety profile of burosumab was similar to
placebo. There were no treatment-related serious adverse events or meaningful
changes from baseline in serum or urine calcium, intact parathyroid hormone, or
nephrocalcinosis. These data support the conclusion that burosumab is a novel
therapeutic addressing an important medical need in adults with XLH.© 2018 The
Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals,
Inc. The most common heritable disorder of renal phosphate wasting, X-linked
hypophosphataemia (XLH), was discovered to be caused by inactivating mutations
in the phosphate regulating gene with homology to endopeptidases on the
X-chromosome (PHEX) gene in 1995. Although the exact molecular mechanisms by
which PHEX mutations cause disturbed phosphate handling in XLH remain unknown,
focus for novel therapies has more recently been based upon the finding that the
bone-produced phosphaturic hormone fibroblast growth factor-23 is elevated in
XLH patient plasma. Previous treatment strategies for XLH were based upon
phosphate repletion plus active vitamin D analogues, which are difficult to
manage, fail to address the primary pathogenesis of the disease, and can have
deleterious side effects. A novel therapy for XLH directly targeting fibroblast
growth factor-23 via a humanized monoclonal antibody (burosumab-twza/CRYSVITA,
henceforth referred to just as burosumab) has emerged as an effective, and
recently approved, pharmacological treatment for both children and adults. This
review will provide an overview of the clinical manifestations of XLH, the
molecular pathophysiology, and summarize its current treatment. Burosumab (Crysvita®), a fully human IgG1 monoclonal antibody directed at
fibroblast growth factor 23 (FGF23), is indicated for the treatment of X-linked
hypophosphatemia (XLH), a condition associated with excessive FGF23 production.
It directly addresses the excessive FGF23 activity in patients with XLH by
binding to FGF23, and inhibiting its signaling. This leads to increased
gastrointestinal phosphate absorption and renal phosphate reabsorption, thereby
improving serum phosphate levels, and, ultimately, bone mineralization and the
risk of bone disease. In clinical trials, subcutaneous burosumab increased serum
phosphorus levels in pediatric and adult patients with XLH, as well as
significantly improving the severity of rickets in children, and improving pain,
stiffness, physical functioning, and fracture/pseudofracture healing in adults.
Burosumab is well tolerated by children and adults with XLH, with most
treatment-emergent adverse events being of mild to moderate severity. |
What is the most common monogenic cause of common variable immunodeficiency (CVID) in Europeans? | Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. | Author information:
(1)Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall
d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and
Immunology, Autonomous University of Barcelona (UAB), Barcelona, Catalonia,
Spain; Jeffrey Model Foundation Excellence Center, Barcelona, Catalonia, Spain.
(2)Area of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron
(HUVH), Barcelona, Catalonia, Spain.
(3)Pathology Department, Hospital Universitari Vall d'Hebron (HUVH), Barcelona,
Catalonia, Spain.
(4)Pneumology Department, Hospital Universitari Vall d'Hebron (HUVH), Barcelona,
Catalonia, Spain.
(5)Exocrine Pancreas Research Unit, Department of Digestive Diseases, Hospital
Universitari Vall d'Hebron (HUVH), Autonomous University of Barcelona (UAB),
CiberEHD, Barcelona, Catalonia, Spain.
(6)Jeffrey Model Foundation Excellence Center, Barcelona, Catalonia, Spain;
Pediatric Infectious Diseases and Immunodeficiencies Unit (UPIIP), Hospital
Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR),
Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain.
(7)Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall
d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and
Immunology, Autonomous University of Barcelona (UAB), Barcelona, Catalonia,
Spain; Jeffrey Model Foundation Excellence Center, Barcelona, Catalonia, Spain;
Area of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron
(HUVH), Barcelona, Catalonia, Spain. Electronic address: [email protected]. |
List two indications of Letermovir? | Letermovir is approved for the prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an allogeneic haematopoietic stem cell transplant (HSCT). | Letermovir is being developed for human cytomegalovirus infection treatment and
prophylaxis. In patients receiving transplants, antivirals are coadministered
with cyclosporine A (CsA) or tacrolimus (TAC) immunosuppressants. Therefore, we
investigated the potential for letermovir-immunosuppressant interactions. In 2
phase 1 clinical trials either CsA 50 mg or TAC 5 mg was administered to healthy
males. Following washout, letermovir 80 mg was dosed twice daily for 7 and 11
days in the CsA and TAC trials, respectively, with a second dose of
immunosuppressant coadministered with letermovir at steady state. In addition,
letermovir 40 mg twice daily was administered for 14 days, and either CsA 50 or
200 mg administered on days 7 and 14. Pharmacokinetics and tolerability were
assessed. Letermovir increased CsA and TAC Cmax by 37% and 70%, respectively,
and exposure by 70% and 78%, respectively, compared with immunosuppressant
alone; t½ was also increased from 10.7 to 17.9 hours for CsA. CsA (50/200 mg)
increased letermovir Cmax,ss (109%/167%) and AUCss,τ (126%/237%) and decreased
t½ (4.33 to 3.68/3.04 hours) versus letermovir alone. TAC did not significantly
affect letermovir pharmacokinetics. All treatments were well tolerated.
Concomitant letermovir increased TAC and CsA exposure. CsA altered letermovir
pharmacokinetics, whereas TAC did not. Letermovir (Prevymis™) is an orally or intravenously administered
cytomegalovirus (CMV) DNA terminase complex inhibitor being developed by Merck &
Co., Inc., under a global license from AiCuris Anti-infective Cures GmbH.
Letermovir has been approved in Canada and the USA for the prophylaxis of CMV
infection and disease in adult CMV-seropositive recipients of an allogeneic
haematopoietic stem cell transplant (HSCT). In addition, letermovir has received
a positive opinion from the European Medicines Agency's Committee for Medicinal
Products for Human Use, and is under review in several countries, including
Japan. This article summarizes the milestones in the development of letermovir
leading to its first global approval in Canada as well as the USA for the
prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of
an allogeneic HSCT. Latanoprostene bunod ophthalmic solution (Vyzulta) for the reduction of
intraocular pressure; letermovir (Prevymis) for prophylaxis of cytomegalovirus
infection and disease after stem cell transplant; benralizumab (Fasenra) for the
add-on maintece treatment of severe asthma of an eosinophilic phenotype. Human cytomegalovirus (HCMV) is responsible for life-threatening infections in
immunocompromised individuals and can cause serious congenital malformations.
Available antivirals target the viral polymerase but are subject to
cross-resistance and toxicity. New antivirals targeting other replication steps
and inducing fewer adverse effects are therefore needed. During HCMV
replication, DNA maturation and packaging are performed by the terminase
complex, which cleaves DNA to package the genome into the capsid. Identified in
herpesviruses and bacteriophages, and with no counterpart in mammalian cells,
these terminase proteins are ideal targets for highly specific antivirals. A new
terminase inhibitor, letermovir, recently proved effective against HCMV in phase
III clinical trials, but the mechanism of action is unclear. Letermovir has no
significant activity against other herpesvirus or non-human CMV. This review
focuses on the highly conserved mechanism of HCMV DNA-packaging and the
potential of the terminase complex to serve as an antiviral target. We describe
the intrinsic mechanism of DNA-packaging, highlighting the structure-function
relationship of HCMV terminase complex components. Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus
infection prophylaxis in hematopoietic stem cell transplant recipients.
Posaconazole (POS), a substrate of glucuronosyltransferase and P-glycoprotein,
and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to
transplant recipients. Because coadministration of these azoles with letermovir
is expected, the effect of letermovir on exposure to these antifungals was
investigated. Two trials were conducted in healthy female subjects 18 to 55
years of age. In trial 1, single-dose POS 300 mg was administered alone,
followed by a 7-day washout; then letermovir 480 mg once daily was given for 14
days with POS 300 mg coadministered on day 14. In trial 2, on day 1 VRC 400 mg
was given every 12 hours; on days 2 and 3, VRC 200 mg was given every 12 hours,
and on day 4 VRC 200 mg. On days 5 to 8, letermovir 480 mg was given once daily.
Days 9 to 12 repeated days 1 to 4 coadministered with letermovir 480 mg once
daily. In both trials, blood samples were collected for the assessment of the
pharmacokinetic profiles of the antifungals, and safety was assessed. The
geometric mean ratios (90%CIs) for POS+letermovir/POS area under the curve and
peak concentration were 0.98 (0.83, 1.17) and 1.11 (0.95, 1.29), respectively.
Voriconazole+letermovir/VRC area under the curve and peak concentration
geometric mean ratios were 0.56 (0.51, 0.62) and 0.61 (0.53, 0.71),
respectively. All treatments were generally well tolerated. Letermovir did not
affect POS pharmacokinetics to a clinically meaningful extent but decreased VRC
exposure. These results suggest that letermovir may be a perpetrator of
CYP2C9/19-mediated drug-drug interactions. Letermovir is a human cytomegalovirus (CMV) terminase inhibitor recently
approved as prophylaxis in stem cell transplant recipients. In further studies
of emerging drug resistance, a baseline laboratory CMV strain was serially
propagated in cell culture under a combination of letermovir and ganciclovir. In
eight experiments, UL56 terminase gene mutations were detected beginning at 10
passages and included novel amino acid substitutions V236A, L328V, and A365S in
a region previously associated with letermovir resistance. Outside this region,
the UL56 substitution C25F was detected at moderate drug concentrations in two
experiments as either the first detected mutation or an addition to a
preexisting V231L substitution. In all cases, mutation at UL56 codon 325
conferring absolute letermovir resistance eventually developed at a median of 20
passages. No UL97 kinase or UL54 DNA polymerase mutations relevant to
ganciclovir resistance were detected until many passages after the first
detection of the UL56 mutations. UL56 substitutions V236A, L328V, and A365S were
shown to confer borderline or low-grade letermovir resistance, while C25F
conferred a 5.4-fold increase in letermovir resistance (50% effective
concentration [EC50]) by itself and a 46-fold increase in combination with
V231L. The evolution of resistance mutations sooner in UL56 than in UL54 or UL97
is consistent with prior in vitro observations, and UL56 codon 25 is a genetic
locus for letermovir resistance distinct from loci previously described. |
What is achalasia? | Achalasia is a primary esophageal motility disorder characterized by aperistalsis of the esophagus and failed relaxation of the lower esophageal sphincter that presents rarely in childhood. | Achalasia is a motility disorder of the esophagus characterized by total loss of
esophageal peristalsis and by defective lower esophageal sphincter function. The
etiology of achalasia is poorly understood. Achalasia occurs across the
lifespan, but is uncommon in children. Most patients have progressive dysphagia
for both liquids and solids. This article describes the symptoms of achalasia,
its diagnosis, and treatment. The emphasis is on primary achalasia. Case studies
illustrate common findings in patients with achalasia. The importance of patient
education for effective management of this chronic illness is discussed. BACKGROUND & AIMS: Idiopathic achalasia is a motility disorder of the esophagus
characterized by incomplete relaxation of the lower esophageal sphincter and a
loss of normal peristaltic activity in the body of the esophagus. The loss of
inhibitory neurons in the distal esophagus, as well as abnormalities in the
vagus nerve, dorsal motor nucleus of the vagus nerve, and autonomic nervous
system, have been described in achalasia. Although the underlying cause of
idiopathic achalasia is unknown, the diffuse neuronal effects found suggest a
possible viral or neurodegenerative mechanism. By use of serological methods, a
significant association between the HLA-DQ1 phenotype and idiopathic achalasia
has been found, suggesting a possible immunogenetic mechanism. To further define
immunogenetics in the pathogenesis of idiopathic achalasia, we performed tissue
typing in patients with achalasia to determine their specific HLA phenotypes.
METHODS: We prospectively studied 32 patients (23 white and 9 black) with
idiopathic achalasia. Peripheral blood was collected, and HLA-DR and -DQ typing
by polymerase chain reaction with sequence-specific primers was performed.
Results were compared with those from 268 racially matched local controls.
RESULTS: Idiopathic achalasia and the broad HLA-DQ1 allele were not
significantly associated in either population, although a trend was found in
white subjects (odds ratio [OR], 2.16; chi2 = 5.36, P corrected [Pc] = 0.0824).
Further subtyping in white subjects revealed a significant association between
idiopathic achalasia and the DQB1*0602 allele (OR, 3.10; chi2 = 7.32, Pc =
0.0408). A strong trend was also found with the DRB1*15 allele (OR, 2.83; chi2 =
8.11, Pc = 0.0572). In the black population, there was no association between
idiopathic achalasia and DQB1*0602 or DRB1*15, but a trend was found with
DRB1*12 (OR, 6. 19; chi2 = 5.19, P = 0.0227 uncorrected, Pc = 0.295).
CONCLUSIONS: Idiopathic achalasia is associated with HLA alleles in a
race-specific manner. These results support an immunogenetic mechanism in the
pathogenesis of idiopathic achalasia. Achalasia is a disorder characterized by abnormal motility of the esophageal
body and the lower esophageal sphincter, resulting in dysphagia, regurgitation,
and chest pain. Treatment options for achalasia include Botulinum toxin
injection, pneumatic balloon dilation, and surgical esophagomyotomy. The aim of
this study was to determine the cost-effectiveness of these three strategies in
the treatment of achalasia in adults. We constructed a Markov cost-effectiveness
model comparing Botox injection, pneumatic balloon dilation, and laparoscopic
esophagomyotomy as initial treatments of achalasia. Costs and probabilities were
derived from the published literature. The utility for symptomatic achalasia was
derived from a sample of patients with achalasia. Sensitivity analyses were
performed. Over a five-year time horizon, pneumatic dilation was the most
cost-effective treatment strategy for achalasia, with an incremental
cost-effectiveness ratio of $1348 per quality-adjusted life-year compared to
Botox. Although laparoscopic esophagomyotomy was more effective than the other
treatment options, it was not cost-effective because of its high initial cost.
In conclusion, pneumatic dilation is the most cost-effective treatment option
for adults with achalasia. Further studies should examine the long-term relapse
rates following treatment with Botox and more precisely determine the quality of
life of symptomatic achalasia. BACKGROUND: Achalasia is defined manometrically by an aperistaltic esophagus.
Variations in the manometric findings occur in achalasia suggesting that all
manometric features should not be required to diagnose achalasia. Combined
multichannel intraluminal impedance and esophageal manometry (MII-EM) allows
both a functional and a manometric evaluation of esophageal motility and
identifies chronic fluid retention.
AIM: To compare manometric and MII characteristics in patients with achalasia.
METHODS: Retrospective review of 73 MII-EM tracings from patients with achalasia
done in our laboratory between October 2001 and December 2004 (38 females; mean
age=53.5 y). Patients with previous esophageal interventions were excluded.
Manometric and MII characteristics were identified and compared during 10 liquid
and 10 viscous swallows. Patients were also divided into 2 groups: vigorous
achalasia (VA) and achalasia.
RESULTS: Twenty-two of the seventy-one (31%) achalasia patients had a
hypertensive lower esophageal sphincter (LES). The mean lower esophageal
sphincter pressure (LESP) for the 71 patients with achalasia was 37.9+/-21.2 mm
Hg compared with 27.3+/-9.3 mm Hg (P<0.05) in the 73 patients with normal
motility. The mean LESP in patients with achalasia was 36+/-20.3 mm Hg compared
with 47+/-23.2 mm Hg (P<0.05) in patients with VA. Elevated intraesophageal
pressure (IEP) was noted in 45/73 (61.6%). The mean LESP in this group was
41.1+/-22.9 mm Hg compared with 32.5+/-17 mm Hg (P<0.05) with normal IEP. The
mean baseline impedance for achalasia was 801+/-732 compared with 1265.2+/-829.5
Omega (P<0.05) for the VA patients.
CONCLUSIONS: Most patients with achalasia have elevated IEP, elevated LES
residual pressure, normal LES pressure, and low baseline impedance. All
manometric features should not be required to diagnose achalasia. Patients with
an elevated IEP are likely to have an elevated LES pressure and LES residual
pressure. Low MII values identify chronic fluid retention and helps confirm the
diagnosis. Author information:
(1)Translational Research Center for Gastrointestinal Disorders (TARGID),
University of Leuven, Leuven, Belgium.
(2)Vesalius Research Center, VIB, Leuven University, Leuven, Belgium Laboratory
for Translational Genetics, University of Leuven, Leuven, Belgium.
(3)Department of Genomics, Life & Brain Center, University of Bonn, Bonn,
Germany Institute of Human Genetics, University of Bonn, Bonn, Germany.
(4)Immunology and Gastroenterology Departments, Instituto de Investigacion
Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
(5)Department of Gastroenterology and Hepatology, Academic Medical Centre,
Amsterdam, The Netherlands.
(6)Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza'
Hospital, San Giovanni Rotondo, Italy Unit of Gastroenterology SOD2, Azienda
Ospedaliera Universitaria, Careggi, Firenze, Italy.
(7)Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza'
Hospital, San Giovanni Rotondo, Italy.
(8)Department of Genomics, Life & Brain Center, University of Bonn, Bonn,
Germany Institute of Human Genetics, University of Bonn, Bonn, Germany Institute
for Genomic Mathematics, University of Bonn, Bonn, Germany Department of
Biostatistics, Harvard School of Public Health, Boston, USA.
(9)Department of Gastroenterology, German Clinic of Diagnostics, Wiesbaden,
Germany.
(10)Department of General, Visceral and Transplant Surgery, University Medical
Center of Mainz, Mainz, Germany.
(11)Department of Gastroenterology, Humanitas Clinical and Research
Center-Istituto Clinico Humanitas IRCCS, Milan, Italy.
(12)Department of Surgery, Oncology and Gastroenterology, University of Padova,
Padova, Italy.
(13)Gastroenterology Unit, Department of Clinical and Experimental Medicine,
Federico II University, Napoli, Italy.
(14)Institute for Medical Biometry, Informatics and Epidemiology, University of
Bonn, Bonn, Germany. Berardinelli-Seip congenital lipodystrophy (BSCL) is an uncommon autosomal
recessive disorder. Patients with BSCL present with a distinct phenotype since
subcutaneous fat is largely lacking and musculature has become more prominent.
During childhood, diabetes and acanthosis nigricans evolve and female patients
may develop hirsutism. Different genes encoding this entity have been described.
Achalasia is a rare esophageal motility disorder, characterized by its distinct
motility pattern with absent or incomplete lower esophageal sphincter (LES)
relaxations. The exact cause of achalasia is yet unknown. Here, we describe a
patient with achalasia in the context of BSCL, which might be linked by a shared
pathophysiologic background, as evaluated in this case report.
CONCLUSION: In a BSCL patient presenting with gastrointestinal symptoms, a
motility disorder of the gastrointestinal tract should be considered.
WHAT IS KNOWN: • Berardinelli-Seip congenital lipodystrophy (BSCL) and achalasia
are both disorders characterized by low prevalence. What is New: • Co-existence
of both diseases is described in this report. Linkage by a potential common
pathophysiologic background is discussed in this paper. Achalasia is a chronic incurable esophageal motility disorder characterized by
impaired lower esophageal sphincter (LES) relaxation and loss of esophageal
peristalsis. Although rare, it is currently the most common primary esophageal
motility disorder, with an annual incidence of around 1.6 per 100,000 persons
and prevalence of around 10.8/100,000 persons. Symptoms of achalasia include
dysphagia to both solids and liquids, regurgitation, aspiration, chest pain and
weight loss. As the underlying etiology of achalasia remains unclear, there is
currently no curative treatment for achalasia. Management of achalasia mainly
involves improving the esophageal outflow in order to provide symptomatic relief
to patients. The most effective treatment options for achalasia include
pneumatic dilation, Heller myotomy and peroral endoscopic myotomy (POEM), with
the latter increasingly emerging as the treatment of choice for many patients.
This review focusses on evidence for current and emerging treatment options for
achalasia with a particular emphasis on POEM. Achalasia is one of the most studied esophageal motility disorders. However, the
pathophysiology and reasons that patients develop achalasia are still unclear.
Patients often present with dysphagia to solids and liquids, regurgitation, and
varying degrees of weight loss. There is significant latency prior to diagnosis,
which can have nutritional implications. The diagnosis is suspected based on
clinical history and confirmed by esophageal high-resolution manometry testing.
Esophagogastroduodenoscopy is necessary to rule out potential maligcy that
can mimic achalasia. Recent data presented in abstract form suggest that
patients with type II achalasia may be most likely, and patients with type III
achalasia may be least likely, to report weight loss compared to patients with
type I achalasia. Although achalasia cannot be permanently cured, palliation of
symptoms is possible in over 90% of patients with the treatment modalities
currently available (pneumatic dilation, Heller myotomy, or peroral endoscopic
myotomy). This article reviews the clinical presentation, diagnosis, and
management options in patients with achalasia, as well as potential insights
into histopathologic differences and nutritional implications of the subtypes of
achalasia. The pathophysiology of achalasia is largely unknown, and involves the
destruction of ganglion cell in the esophageal myenteric plexus. High-resolution
esophageal manometry is the key investigation. Endoscopic pneumodilatation and
laparoscopic Heller myotomy have comparable short-term success rates, around
90%. The main complication after pneumodilatation is esophageal perforation,
occurring in about 1% of cases. Peroral endoscopic myotomy is a promising
treatment modality, however with frequent post-procedural gastroesophageal
reflux. |
Does allele phasing improve the phylogenetic utility of ultraconserved elements? | Yes. Allele phasing greatly improves the phylogenetic utility of ultraconserved elements. Analyzing allele sequences leads to more accurate estimates of tree topology and divergence times than the more common approach of using contig sequences. | Advances in high-throughput sequencing techniques now allow relatively easy and
affordable sequencing of large portions of the genome, even for nonmodel
organisms. Many phylogenetic studies reduce costs by focusing their sequencing
efforts on a selected set of targeted loci, commonly enriched using sequence
capture. The advantage of this approach is that it recovers a consistent set of
loci, each with high sequencing depth, which leads to more confidence in the
assembly of target sequences. High sequencing depth can also be used to identify
phylogenetically informative allelic variation within sequenced individuals, but
allele sequences are infrequently assembled in phylogenetic studies. Instead,
many scientists perform their phylogenetic analyses using contig sequences which
result from the de novo assembly of sequencing reads into contigs containing
only canonical nucleobases, and this may reduce both statistical power and
phylogenetic accuracy. Here, we develop an easy-to-use pipeline to recover
allele sequences from sequence capture data, and we use simulated and empirical
data to demonstrate the utility of integrating these allele sequences to
analyses performed under the multispecies coalescent model. Our empirical
analyses of ultraconserved element locus data collected from the South American
hummingbird genus Topaza demonstrate that phased allele sequences carry
sufficient phylogenetic information to infer the genetic structure, lineage
divergence, and biogeographic history of a genus that diversified during the
last 3 myr. The phylogenetic results support the recognition of two species and
suggest a high rate of gene flow across large distances of rainforest habitats
but rare admixture across the Amazon River. Our simulations provide evidence
that analyzing allele sequences leads to more accurate estimates of tree
topology and divergence times than the more common approach of using contig
sequences. |
What is Burning Mouth Syndrome(BMS)? | Burning Mouth Syndrome (BMS), a chronic intraoral burning sensation or dysesthesia without clinically evident causes, is one of the most common medically unexplained oral symptoms/syndromes. It predominately affects middle-aged women in the postmenopausal period. The condition is distinguished by burning symptoms of the oral mucosa and the absence of any clinical signs. | The burning mouth syndrome is characterized by an unpleasant sensation of
burning in the oral cavity, without clinical signs. Causal factors may be
psychogenic, systemic or local. The aim of the study was to determine the
significance of contact allergy in the pathogenesis of burning mouth syndrome.
Fifteen patients with burning mouth syndrome were studied through anamnesis and
laboratory analysis. Epicutaneous patch tests were performed with the Italian
standard series (GIRDCA - Gruppo Italiano di Ricerca Dermatiti da Contatto ed
Ambientali), preservative and dental series. The same tests were carried out in
12 healthy age- and sex-matched subjects. The number of patients affected by
burning mouth syndrome with a positive reaction to patchtesting was 6 out of 15,
while the number of allergic patients in the control group was 3 out of 12. No
association could be found between positive reaction at patchtesting and
exposure to allergens. Contact allergy in burning mouth syndrome seems not to
play a primary role; nevertheless, it is advisable to perform patch tests in
selected patients to identify a possible aetiological agent. Burning mouth syndrome is a complicated, poorly understood, predomitly oral
condition that affects more than 1 million people in the United States. Women
are particularly affected by the condition; they are diagnosed with symptoms
seven times more frequently than males. Burning mouth syndrome is characterized
by a burning, painful sensation of the oral mucosa that most commonly involves
the anterior tongue. Many precipitating factors to burning mouth syndrome have
been proposed, and treatment addressing these factors has had limited success.
Patients with burning mouth syndrome are more likely to be evaluated by
physicians, and therefore it is advantageous for the physician to be familiar
with this oral condition. This paper reviews burning mouth syndrome, associated
causative factors, and treatment strategies for the physician. Burning mouth syndrome is characterized by a burning sensation in the tongue or
other oral sites, usually in the absence of clinical and laboratory findings.
Affected patients often present with multiple oral complaints, including
burning, dryness and taste alterations. Burning mouth complaints are reported
more often in women, especially after menopause. Typically, patients awaken
without pain but note increasing symptoms through the day and into the evening.
Conditions that have been reported in association with burning mouth syndrome
include chronic anxiety or depression, various nutritional deficiencies, type 2
diabetes (formerly known as non-insulin-dependent diabetes) and changes in
salivary function. However, these conditions have not been consistently linked
with the syndrome, and their treatment has had little impact on burning mouth
symptoms. Recent studies have pointed to dysfunction of several cranial nerves
associated with taste sensation as a possible cause of burning mouth syndrome.
Given in low dosages, benzodiazepines, tricyclic antidepressants or
anticonvulsants may be effective in patients with burning mouth syndrome.
Topical capsaicin has been used in some patients. We present a 63-year-old male patient with major depression, characterised by
prominent somatic symptoms localised especially around the mouth, whose
complaints started just after a prostate operation. The symptoms consisting of
burning in the mouth, pain, dry mouth (xerostomia), an unpleasant and strange
feeling of taste and itching, are all consistent with burning mouth syndrome.
Burning mouth syndrome is a common disorder, usually affecting elderly females,
characterised by intractable pain and burning in the oral cavity, evident
especially in the tongue, together with a normal mouth mucosa. In the scientific
literature a variety of terms are used to describe similar symptoms, such as
glossodynia, glossopyrosis, stomatodynia and oral dysestesia. Most patients
suffer from the syndrome for a long time, ranging from months up to years. The
onset was reported to be gradual for most of the subjects, although many
patients relate the onset of symptoms to previous dental procedures or to a
previous medical illness. Burning mouth syndrome has a multifactorial etiology.
Anxiety disorder, hypochondriasis, conversion disorder and especially depression
may be considered amongst the psychological factors responsible for this
situation. The psychological findings in burning mouth syndrome patients may be
either the consequence of the chronic pain condition or its cause. It is well
known that those patients had a relatively high percentage of psychiatric or
psychological treatment in the past and/or present. After excluding organic
factors, depression should be considered in old patients with predomit mouth
complaints. Burning mouth syndrome (BMS) is a predomitly oral condition characterized by
the occurrence of a chronic burning that commonly involves the anterior tongue,
painful sensation, dryness and taste alterations. The syndrome is reported more
often in women, usually without any oral mucosal signs and laboratory
abnormalities. Its etiopathogenesis remains poorly understood, and there is no
consensus on diagnostic criteria and treatment strategies. Tongue burning is
though to be also one of a non-oesophageal symptom of gastro-oesophageal reflux
disease. As reported below, although this symptom may well be diagnostically
misleading, careful diagnosis based on clinical signs may distinguish patients
with BMS from those with reflux disease, and successful management of burning
mouth is often enables. Burning mouth syndrome (BMS) is characterized by burning sensations of the oral
cavity in the absence of abnormalities of the oral mucosa. BMS predomitly
affects middle-aged women. This condition has a multifactorial etiology.
Multiple approaches to treatment have been described. This article examines BMS,
its related factors, and treatment options. Burning in the mouth in and of itself is not all that uncommon. It may result
from a variety of local or generalized oral mucosal disorders, or may be
secondary to referred phenomena from other locations. Primary burning mouth
syndrome, on the other hand, is relatively uncommon. Burning mouth syndrome is
an idiopathic pain disorder, which appears to be neuropathic in origin. Thoughts
on management of secondary and particularly primary burning mouth syndrome are
discussed. BACKGROUND: Burning mouth syndrome is a disorder usually associated with an
unexplained, prolonged sensation of burning inside the oral cavity. Although the
etiology is unknown, neural and psychologic factors and cytokines may be
implicated in the pathogenesis of burning mouth syndrome. The aim of this study
was to investigate the relationship between serum cytokine and T regulatory cell
levels in patients with burning mouth syndrome with regard to depression and
anxiety.
METHODS: Thirty patients with burning mouth syndrome and 30 matched controls
participated in the study. Serum cytokine levels were measured with cytometric
bead array and T regulatory cells were defined as CD4(+)CD25(+)Foxp-3(+) cells
by flow cytometry. The level of anxiety and depression were analyzed by means of
the Speilberger State-Trait Anxiety Inventory and Zung Self-Rating Depression
Scale. Visual analogue scale was used in the quantification of burning levels of
patients.
RESULTS: Serum IL-2 and TNF-alpha levels were significantly decreased in
patients with burning mouth syndrome compared with controls [mean 16.79 +/- 8.70
vs. 37.73 +/- 41.05 pg / ml (P < 0.05) and mean 39.09 +/- 29.40 vs. 70.83 +/-
42.44 pg / ml (P < 0.01) respectively].
CONCLUSIONS: IL-2 and TNF-alpha might play a role in burning mouth syndrome.
Burning mouth syndrome may occur as a sign of predisposition to autoimmunity.
Presence of low levels of CD28(+) supports the provision that BMS might be a
pre-autoimmune disease. Burning mouth syndrome (BMS) is a chronic disease characterized by burning of
the oral mucosa associated with a sensation of dry mouth and/or taste
alterations. BMS occurs more frequently among postmenopausal women. The
pathophysiology of the disease is still unknown, and evidence is conflicting;
although some studies suggest a central origin, others point to a peripheral
neuropathic origin. The efficacy of some medications in the treatment of BMS
suggests that the dopaminergic system may be involved. BACKGROUND: Burning mouth syndrome is a burning sensation or stinging disorder
affecting the oral mucosa in the absence of any clinical signs or mucosal
lesions. Some studies have suggested that burning mouth syndrome could be caused
by the metals used in dental prostheses, as well as by acrylate monomers,
additives and flavouring agents, although others have not found any aetiologic
role for hypersensitivity to dental materials.
OBJECTIVE: To evaluate the extent and severity of adverse reactions to dental
materials in a group of patients with burning mouth syndrome, and investigate
the possible role of contact allergy in its pathogenesis.
MATERIALS AND METHODS: We prospectively studied 124 consecutive patients with
burning mouth syndrome (108 males; mean age 57 years, range 41-83), all of whom
underwent allergen patch testing between 2004 and 2007.
RESULTS: Sixteen patients (13%) showed positive patch test reactions and were
classified as having burning mouth syndrome type 3 or secondary burning mouth
syndrome (Lamey's and Scala's classifications).
CONCLUSION: Although we did not find any significant association between the
patients and positive patch test reactions, it would be advisable to include
hypersensitivity to dental components when evaluating patients experiencing
intermittent oral burning without any clinical signs. Pain in the tongue or oral tissues described as "burning" has been referred to
by many terms including burning mouth syndrome. When a burning sensation in the
mouth is caused by local or systemic factors, it is called secondary burning
mouth syndrome and when these factors are treated the pain will resolve. When
burning mouth syndrome occurs in the absence of identified risk indicators, the
term primary burning mouth syndrome is utilized. This article focuses on
descriptions, etiologic theories, and management of primary burning mouth
syndrome, a condition for which underlying causative agents have been ruled out. Burning mouth syndrome (BMS) is characterized by the presence of burning
sensation of the oral mucosa in the absence of clinically apparent mucosal
alterations. It occurs more commonly in middle-aged and elderly women and often
affects the tongue tip and lateral borders, lips, and hard and soft palate. In
addition to a burning sensation, the patients with BMS may also complain
unremitting oral mucosal pain, dysgeusia, and xerostomia. BMS can be classified
into two clinical forms: primary and secondary BMS. The primary BMS is essential
or idiopathic, in which the organic local/systemic causes cannot be identified
and a neuropathological cause is likely. The diagnosis of primary BMS depends
mainly on exclusion of etiological factors. The secondary BMS is caused by
local, systemic, and/or psychological factors; thus, its diagnosis depends on
identification of the exact causative factor. When local, systemic or
psychological factors are present, treatment or elimination of these factors
usually results in a significant clinical improvement of BMS symptoms. Vitamin,
zinc, or hormone replacement therapy has been found to be effective for reducing
the oral burning or pain symptom in some BMS patients with deficiency of the
corresponding factor. If patients still have the symptoms after the removal of
potential causes, drug therapy should be instituted. Previous randomized
controlled clinical trials found that drug therapy with capsaicin, alpha-lipoic
acid, clonazepam, and antidepressants may provide relief of oral burning or pain
symptom. In addition, psychotherapy and behavioral feedback may also help
eliminate the BMS symptoms. BACKGROUND: Burning mouth syndrome (BMS) is common conditions that affects
menopause women, patients suffer from sever burning sensation. Up to now there
is no definitive treatment for this disease. Present study was undertaken to
evaluate the efficacy of low-level laser (LLL) in improving the symptoms of
burning mouth syndrome.
MATERIAL AND METHODS: Twenty patients with BMS were enrolled in this study; they
were divided in two groups randomly. In the laser group, in each patient, 10
areas on the oral mucosa were selected and underwent LLL irradiation at a
wavelength of 630 nm, and a power of 30 mW for 10 seconds twice a week for 4
weeks. In the placebo group, silent/off laser therapy was carried out during the
same period in the same areas. Burning sensation and quality of life were
evaluated.
RESULTS: Burning sensation severity and quality of life in the two groups after
intervention were different significant statistically, (p= 0.004, p= 0.01
respectively) .Patients in laser group had better results.
CONCLUSIONS: It can be concluded that low level laser might decrease the
intensity of burning mouth syndrome.
KEY WORDS: Pain, low-level laser, burning mouth syndrome, oral mucosa. Burning mouth syndrome (BMS) is characterized by pain in the mouth with or with
no inflammatory signs and no specific lesions. Synonyms found in literature
include glossodynia, oral dysesthesia, glossopyrosis, glossalgia,
stomatopyrosis, and stomatodynia. Burning mouth syndrome generally presents as a
triad: Mouth pain, alteration in taste, and altered salivation, in the absence
of visible mucosal lesions in the mouth. The syndrome generally manifests
spontaneously, and the discomfort is typically of a continuous nature but
increases in intensity during evening and at night. The etiopathogenesis seems
to be complex and in a large number of patients probably involves interactions
among local, systemic, and/or psychogenic factors. The differential diagnosis
requires the exclusion of oral mucosal lesions or blood test alterations that
can produce burning mouth sensation. Management is always based on the
etiological agents involved. If burning persists after local or systemic
conditions are treated, then treatment is aimed at controlling neuropathic
symptoms. Treatment of BMS is still unsatisfactory, and there is no definitive
cure. As a result, a multidisciplinary approach is required to bring the
condition under better control. The aim of this review was to discuss several
aspects of BMS, update current knowledge, and provide guidelines for patient
management. Burning mouth syndrome is distressing to both the patient and practitioner
unable to determine the cause of the patient's symptoms. Burning mouth syndrome
is a diagnosis of exclusion, which is used only after nutritional deficiencies,
mucosal disease, fungal infections, hormonal disturbances and contact stomatitis
have been ruled out. This article will explore the many causes and treatment of
patients who present with a chief complaint of "my mouth burns," including
symptomatic treatment for those with burning mouth syndrome. Burning mouth syndrome (BMS) is a chronic oral pain syndrome that primarily
affects peri- and postmenopausal women. It is characterized by oral mucosal
burning and may be associated with dysgeusia, paresthesia, dysesthesia, and
xerostomia. The etiology of the disease process is unknown, but is thought to be
neuropathic in origin. The goal of this systematic review was to assess the
efficacy of the various treatments for BMS. Literature searches were conducted
through PubMed, Web of Science, and Cochrane Library databases, which identified
22 randomized controlled trials. Eight studies examined alpha-lipoic acid (ALA),
three clonazepam, three psychotherapy, and two capsaicin, which all showed
modest evidence of potentially decreasing pain/burning. Gabapentin was seen in
one study to work alone and synergistically with ALA. Other treatments included
vitamins, benzydamine hydrochloride, bupivacaine, Catuama, olive oil, trazodone,
urea, and Hypericum perforatum. Of these other treatments, Catuama and
bupivacaine were the only ones with significant positive results in symptom
improvement. ALA, topical clonazepam, gabapentin, and psychotherapy may provide
modest relief of pain in BMS. Gabapentin may also boost the effect of ALA.
Capsaicin is limited by its side effects. Catuama showed potential for benefit.
Future studies with standardized methodology and outcomes containing more
patients are needed. Primary burning mouth syndrome (BMS) is defined as an "intraoral burning or
dysaesthetic sensation, recurring daily… more than 3 months, without clinically
evident causative lesions" (IHS 2013). In addition to pain, taste alterations
are frequent (dysgeusia, xerostomia). Although lacking clinical signs of
neuropathy, more accurate diagnostic methods have shown neuropathic involvement
at various levels of the neuraxis in BMS: peripheral small fiber damage (thermal
quantitative sensory testing, electrogustatometry, epithelial nerve fiber
density), trigeminal system lesions in the periphery or the brainstem (brainstem
reflex recordings, trigeminal neurography, evoked potentials), or signs of
decreased inhibition within the central nervous system (deficient brainstem
reflex habituation, positive signs in quantitative sensory testing,
neurotransmitter-positron emission tomography findings indicative of deficient
striatal dopamine function). Abnormalities in electrogustatometry indicate the
involvement of the small Aδ taste afferents, in addition to somatosensory small
fibers. According to these findings, the clinical entity of BMS can be divided
into 2 main subtypes compatible with either peripheral or central neuropathic
pain, which may overlap in individual patients. The central type does not
respond to local treatments and associates often with psychiatric comorbidity
(depression or anxiety), whereas the peripheral type responds to peripheral
lidocaine blocks and topical clonazepam. Burning mouth syndrome is most
prevalent in postmenopausal women, having led to a hypothesis that BMS is
triggered as a consequence of nervous system damage caused by neurotoxic factors
affecting especially vulnerable small fibers and basal ganglia in a setting of
decrease in neuroprotective gonadal hormones and increase in stress hormone
levels, typical for menopause. OBJECTIVE: Burning mouth syndrome (BMS) is a chronic orofacial pain disorder
that is defined by a burning sensation in the oral mucosa. The aim of this study
was to investigate the underlying factors, clinical characteristics and
self-reported oral and general health factors associated with BMS.
MATERIAL AND METHODS: Fifty-six women with BMS (mean age: 67.7) and their
age-matched controls were included in the study. A general questionnaire, an
OHRQL index and BMS-specific questionnaires were used. Each subject underwent an
oral examination.
RESULTS: The mean severity of the BMS symptoms (VAS, 0-100) was 66.2 (SD 19.7).
Overall, 45% of the patients reported taste disturbances. More of the patients
than the controls rated their general health, oral health and life situation as
'less satisfactory'. The patients also reported more frequently on-going
medications, diseases/disorders, xerostomia, allergy and skin diseases. Except
for more bruxofacets among the patients, there were no significant differences
regarding signs of parafunction. In a multiple logistic regression analysis,
xerostomia and skin diseases showed the strongest prediction for BMS and no
significant effect was found for medication, allergy or bruxofacets.
CONCLUSIONS: Skin diseases and xerostomia but not parafunction were strongly
associated with BMS. Our findings provide the basis for additional studies to
elucidate the causal factors of BMS. |
When is serum AFP used as marker? | Serum α-Fetoprotein (AFP) is a widely used diagnostic biomarker, but it has limited sensitivity and is not elevated in all Hepato cellular carcinoma (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. | BACKGROUND AND AIM: Extremely poor prognosis in hepatocellular carcinoma (HCC)
patients with progressing disease was denoted by vascular invasion. Cytokeratin
18 (CK18) has been shown to be overexpressed in hepatocellular carcinoma so it
is a valuable tumor marker; however, its role in vascular invasion is still
unclear. This study aimed to predict CK18 as a predictive marker for
macrovascular maligt invasion.
METHODS: The present study was conducted on three groups of patients: group I
included 91 HCC patients without macrovascular invasion, group II included 34
HCC patients with radiological evidence of vascular invasion, and group III
included 110 control individuals subdivided into IIIA as healthy blood donors
and IIIB as post-HCV cirrhotic patients without HCC.
RESULTS: ROC curve of M30 fragments of CK18 was constructed for discrimination
between HCC with and without macrovascular invasion. Optimum cutoff value was
304.5 ng/mL (AUC = 0.997, P < 0.001), sensitivity (100%) and specificity
(98.8%). Regression analysis was conducted for prediction of macrovascular
invasion within HCC patients. The following variables: higher levels of AST,
M30, bilirubin, and AFP, lower levels of serum albumin, larger tumor size, child
B score, and multiple lesions were associated with vascular invasion in
univariate analysis. While in multivariate analysis, higher levels of AST and
bilirubin and elevated levels of M30 and AFP serum were considered independent
predictors for macrovascular invasion in HCC patients.
CONCLUSION: The present study suggests that increased M30 fragments of CK18
levels may be useful as a possible marker of early tumor invasiveness. 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. AIMS: We tested whether transforming growth factor β1 (TGF-β1) signaling plays
an important role in hepatic stellate cell differentiation fate and investigated
the role of Jagged1/Notch in this process.
MATERIALS AND METHODS: TGF-β1 was overexpressed and transforming growth factor
receptor 1 (TGF-β-R1) was knocked down by a lentiviral vector in mouse hepatic
stellate cells (mHSCs). Transfection efficiency was assessed with
immunofluorescence, quantitative reverse-transcriptase polymerase chain reaction
(qRT-PCR) and western blotting. The downstream genes alpha-smooth muscle actin
(α-SMA), Jagged1 and the differentiation markers alpha-fetoprotein (AFP),
albumin (ALB), cytokeratin19 (CK19), SRY (sex determining region Y)-box 9
(SOX9), and hairy and enhancer of split-1 (Hes1) were measured with qRT-PCR and
western blotting.
KEY FINDINGS: SpHBLV-CMVIE-TGF-β1, pHBLV-CMVIE-GFP, pHBLV-U6-TGF-β-R1 shRNA, and
pHBLV-U6-RFP were successfully transfected. Over-expression of the TGF-β1 gene
caused mHSCs to transform into myofibroblasts (MFs) and expression of Jagged1
and cholangiocyte markers (CK19, SOX9, Hes1) were significantly upregulated
(P<0.01). Importantly, after blocking TGF-β1 signaling via gene silencing,
expression of Jagged1 was much reduced, but the mature hepatocyte marker (ALB)
was obviously increased. In addition, AFP, a hepatic stem cell marker, was
expressed at the highest level in the control groups.
SIGNIFICANCE: Our findings emphasize that the TGF-β1 signaling pathway regulates
expression of Jagged1 in mHSCs which is associated with transformation of mHSCs
into MFs, thus demonstrating a novel mechanism via which TGF-β1 signaling
controls the differentiation fate of mHSCs through regulation of the
Jagged1/Notch pathway. |
Have yeast prions become important models for the study of the basic mechanisms underlying human amyloid diseases? | infectious proteins) were discovered by their outré genetic properties and have become important models for an array of human prion and amyloid diseases. | More than 20 human diseases are related to protein misfolding which causes
formation of amyloids, fibrillar aggregates of normally soluble proteins. Such
diseases are called amyloid diseases or amyloidoses. Of them only prion diseases
are transmissible. Amyloids of the prion type are described in lower eukaryotes.
However, in contrast to mammalian prions, which cause incurable
neurodegenerative diseases, prions of lower eukaryotes are related to some
non-chromosomally inherited phenotypic traits. Here we summarize the results of
studies of prions of the yeast Saccharomyces cerevisiae and of the use of yeast
model for investigation of some human amyloidoses, such as prion diseases,
Alzheimer's, Parkinson's, and Huntington's diseases. The yeast system has provided considerable insight into the biology of amyloid
and prions. Here we focus on how alterations in abundance or function of protein
chaperones and co-chaperones affect propagation of yeast prions. In spite of a
considerable amount of information, a clear understanding of the molecular
mechanisms underlying these effects remains wanting. Amyloid fibril formation is associated with a range of neurodegenerative
diseases in humans, including Alzheimer's, Parkinson's, and prion diseases. In
yeast, amyloid underlies several non-Mendelian phenotypes referred to as yeast
prions. Mechanism of amyloid formation is critical for a complete understanding
of the yeast prion phenomenon and human amyloid-related diseases. Ure2 protein
is the basis of yeast prion [URE3]. The Ure2p prion domain is largely
disordered. Residual structures, if any, in the disordered region may play an
important role in the aggregation process. Studies of Ure2p prion domain are
complicated by its high aggregation propensity, which results in a mixture of
monomer and aggregates in solution. Previously we have developed a solid-support
electron paramagnetic resoce (EPR) approach to address this problem and have
identified a structured state for the Alzheimer's amyloid-β monomer. Here we use
solid-support EPR to study the structure of Ure2p prion domain. EPR spectra of
Ure2p prion domain with spin labels at every fifth residue from position 10 to
position 75 show similar residue mobility profile for denaturing and native
buffers after accounting for the effect of solution viscosity. These results
suggest that Ure2p prion domain adopts a completely disordered structure in the
native buffer. A completely disordered Ure2p prion domain implies that the
amyloid formation of Ure2p, and likely other Q/N-rich yeast prion proteins, is
primarily driven by inter-molecular interactions. The prions (infectious proteins) of Saccharomyces cerevisiae are proteins acting
as genes, by templating their conformation from one molecule to another in
analogy to DNA templating its sequence. Most yeast prions are amyloid forms of
normally soluble proteins, and a single protein sequence can have any of several
self-propagating forms (called prion strains or variants), analogous to the
different possible alleles of a DNA gene. A central issue in prion biology is
the structural basis of this conformational templating process. The in-register
parallel β sheet structure found for several infectious yeast prion amyloids
naturally suggests an explanation for this conformational templating. While most
prions are plainly diseases, the [Het-s] prion of Podospora anserina may be a
functional amyloid, with important structural implications. Yeast prions are
important models for human amyloid diseases in general, particularly because new
evidence is showing infectious aspects of several human amyloidoses not
previously classified as prions. We also review studies of the roles of
chaperones, aggregate-collecting proteins, and other cellular components using
yeast that have led the way in improving the understanding of similar processes
that must be operating in many human amyloidoses. A prion is an infectious protein horizontally transmitting a disease or trait
without a required nucleic acid. Yeast and fungal prions are nonchromosomal
genes composed of protein, generally an altered form of a protein that catalyzes
the same alteration of the protein. Yeast prions are thus transmitted both
vertically (as genes composed of protein) and horizontally (as infectious
proteins, or prions). Formation of amyloids (linear ordered β-sheet-rich protein
aggregates with β-strands perpendicular to the long axis of the filament)
underlies most yeast and fungal prions, and a single prion protein can have any
of several distinct self-propagating amyloid forms with different biological
properties (prion variants). Here we review the mechanism of faithful templating
of protein conformation, the biological roles of these prions, and their
interactions with cellular chaperones, the Btn2 and Cur1 aggregate-handling
systems, and other cellular factors governing prion generation and propagation.
Human amyloidoses include the PrP-based prion conditions and many other, more
common amyloid-based diseases, several of which show prion-like features. Yeast
prions increasingly are serving as models for the understanding and treatment of
many mammalian amyloidoses. Patients with different clinical pictures of the
same amyloidosis may be the equivalent of yeasts with different prion variants. Yeast prions (infectious proteins) were discovered by their outré genetic
properties and have become important models for an array of human prion and
amyloid diseases. A single prion protein can become any of many distinct amyloid
forms (called prion variants or strains), each of which is self-propagating, but
with different biological properties (eg, lethal vs mild). The folded
in-register parallel β sheet architecture of the yeast prion amyloids naturally
suggests a mechanism by which prion variant information can be faithfully
transmitted for many generations. The yeast prions rely on cellular chaperones
for their propagation, but can be cured by various chaperone imbalances. The
Btn2/Cur1 system normally cures most variants of the [URE3] prion that arise.
Although most variants of the [PSI+] and [URE3] prions are toxic or lethal, some
are mild in their effects. Even the most mild forms of these prions are rare in
the wild, indicating that they too are detrimental to yeast. The beneficial
[Het-s] prion of Podospora anserina poses an important contrast in its
structure, biology, and evolution to the yeast prions characterized thus far. Saccharomyces cerevisiae is an occasional host to an array of prions, most based
on self-propagating, self-templating amyloid filaments of a normally soluble
protein. [URE3] is a prion of Ure2p, a regulator of nitrogen catabolism, while
[PSI+] is a prion of Sup35p, a subunit of the translation termination factor
Sup35p. In contrast to the functional prions, [Het-s] of Podospora anserina and
[BETA] of yeast, the amyloid-based yeast prions are rare in wild strains, arise
sporadically, have an array of prion variants for a single prion protein
sequence, have a folded in-register parallel β-sheet amyloid architecture, are
detrimental to their hosts, arouse a stress response in the host, and are
subject to curing by various host anti-prion systems. These characteristics
allow a logical basis for distinction between functional amyloids/prions and
prion diseases. These infectious yeast amyloidoses are outstanding models for
the many common human amyloid-based diseases that are increasingly found to have
some infectious characteristics. |
RV3-BB vaccine is used for prevention of which viral infection? | The RV3-BB human neonatal rotavirus vaccine aims to provide protection from severe rotavirus disease from birth. | INTRODUCTION: RV3 is a human neonatal rotavirus strain (G3P[6]) that has been
associated with asymptomatic neonatal infection and replicates well in the
infant gut. RV3-BB rotavirus vaccine has been developed as a rotavirus vaccine
candidate for administration at birth.
METHODS: A single-centre, double-blind, randomised placebo-controlled Phase I
study evaluated the safety and tolerability of a single oral dose of the second
generation RV3-BB rotavirus vaccine (8.3×10(6)FFU/mL) in 20 adults, 20 children
and 20 infants (10 vaccine and 10 placebo per age cohort). Vaccine take was
defined as seroconversion (a 3-fold increase in serum anti-rotavirus IgA or
serum neutralising antibody (SNA) from baseline at day 28 post-dose) or evidence
of RV3-BB viral replication in the faeces by RT-PCR analysis 3-6 days
post-vaccination. RV3-BB presence was confirmed by sequence analysis.
RESULTS: The RV3-BB vaccine was well tolerated in all participants, with no
pattern of adverse events shown to be associated with the study vaccine. In the
infant cohort, vaccine take was demonstrated in 8/9 infants following a single
dose of vaccine compared with 2/7 placebo recipients. In the infant vaccine
group, 5/9 infants exhibited either IgA or SNA seroconversion and 7/9 infants
had evidence of RV3-BB replication on days 3-6, compared with 2/7 infants who
seroconverted and 0/10 infants with evidence of replication in the placebo
group. Two infants in the placebo group had serological evidence of a rotavirus
infection within the 28-day study period: one demonstrated an IgA and the other
an SNA response, with wild-type virus replication detected in another infant.
CONCLUSION: A single dose of RV3-BB rotavirus vaccine was well tolerated in
adults, children and infants. Most infants (8/9) who received RV3-BB
demonstrated vaccine take following a single dose. These data support
progression of RV3-BB to Phase II immunogenicity and efficacy trials. BACKGROUND: Maternal antibodies, acquired passively via placenta and/or breast
milk, may contribute to the reduced efficacy of oral rotavirus vaccines observed
in children in developing countries. This study aimed to investigate the effect
of rotavirus specific maternal antibodies on the serum IgA response or stool
excretion of vaccine virus after any dose of an oral rotavirus vaccine, RV3-BB,
in parallel to a Phase IIa clinical trial conducted at Dunedin Hospital, New
Zealand. At the time of the study rotavirus vaccines had not been introduced in
New Zealand and the burden of rotavirus disease was evident.
METHODS: Rotavirus specific IgG and serum neutralizing antibody (SNA) levels in
cord blood and IgA levels in colostrum and breast milk samples collected
∼4 weeks, ∼20 weeks and ∼28 weeks after birth were measured. Infants were
randomized to receive the first dose of vaccine at 0-5 d (neonatal schedule) or
8 weeks (infant schedule). Breast feeding was with-held for 30 minutes before
and after vaccine administration. The relationship between rotavirus specific
IgG and SNA levels in cord blood and IgA in colostrum and breast milk at the
time of first active dose of RV3-BB vaccine and level of IgA response and stool
excretion after 3 doses of vaccine was assessed using linear and logistic
regression.
RESULTS: Forty infants received 3 doses of RV3-BB rotavirus vaccine and were
included in the analysis of the neonatal and infant groups. Rotavirus specific
IgA in colostrum (neonatal schedule group) and breast milk at 4 weeks (infant
schedule group) was identified in 14/21 (67%) and 14/17 (82%) of infants
respectively. There was little evidence of an association between IgA in
colostrum or breast milk IgA at 4 weeks, or between cord IgG or SNA level, and
IgA response or stool excretion after 3 doses of RV3-BB, or after one dose
(neonatal schedule) (all p>0.05).
CONCLUSIONS: The level of IgA in colostrum or breast milk and level of placental
IgG and SNA did not impact on the serum IgA response or stool excretion
following 3 doses of RV3-BB Rotavirus Vaccine administered using either a
neonatal or infant schedule in New Zealand infants. The RV3-BB human neonatal rotavirus vaccine aims to provide protection from
severe rotavirus disease from birth. A phase IIa safety and immunogenicity trial
was undertaken in Dunedin, New Zealand between January 2012 and April 2014.
Healthy, full-term (≥ 36 weeks gestation) babies, who were 0-5 d old were
randomly assigned (1:1:1) to receive 3 doses of oral RV3-BB vaccine with the
first dose given at 0-5 d after birth (neonatal schedule), or the first dose
given at about 8 weeks after birth (infant schedule), or to receive placebo
(placebo schedule). Vaccine take (serum immune response or stool shedding of
vaccine virus after any dose) was detected after 3 doses of RV3-BB vaccine in
>90% of participants when the first dose was administered in the neonatal and
infant schedules. The aim of the current study was to characterize RV3-BB
shedding and virus replication following administration of RV3-BB in a neonatal
and infant vaccination schedule. Shedding was defined as detection of rotavirus
by VP6 reverse transcription polymerase chain reaction (RT-PCR) in stool on days
3-7 after administration of RV3-BB. Shedding of rotavirus was highest following
vaccination at 8 weeks of age in both neonatal and infant schedules (19/30 and
17/27, respectively). Rotavirus was detected in stool on days 3-7, after at
least one dose of RV3-BB, in 70% (21/30) of neonate, 78% (21/27) of infant and
3% (1/32) placebo participants. In participants who shed RV3-BB, rotavirus was
detectable in stool on day 1 following RV3-BB administration and remained
positive until day 4-5 after administration. The distinct pattern of RV3-BB
stool viral load demonstrated using a NSP3 quantitative qRT-PCR in participants
who shed RV3-BB, suggests that detection of RV3-BB at day 3-7 was the result of
replication rather than passage through the gastrointestinal tract. Serum rotavirus IgA responses are an imperfect non-mechanistic correlate of
protection, and the lack of an accurate serological marker is a challenge to the
development of new rotavirus vaccines. Serological responses to rotavirus NSP2
occur following wild-type infection; however, it is unknown if serological
responses to NSP2 occur following administration of rotavirus vaccines. The
phase IIa immunogenicity trial of RV3-BB provided an opportunity to investigate
the serological responses to NSP2 following vaccination. Healthy, full-term
babies (n = 96) were previously recruited as part of a phase IIa safety and
immunogenicity trial in Dunedin, New Zealand between January 2012 and April
2014. Participants received three doses of oral RV3-BB vaccine with the first
dose given at 0-5 days after birth (neonatal schedule), or the first dose given
at about 8 weeks after birth (infant schedule), or to receive placebo (placebo
schedule). Serum IgA and IgG antibody responses to total RV3-BB and NSP2 protein
(RV3-BB) were assessed using ELISA. Despite significant serum IgA response
against total RV3-BB, we were unable to demonstrate a significant serological
response to NSP2 in participants receiving RV3-BB when compared to placebo.
Heterotypic antibodies against multiple NSP2 genotypes were detected following
RV3-BB vaccination. Our data demonstrates that while serological responses to
NSP2 were detectable in a subset of participants, it is a less useful marker
when compared to total rotavirus serum IgA response. |
Is dupilumab effective for treatment of asthma? | Yes, dupilumab is effective for treatment of asthma. It works by simultaneous targeting of both IL-4 and IL-13 by blocking IL-4 receptor α. | Simultaneously with the steady progress towards a better knowledge of the
pathobiology of asthma, the potential usefulness of anticytokine therapies is
emerging as one of the key concepts in the newly developing treatments of this
widespread airway disease. In particular, given the key role played by
interleukin (IL)-4 and IL-13 in the pathophysiology of the most typical aspects
of asthma, such as chronic airway inflammation, tissue remodeling, and bronchial
hyperresponsiveness, these pleiotropic cytokines are now considered as suitable
therapeutic targets. Among the recently developed antiasthma biologic drugs, the
monoclonal antibody dupilumab is very promising because of its ability to
inhibit the biological effects of both IL-4 and IL-13. Indeed, dupilumab
prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex. A
recent trial showed that in patients with difficult-to-control asthma, dupilumab
can markedly decrease asthma exacerbations and improve respiratory symptoms and
lung function; these effects were paralleled by significant reductions in
T-helper 2-associated inflammatory biomarkers. However, further larger and
longer trials are required to extend and validate these preliminary results, and
also to carefully study the safety and tolerability profile of dupilumab. INTRODUCTION: Current treatment options for moderate-to-severe atopic dermatitis
(AD) are limited and have potentially dangerous side effects. Dupilumab is a
novel monoclonal antibody that was recently studied in adult patients with
moderate-to-severe AD. Dupilumab inhibits interleukin-4 (IL-4) and
interleukin-13 (IL-13) signaling and was previously found to be effective in
asthma. Considering that both AD and asthma are Th2 cell-mediated inflammatory
processes, it is reasonable to suspect that dupilumab would be beneficial in
AD.`
AREAS COVERED: This article is a review of the one major clinical trial that
assessed the efficacy of dupilumab in patients with AD. Its goal is to provide a
comparison to the current modalities for the treatment of AD and expert insight
regarding future studies.
EXPERT OPINION: The results of this study are a significant therapeutic
advancement. Dupilumab was shown to provide a mean percent change in Eczema Area
and Severity Index score of -74% ± 3.6, in addition to, statistically and
clinically significant reductions the severity, symptomatology, and morbidity
associated with AD. However, the small sample size makes it difficult to assess
the magnitude of this effect. As a result, dupilumab will likely be reserved for
cases of severe AD unresponsive to traditional modalities. Asthma is a heterogeneous inflammatory disease. Most patients respond to current
standard of care, i.e., bronchodilators, inhaled glucocorticosteroids and other
anti-inflammatory drugs, but in some adequate asthma control cannot be achieved
with standard treatments. These difficult-to-treat patients would be the target
population for new biological therapies. At present, omalizumab is the only
biological agent approved for the treatment of early-onset, severe IgE-dependent
asthma. It is safe, effective, and well tolerated. Also, discovery of asthma
subtypes suggests new treatments. Half of patients with severe asthma have
T-helper type 2 (Th-2) inflammation and they are expected to benefit from
monoclonal antibody-based treatments. The efficacy of the investigational
monoclonal antibody mepolizumab which targets IL-5 has been well documented in
late onset non-atopic asthma with persistent eosinophilic airway inflammation.
Anti-IL-4 and IL-13 agents (dupilumab, lebrikizumab, and tralokinumab) which
block different Th-2 inflammatory pathways and agents targeting the Th-17
inflammatory pathway in severe refractory asthma are under development. In
clinical trials, these drugs reduce disease activity and improve lung function,
asthma symptoms, and quality of life. However, studies on larger groups of
patients are needed to confirm their safety and efficacy. Dupilumab (REGN668/SAR231893), produced by a collaboration between Regeneron and
Sanofi, is a monoclonal antibody currently in phase III for moderate-to-severe
asthma. Dupilumab is directed against the α-subunit of the interleukin (IL)-4
receptor and blocks the IL-4 and IL-13 signal transduction. Areas covered:
Pathophysiological role of IL-4 and IL-13 in asthma; mechanism of action of
dupilumab; pharmacology of IL-4 receptor; phase I and phase II studies with
dupilumab; regulatory affairs. Expert opinion: Patients with severe asthma who
are not sufficiently controlled with standard-of-care represent the target
asthma population for dupilumab. If confirmed, efficacy of dupilumab in both
eosinophilic and non-eosinophilic severe asthma phenotype might represent an
advantage over approved biologics for asthma, including omalizumab, mepolizumab,
and reslizumab. Head-to-head studies to compare dupilumab versus other biologics
with different mechanism of action are required. Pediatric studies with
dupilumab are currently lacking and should be undertaken to assess efficacy and
safety of this drug in children with severe asthma. The lack of preclinical data
and published results of the completed four phase I studies precludes a complete
assessment of the pharmacological profile of dupilumab. Dupilumab seems to be
generally well tolerated, but large studies are required to establish its
long-term safety and tolerability. BACKGROUND: Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody)
blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines
implicated in numerous allergic diseases ranging from asthma to atopic
dermatitis. Previous 16-week monotherapy studies showed that dupilumab
substantially improved signs and symptoms of moderate-to-severe atopic
dermatitis with acceptable safety, validating the crucial role of interleukin 4
and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the
long-term efficacy and safety of dupilumab with medium-potency topical
corticosteroids versus placebo with topical corticosteroids in adults with
moderate-to-severe atopic dermatitis.
METHODS: In this 1-year, randomised, double-blinded, placebo-controlled, phase 3
study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and
inadequate response to topical corticosteroids were enrolled at 161 hospitals,
clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and
North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab
300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a
central interactive voice/web response system, stratified by severity and global
region. All three groups were given concomitant topical corticosteroids with or
without topical calcineurin inhibitors where inadvisable for topical
corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted
on the basis of disease activity. Coprimary endpoints were patients (%)
achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher
improvement from baseline, and Eczema Area and Severity Index 75% improvement
from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses
included all randomised patients; week 52 efficacy included patients who
completed treatment by US regulatory submission cutoff. This study is registered
with ClinicalTrials.gov, NCT02260986.
FINDINGS: Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled:
319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to
dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical
corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52
efficacy. At week 16, more patients who received dupilumab plus topical
corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients]
who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who
received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who
received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204]
and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse
events were reported in 261 (83%) patients who received dupilumab qw plus
topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266
(84%) patients who received placebo, and serious adverse events in nine (3%),
four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced
laboratory abnormalities were noted. Injection-site reactions and conjunctivitis
were more common in patients treated with dupilumab plus topical
corticosteroids-treated patients than in patients treated with placebo plus
topical corticosteroids.
INTERPRETATION: Dupilumab added to standard topical corticosteroid treatment for
1 year improved atopic dermatitis signs and symptoms, with acceptable safety.
FUNDING: Sanofi and Regeneron Pharmaceuticals Inc. Asthma is an inflammatory disease which affects millions of people worldwide.
Therefore, it is necessary to search for new sources of therapies for the
treatment of these patients in order to improve their quality of life. From
content analysis of literature of new therapeutic targets, there are various
targets and drugs reported to be promising for the treatment of asthma.
Interleukins involved in inflammatory processes are often presented as candidate
targets for new drugs. The action of such therapeutics would not only affect
interleukins, but also their receptors. Small molecules (e.g. ligustrazine and
SP600125) and large molecule antibodies (e.g. lebrikizumab, benralizumab,
dupilumab) are being considered as novel agents for the pharmacotherapy of
asthma. Therefore, through this research, we can see advances in the search for
new targets and promising drugs to treat asthma. It is expected that these new
drug candidates will eventually be approved and marketed so that asthma patients
can use them to enhance their quality of life. Severe asthma constitutes illness in a relatively small proportion of all
patients with asthma, but it is a major public health problem - with
considerable effect on morbidity, mortality, as well as a high burden on health
care resources. Regardless of effective treatments being widely available and
the existence of treatment guidelines, a large population of severe asthma cases
remain uncontrolled. Achieving and maintaining asthma control in this group of
patients is, therefore, of utmost importance. The recognition of distinct
inflammatory phenotypes within this population has driven the development of
targeted biological therapies - particularly, selective targeted monoclonal
antibodies (mAbs). It is noteworthy that in approximately 50% of these patients,
there is strong evidence of the pathogenic role of T helper type-2 (Th2)
cytokines, such as interleukin (IL)-4 and IL-13, orchestrating the eosinophilic
and allergic inflammatory processes. Among the recently developed antiasthma
biologic drugs, the mAb dupilumab is very promising given its ability to inhibit
the biological effects of both IL-4 and IL-13. In this review, we focused on
IL-4 and IL-13, as these interleukins are considered to play a key role in the
pathophysiology of asthma, and on dupilumab, an anti-IL-4 receptor human mAb, as
a forthcoming treatment for uncontrolled severe asthma in the near future. Dupilumab is a fully human IgG4 monoclonal antibody directed against the α
subunit of the interleukin (IL)-4 receptor (IL-4Rα). Since the activation of
IL-4Rα is utilized by both IL-4 and IL-13 to mediate their pathophysiological
effects, dupilumab behaves as a dual antagonist of these two sister cytokines,
which blocks IL-4/IL-13-dependent signal transduction. Areas covered: Herein,
the authors review the cellular and molecular pathways activated by IL-4 and
IL-13, which are relevant to asthma pathobiology. They also review: the
mechanism of action of dupilumab, the phase I, II and III studies evaluating the
pharmacokinetics as well as the safety, tolerability and clinical efficacy of
dupilumab in asthma therapy. Expert opinion: Supported by a strategic mechanism
of action, as well as by convincing preliminary clinical results, dupilumab
currently appears to be a very promising biological drug for the treatment of
severe uncontrolled asthma. It also may have benefits to comorbidities of asthma
including atopic dermatitis, chronic sinusitis and nasal polyposis. PURPOSE OF REVIEW: Severe asthma is a heterogeneous disease that can be
classified into phenotypes and endotypes based upon clinical or biological
characteristics. Interleukin (IL)-4 and IL-13 play a key role in type 2 (T2)
asthma. This article reviews the signaling pathway of IL-4 and IL-13 and
highlights its targeted therapy in severe asthma.
RECENT FINDINGS: Several clinical trials of biologics targeting the IL-4/IL-13
pathway have recently been completed. In patients with severe, uncontrolled
asthma, targeting IL-13 alone with biologics including lebrikizumab and
tralokinumab has not shown consistent reduction in asthma exacerbations.
Simultaneous targeting of both IL-4 and IL-13 by blocking IL-4 receptor α using
dupilumab has yielded more consistent results in reducing asthma exacerbations
and improving lung function, especially in patients with increased blood
eosinophils. Other biomarkers of T2 inflammation such as exhaled nitric oxide
and serum periostin may also predict response to biologics targeting the
IL-4/IL-13 pathway.
SUMMARY: No biologic targeting the IL-4/IL-13 pathway is currently available for
treatment of asthma, but emerging data suggest that biologics targeting IL-4 and
IL-13 together may benefit patients with T2 high asthma. Additional data are
needed about long-term efficacy and safety prior to incorporating these drugs
into routine clinical practice. BACKGROUND: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal
antibody that blocks both interleukin-4 and interleukin-13 signaling. We
assessed its efficacy and safety in patients with uncontrolled asthma.
METHODS: We randomly assigned 1902 patients 12 years of age or older with
uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab
at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52
weeks. The primary end points were the annualized rate of severe asthma
exacerbations and the absolute change from baseline to week 12 in the forced
expiratory volume in 1 second (FEV1) before bronchodilator use in the overall
trial population. Secondary end points included the exacerbation rate and FEV1
in patients with a blood eosinophil count of 300 or more per cubic millimeter.
Asthma control and dupilumab safety were also assessed.
RESULTS: The annualized rate of severe asthma exacerbations was 0.46 (95%
confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of
dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to
a matched placebo, for a 47.7% lower rate with dupilumab than with placebo
(P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2
weeks. At week 12, the FEV1 had increased by 0.32 liters in patients assigned to
the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters;
P<0.001); similar results were seen with the higher dose. Among patients with a
blood eosinophil count of 300 or more per cubic millimeter, the annualized rate
of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those
receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those
receiving a matched placebo (65.8% lower rate with dupilumab than with placebo;
95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood
eosinophilia occurred after the start of the intervention in 52 patients (4.1%)
who received dupilumab as compared with 4 patients (0.6%) who received placebo.
CONCLUSIONS: In this trial, patients who received dupilumab had significantly
lower rates of severe asthma exacerbation than those who received placebo, as
well as better lung function and asthma control. Greater benefits were seen in
patients with higher baseline levels of eosinophils. Hypereosinophilia was
observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals;
LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .). BACKGROUND: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal
antibody that blocks both interleukin-4 and interleukin-13 signaling. Its
effectiveness in reducing oral glucocorticoid use in patients with severe asthma
while maintaining asthma control is unknown.
METHODS: We randomly assigned 210 patients with oral glucocorticoid-treated
asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2
weeks for 24 weeks. After a glucocorticoid dose-adjustment period before
randomization, glucocorticoid doses were adjusted in a downward trend from week
4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end
point was the percentage reduction in the glucocorticoid dose at week 24. Key
secondary end points were the proportion of patients at week 24 with a reduction
of at least 50% in the glucocorticoid dose and the proportion of patients with a
reduction to a glucocorticoid dose of less than 5 mg per day. Severe
exacerbation rates and the forced expiratory volume in 1 second (FEV1) before
bronchodilator use were also assessed.
RESULTS: The percentage change in the glucocorticoid dose was -70.1% in the
dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80%
versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33%
had a dose reduction to less than 5 mg per day, and 48% versus 25% completely
discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid
dose, in the overall population, dupilumab treatment resulted in a severe
exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower
than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95%
CI, 0.09 to 0.34) higher. Injection-site reactions were more common with
dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was
observed in more patients in the dupilumab group than in the placebo group (14%
vs. 1%).
CONCLUSIONS: In patients with glucocorticoid-dependent severe asthma, dupilumab
treatment reduced oral glucocorticoid use while decreasing the rate of severe
exacerbations and increasing the FEV1. Transient eosinophilia was observed in
approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron
Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214
.). Moderate and severe forms of allergic diseases such as atopic dermatitis and
asthma are a challenge for clinicians. In these conditions, which severely
affect the quality of life of the patient and frequently have associated
allergic comorbidities, the therapeutic options are often very limited.
Treatment with systemic corticosteroids and immunosuppressants has adverse
effects in the long term, and a significant proportion of patients remain
refractory to therapy. In this context, the emerging biological drugs constitute
a truly innovative therapeutic approach. A leading example is dupilumab, a
monoclonal antibody targeting the α chain of the interleukin (IL)-4 receptor.
Dupilumab inhibits the biological effects of the cytokines IL-4 and IL-13, which
are key drivers in the TH2 response. The efficacy and safety profile of
dupilumab in the treatment of allergic diseases has been tested for more than 10
years in a variety of large clinical trials in atopic dermatitis, asthma,
chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis. In
2017, the United States Food and Drug Administration and the European Medicines
Agency approved the use of dupilumab for the treatment of adult patients with
moderateto-severe atopic dermatitis whose disease is not adequately controlled
with prescribed topical treatment. The results of phase III clinical studies of
dupilumab in patients with persistent, uncontrolled asthma have been highly
promising. The safety and tolerability profile of dupilumab has proven to be
very favorable in long-term clinical trials. In this review, we focus on the
mechanism of action of dupilumab, its development, and its impact on daily
clinical practice in allergic diseases. BACKGROUND: Several new biologics have been studied in patients with
eosinophilic asthma with varying degrees of response on clinical outcomes. No
head-to-head trial has directly compared the efficacy of these drugs.
OBJECTIVE: To synthesize data on the relative efficacy of benralizumab,
dupilumab, lebrikizumab, mepolizumab, reslizumab, and tralokinumab using network
meta-analysis.
DATA SOURCES: We searched PubMed from inception to December 15th, 2017.
DATA EXTRACTION AND SYNTHESIS: We used the 'frequentist' methodology with random
effect models using primarily 'netmeta' function in R to generate network
meta-analysis results. Outcomes assessed included changes in forced expiratory
volume-in 1 s (FEV1), asthma control questionnaire (ACQ), and asthma quality of
life questionnaire (AQLQ). We also separately analyzed the annualized rate
ratios for asthma exacerbations for each drug and compared to placebo. For all
outcomes assessed, all drugs were superior to placebo except tralokinumab. In
terms of magnitude of effect, dupilumab, followed by reslizumab and benralizumab
showed the greatest increase in FEV1, 0.16L (95% CIs: 0.08-0.24), 0.13L
(0.10-0.17), and 0.12L (0.08-0.17), compared to placebo. While mepolizumab,
followed by dupliumab, benralizumab, and reslizumab showed reductions in ACQ
scores, in order of magnitude of effect, dupilumab, followed by mepolizumab,
benralizumab, and reslizumab showed the greatest increase in AQLQ scores. All
drugs decreased asthma exacerbations but the results were only significant for
reslizumab and dupilumab.
CONCLUSIONS: All drugs except for tralokinumab showed improvements in FEV1, ACQ,
and AQLQ. Only reslizumab and dupilumab were associated with statistically
significant reductions in asthma exacerbation rates. |
What is the role of the Mcm2-Ctf4-Polα axis? | The Mcm2-Ctf4-Polα axis facilitates parental histone H3-H4 transfer to lagging strands. | |
What is anophthalmia? | Microphthalmia, anophthalmia are the malformations of the eye, referring to a congenital absence, and a reduced size of the eyeball. | BACKGROUND: Developmental eye anomalies, which include anophthalmia (absent eye)
or microphthalmia (small eye) are an important cause of severe visual impairment
in infants and young children. Heterozygous mutations in SOX2, a SOX1B-HMG box
transcription factor, have been found in up to 10% of individuals with severe
microphthalmia or anophthalmia and such mutations could also be associated with
a range of non-ocular abnormalities.
METHODS: We performed mutation analysis on a new cohort of 120 patients with
congenital eye abnormalities, mainly anophthalmia, microphthalmia and coloboma.
Multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ
hybridisation (FISH) were used to detect whole gene deletion.
RESULTS: We identified four novel intragenic SOX2 mutations (one single base
deletion, one single base duplication and two point mutations generating
premature translational termination codons) and two further cases with the
previously reported c.70del20 mutation. Of 52 patients with severe
microphthalmia or anophthalmia analysed by MLPA, 5 were found to be deleted for
the whole SOX2 gene and 1 had a partial deletion. In two of these, FISH studies
identified sub-microscopic deletions involving a minimum of 328 Kb and 550 Kb.
The SOX2 phenotypes include a patient with anophthalmia, oesophageal
abnormalities and horseshoe kidney, and a patient with a retinal dystrophy
implicating SOX2 in retinal development.
CONCLUSION: Our results provide further evidence that SOX2 haploinsufficiency is
a common cause of severe developmental ocular malformations and that background
genetic variation determines the varying phenotypes. Given the high incidence of
whole gene deletion we recommend that all patients with severe microphthalmia or
anophthalmia, including unilateral cases be screened by MLPA and FISH for SOX2
deletions. Anophthalmia is a condition of the absence of an eye and the presence of a small
eye within the orbit. It is associated with many known syndromes. Clinical
findings, as well as imaging modalities and genetic analysis, are important in
making the diagnosis. Imaging modalities are crucial scanning methods.
Cryptophthalmos, cyclopia, synophthalmia and congenital cystic eye should be
considered in differential diagnoses. We report two clinical anophthalmic
siblings, emphasizing the importance of neuroradiological and orbital imaging
findings in distinguishing true congenital anophthalmia from clinical
anophthalmia. SOX2 anophthalmia syndrome is an uncommon autosomal domit syndrome caused by
mutations in the SOX2 gene and clinically characterized by severe eye
malformations (anophthalmia/microphthalmia) and extraocular anomalies mainly
involving brain, esophagus, and genitalia. In this work, a patient with the SOX2
anophthalmia syndrome and exhibiting a novel dental anomaly is described. SOX2
genotyping in this patient revealed an apparently de novo c.70del20 deletion, a
commonly reported SOX2 mutation. A review of the phenotypic variation observed
in patients carrying the recurrent SOX2 c.70del20 mutation is presented.
Although dental anomalies are uncommonly reported in the SOX2 anophthalmia
syndrome, we suggest that a dental examination should be performed in patients
with SOX2 mutations. Anophthalmia is a rare eye development anomaly resulting in absent ocular globes
or tissue in the orbit since birth. Here, we investigated a newborn with
bilateral anophthalmia in a Chinese family. Exome sequencing revealed that
compound heterozygous mutations c.287G > A (p.(Arg96His)) and c.709G > A
(p.(Gly237Arg)) of the ALDH1A3 gene were present in the affected newborn. Both
mutations were absent in all of the searched databases, including 10,000
in-house Chinese exome sequences, and these mutations were confirmed as having
been transmitted from the parents. Comparative amino acid sequence analysis
across distantly related species revealed that the residues at positions 96 and
234 were evolutionarily highly conserved. In silico analysis predicted these
changes to be damaging, and in vitro expression analysis revealed that the
mutated alleles were associated with decreased protein production and impaired
tetrameric protein formation. This study firstly reported that compound
heterozygous mutations of the ALDH1A3 gene can result in anophthalmia in humans,
thus highlighting those heterozygous mutations in ALDH1A3 should be considered
for molecular screening in anophthalmia, particularly in cases from families
without consanguineous relationships. |
What are the roles of LEM-3? | LEM-3 is a midbody-tethered DNA nuclease that resolves chromatin bridges during late mitosis. The conserved LEM-3/Ankle1 nuclease is involved in the combinatorial regulation of meiotic recombination repair and chromosome segregation in Caenorhabditis elegans. LEM-3 is able to process erroneous recombination intermediates that persist into the second meiotic division. | |
What is the contribution of ultraconserved elements in Australasian smurf-weevils? | Ultraconserved elements (UCEs) resolve the phylogeny of Australasian smurf-weevils. | Weevils (Curculionoidea) comprise one of the most diverse groups of organisms on
earth. There is hardly a vascular plant or plant part without its own species of
weevil feeding on it and weevil species diversity is greater than the number of
fishes, birds, reptiles, amphibians and mammals combined. Here, we employ
ultraconserved elements (UCEs) designed for beetles and a novel partitioning
strategy of loci to help resolve phylogenetic relationships within the radiation
of Australasian smurf-weevils (Eupholini). Despite being emblematic of the New
Guinea fauna, no previous phylogenetic studies have been conducted on the
Eupholini. In addition to a comprehensive collection of fresh specimens, we
supplement our taxon sampling with museum specimens, and this study is the first
target enrichment phylogenomic dataset incorporating beetle specimens from
museum collections. We use both concatenated and species tree analyses to
examine the relationships and taxonomy of this group. For species tree analyses
we present a novel partitioning strategy to better model the molecular
evolutionary process in UCEs. We found that the current taxonomy is problematic,
largely grouping species on the basis of similar color patterns. Finally, our
results show that most loci required multiple partitions for nucleotide rate
substitution, suggesting that single partitions may not be the optimal
partitioning strategy to accommodate rate heterogeneity for UCE loci. |
How does botulism toxin act on the muscle? | . The seven immunologically distinct serotypes of BoNTs (A-G), each produced by various strains of Clostridium botulinum, act on the neuromuscular junction by blocking the release of the neurotransmitter acetylcholine, thereby resulting in flaccid muscle paralysis. | The neurotoxins produced by Clostridium botulinum are the most potent acute
toxins known and are the causative agents of the neuroparalytic disease
botulism. The toxins act primarily at peripheral cholinergic synapses by
blocking the evoked release of the neurotransmitter acetylcholine. There are
seven distinct serotypes of toxin. All are polypeptides of Mr about 150 kDa that
have similar structure and pharmacological action. In their most active forms
the toxins exist as dichain molecules in which a heavy (H) chain is linked by
disulphide bonding to a light (L) chain. The H chain is believed to be
associated with the highly specific and avid binding of toxin to the motor nerve
end plates and also with the process of internalisation of the toxin. The toxic
activity appears to be associated with the L chain which blockades the
calcium-mediated release of acetylcholine, probably by interfering at the
molecular level with the mechanisms whereby neurotransmitter-containing vesicles
merge with the plasmalemma. The type A toxin is now used therapeutically to
treat a variety of conditions involving involuntary muscle spasm. The
therapeutic toxin is a neurotoxin-haemagglutinin complex isolated from cultures
of C. botulinum. A controlled manufacturing process has been developed for the
therapeutic toxin which is specially formulated to give a freeze-dried product
having good stability. Botulinum toxins, exotoxins of Clostridium botulinum, are the most toxic
naturally occurring substances known to man. For more than a century they are
known to be the cause of botulism, a nowadays rare intoxication with spoiled
food that leads to generalized flaccid weakness of striated muscle including
pharyngeal and respiratory musculature. The toxins act primarily at peripheral
cholinergic motor nerve endings by blocking the release of the neurotransmitter
acetylcholine. As a consequence, action potentials in the motor nerve can no
longer be transmitted to the muscle. This lack in transmission, clinically
appearing as weakness, may disable or actually critically endanger affected
patients. However, in certain neurological diseases characterized by an abnormal
increase in muscle tone or activity, for example dystonia or spasticity, a
reduction in signal transmission may actually be beneficial. Around 1980 local
injections of minute amounts (in the order of 0.5 ng) of Botulinum toxin type A
were first successfully used in a neurological disorder named blepharospasm
which is characterized by an involuntary squinting of the eyes. Since then
Botulinum toxin has developed rapidly from a frightful poison to a safe
therapeutic agent with a remarkable beneficial impact on the quality of life of
many thousands of patients worldwide. This review tries to outline in brief the
characteristics of Botulinum toxins, their mechanism of action and the various
indications for clinical use as a therapeutic agent. Infant botulism represents a distinct entity of botulism. Ingestion of the
ubiquitously present spores of Clostridium botulinum leads to germination of the
organism and neurotoxin production in the infant intestine. Symptoms typically
develop gradually in contrast to classical food botulism in which an acute onset
of symptoms shortly after the ingestion of preformed toxin in a food is
characteristic. Microbiologically, the diagnosis is established by
identification of Clostridium botulinum organism and toxin in stool specimen.
However, positive results in these tests provide only indirect evidence for the
clinical relevance of the neurotoxin since asymptomatic carriers have been
found. The toxin irreversibly blocks the release of acetylcholin from the
motoric end plate which results in muscle weakness and paralysis. Depending on
the amount of toxin produced, infant botulism exhibits a broad clinical spectrum
ranging from oligosymptomatic forms to a fulmit course with acute respiratory
failure within hours leading to sudden death. Unrecognized mild forms or
beginning muscle weakness can be a co-factor for other risk factors of sudden
infant death (SIDS). In studies analyzing infants who died from SIDS, botulism
bacteria or toxin were found in up to 20 % of cases. Infant botulism therefore
represents an important differential diagnosis of unexplained and inconclusive
muscular hypotonia in the first year of life. |
What is the most common pediatric glioma? | Pilocytic astrocytoma is the most common pediatric glioma. | Gliomas are the most common maligt primary brain tumors, of which
glioblastoma is the most maligt form (WHO grade IV), and notorious for
treatment resistance. Over the last decade mutations in epigenetic regulator
genes have been identified as key drivers of subtypes of gliomas with distinct
clinical features. Most characteristic are mutations in IDH1 or IDH2 in lower
grade gliomas, and histone 3 mutations in pediatric high grade gliomas that are
also associated with characteristic DNA methylation patterns. Furthermore, in
adult glioblastoma patients epigenetic silencing of the DNA repair gene MGMT by
promoter methylation is predictive for benefit from alkylating agent therapy.
These epigenetic alterations are used as biomarkers and play a central role for
classification of gliomas (WHO 2016) and treatment decisions. Here we review the
pivotal role of epigenetic alterations in the etiology and biology of gliomas.
We summarize the complex interactions between "driver" mutations, DNA
methylation, histone post-translational modifications, and overall chromatin
organization, and how they inform current efforts of testing epigenetic
compounds and combinations in preclinical and clinical studies. Gliomas are the most common type of brain cancer in the pediatric patients,
constituting about 50% of all childhood intracranial tumors. This is a highly
heterogeneous group, varying from the benign WHO histopathological grades I and
II to maligt WHO grades III and IV. The histology and location are
significant prognostic factors, which influence the decision for surgical
intervention, as well as the extent of possible tumor removal. In low-grade
gliomas, surgery remains the initial option and should be directed at gross
total resection in favorable locations, such as the cerebral hemispheres and the
cerebellum. Management of high-grade gliomas (HGG), which are less common in
children compared to adults, continue to pose a significant challenge. In
non-brainstem HGG, the goal is safe maximal tumor removal, while it generally
does not play any role in diffuse intrinsic pontine gliomas. Treatment must,
thus, be individualized in the majority of cases of HGG. Surgery for gliomas in
children continues to be aided by technological advancements facilitating tumor
resection and improving patient safety and outcomes. Gliomas are the most common primary central nervous system (CNS) neoplasms in
children and adolescents and are thought to arise from their glial progenitors
or stem cells. Although the exact cells of origin for most pediatric gliomas
remain to be identified, our current understanding is that specific cell
populations during CNS development are susceptible to particular oncogenic
events during certain time windows and thus give rise to pediatric gliomas with
distinct histological, molecular, and clinical features. These may be roughly
segregated into low-grade gliomas (WHO grades I or II; including most mixed
glial-neuronal tumors) and high-grade gliomas (WHO grades III or IV) according
to their clinical course when untreated, even though this is not yet entirely
clear for some of the recently emerging groups. The genetic and epigenetic
characterization of pediatric gliomas across ages and histologies has
facilitated the delineation of biologically relevant subgroups and have revealed
potentially targetable alterations in some of them. This review outlines
diagnostic features and molecular alterations in pediatric low- and high-grade
gliomas and how the latter might be exploited with future targeted therapeutic
strategies. Pilocytic astrocytoma (PA) is the most common glioma in pediatric patients and
occurs in different locations. Chromosomal alterations are mostly located at
chromosome 7q34 comprising the BRAF oncogene with consequent activation of the
mitogen-activated protein kinase pathway. Although genetic and epigenetic
alterations characterizing PA from different localizations have been reported,
the role of epigenetic alterations in PA development is still not clear. The aim
of this study was to investigate whether distinctive methylation patterns may
define biologically relevant groups of PAs. Integrated DNA methylation analysis
was performed on 20 PAs and 4 normal brain samples by Illumina Infinium
HumanMethylation27 BeadChips. We identified distinct methylation profiles
characterizing PAs from different locations (infratentorial vs supratentorial)
and tumors with onset before and after 3 years of age. These results suggest
that PA may be related to the specific brain site where the tumor arises from
region-specific cells of origin. We identified and validated in silico the
methylation alterations of some CpG islands. Furthermore, we evaluated the
expression levels of selected differentially methylated genes and identified two
biomarkers, one, IRX2, related to the tumor localization and the other, TOX2, as
tumoral biomarker. Pilocytic astrocytomas (PAs) are benign glial tumors and one of the most common
childhood posterior fossa tumors. Spontaneous intratumoral hemorrhage in PAs
occurs occasionally, in about 8-20% of cases. Cerebellar hemorrhages in
pediatric population are rare and mainly due to head injuries, rupture of
vascular malformations, infections, or hematological diseases. We have
investigated the still controversial and unclear pathophysiology underlying
intratumoral hemorrhage in PAs. Bleeding in low-grade tumors might be related to
structural abnormalities and specific angio-architecture of tumor vessels, such
as degenerative mural hyalinization, "glomeruloid" endothelial proliferation,
presence of encased micro-aneurysms, and glioma-induced neoangiogenesis. The
acute hemorrhagic presentation of cerebellar PA in childhood although extremely
uncommon is of critical clinical importance and necessitates promptly treatment.
We described a case of hemorrhagic cerebellar PA in a 9-year-old child and
reviewed the English-language literature that reported spontaneous hemorrhagic
histologically proven cerebellar PA in pediatric patients (0-18 years).
According to our analysis, the mortality was not related to symptom onset, tumor
location, hemorrhage distribution, presence of acute hydrocephalous, and timing
of surgery, while the GCS at hospital admission resulted to be the only
statistically significant prognostic factor affecting survival outcome. The
abrupt onset of signs and symptoms of acute hydrocephalous and consequent raised
intracranial pressure are life-threatening conditions, which need emergent
medical and neurosurgical treatments. At a later time, the identification of
posterior fossa hemorrhage etiology is crucial to select the appropriate
treatment and address the surgical strategy, optimizing the postoperative
results. |
What is the function of the protein encoded by the gene STING? | Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to cytosolic nucleic acid ligands. Recent evidence indicates involvement of the STING pathway in the induction of antitumor immune response. | Stimulator of interferon genes (STING) is an adaptor protein that plays an
important role in the activation of type I interferons in response to cytosolic
nucleic acid ligands. Recent evidence indicates involvement of the STING pathway
in the induction of antitumor immune response. Therefore, STING agonists are now
being extensively developed as a new class of cancer therapeutics. However,
little is known about the consequences of activated STING-mediated signaling in
cancer cells on the efficacy of the antitumor treatment. It has been shown that
activation of the STING-dependent pathway in cancer cells can result in tumor
infiltration with immune cells and modulation of the anticancer immune response.
Understanding the function of STING pathway in cancer cells might provide
important insights into the development of effective therapeutic strategies.
This review focuses on the role of STING pathway in cancer cells, the largely
unknown topic that has recently emerged to be important in the context of
STING-mediated antitumor responses. The production of cytokines in response to DNA-damage events may be an important
host defense response to help prevent the escape of pre-cancerous cells. The
innate immune pathways involved in these events are known to be regulated by
cellular molecules such as stimulator of interferon genes (STING), which
controls type I interferon and pro-inflammatory cytokine production in response
to the presence of microbial DNA or cytosolic DNA that has escaped from the
nucleus. STING signaling has been shown to be defective in a variety of cancers,
such as colon cancer and melanoma, actions that may enable damaged cells to
escape the immunosurveillance system. Here, we report through examination of
databases that STING signaling may be commonly suppressed in a greater variety
of tumors due to loss-of-function mutation or epigenetic silencing of the
STING/cGAS promoter regions. In comparison, RNA activated innate immune pathways
controlled by RIG-I/MDA5 were significantly less affected. Examination of
reported missense STING variants confirmed that many exhibited a
loss-of-function phenotype and could not activate cytokine production following
exposure to cytosolic DNA or DNA-damage events. Our data imply that the STING
signaling pathway may be recurrently suppressed by a number of mechanisms in a
considerable variety of maligt disease and be a requirement for cellular
transformation. |
List uniparental disomy (UPD) detection algorithms | UPDtool and AsCNAR are tools for detecting uniparental disomy (UPD). UPDtool is a computational tool for detection and classification of uniparental disomy (UPD) in trio SNP-microarray experiments. AsCNAR (allele-specific copy-number analysis using anonymous references) detects the copy-number neutral LOH, or uniparental disomy (UPD), in a large number of acute leukemia samples. | Loss of heterozygosity (LOH), either with or without accompanying copy-number
loss, is a cardinal feature of cancer genomes that is tightly linked to cancer
development. However, detection of LOH is frequently hampered by the presence of
normal cell components within tumor specimens and the limitation in availability
of constitutive DNA. Here, we describe a simple but highly sensitive method for
genomewide detection of allelic composition, based on the Affymetrix
single-nucleotide-polymorphism genotyping microarray platform, without
dependence on the availability of constitutive DNA. By sensing subtle
distortions in allele-specific signals caused by allelic imbalance with the use
of anonymous controls, sensitive detection of LOH is enabled with accurate
determination of allele-specific copy numbers, even in the presence of up to
70%-80% normal cell contamination. The performance of the new algorithm, called
"AsCNAR" (allele-specific copy-number analysis using anonymous references), was
demonstrated by detecting the copy-number neutral LOH, or uniparental disomy
(UPD), in a large number of acute leukemia samples. We next applied this
technique to detection of UPD involving the 9p arm in myeloproliferative
disorders (MPDs), which is tightly associated with a homozygous JAK2 mutation.
It revealed an unexpectedly high frequency of 9p UPD that otherwise would have
been undetected and also disclosed the existence of multiple subpopulations
having distinct 9p UPD within the same MPD specimen. In conclusion, AsCNAR
should substantially improve our ability to dissect the complexity of cancer
genomes and should contribute to our understanding of the genetic basis of human
cancers. |
Describe the mechanism of action of apalutamide. | Apalutamide is a second-generation antiandrogen that inhibits the binding of androgen to androgen receptor (AR), nuclear translocation of the androgen-AR complex, and binding of AR transcription complex to DNA-binding sites and transcription elements. It does not show antagonist-to-agonist switch like bicalutamide. It is emerging as additional new option to treat castration-resistant prostate cancer. | Conflict of interest statement: Ficial disclosures: Matthew R. Smith
certifies that all conflicts of interest, including specific ficial interests
and relationships and affiliations relevant to the subject matter or materials
discussed in the manuscript (eg, employment/affiliation, grants or funding,
consultancies, honoraria, stock ownership or options, expert testimony,
royalties, or patents filed, received, or pending), are the following: Matthew
R. Smith has served as a consultant to Janssen Research & Development. Emmanuel
S. Antonarakis has served as a consultant/adviser to Janssen Biotech, Astellas,
Medivation, ESSA, Sanofi, and Dendreon; he has received research funding from
Aragon Pharmaceuticals, Johnson & Johnson, Janssen Biotech, Astellas, Tokai,
Sanofi, Dendreon, Exelixis, Novartis, and Genentech. Charles J. Ryan has
received honoraria from Janssen Research & Development. William R. Berry has
received research grants from AHRQ. Neal D. Shore is a consultant/adviser to
Algeta, Amgen, Bayer, BNI, Dendreon, Ferring, Janssen, Millennium, and Sanofi.
Glenn Liu has nothing to report. Joshi J. Alumkal has received research funding
from Aragon Pharmaceuticals. Celestia S. Higano received consulting fees or
honoraria from AbbVie, Algeta, Astellas, Bayer, Dendreon, Genentech, Johnson &
Johnson, Medivation, Novartis, Pfizer, and Veridex; grants or research support
from Amgen, Aragon Pharmaceuticals, AstraZeneca, Bayer, Dendreon, Exelixis,
Genentech, Johnson & Johnson, Medivation, Millennium, Novartis, OncoGenex,
Sanofi-Aventis US, Taxynergy, and Teva; and other ficial benefits from Cell
Therapeutics. Edna Chow Maneval was an employee at Aragon Pharmaceuticals.
Rajesh Bandekar is an employee of Janssen Research & Development and holds stock
and stock options in Johnson & Johnson. Carla J. de Boer is an employee of
Janssen Biologics and holds stock and stock options in Johnson & Johnson.
Margaret K. Yu is an employee of Janssen Research & Development and holds stock
and stock options in Johnson & Johnson. Dana E. Rathkopf has served as a
consultant/adviser to and has received research funding from Janssen Research &
Development, AstraZeneca, Celgene, Ferring, Medivation, Millennium/ Takeda, and
Novartis. Prostate cancer is the most common cancer and one of the leading causes of
cancer deaths in men. One of the commonly used approaches to treat metastatic
prostate cancer was via first-generation nonsteroidal anti-androgens (NSAAs),
namely flutamide, nilutamide, bicalutamide and topilutamide. Most prostate
cancer patients who are initially responsive develop the most aggressive form of
disease called castration-resistant prostate cancer. Second-generation NSAA
receptor antagonists (enzalutamide, apalutamide and darolutamide) are emerging
as additional new options to treat castration-resistant prostate cancer. The
objective of this work was to review the literature on the bioanalytical methods
for the quantification of first- and second-generation NSAA inhibitors in
clinical (human plasma) and preclinical (mouse plasma, rat plasma, urine and
tissue homogenates etc.) studies along with relevant case studies for some
chosen drugs. Based on the review, it was concluded that the published
methodologies using either HPLC or LC-MS/MS are well suited for the
quantification of NSAA inhibitors in various biological fluids to delineate
pharmacokinetic data. Apalutamide (ARN-509) is an antiandrogen that binds selectively to androgen
receptors (AR) and does not show antagonist-to-agonist switch like bicalutamide.
We compared the activity of ARN versus bicalutamide on prostate cancer cell
lines. The 22Rv1, PC3, and DU145 cell lines were used to study the effect of ARN
and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7
variant, phosphorylated AR, as well as the levels of the AR downstream proteins
prostate-specific antigen and TMPRSS2, under exposure to testosterone and/or
hypoxia. The effects on autophagic flux (LC3A, p62, TFEB, LAMP2a, cathepsin D)
and cell metabolism-related enzymes (hypoxia-inducible factor 1α/2α, BNIP3,
carbonic anhydrase 9, LDHA, PDH, PDH-kinase) were also studied. The 22Rv1 cell
line responded to testosterone by increasing the nuclear entry of AR, AR-V7, and
phosphorylated AR and by increasing the levels of prostate-specific antigen and
TMPRSS2. This effect was strongly abrogated by ARN and to a clearly lower extent
by bicalutamide at 10 μmol/l, both in normoxia and in hypoxia. ARN had a
stronger antiproliferative effect than bicalutamide, which was prominent in the
22Rv1 hormone-responsive cell line, and completely repressed cell proliferation
at a concentration of 100 μmol/l. No effect of testosterone or of antiandrogens
on autophagy flux, hypoxia-related proteins, or metabolism enzyme levels was
noted. The PC3 and DU145 cell lines showed poor expression of the proteins and
were not responsive to testosterone. On the basis of in-vitro studies, evidence
has been reported that ARN is more potent than bicalutamide in blocking the AR
pathway in normoxia and in hypoxia. This reflects a more robust, dose-dependent,
repressive effect on cell proliferation. Collaborators: Horvath L, Nott L, Mathlum M, Coward J, Ng S, Epstein R, Tran B,
Guminski A, Bastick P, Pittman K, Tan H, Wei C, Kukard C, Nasser E, Parente P,
Marx G, Krainer M, Loidl W, Hutterer G, Tombal B, Sautois B, Werbrouck P,
Roumeguère T, Ameye F, Joniau S, Lumen N, Renaud P, North S, Chin J, Barkin J,
Carmel M, Casey R, Gleave M, Klotz L, Ouellette P Jr, Eiley D, Hamilton R,
Attwell A, Lacombe L, Wood L, Aaron L, Abdelsalam M, Canil C, Ellard S, Webster
T, Reiman A, Flax S, Vrabec G, Bladou F, Donnelly B, Giddens J, Leung W,
Shayegan B, Lukka H, Simard J, Zadra J, Archambault R, Melichar B, Stahalova V,
Stanek R, Matouskova M, Pavlik I, Sochor M, Jarolím L, Zachoval M, Klecka J,
Brasso K, Harving N, Holm-Nielsen A, Poulsen M, Taari K, Tammela T, Boström P,
Ronkainen H, Marttila T, Vincendeau S, Berdah JF, Villers A, Pfister C, Flechon
A, Mouillet G, Bompas E, Delva R, Joly F, Beuzeboc P, Eymard JC, Colombel M,
Ferrero JM, Gravis G, Krakowski I, Voog E, Barthelemy P, Robert G, Priou F,
Barry-Delongchamps N, Larré S, Theodore C, Azzouzi AR, Deville JL, Linassier C,
Mahammedi H, Houédé N, Artig X, Feyerabend S, Gleissner J, von Klot C,
Stöckle M, van Essen J, Ritter M, Stenzl A, Grimm MO, Suttmann H, Rodemer G,
Steuber T, Rudolph R, Tsaur I, Bögemann M, Klotz T, Thomas C, Reichle A, Huebner
A, Koenig F, Spiegelhalder P, Bismarck E, Hellmis E, Carl S, Strauss A, Berse M,
Kretz T, Zimmermann U, Hammerer P, Lehmann J, Geiges G, Machtens S, Katona F,
Szilágyi L, Kulcsár D, Lakatos Á, Géczi L, Berger R, Sella A, Nativ O, Frank S,
Rosenbaum E, Peer A, Keizman D, Stein A, Sarid D, Sternberg C, Bracarda S,
Paglino C, Gallucci M, Alabiso O, Bertolini A, Cianci C, Ciuffreda L, Rocco F,
De Giorgi U, Boccardo F, Cappuzzo F, Emarcora P, Battaglia M, Scagliotti G, Nolè
F, Cicalese V, Sakai H, Tsunemori H, Maruyama S, Suzuki H, Kawano Y, Heshine K,
Fukumori T, Mizokami A, Tamada S, Tsumura H, Tozawa K, Yamaguchi A, Arai G,
Tsuchiya T, Matsubara A, Matsubara N, Furukawa J, Azumi M, Uemura H, Kinoshita
H, Igawa T, Tanabe K, Kasahara T, Saito S, Sugimoto T, Iijima K, Matsumoto H,
Narita S, Hara I, Kobayashi H, Takahashi A, de Wildt M, Beeker A, Hamberg P,
Mulders P, Helgason H, Vergunst H, Roeleveld T, Beaven A, Gilling P, Buchan N,
Nixon T, Angelsen A, Heinrich D, Zurawski B, Milecki P, Walaszkowska-Czyz A,
Jassem J, Humanski P, Darewicz B, Pikiel J, Drewa T, Sosnowski M, Radziszewski
P, Slojewski M, Zdrojowy R, Ciurescu D, Jinga V, Toganel C, Udrea A, Herzal A,
Semenov A, Alekseev B, Ivanov S, Kopyltsov E, Kheyfets V, Varlamov S, Kovalenko
R, Cheporov S, Karyakin O, Izmailov A, Kulikov E, Khvorostenko D, Gorelov A,
Matveev V, Kopp M, Goncalves F, Sokol R, Kliment J, Knazik R, Brezovsky M, Chung
BH, Lee HM, Choi YD, Ha HK, Kwak C, Byun SS, Kim CS, Kim CI, Kang TW, Moon G,
Kwon TG, García-Donás J, Maroto JP, Arranz JA, Carles J, Castellano D, Perez
Gracia JL, Iborra I, Barretina Ginesta MP, Font A, Gallardo E, Gonzalez del Alba
A, Casinnello J, Rubio G, Gonzalez Larriba JL, Carballido J, Juarez A, Miñana B,
Ribal MJ, Ferrer C, Angulo J, Rios Gonzalez E, Medina R, Chantada V, Guttierez
JL, Sanchez E, Lara P, Llarena R, Gomez Veiga F, Damber JE, Häggman M, Widmark
A, Andren O, Kjellman A, Wu T, Chung HJ, Wu HC, Ou YC, Chiang PH, Pang ST, Huang
CY, Mills J, Jones R, McInerney P, Attard G, Malik Z, Pandha H, Mazhar D,
Bottomley D, Button M, Beesley S, Nabi G, Sayers I, Parikh O, Crabb S, Wagstaff
J, Falconer A, Aggarwal R, Shore N, Antonarakis ES, Liu G, Sieber P, Tutrone R
Jr, Belkoff L, Hainsworth J, Higano C, Twardowski P, Rathkopf D, Given R, Karlin
G, Lara P Jr, Nordquist L, Srinivas S, Dakhil S, Bracken RB, Westenfelder K,
Frankel J, Brand T, Drakaki A, Sonpavde G, Tejwani S, Cook D, Israel A, Dato P,
Perzin A, Williams T, Alter R, Gingrich J, Uchio E, Williams J, Zibelman M,
Prasad S, Karsh L, Patsias G, Savage S, Van Veldhuizen P, Miller L, Pieczonka C,
Kambhampati S, Deguenther M, Keller L III, Omarbasha B, Clark W, Bertram R,
Saslawsky M, Hauke R, Myrick S, Ghaddar H, Foreno L, Forero G, Doshi G, Fleming
M, Troner M, Shaffer D, Vogelzang N, Hirsch B, Schnadig I, Bailen J, Gittelman
M, Goldfischer E, Fisher H, Grable M, Corn P, Lim E, Cosgriff T, Chu F, Acs P,
Reeves J Jr, Stein M, Al-Janadi A, Siegel R, Patel K, Kella N, Willard TB,
Gatrell B, Schiffman Z, Bidair M, Ornstein D, Bylow K, Agrawal M, Suh R, Busby
JE, Bardot S, Taylor J, Wolk F, Courtney K, Vaishampayan U, Sharifi R, Hoimes C,
Harris R, Nickols N, Rosales J, Wrenn J, Goueli B, Dorff T, Yee D, David R,
Bianco F, Henry E, Jaslowski A, Mannuel H, Krejci K, Gervasi L, Clement J,
Bernstein G, Somer B, Lipsitz D, Heron S, Nemoy N, Rosenberg S, Miller A, Shetty
S, Weckstein D, Salazar M, Margolis E, Katz A, Renzuli J II, Tan W, Van Echo D,
Haluschak J, Showel J, Schmidt W Jr, Sharma S, Hancock M, Morris D, Tebyani N,
Armas A, Tarter T, Balaji KC, Franks M, Williams R, Snoy F, Pachynski R,
Ahaghotu C, Kemeny M. Apalutamide (ErleadaTM) is a next-generation oral androgen receptor (AR)
inhibitor that is being developed by Janssen for the treatment of prostate
cancer (PC). It binds directly to the ligand-binding domain of the AR and blocks
the effects of androgens. In February 2018, apalutamide received its first
global approval in the USA for the treatment of non-metastatic
castration-resistant PC (nmCRPC). Apalutamide is undergoing phase III
investigation in chemotherapy-naive patients with metastatic CRPC (in
combination with abiraterone acetate plus prednisone), patients with high-risk
localized or locally advanced PC receiving primary radiation therapy, and in
patients with metastatic hormone-sensitive PC and biochemically-relapsed PC.
This article summarizes the milestones in the development of apalutamide leading
to this first approval in nmCRPC. Advances in therapies have led to the approval of six therapeutic agents since
2004, each demonstrating overall survival benefit in randomized studies, and
these have significantly improved the outlook for men facing metastatic
castration-resistant prostate cancer (CRPC). More recently, efforts have been
directed at trying to effect change at earlier phases of the disease.
Apalutamide (ARN-509), a second-generation androgen receptor antagonist,
recently received approval in the nonmetastatic (M0) CRPC space. Similar to
enzalutamide, apalutamide inhibits the binding of androgen to androgen receptor
(AR), nuclear translocation of the androgen-AR complex, and binding of AR
transcription complex to DNA-binding sites and transcription elements. Phase I
and II trial experience demonstrates the safety and tolerability of apalutamide,
as well as its efficacy in effecting prostate-specific antigen response and
radiographic-free survival in CRPC. US Food and Drug Administration approval in
M0 CRPC was granted following positive results from the phase III SPARTAN study,
where apalutamide demonstrated significant improvements in metastasis-free
survival and time to symptomatic progression as compared to placebo. High-risk nonmetastatic castration-resistant prostate cancer is a lethal disease
that previously lacked clear treatment options. Progression to bone metastases
is associated with significant morbidity and high cost. Apalutamide, an androgen
receptor inhibitor, has substantial clinical response in nonmetastatic
castration-resistant prostate cancer. Apalutamide + androgen deprivation therapy
is well tolerated and improves metastasis-free survival, progression-free
survival and time to symptomatic progression, and is associated with a favorable
trend of improved overall survival. Future research is needed to elucidate
mechanisms of resistance to treatment with androgen signaling inhibitors. |
Which molecule is inhibited by larotrectinib? | Larotrectinib is oral, potent, and selective inhibitor of tropomyosin receptor kinases (TRK). It demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase (NTRK)-fusion proteins in adult and pediatric patients. | Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated
histology-agnostic efficacy in patients with TRK fusion-positive cancers.
Although responses to TRK inhibition can be dramatic and durable, duration of
response may eventually be limited by acquired resistance. LOXO-195 is a
selective TRK TKI designed to overcome acquired resistance mediated by recurrent
kinase domain (solvent front and xDFG) mutations identified in multiple patients
who have developed resistance to TRK TKIs. Activity against these acquired
mutations was confirmed in enzyme and cell-based assays and in vivo tumor
models. As clinical proof of concept, the first 2 patients with TRK
fusion-positive cancers who developed acquired resistance mutations on
larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing
rapid dose titration guided by pharmacokinetic assessments. This approach led to
rapid tumor responses and extended the overall duration of disease control
achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated
resistance in TRK fusion-positive cancers that acquired kinase domain mutations,
a shared liability with all existing TRK TKIs. This establishes a role for
sequential treatment by demonstrating continued TRK dependence and validates a
paradigm for the accelerated development of next-generation inhibitors against
validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related
commentary by Parikh and Corcoran, p. 934This article is highlighted in the In
This Issue feature, p. 920. Merestinib is an oral multi-kinase inhibitor targeting a limited number of
oncokinases including MET, AXL, RON and MKNK1/2. Here, we report that merestinib
inhibits neurotrophic receptor tyrosine kinases NTRK1/2/3 which are oncogenic
drivers in tumors bearing NTRK fusion resulting from chromosomal rearrangements.
Merestinib is shown to be a type II NTRK1 kinase inhibitor as determined by
x-ray crystallography. In KM-12 cells harboring TPM3-NTRK1 fusion, merestinib
exhibits potent p-NTRK1 inhibition in vitro by western blot and elicits an
anti-proliferative response in two- and three-dimensional growth. Merestinib
treatment demonstrated profound tumor growth inhibition in in vivo cancer models
harboring either a TPM3-NTRK1 or an ETV6-NTRK3 gene fusion. To recapitulate
resistance observed from type I NTRK kinase inhibitors entrectinib and
larotrectinib, we generated NIH-3T3 cells exogenously expressing TPM3-NTRK1
wild-type, or acquired mutations G595R and G667C in vitro and in vivo.
Merestinib blocks tumor growth of both wild-type and mutant G667C TPM3-NTRK1
expressing NIH-3T3 cell-derived tumors. These preclinical data support the
clinical evaluation of merestinib, a type II NTRK kinase inhibitor
(NCT02920996), both in treatment naïve patients and in patients progressed on
type I NTRK kinase inhibitors with acquired secondary G667C mutation in NTRK
fusion bearing tumors. 1. Precision medicine just witnessed two breakthroughs in oncology in 2017.
Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal
antibody (mAb), received accelerated approval in May 2017 by the US Food and
Drug Administration for the treatment of adult and pediatric patients with
unresectable or metastatic solid tumors that have been identified as having
microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR).
Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained
an accelerated approval in August 2017 for adult and pediatric patients with
MSI-H or dMMR metastatic colorectal cancer that has progressed after standard
chemotherapy. These regulatory approvals marked an important milestone that a
cancer treatment may be approved based on a common biomarker rather than the
anatomic location in the body where the tumor originated, and therefore
established a precedent for tumor type-agnostic therapy. In the 2017 American
Society for Clinical Oncology annual meeting, larotrectinib (LOXO-101),
Loxooncology's oral, potent, and selective inhibitor of tropomyosin receptor
kinases (TRK), demonstrated unprecedented efficacy on unresectable or metastatic
solid tumors with neurotrophic tropomyosin receptor kinase (NTRK)-fusion
proteins in adult and pediatric patients. Both the anti-PD-1 mAbs and the
TRK-targeting therapies share some basic features: (a) biomarker-based,
well-defined rare patient population; (b) exceptionally high clinical efficacy,
e.g., near 40% overall response rate (ORR) for pembrolizumab across 15 tumor
types with MSI-H/dMMR and 75% ORR for larotrectinib across more than 12 tumor
types with NTRK-fusion proteins; (c) durable responses lasting at least 6 months
with complete responses observed; and (d) parallel development in adult and
pediatric populations. With increasing accessibility to genetic analysis tools
such as next-generation sequencing, tumor type-agnostic therapy has become a
reality, both during clinical development and in clinical practice. Adjustments
in our approaches to developing new anti-cancer drugs and to adopting these new
cancer treatments in clinical practice need to occur in order to prepare
ourselves for the new era of precision medicine. One of the most challenging issues in oncology research and treatment is
identifying oncogenic drivers within an individual patient's tumor which can be
directly targeted by a clinically available therapeutic drug. In this context,
gene fusions as one important example of genetic aberrations leading to
carcinogenesis follow the widely accepted concept that cell growth and
proliferation are driven by the accomplished fusion (usually involving former
proto-oncogenes) and may therefore be successfully inhibited by substances
directed against the fusion. This concept has already been established with
oncogenic gene fusions like BCR-ABL in chronic myelogenous leukemia (CML) or
anaplastic lymphoma kinase (ALK) in lung cancer, including special tyrosine
kinase inhibitors (TKIs) which are able to block the activation of the depending
downstream proliferation pathways and, consequently, tumor growth. During the
last decade, the NTRK1, 2, and 3 genes, encoding the TRKA, B, and C proteins,
have attracted increasing attention as another significant and targetable gene
fusion in a variety of cancers. Several TRK inhibitors have been developed, and
one of them, Larotrectinib (formerly known as LOXO-101), represents an orally
available, selective inhibitor of the TRK receptor family that has already shown
substantial clinical benefit in both pediatric and adult patients harboring an
NTRK gene fusion over the last few years. BACKGROUND: The highly selective oral tropomyosin receptor kinase (TRK)
inhibitor larotrectinib has demonstrated significant activity in adult and
pediatric TRK fusion cancers. In the current study, the authors describe the
clinical course of children with locally advanced TRK fusion sarcoma who were
treated preoperatively with larotrectinib and underwent subsequent surgical
resection.
METHODS: A total of 24 children were treated on a pediatric phase 1 trial of
larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had
a documented TRK fusion sarcoma and underwent surgical resection were included
in the current analysis. Tumor response (Response Evaluation Criteria In Solid
Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively.
RESULTS: A total of 5 patients (median age, 2 years; range, 0.4-12 years) had
locally advanced infantile fibrosarcoma (3 patients) or soft-tissue sarcoma (2
patients). Four patients had disease that was refractory to standard therapy.
All 5 patients achieved a partial response to larotrectinib by version 1.1 of
RECIST and underwent surgical resection after a median of 6 cycles (range, 4-9
cycles) of treatment. Surgical resections were R0 (negative resection margins
with no tumor at the inked resection margin) in 3 patients, R1 (microscopic
residual tumor at the resection margin) in 1 patient, and R2 (macroscopic
residual tumor at the resection margin) in 1 patient. Three patients achieved
complete (2 patients) or near-complete (>98% treatment effect; 1 patient)
pathologic responses. These patients remained in follow-up and were no longer
receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two
patients had viable tumor at the time of surgical resection and positive
resection margins and continued to receive adjuvant larotrectinib. No patients
experienced postoperative complications or wound healing issues.
CONCLUSIONS: Children with locally advanced TRK fusion sarcomas may proceed to
surgical resection after treatment with the selective TRK inhibitor
larotrectinib, thereby sparing them the potentially significant morbidity noted
with current approaches. These results support the evaluation of larotrectinib
as presurgical therapy in children with newly diagnosed TRK fusion sarcomas. Introduction: TRK fusions occur across a wide range of cancers in children and
adults. These fusions drive constitutive expression and ligand-independent
activation of the TRK kinase and are oncogenic. Larotrectinib is the first
highly potent and selective small molecule ATP competitive inhibitor of all
three TRK kinases to enter clinical development. Areas covered: This review
covers the current preclinical and clinical evidence for TRK inhibitors for TRK
fusion cancers, focusing on larotrectinib. Expert commentary: Larotrectinib has
demonstrated a remarkable 75% centrally confirmed objective response rate in
patients with TRK fusion cancers in phase 1 and phase 2 clinical trials with
generally mild side effects. Responses appear independent of the patient's age,
underlying histology, and specific fusion partner and are durable in many
patients. Larotrectinib is likely to be the first FDA-approved
histology-agnostic molecularly targeted therapy. The evolving role of molecular
profiling of advanced cancers is discussed. |
What is Bayesian haplotyping used for? | Bayesian haplotype inference is used for phylogenetic analysis, specifcially multiple linked single-nucleotide polymorphisms and analysis of chromosome copy number and deletions. | BACKGROUND: Australian scorpions have received far less attention from
researchers than their overseas counterparts. Here we provide the first insight
into the molecular variation and evolutionary history of the endemic Australian
scorpion Urodacus yaschenkoi. Also known as the inland robust scorpion, it is
widely distributed throughout arid zones of the continent and is emerging as a
model organism in biomedical research due to the chemical nature of its venom.
METHODS: We employed Bayesian Inference (BI) methods for the phylogenetic
reconstructions and divergence dating among lineages, using unique haplotype
sequences from two mitochondrial loci (COXI, 16S) and one nuclear locus (28S).
We also implemented two DNA taxonomy approaches (GMYC and PTP/dPTP) to evaluate
the presence of cryptic species. Linear Discrimit Analysis was used to test
whether the linear combination of 21 variables (ratios of morphological
measurements) can predict individual's membership to a putative species.
RESULTS: Genetic and morphological data suggest that U. yaschenkoi is a species
complex. High statistical support for the monophyly of several divergent
lineages was found both at the mitochondrial loci and at a nuclear locus. The
extent of mitochondrial divergence between these lineages exceeds estimates of
interspecific divergence reported for other scorpion groups. The GMYC model and
the PTP/bPTP approach identified major lineages and several sub-lineages as
putative species. Ratios of several traits that approximate body shape had a
strong predictive power (83-100%) in discriminating two major molecular
lineages. A time-calibrated phylogeny dates the early divergence at the onset of
continental-wide aridification in late Miocene and Pliocene, with finer-scale
phylogeographic patterns emerging during the Pleistocene. This structuring
dynamics is congruent with the diversification history of other fauna of the
Australian arid zones.
DISCUSSION: Our results indicate that the taxonomic status of U. yaschenkoi
requires revision, and we provide recommendations for such future efforts. A
complex evolutionary history and extensive diversity highlights the importance
of conserving U. yaschenkoi populations from different Australian arid zones in
order to preserve patterns of endemism and evolutionary potential. |
List major features of TEMPI Syndrome. | TEMPI syndrome includes telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal gammopathy, perinephric fluid collections, intrapulmonary shunting. It is a newly described clinical entity that is generally considered a plasma cell dyscrasia with multiple system involvement. | TEMPI syndrome (telangiectasias, elevated erythropoietin level and
erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and
intrapulmonary shunting) is a recently described syndrome that, owing to
erythrocytosis, may be confused with polycythemia vera. It is best classified as
a type of plasma cell dyscrasia with paraneoplastic manifestations, similar to
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and
skin abnormalities). To date, 11 patients have been identified. This is the
first morphologic review of TEMPI syndrome bone marrow samples, in order to
define pathologic features that may aid in the recognition of the syndrome and
to identify post-therapy changes. Seven bone marrow aspirates and biopsies from
three patients, including two post-treatment marrows, were examined. Patients
were 36, 49, and 49 years old at time of diagnosis. In all cases, erythropoietin
levels were extremely elevated at >5000 IU/l, the paraprotein was IgG kappa,
JAK2 V617F was negative and vascular endothelial growth factor levels were
normal. In one case, the increase in clonal plasma cells reached levels of
smoldering myeloma (18%), but remaining marrows showed few monoclonal plasma
cells (<5%). All pre-treatment biopsies showed erythroid hyperplasia, with mild
nonspecific megakaryocytic, and erythroid cytologic atypia in one marrow.
Prominent plasma cell vacuolization and reactive-appearing lymphoid aggregates
were noted in one case. Findings of myeloproliferative neoplasms, including
megakaryocyte clusters and fibrosis, were not identified. In conclusion, TEMPI
syndrome should be considered when erythrocytosis and plasma cell dyscrasia
coexist. The bone marrow findings, although nonspecific, differ significantly
from polycythemia vera. Peculiar clinical and laboratorial findings of TEMPI,
including elevated erythropoietin and normal vascular endothelial growth factor
level, allow the diagnosis and distinction from POEMS syndrome. Significant
decrease in erythropoietin level following treatment suggests a role of
erythropoietin in monitoring therapeutic response. BACKGROUND: Collection of hematopoietic progenitor cells by apheresis (HPC-A)
requires separation of cells by density. Previous studies highlighted the
challenges of HPC-A collection from patients with abnormal red blood cells
(RBCs). TEMPI syndrome is a recently described condition defined by
teleangiectasias, elevated erythropoietin and erythrocytosis, monoclonal
gammopathy, perinephric fluid collections, and intrapulmonary shunting. Patients
with TEMPI syndrome have responded to therapies used to treat plasma cell
dyscrasias and may benefit from autologous HPC transplantation. We report HPC-A
collection from a patient with TEMPI syndrome that was complicated by severe
iron deficiency.
STUDY DESIGN AND METHODS: The patient received granulocyte-colony-stimulating
factor (G-CSF) and plerixafor for HPC mobilization and underwent 3 days of HPC-A
collection.
RESULTS: The patient presented for collection with a microcytic erythrocytosis.
Over 3 days, approximately 50 L of whole blood was processed, and 2 × 10(8)
CD34+ cells were collected (2.8 × 10(6) CD34+ cells/kg). The mean collection
efficiency (CE), percentage of mononuclear cells, hematocrit (Hct), and RBC
count were 18%, 90%, 14%, and 9 × 10(11) , respectively. Altering collection
variables to avoid RBC contamination reduced CE. Ficoll preparations of the
products after freeze-thaw showed RBC contamination and hemolysis. Postthaw
viability exceeded 95%. The products were not RBC reduced or washed. There were
no adverse reactions during or after infusion.
CONCLUSIONS: HPC-A collection from a patient with TEMPI syndrome was complicated
by microcytic erythrocytosis, leading to RBC contamination and hemolysis in the
product. Adequate HPCs were collected and the patient tolerated infusion without
RBC depletion or washing. Our report highlights difficulties of HPC-A collection
from iron-deficient patients. TEMPI (telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal
gammopathy, perinephric fluid collections, intrapulmonary shunting) syndrome is
a newly described clinical entity that is generally considered a plasma cell
dyscrasia with multiple system involvement. The etiology and pathophysiology of
this condition remains elusive. Nevertheless, clonal plasma cells and monoclonal
protein appear to be major contributors. The early diagnosis of TEMPI syndrome
is essential because therapies targeting the underlying plasma cells can lead to
a dramatic response. Bortezomib-based chemotherapy, daratumumab monotherapy, and
autologous hematopoietic stem cell transplantation can result in reversal of
most manifestations. Nevertheless, the diagnosis of TEMPI syndrome remains a
substantial challenge owing to its rarity and the complexity of clinical
presentations. TEMPI syndrome is often misdiagnosed as other causes of
erythrocytosis, resulting in a delayed diagnosis and further clinical
deterioration. The aim of the present review was to present the clinical and
biologic features of TEMPI syndrome, highlighting the differential diagnosis and
outlining the present understanding of its pathophysiology and treatment. |
Describe Herpetic Whitlow. | Herpetic whitlow is an acute viral infection of the hand caused by either herpes simplex virus (HSV) 1 or 2. Its characteristic findings are significant pain and erythema with overlying nonpurulent vesicles. It can be confirmed by polymerase chain reaction testing. | Herpetic whitlow is a herpes simplex virus infection of the finger. It may be
caused by either herpes simplex type 1 or 2. It is characterized by pain,
erythema, and nonpurulent vesicle or bullae formation. It may be due to a
primary or recurrent infection. It is a common infection in health care
professionals who have frequent contact with the secretions of patients' mouths
and respiratory tracts. The diagnosis of herpetic whitlow may be confirmed by
Tzanck test, acute and convalescent herpes simplex antibody titers, viral
culture, and fluorescent antibody tests. The infection is self-limited, and
surgical intervention generally should be avoided. Techniques for prevention and
control of the infection include appropriate isolation of patients with herpes
infections, avoidance of patient care by health care personnel with active
infections, and the use of gloves when handling secretions. Herpetic whitlow is a herpes simplex virus type 1 or 2 infection of the fingers
characterised by erythema and painful, non-purulent vesicles. In children it
typically occurs after auto-inoculation from herpes stomatitis, herpes labialis
or genitalis. Occasionally, person-to-person transmission occurs from family
members with herpes labialis. We report a 4-year-old girl with multiple herpetic
whitlows secondary to herpetic stomatitis and present a review of the medical
literature based on a systematic MEDLINE search of published paediatric patients
(English, French and German language). Of 42 identified patients, 72% were
younger than 2 years, most had endogenous or exogenous inoculation of herpes
simplex virus type 1 and 65% were initially misdiagnosed as having "bacterial
felon". Recurrences were reported in 23%.
CONCLUSION: herpetic whitlow should be suspected based on clinical signs.
Specific diagnosis can be made by polymerase chain reaction or culture. The high
rate of misdiagnosed cases indicates that this entity is not sufficiently known.
Lesions are self-limited; surgical interventions can be harmful and should be
avoided. Recurrences occur as frequently as in adults. Herpetic whitlow is an acute viral infection of the hand caused by either herpes
simplex virus (HSV) 1 or 2. Its characteristic findings are significant pain and
erythema with overlying nonpurulent vesicles. The differential diagnosis
includes flexor tenosynovitis. We present a case of recurrent infection of the
middle finger in an immunocompetent 19-year-old girl. Multiple painful pustules
with tracking cellulitis were partially treated by oral antibiotics. A
recurrence with positive Kanavel's signs suggested flexor tenosynovitis at seven
months. Her symptoms improved transiently following emergent surgical open
flexor sheath exploration and washout however, she required two further
washouts; at eleven and thirteen months to improve symptoms. Viral cultures were
obtained from the third washout as HSV infection was disclosed from further
history taking. These were positive for HSV2. Treatment with acyclovir at
thirteen months after presentation led to a complete resolution of her symptoms
with no further recurrences to date. This rare case highlights the similarity in
presentation between flexor sheath infection and herpetic whitlow which can lead
to diagnostic confusion and mismanagement. We emphasise the importance of
careful past medical history taking as well as considering herpetic whitlow as a
differential diagnosis despite the presence of strongly positive Kanavel's
signs. INTRODUCTION: Whitlow is an infection of a finger or around the fingernails,
generally caused by bacterium. However, in rare cases, it may also be caused by
the herpes simplex virus. As herpetic whitlow is not seen often, it may go
under-recognised or be mistaken for a different kind of infection of the finger.
Delayed recognition and/or treatment puts patients at risk of complications
ranging from superinfection to herpetic encephalitis.
CASE PRESENTATION: A 23-year-old Caucasian man with no medical history was
referred by his primary care physician because of erythema and swelling of the
little finger of his left hand. The primary care physician had already treated
him with the oral antibiotic Augmentin® (amoxicillin-clavulanic acid) and
incision of the finger, but this had not resolved his complaints. He had
multiple vesicles on the finger, which led to the diagnosis of herpetic whitlow,
which we confirmed by polymerase chain reaction testing. All cutaneous
abnormalities disappeared after treatment.
CONCLUSIONS: Whitlow is rarely caused by the herpes simplex virus, but this
disease requires a swift recognition and treatment to prevent complications.
This case serves to emphasise that not all whitlow is caused by a bacterial
infection, and that it is important to differentiate between herpetic and
bacterial whitlow, as these diseases require a different treatment. Hand and wrist infections can present with a spectrum of manifestations ranging
from cellulitis to deep-space collections. The various infectious processes can
be categorised as superficial or deep infections based on their respective
locations relative to the tendons. Superficial hand infections are located
superficial to the tendons and are comprised of cellulitis, lymphangitis,
paronychia, pulp-space infections, herpetic whitlow, and include volar as well
as dorsal subcutaneous abscesses. Deep hand infections are located deep to the
tendon sheaths and include synovial space infections, such as infectious
tenosynovitis, deep fascial space infections, septic arthritis, necrotising
fasciitis, and osteomyelitis. Knowledge of hand and wrist compartmental anatomy
is essential for the accurate diagnosis and management of hand infections.
Although early and superficial infections of the hand may respond to
non-surgical management, most hand infections are surgical emergencies.
Multidetector computed tomography (MDCT), with its muliplanar reformation (MPR)
and three-dimensional (3D) capabilities, is a powerful tool in the emergency
setting for the evaluation of acute hand and wrist pathology. The clinical and
imaging features of hand and wrist infections as evident on MDCT will be
reviewed with emphasis on contiguous and closed synovial and deep fascial
spaces. Knowledge of hand compartmental anatomy enables accurate
characterisation of the infectious process and localise the extent of disease in
the acute setting. CONTEXT: Herpetic whitlow is caused by herpes virus (type1 or 2) during primary
infection or as result of autoinoculation. Commonly, it is caused by HSV-2 in
adults with positive history for genital infection.
CASE DESCRIPTION: We report the case of a 44-year-old woman that came to our
attention with a 3- year history of recurrent cutaneous eruption on the ring
finger of her left hand associated to lymphangitis of the homolateral arm.
Laboratory exams including PCR on blood and cutaneous swab allowed to diagnosis
it as a rare case of herpetic whitlow.
CONCLUSION: The case here reported demonstrates that herpetic whitlow should be
kept in mind by physicians in recurrent cases of fingers infection. Advanced
diagnostic techniques as PCR are required to help clinicians to achieve a
definite diagnosis and to choose the right treatment. |
Sweat Chloride Testing is used for which disease? | Sweat Chloride Testing is used to diagnose cystic fibrosis. CFTR dysfunction can be demonstrated using sweat chloride testing. | In cystic fibrosis (CF), sweat chloride concentration has been proposed as an
index of CFTR function for testing systemic drugs designed to activate mutant
CFTR. This suggestion arises from the assumption that greater residual CFTR
function should lead to a lower sweat chloride concentration, as well as
protection against severe lung disease. This logic gives rise to the hypothesis
that the lower the sweat chloride concentration, the less severe the lung
disease. In order to test this hypothesis, we studied 230 patients homozygous
for the DeltaF508 allele, and 34 patients with at least one allele associated
with pancreatic sufficiency, born since January 1, 1955, who have pulmonary
function data and sweat chloride concentrations recorded in our CF center
database, and no culture positive for B. cepacia. We calculated a severity index
for pulmonary disease, using an approach which takes into account all available
pulmonary function data as well as the patient's current age and survival
status. Patients with alleles associated with pancreatic sufficiency had
significantly better survival (P = 0.0083), lower sweat chloride concentration
(81.4 +/- 23.8 vs. 103.2 +/- 14.2 mEq/l, P < 0.0001), slower rate of decline of
FEV(1) % predicted (-0.75 +/- 0.34 vs. -2.34 +/- 0.17% predicted per year), and
a better severity index than patients homozygous for the DeltaF508 allele
(median 73rd percentile vs. median 55th percentile, P = 0.0004). However, the
sweat chloride concentration did not correlate with the severity index, either
in the population as a whole, or in the population of patients with alleles
associated with pancreatic sufficiency, who are thought to have some residual
CFTR function. These data suggest that, by itself, sweat chloride concentration
does not necessarily predict a milder pulmonary course in patients with cystic
fibrosis. BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive condition that has an
incidence of 1:2500 live births in Northern Europe. Due to the large number of
mutations that can result in classical or atypical CF phenotype, the sweat test,
which quantifies the amount of chloride and sodium in sweat, is vital in
supporting the diagnosis of CF. Patients with CF have raised concentrations of
chloride and sodium in their sweat; however, it is the concentration of chloride
in sweat which provides the greatest diagnostic sensitivity for CF.
METHOD: An inductively coupled plasma mass spectrometry (ICP-MS) method for the
analysis of sweat chloride and sodium was evaluated for the routine measurement
of sweat collected using the Wescor Macroduct(®) Sweat Collection System. The
precision, linearity and agreement with the all laboratories trimmed means
(ALTMs) and 'weighed-in' concentrations of sodium and chloride in samples
supplied by the UK NEQAS external quality assessment (EQA) Sweat Testing Scheme
were assessed.
RESULTS: This ICP-MS method for the quantification of chloride and sodium in
sweat samples was shown to be accurate, precise and suitable for the routine
analysis of sweat chloride and sodium.
CONCLUSION: The method performs well and is now used in the routine analysis of
sweat in this laboratory. OBJECTIVE: Although the majority of cases of cystic fibrosis (CF) are now
diagnosed through newborn screening, there is still a need to standardize the
diagnostic criteria for those diagnosed outside of the neonatal period. This is
because newborn screening started relatively recently, it is not performed
everywhere, and even for individuals who were screened, there is the possibility
of a false negative. To limit irreversible organ pathology, a timely diagnosis
of CF and institution of CF therapies can greatly benefit these patients.
STUDY DESIGN: Experts on CF diagnosis were convened at the 2015 CF Foundation
Diagnosis Consensus Conference. The participants reviewed and discussed
published works and instructive cases of CF diagnosis in individuals presenting
with signs, symptoms, or a family history of CF. Through a modified Delphi
methodology, several consensus statements were agreed upon. These consensus
statements were updates of prior CF diagnosis conferences and recommendations.
RESULTS: CF diagnosis in individuals outside of newborn screening relies on the
clinical evidence and on evidence of CF transmembrane conductance regulator
(CFTR) dysfunction. Clinical evidence can include typical organ pathologies seen
in CF such as bronchiectasis or pancreatic insufficiency but often represent a
broad range of severity including mild cases. CFTR dysfunction can be
demonstrated using sweat chloride testing, CFTR molecular genetic analysis, or
CFTR physiologic tests. On the basis of the large number of patients with bona
fide CF currently followed in registries with sweat chloride levels between 30
and 40 mmol/L, the threshold considered "intermediate" was lowered from
40 mmol/L in the prior diagnostic guidelines to 30 mmol/L. The CF diagnosis was
also discussed in the context of CFTR-related disorders in which CFTR
dysfunction may be present, but the individual does not meet criteria for CF.
CONCLUSIONS: CF diagnosis remains a rare but important condition that can be
diagnosed when characteristic clinical features are seen in an individual with
demonstrated CFTR dysfunction. The components of sweat provide an array of potential biomarkers for health and
disease. Sweat chloride is of interest as a biomarker for cystic fibrosis,
electrolyte metabolism disorders, electrolyte balance, and electrolyte loss
during exercise. Developing wearable sensors for biomarkers in sweat is a major
technological challenge. Potentiometric sensors provide a relatively simple
technology for on-body sweat chloride measurement, however, equilibration
between reference and test solutions has limited the time over which accurate
measurements can be made. Here, we report on a wearable potentiometric chloride
sweat sensor. We performed parametric studies to show how the salt bridge
geometry determines equilibration between the reference and test solutions. From
these results, we show a sweat chloride sensor can be designed to provide
accurate measurements over extended times. We then performed on-body tests on
healthy subjects while exercising to establish the feasibility of using this
technology as a wearable device. BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) gene
mutation identification is being used with increased frequency to aid in the
diagnosis of cystic fibrosis (CF) in those suspected with CF. Aim of this study
was to identify diagnostic outcomes when CFTR mutational analysis was used in CF
diagnosis. CFTR mutational analysis results were also compared with sweat
chloride results.
METHODS: This study was done on all patients at our institution who had CFTR
mutation analysis over a sevenyear period since August 2006.
RESULTS: A total of 315 patients underwent CFTR mutational analysis. Fifty-one
(16.2%) patients had two mutations identified. Among them 32 had positive sweat
chloride levels (≥60 mmol/L), while seven had borderline sweat chloride levels
(40-59 mmol/L). An additional 70 patients (22.3%) had only one mutation
identified. Among them eight had positive sweat chloride levels, and 17 had
borderline sweat chloride levels. Fifty-five patients (17.5%) without CFTR
mutations had either borderline (n=45) or positive (n=10) sweat chloride
results. Three patients with a CF phenotype had negative CFTR analysis but
elevated sweat chloride levels. In eighty-three patients (26.4%) CFTR mutational
analysis was done without corresponding sweat chloride testing.
CONCLUSIONS: Although CFTR mutation analysis has improved the diagnostic
capability for CF, its use either as the first step or the only test to diagnose
CFTR dysfunction should be discouraged and CF diagnostic guidelines need to be
followed. INTRODUCTION: Cystic Fibrosis (CF) is an autosomal recessive disorder and the
incidence of this disease is undermined in Northern India. The distinguishable
salty character of the sweat belonging to individuals suffering from CF makes
sweat chloride estimation essential for diagnosis of CF disease.
AIM: The aim of this prospective study was to elucidate the relationship of
sweat chloride levels with clinical features and pattern of CF.
MATERIALS AND METHODS: A total of 182 patients, with clinical features of CF
were included in this study for quantitative measurement of sweat chloride.
Sweat stimulation and collection involved pilocarpine iontophoresis based on the
Gibson and Cooks methodology. The quantitative estimation of chloride was done
by Schales and Schales method with some modifications. Cystic Fibrosis Trans
Membrane Conductance Regulator (CFTR) mutation status was recorded in case of
patients with borderline sweat chloride levels to correlate the results and for
follow-up.
RESULTS: Out of 182 patients having clinical features consistent with CF,
borderline and elevated sweat chloride levels were present in 9 (5%) and 41
(22.5%) subjects respectively. Elevated sweat chloride levels were significantly
associated with wheeze, Failure To Thrive (FTT), history of CF in Siblings,
product of Consanguineous Marriage (CM), digital clubbing and steatorrhoea on
univariate analysis. On multivariate analysis only wheeze, FTT and steatorrhoea
were found to be significantly associated with elevated sweat chloride levels
(p<0.05). Among the nine borderline cases six cases were positive for at least
two CFTR mutations and rest of the three cases were not having any mutation in
CFTR gene.
CONCLUSION: The diagnosis is often delayed and the disease is advanced in most
patients at the time of diagnosis. Sweat testing is a gold standard for
diagnosis of CF patients as genetic mutation profile being heterozygous and
unlikely to become diagnostic test. The sweat chloride test remains the gold standard for confirmatory diagnosis of
cystic fibrosis (CF) in support of universal newborn screening programs.
However, it provides ambiguous results for intermediate sweat chloride cases
while not reflecting disease progression when classifying the complex CF disease
spectrum given the pleiotropic effects of gene modifiers and environment. Herein
we report the first characterization of the sweat metabolome from
screen-positive CF infants and identify metabolites associated with disease
status that complement sweat chloride testing. Pilocarpine-stimulated sweat
specimens were collected independently from two CF clinics, including 50
unaffected infants (e.g., carriers) and 18 confirmed CF cases. Nontargeted
metabolite profiling was performed using multisegment injection-capillary
electrophoresis-mass spectrometry as a high throughput platform for analysis of
polar/ionic metabolites in volume-restricted sweat samples. Amino acids, organic
acids, amino acid derivatives, dipeptides, purine derivatives, and unknown
exogenous compounds were identified in sweat when using high resolution tandem
mass spectrometry, including metabolites associated with affected yet
asymptomatic CF infants, such as asparagine and glutamine. Unexpectedly, a
metabolite of pilocarpine, used to stimulate sweat secretion, pilocarpic acid,
and a plasticizer metabolite from environmental exposure,
mono(2-ethylhexyl)phthalic acid, were secreted in the sweat of CF infants at
significantly lower concentrations relative to unaffected CF screen-positive
controls. These results indicated a deficiency in human paraoxonase, an enzyme
unrelated to mutations to the cystic fibrosis transmembrane conductance
regulator (CFTR) and impaired chloride transport, which is a nonspecific
arylesterase/lactonase known to mediate inflammation, bacterial biofilm
formation, and recurrent lung infections in affected CF children later in life.
This work sheds new light into the underlying mechanisms of CF pathophysiology
as required for new advances in precision medicine of orphan diseases that
benefit from early detection and intervention, including new molecular targets
for therapeutic intervention. OBJECTIVE: To conduct a descriptive analysis of the sweat test (ST), associating
ST results with epidemiological data, CFTR (cystic fibrosis transmembrane
conductance regulator) mutations and reasons to indicate the ST, as well as
correlating sweat sodium and sweat chloride concentrations in subjects.
METHODS: Retrospective survey and descriptive analysis of 5,721 ST at a
university referral center.
RESULTS: The inclusion of the subjects was based on clinical data related with
cystic fibrosis (CF) phenotype. The samples were grouped by (i) sweat chloride
concentrations (mEq/L): <30: 3,249/5,277 (61.6%); ≥30 to <60: 1,326/5,277
(25.1%); ≥60: 702/5,277 (13.3%) and (ii) age: (Group A--GA) 0 to <6 months;
(Group B--GB) ≥6 months to <18 years; (Group C--GC) ≥18 years. Digestive
symptoms showed higher prevalence ratio for the CF diagnosis as well as
association between younger age and higher values of sweat chloride, sweat
sodium, and chloride/sodium ratio. The indication of ST due to respiratory
symptoms was higher in GB and associated with greater age, lower values of sweat
chloride, sweat sodium, and chloride/sodium ratio. There was higher prevalence
of ST with sweat chloride levels <30 mEq/L in GB, ≥60 mEq/L in GC, and with
borderline level in GB. There was positive correlation between sweat sodium and
sweat chloride. Sweat chloride/sweat sodium and sweat sodium-sweat chloride
indexes showed association with sex, reason for ST indication, and CFTR
mutations. Sex alters some values presented in the ST. The number of ST/year
performed before and after the newborn screening implementation was the same;
however, we observed a higher number of borderlines values. A wide spectrum of
CFTR mutation was found. Severe CFTR mutations and F508del/F508del genotype were
associated with highest probability of ST chloride levels ≥60 mEq/L, and the
absence of CFTR mutations identified was associated with borderline ST and
respiratory symptoms.
CONCLUSIONS: ST data showed wide variability dependent on age, sex, reason for
examination indication, CFTR mutations, and weight of the collected sweat
sample. Sweat sodium concentration is directly correlated with sweat chloride
levels and it could be used as a quality parameter. BACKGROUND: Cystic fibrosis (CF) is a complex autosomal recessive disease that
continues to present unique diagnostic challenges. Because CF was first
described in 1938, there has been a substantial growth of genetic and phenotypic
information about the disorder. During the past few years, as more evidence has
become available, a consortium of international experts determined that the 2008
guidelines from the CF Foundation needed to be reviewed and updated.
CONTENT: The goal of this review is to highlight the latest advances in CF
multidisciplinary care, together with the recent updates to the 2017 CF
Foundation diagnostic guidelines.
SUMMARY: Data from newborn screening programs, patient registries, clinical
databases, and functional research have led to a better understanding of the CF
transmembrane conductance regulator (CFTR) gene. Recent consensus guidelines
have provided recommendations for clinicians and laboratorians to better assist
with interpretation of disease status and related CF mutations. The highly
recommended Clinical and Functional Translation of CFTR project should be the
first resource in the evaluation of disease severity for CF mutations.
Screen-positive newborns and patients with high clinical suspicion for CF are
always recommended to undergo confirmatory sweat chloride testing with
interpretations based on updated reference intervals. Every patient diagnosed
with CF should receive genotyping, as novel molecular therapies are becoming
standard of practice. The future of CF management must consider healthcare
system disparities as CF transitions from a historically childhood disease to a
predomitly adult epidemic. BACKGROUND: Sweat chloride testing for diagnosis of cystic fibrosis (CF)
involves sweat induction, collection and handling, and measurement in an
analytical lab. We have developed a wearable sensor with an integrated salt
bridge for real-time measurement of sweat chloride concentration. Here, in a
proof-of-concept study, we compare the performance of the sensor to current
clinical practice in CF patients and healthy subjects.
METHOD: Sweat was induced on both forearms of 10 individuals with CF and 10
healthy subjects using pilocarpine iontophoresis. A Macroduct sweat collection
device was attached to one arm and sweat was collected for 30 min and then sent
for laboratory analysis. A sensor was attached to the other arm and the chloride
ion concentration monitored in real time for 30 min using a Bluetooth
transceiver and smart phone app.
RESULTS: Stable sweat chloride measurements were obtained within 15 min
following sweat induction using the wearable sensor. We define the detection
time as the time at which the standard deviation of the real-time chloride ion
concentration remained below 2 mEq/L for 5 min. The sweat volume for sensor
measurements at the detection time was 13.1 ± 11.4 μL (SD), in many cases lower
than the minimum sweat volume of 15 μL for conventional testing. The mean
difference between sweat chloride concentrations measured by the sensor and the
conventional laboratory practice was 6.2 ± 9.5 mEq/L (SD), close to the
arm-to-arm variation of about 3 mEq/L. The Pearson correlation coefficient
between the two measurements was 0.97 highlighting the excellent agreement
between the two methods.
CONCLUSION: A wearable sensor can be used to make real-time measurements of
sweat chloride within 15 min following sweat induction, requiring a small sweat
volume, and with excellent agreement to standard methods. |
What is nyctinasty in plants? | Nyctinasty is the circadian rhythmic nastic movement of leguminous plants in response to the onset of darkness; a unique and intriguing phenomenon that has attracted attention for centuries. | The chemical aspects of the circadian leaf movement known as "nyctinasty" are
discussed in this paper. Each of the nyctinastic plants of five different genera
so far examined contained a pair of factors, one of which induced leaf closure
and another induced leaf opening. The relative contents of the closing and
opening factors changed correlating with the nyctinastic leaf movement. The use
of fluorescence-labeled and photoaffinity-labeled factors revealed that the
factors bind to specific cells, the motor cells, present in the pulvini, and
that the membrane fraction of the motor cells contained two proteins of 210 and
180 kDa, which can bind to the factors. Leguminous plants open their leaves during the daytime and close them at night
as if sleeping, a type of movement that follows circadian rhythms, and is known
as nyctinastic movement. This phenomenon is controlled by two endogenous
bioactive substances that exhibit opposing activities: Leaf-Opening Factor
(LOF), which opens the leaves, and Leaf-Closing Factor (LCF), which closes them.
The authors have carried out chemical biological research using these bioactive
substances as molecular probes in order to clarify the mechanisms of nyctinastic
movement. Here, we report on the detection and identification of the target
proteins of these compounds using original methodology. |
Does Eucommia ulmoides leaf extract ameliorates steatosis/fatty liver induced by high-fat diet? | Yes, Eucommia ulmoides leaf extract can ameliorate steatosis induced by high-fat diet. | This study examined the effect of a Du-zhong (Eucommia ulmoides Oliver) leaf
extract (0.175 g/100 g diet) that was supplemented with a high-fat diet (10%
coconut oil, 0.2% cholesterol, wt/wt) on hyperlipidemic hamsters. Hamsters fed
with Du-zhong leaf extract for 10 weeks showed a smaller size of epididymal
adipocytes compared to the control group. The supplementation of the Du-zhong
leaf extract significantly lowered the plasma levels of triglyceride, total
cholesterol, LDL-cholesterol, non HDL-cholesterol, and free fatty acid, whereas
it elevated the HDL-cholesterol/total cholesterol ratio and apolipoprotein A-I
levels. The hepatic cholesterol concentration was lower in the Du-zhong group
than in the control group. The plasma total cholesterol concentration was
positively correlated with hepatic HMG-CoA reductase activity (r = 0.547, p <
0.05) and hepatic cholesterol concentration (r = 0.769, p < 0.001). The hepatic
fatty acid synthase and HMG-CoA reductase activities were significantly lowered
by a Du-zhong leaf extract supplement in high fat-fed hamsters. Hepatic fatty
acid synthase activity was positively correlated with plasma fatty acid
concentration (r = 0.513, p < 0.05) that was lower in the Du-zhong group. These
results demonstrate that the Du-zhong leaf extract exhibits antihyperlipidemic
properties by suppressing hepatic fatty acid and cholesterol biosynthesis with
the simultaneous reduction of plasma and hepatic lipids in high fat-fed
hamsters. Eucommia ulmoides Oliver leaf extract (ELE) has been shown to have
anti-hypertensive and anti-obesity effects in rats that are fed a high-fat diet
(HFD). To explore the effects of chronic administration of ELE on body weight,
blood pressure and aortic media thickness, 7-week-old male Wistar-Kyoto (WKY)
rats were orally administered a normal diet, a 30% HFD, or a 5% ELE plus HFD ad
libitum for 10 weeks. The HFD treatment caused mild obesity and hypertension in
the normotensive rats, while rats receiving both ELE and the HFD had
significantly lower body weights, less visceral and perirenal fat, lower blood
pressure and thinner aortic media than the control rats receiving the HFD only.
The plasma adiponectin/leptin ratio also improved in ELE-treated rats. Although
plasma leptin levels were elevated in all HFD rats, adiponectin levels increased
only in the ELE-treated rats. Anti-hypertensive and anti-obesity effects may be
caused by the geniposidic acid (GEA) and/or asperuloside present in ELE. These
findings suggest that chronic ELE administration prevents aortic media
hypertrophy in early-stage obesity with hypertension. Long-term administration
of ELE might inhibit the development of arteriosclerosis. |
List the releases of tmVar | TmVar is a text mining approach for extracting sequence variants in biomedical literature. TmVar 2.0 integrates genomic variant information from literature with dbSNP and ClinVar for precision medicine. | MOTIVATION: Despite significant efforts in expert curation, clinical relevance
about most of the 154 million dbSNP reference variants (RS) remains unknown.
However, a wealth of knowledge about the variant biological function/disease
impact is buried in unstructured literature data. Previous studies have
attempted to harvest and unlock such information with text-mining techniques but
are of limited use because their mutation extraction results are not
standardized or integrated with curated data.
RESULTS: We propose an automatic method to extract and normalize variant
mentions to unique identifiers (dbSNP RSIDs). Our method, in benchmarking
results, demonstrates a high F-measure of ∼90% and compared favorably to the
state of the art. Next, we applied our approach to the entire PubMed and
validated the results by verifying that each extracted variant-gene pair matched
the dbSNP annotation based on mapped genomic position, and by analyzing variants
curated in ClinVar. We then determined which text-mined variants and genes
constituted novel discoveries. Our analysis reveals 41 889 RS numbers
(associated with 9151 genes) not found in ClinVar. Moreover, we obtained a rich
set worth further review: 12 462 rare variants (MAF ≤ 0.01) in 3849 genes which
are presumed to be deleterious and not frequently found in the general
population. To our knowledge, this is the first large-scale study to analyze and
integrate text-mined variant data with curated knowledge in existing databases.
Our results suggest that databases can be significantly enriched by text mining
and that the combined information can greatly assist human efforts in
evaluating/prioritizing variants in genomic research.
AVAILABILITY AND IMPLEMENTATION: The tmVar 2.0 source code and corpus are freely
available at https://www.ncbi.nlm.nih.gov/research/bionlp/Tools/tmvar/.
CONTACT: [email protected]. |
Which deep learning algorithm has been developed for variant calling? | A deep convolutional neural network can call genetic variation in aligned next-generation sequencing read data by learning statistical relationships between images of read pileups around putative variant and true genotype calls. The approach, called DeepVariant, outperforms existing state-of-the-art tools. The learned model generalizes across genome builds and mammalian species, allowing nonhuman sequencing projects to benefit from the wealth of human ground-truth data. | |
What 2 biological processes are regulated by STAMP2 in adipocytes? | Inflammation, insulin resistance and metabolic response are regulated by STAMP2 in adipocytes. | Metabolic and inflammatory pathways crosstalk at many levels, and, while
required for homeostasis, interaction between these pathways can also lead to
metabolic dysregulation under conditions of chronic stress. Thus, we
hypothesized that mechanisms might exist to prevent overt inflammatory responses
during physiological fluctuations in nutrients or under nutrient-rich
conditions, and we identified the six-transmembrane protein STAMP2 as a critical
modulator of this integrated response system of inflammation and metabolism in
adipocytes. Lack of STAMP2 in adipocytes results in aberrant inflammatory
responses to both nutrients and acute inflammatory stimuli. Similarly, in whole
animals, visceral adipose tissue of STAMP2(-/-) mice exhibits overt
inflammation, and these mice develop spontaneous metabolic disease on a regular
diet, manifesting insulin resistance, glucose intolerance, mild hyperglycemia,
dyslipidemia, and fatty liver disease. We conclude that STAMP2 participates in
integrating inflammatory and metabolic responses and thus plays a key role in
systemic metabolic homeostasis. CONTEXT: Six transmembrane protein of prostate 2 (STAMP2) is a counterregulator
of adipose inflammation and insulin resistance in mice. Our hypothesis was that
STAMP2 could be involved in human obesity and insulin resistance.
OBJECTIVE: The objective of the study was to elucidate the role of adipose
STAMP2 expression in human obesity and insulin resistance.
DESIGN: The design was to quantify STAMP2 in human abdominal sc and omental
white adipose tissue (WAT), isolated adipocytes, and stroma and in vitro
differentiated preadipocytes and relate levels of STAMP2 in sc WAT to clinical
and adipocyte phenotypes involved in insulin resistance.
PARTICIPANTS: Nonobese and obese women and men (n = 236) recruited from an
obesity clinic or through local advertisement.
MAIN OUTCOME MEASUREMENT: Clinical measures included body mass index, body fat,
total adiponectin, and homeostasis model assessment as measure of overall
insulin resistance. In adipocytes we determined cell size, sensitivity of
lipolysis and lipogenesis to insulin, adiponectin secretion, and inflammatory
gene expression.
RESULTS: STAMP2 levels in sc and visceral WAT and adipocytes were increased in
obesity (P = 0.0008-0.05) but not influenced by weight loss. Increased WAT
STAMP2 levels associated with a high amount of body fat (P = 0.04), high
homeostasis model assessment (P = 0.01), and large adipocytes (P = 0.02).
Subjects with high STAMP2 levels displayed reduced sensitivity of adipocyte
lipogenesis (P = 0.04) and lipolysis (P = 0.03) to insulin but had normal
adiponectin levels. WAT STAMP2 levels correlated with expression of the
macrophage marker CD68 (P = 0.0006).
CONCLUSION: Human WAT STAMP2 associates with obesity and insulin resistance
independently of adiponectin, but the role of STAMP2 in obesity and its
complications seems different from that in mice. The impact of interleukin (IL)-1beta on tumor necrosis factor alpha-induced
adipose-related protein (TIARP)/six-transmembrane protein of prostate 2 (STAMP2)
was determined in adipocytes. TIARP/STAMP2 mRNA synthesis was significantly
stimulated by IL-1beta in a dose- and time-dependent fashion in 3T3-L1
adipocytes. Signaling studies suggested that janus kinase 2, nuclear factor
kappaB, and p44/42 mitogen-activated protein kinase are involved in
IL-1beta-induced TIARP/STAMP2 mRNA expression. Furthermore, IL-1beta, TNFalpha,
and IL-6 showed synergistic stimulatory effects on TIARP/STAMP2 gene expression.
Moreover, both TIARP/STAMP2 mRNA synthesis and protein expression were induced
by IL-1beta in fully differentiated human mesenchymal stem cell-derived
adipocytes (hMSC-Ad). Taken together, TIARP/STAMP2 is highly upregulated in
3T3-L1 cells and hMSC-Ad by IL-1beta and might, therefore, modulate
proinflammatory and insulin resistance-inducing effects of IL-1beta. CONTEXT: Six-transmembrane protein of prostate 2 (STAMP2) is a counter-regulator
of inflammation and insulin resistance according to findings in mice. However,
there have been contradictory reports in humans.
OBJECTIVE: We aimed to explore STAMP2 in association with inflammatory and
metabolic status of human obesity.
DESIGN, PATIENTS, AND METHODS: STAMP2 gene expression was analyzed in adipose
tissue samples (171 visceral and 67 sc depots) and during human preadipocyte
differentiation. Human adipocytes were treated with macrophage-conditioned
medium, TNF-α, and rosiglitazone.
RESULTS: In visceral adipose tissue, STAMP2 gene expression was significantly
decreased in obese subjects, mainly in obese subjects with type 2 diabetes.
STAMP2 gene expression and protein were significantly and inversely associated
with obesity phenotype measures (body mass index, waist, hip, and fat mass) and
obesity-associated metabolic disturbances (systolic blood pressure and fasting
glucose). In addition, STAMP2 gene expression was positively associated with
lipogenic (FASN, ACC1, SREBP1, THRSP14, TRα, and TRα1), CAV1, IRS1, GLUT4, and
CD206 gene expression. In sc adipose tissue, STAMP2 gene expression was not
associated with metabolic parameters. In both fat depots, STAMP2 gene expression
in stromovascular cells was significantly higher than in mature adipocytes.
STAMP2 gene expression was significantly increased during the differentiation
process in parallel to adipogenic genes, being increased in preadipocytes
derived from lean subjects. Macrophage-conditioned medium (25%) and TNF-α (100
ng/ml) administration increased whereas rosiglitazone (2 μM) decreased
significantly STAMP2 gene expression in human differentiated adipocytes.
CONCLUSIONS: Decreased STAMP2 expression (mRNA and protein) might reflect
visceral adipose dysfunction in subjects with obesity and type 2 diabetes. The six-transmembrane protein Stamp2 plays an important role in metabolically
triggered inflammation and insulin action. We report that Stamp2 is expressed in
human and mouse macrophages, is regulated upon differentiation or activation,
acts as an anti-inflammatory protein, and regulates foam cell formation. Absence
of Stamp2 results in significant increases in cellular NADPH levels, and both
NADPH homeostasis and the exaggerated inflammatory response of Stamp2(-/-)
macrophages are rescued by exogenous wild-type but not by a reductase-deficient
Stamp2 molecule. Chemical and genetic suppression of NADPH production in
Stamp2(-/-) macrophages reverts the heightened inflammatory response. Stamp2 is
detected in mouse and human atherosclerotic plaques, and its deficiency promotes
atherosclerosis in mice. Furthermore, bone marrow transplantation experiments
demonstrated that Stamp2 in myeloid cells is sufficient to protect against
atherosclerosis. Our data reveal a role of Stamp2 in controlling intermediary
metabolites to regulate inflammatory responses in macrophages and in progression
of atherosclerosis. Six transmembrane protein of prostate (Stamp) proteins play an important role in
prostate cancer cell growth. Recently, we found that Stamp2 has a critical role
in the integration of inflammatory and metabolic signals in adipose tissue where
it is highly expressed and regulated by nutritional and metabolic cues. In this
study, we show that all Stamp family members are differentially regulated during
adipogenesis: whereas Stamp1 expression is significantly decreased upon
differentiation, Stamp2 expression is increased. In contrast, Stamp3 expression
is modestly changed in adipocytes compared to preadipocytes, and has a biphasic
expression pattern during the course of differentiation. Suppression of Stamp1
or Stamp2 expression both led to inhibition of 3T3-L1 differentiation in concert
with diminished expression of the key regulators of adipogenesis -
CCAAT/enhancer binding protein alpha (C/ebpα) and peroxisome
proliferator-activated receptor gamma (Pparγ). Upon Stamp1 knockdown, mitotic
clonal expansion was also inhibited. In contrast, Stamp2 knockdown did not
affect mitotic clonal expansion, but resulted in a marked decrease in superoxide
production that is known to affect adipogenesis. These results suggest that
Stamp1 and Stamp2 play critical roles in adipogenesis, but through different
mechanisms. |
What is the mechanism of action of Pitolisant? | Pitolisant is an antagonist/inverse agonist of the human histamine H3 receptor thus increasing histaminergic tone in the wake promoting system of the brain. It is used for the treatment of narcolepsy. | OBJECTIVE: Narcolepsy is a rare disabling sleep disorder characterized by
excessive daytime sleepiness and cataplexy (sudden loss of muscle tone). Drugs
such as pitolisant, which block histamine H3 autoreceptors, constitute a newly
identified class of stimulants because they increase brain histamine and enhance
wakefulness in animal and human adult narcolepsy.
METHODS: We report our experience with the off-label use of pitolisant in 4
teenagers with narcolepsy/cataplexy with severe daytime sleepiness, refractory
to available treatments (modafinil, methylphenidate, mazindol, sodium oxybate,
and D-amphetamine).
RESULTS: All teenagers developed their disease during childhood (11.3 ± 2.4
years; 50% boys) and were 17.3 ± 0.8 years old at the time of pitolisant
therapy. Pitolisant treatment was increased from 10 to 30 mg (n = 1) and 40 mg
(n = 3). The adapted Epworth Sleepiness Score decreased from 14.3 ± 1.1 to 9.5 ±
2.9 (P = 0.03) with pitolisant alone to 7 ± 3.4 when combined with mazindol (n =
1), methylphenidate (n = 1), or sodium oxybate plus modafinil (n = 1). Mean
sleep onset latency increased from 31 ± 14 minutes to 36 ± 8 minutes (P = 0.21)
on the maintece of wakefulness test. The severity and frequency of cataplexy
were slightly improved. Adverse effects were minor (insomnia, headache, hot
flushes, leg pain, and hallucinations) and transitory, except for insomnia,
which persisted in 2 teenagers. The benefit was maintained after a mean of 13
months.
CONCLUSIONS: Pitolisant could constitute an acceptable alternative for the
treatment of refractory sleepiness in teenagers with narcolepsy. OBJECTIVE AND DESIGN: Pitolisant (BF2.649) is a selective inverse agonist for
the histamine H(3) receptor and was developed for the treatment of excessive
daytime sleepiness in Parkinson disease, narcolepsy, and schizophrenia. Since
H(3)-ligands can decrease inflammatory pain, we tested Pitolisant in
inflammatory and neuropathic pain models. MATERIALS AND TREATMENTS: Behavioral
effects of pitolisant and the structural different H(3) receptor inverse
agonists ciproxifan and ST-889 were tested in zymosan-induced inflammation and
the spared nerve injury model for neuropathic pain.
METHODS: Responses to mechanical and thermal stimuli were determined. Calcium
imaging was performed with primary neuronal cultures of dorsal root ganglions.
RESULTS: Clinically relevant doses of pitolisant (10 mg/kg) had no relevant
effect on mechanical or thermal pain thresholds in all animal models. Higher
doses (50 mg/kg) dramatically increased thermal but not mechanical pain
thresholds. Neither ciproxifan nor ST-889 altered thermal pain thresholds. In
peripheral sensory neurons high concentrations of pitolisant (30-500 μM), but
not ciproxifan, partially inhibited calcium increases induced by capsaicin, a
selective activator of transient receptor potential vanilloid receptor 1
(TRPV1). High doses of pitolisant induced a strong hypothermia.
CONCLUSION: The data show a dramatic effect of high dosages of pitolisant on the
thermosensory system, which appears to be H(3) receptor-independent. BACKGROUND AND PURPOSE: Pitolisant, a histamine H₃ receptor inverse
agonist/antagonist is currently under Phase III clinical trials for treatment of
excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse
potential was investigated using in vivo models in rodents and monkeys and
compared with those of Modafinil, a psychostimulant currently used in the same
indications.
EXPERIMENTAL APPROACH: Effects of Pitolisant on dopamine release in the nucleus
accumbens, on spontaneous and cocaine-induced locomotion, locomotor
sensitization were monitored. It was also tested in three standard drug abuse
tests i.e. conditioned place preference in rats, self-administration in monkeys
and cocaine discrimination in mice as well as in a physical dependence model.
KEY RESULTS: Pitolisant did not elicit any significant changes in dopaminergic
indices in rat nucleus accumbens whereas Modafinil increased dopamine release.
In rodents, Pitolisant was without any effect on locomotion and reduced the
cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no
conditioned hyperlocomotion were evidenced with this compound in rats whereas
significant effects were elicited by Modafinil. Finally, Pitolisant was devoid
of any significant effects in the three standard drug abuse tests (including
self-administration in monkeys) and in the physical dependence model.
CONCLUSIONS AND IMPLICATIONS: No potential drug abuse liability for Pitolisant
was evidenced in various in vivo rodent and primate models, whereas the same
does not seem so clear in the case of Modafinil. Pitolisant (Wakix™) is an inverse agonist of the histamine H3 receptor that is
being developed by Bioproject. Oral pitolisant is approved in the EU for the
treatment of narcolepsy with or without cataplexy in adults. Pitolisant has
received a Temporary Authorization of Use in France for this indication in case
of treatment failure, intolerance or contraindication to currently available
treatment. Pitolisant has orphan drug designation in the EU and the USA. In the
pivotal HARMONY I trial, pitolisant significantly decreased excessive daytime
sleepiness versus placebo in adults with narcolepsy with or without cataplexy
(primary endpoint). Pitolisant also significantly decreased cataplexy rate
versus placebo in these patients. This article summarizes the milestones in the
development of pitolisant leading to this first approval for narcolepsy. Previous studies have demonstrated that the histamine H3 receptor inverse
agonist thioperamide potentiates the stimulant and rewarding effects of cocaine.
However, these potentiating effects of thioperamide do not necessarily result
from H3 receptor blockade since thioperamide is an imidazole-based compound
capable of enhancing plasma cocaine concentrations by blocking cytochrome P450
activity. In contrast, Pitolisant is a non-imidazole H3 receptor inverse agonist
that has already been tested in clinical trials but it remains to be determined
whether this compound also potentiates the behavioral effects of cocaine. The
present study tested the effects of Pitolisant on locomotion, on cocaine-induced
hyperactivity and on the development of conditioned place preference induced by
cocaine (2 and 8mg/kg, i.p.) in male C57BL/6J mice. Pitolisant was injected
30min before each cocaine-pairing session. Locomotion recorded on the first
cocaine-pairing session was used to test the effects of Pitolisant on the
locomotor effects of cocaine. Our results show that doses of Pitolisant higher
than 10mg/kg depressed locomotion. When injected alone at doses that did not
affect locomotion, Pitolisant (2.5-10mg/kg, i.p.) had no rewarding properties in
the place conditioning technique. Additionally, Pitolisant did not significantly
alter cocaine-induced hyperactivity and cocaine-induced conditioned place
preference. Taken together, our study indicates that Pitolisant has no addictive
properties alone. Moreover, this compound does not significantly affect the
stimulant and rewarding effects of cocaine. These results add further evidence
to support the hypothesis that a pharmacokinetic interaction is involved in the
ability of thioperamide to potentiate cocaine's psychomotor effects. The Gi/o protein-coupled histamine H3 receptor is distributed throughout the
central nervous system including areas like cerebral cortex, hippocampus and
striatum with the density being highest in the posterior hypothalamus, i.e. the
area in which the histaminergic cell bodies are located. In contrast to the
other histamine receptor subtypes (H1, H2 and H4), the H3 receptor is located
presynaptically and shows a constitutive activity. In detail, H3 receptors are
involved in the inhibition of histamine release (presynaptic autoreceptor),
impulse flow along the histaminergic neurones (somadendritic autoreceptor) and
histamine synthesis. Moreover, they occur as inhibitory presynaptic
heteroreceptors on serotoninergic, noradrenergic, dopaminergic, glutamatergic,
GABAergic and perhaps cholinergic neurones. This review shows for four functions
of the brain that the H3 receptor represents a brake against the wake-promoting,
anticonvulsant and anorectic effect of histamine (via postsynaptic H1 receptors)
and its procognitive activity (via postsynaptic H1 and H2 receptors). Indeed, H1
agonists and H3 inverse agonists elicit essentially the same effects, at least
in rodents; these effects are opposite in direction to those elicited by
brain-penetrating H1 receptor antagonists in humans. Although the benefit for H3
inverse agonists for the symptomatic treatment of dementias is inconclusive,
several members of this group have shown a marked potential for the treatment of
disorders associated with excessive daytime sleepiness. In March 2016, the
European Commission granted a marketing authorisation for pitolisant (WakixR)
(as the first representative of the H3 inverse agonists) for the treatment of
narcolepsy. BACKGROUND: Histaminergic neurons are crucial to maintain wakefulness, but their
role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant,
a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients
with narcolepsy.
METHODS: For this randomised, double-blind, placebo-controlled trial we
recruited patients with narcolepsy from 16 sleep centres in nine countries
(Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey,
and Ukraine). Patients were eligible if they were aged 18 years or older,
diagnosed with narcolepsy with cataplexy according to version two of the
International Classification of Sleep Disorders criteria, experienced at least
three cataplexies per week, and had excessive daytime sleepiness (defined as an
Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via
an interactive web response system to randomly assign patients to receive either
pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks
of four. Participants and investigators were masked to treatment allocation.
Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by
investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral
pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40
mg). The primary endpoint was the change in the average number of cataplexy
attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR])
between the 2 weeks of baseline and the 4 weeks of stable dosing period.
Analysis was by intention to treat. This trial is registered with
ClinicalTrials.gov, number NCT01800045.
FINDINGS: The trial was done between April 19, 2013, and Jan 28, 2015. We
screened 117 patients, 106 of whom were randomly assigned to treatment (54 to
pitolisant and 52 to placebo) and, after dropout, 54 patients from the
pitolisant group and 51 from the placebo group were included in the
intention-to-treat analysis. The WCR during the stable dosing period compared
with baseline was decreased by 75% (WCRfinal=2·27; WCRbaseline=9·15;
WCRfinal/baseline=0·25) in patients who received pitolisant and 38%
(WCRfinal=4·52; WCRbaseline=7·31; WCRfinal/baseline=0·62) in patients who
received placebo (rate ratio 0·512; 95% CI 0·43-0·60, p<0·0001).
Treatment-related adverse events were significantly more common in the
pitolisant group than in the placebo group (15 [28%] of 54 vs 6 [12%] of 51;
p=0·048). There were no serious adverse events, but one case of severe nausea in
the pitolisant group. The most frequent adverse events in the pitolisant group
(headache, irritability, anxiety, and nausea) were mild or moderate except one
case of severe nausea. No withdrawal syndrome was detected following pitolisant
treatment; one case was detected in the placebo group.
INTERPRETATION: Pitolisant was well tolerated and efficacious in reducing
cataplexy. If confirmed in long-term studies, pitolisant might constitute a
useful first-line therapy for cataplexy in patients with narcolepsy, for whom
there are currently few therapeutic options.
FUNDING: Bioprojet, France. On 31 March 2016, the European Commission issued a decision for a marketing
authorisation valid throughout the European Union (EU) for pitolisant (Wakix)
for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant
is an antagonist/inverse agonist of the human histamine H3 receptor. The dose
should be selected using an up-titration scheme depending on individual patient
response and tolerance and should not exceed 36 mg/day. The main evidence of
efficacy of pitolisant was based on two Phase III clinical trials. The
improvement on excessive daytime sleepiness was shown against placebo in the
Harmony I study (-3.33 points; 95% confidence interval (CI) [-5.83; -0.83];
p = 0.024) and in Harmony CTP (-3.41 points; 95% CI [-4.95; -1.87]; p < 0.0001).
The daily cataplexy rate in Harmony I improved against placebo with a rate ratio
(rR) of 0.38 whilst in the Harmony CTP the ratio of improvement on weekly
cataplexy rate against placebo was 0.512. The most commonly reported adverse
reactions were headache, insomnia and nausea. This article summarizes the
scientific review leading to approval of pitolisant in the EU. The assessment
report and product information are available on the European Medicines Agency
website (http://www.ema.europa.eu). Narcolepsy is a neurological disease that affects 1 in 2,000 individuals and is
characterized by excessive daytime sleepiness (EDS). In 60-70% of individuals
with narcolepsy, it is also characterized by cataplexy or a sudden loss of
muscle tone that is triggered by positive or negative emotions. Narcolepsy
decreases the quality of life of the afflicted individuals. Currently used drugs
treat EDS alone (modafinil/armodafinil, methylphenidate, and amphetamine),
cataplexy alone ("off-label" use of antidepressants), or both EDS and cataplexy
(sodium oxybate). These drugs have abuse, tolerability, and adherence issues. A
greater diversity of drug options is needed to treat narcolepsy. The small
molecule drug, pitolisant, acts as an inverse agonist/antagonist at the H3
receptor, thus increasing histaminergic tone in the wake promoting system of the
brain. Pitolisant has been studied in animal models of narcolepsy and used in
clinical trials as a treatment for narcolepsy. A comprehensive search of online
databases (eg, Medline, PubMed, EMBASE, the Cochrane Library Database, Ovid
MEDLINE, Europe PubMed Central, EBSCOhost CINAHL, ProQuest Research Library,
Google Scholar, and ClinicalTrials.gov) was performed. Nonrandomized and
randomized studies were included. This review focuses on the outcomes of four
clinical trials of pitolisant to treat narcolepsy. These four trials show that
pitolisant is an effective drug to treat EDS and cataplexy in narcolepsy. The pharmacological profile of pitolisant, a histamine H3 receptor
antagonist/inverse agonist, indicates that this compound might reduce body
weight and metabolic disturbances. Therefore, we studied the influence of
pitolisant on body weight, water and sucrose intake as well as metabolic
disturbances in the high-fat and high-sugar diet-induced obesity model in mice.
To induce obesity, male CD-1 mice were fed a high-fat diet consisting of 40% fat
blend for 14 weeks, water and 30% sucrose solution available ad libitum. Glucose
tolerance test was performed at the beginning of week 15. Insulin tolerance was
tested the day after. At the end of study, plasma levels of triglycerides and
cholesterol were determined. Pitolisant at dose of 10 mg/kg bw (ip) was
administrated during 14 days, starting from the beginning of week 13. Metformin
at dose of 100 mg/kg bw (ip) was used as reference drug. Mice fed with high-fat
diet and sucrose solution showed more weight gain throughout the 12-week period
of inducing obesity. Animals fed with high-fat diet and treated with pitolisant
(for the next 14 days) showed significantly less weight gain than mice from the
control group consuming a high-fat feed. In the group treated with pitolisant,
glucose levels were significantly lower than glucose levels of control obese
mice after glucose load. The plasma triglyceride levels in pitolisant-treated
mice were significantly lower compared with those in control obese group. In
conclusion, pitolisant has a favorable influence of body weight and improves
glucose tolerance and the lipid profile in obese mice. The histamine H3 receptor is a G protein-coupled receptor (GPCR) drug target
that is highly expressed in the CNS, where it acts as both an auto- and
hetero-receptor to regulate neurotransmission. As such, it has been considered
as a relevant target in disorders as varied as Alzheimer's disease,
schizophrenia, neuropathic pain and attention deficit hyperactivity disorder. A
range of competitive antagonists/inverse agonists have progressed into clinical
development, with pitolisant approved for the treatment of narcolepsy. Given the
breadth of compounds developed and potential therapeutic indications, we
assessed the comparative pharmacology of six investigational histamine H3
agents, including pitolisant, using native tissue and recombit cells. Whilst
all of the compounds tested displayed robust histamine H3 receptor inverse
agonism and did not differentiate between the main H3 receptor splice variants,
they displayed a wide range of affinities and kinetic properties, and included
rapidly dissociating (pitolisant, S 38093-2, ABT-239) and slowly dissociating
(GSK189254, JNJ-5207852, PF-3654746) agents. S 38093-2 had the lowest histamine
H3 receptor affinity (pKB values 5.7-6.2), seemingly at odds with previously
reported, potent in vivo activity in models of cognition. We show here that at
pro-cognitive and anti-hyperalgesic/anti-allodynic doses, S 38093-2
preferentially occupies the mouse sigma-1 receptor in vivo, only engaging the
histamine H3 receptor at doses associated with wakefulness promotion and
neurotransmitter (histamine, ACh) release. Furthermore, pitolisant, ABT-239 and
PF-3654746 also displayed appreciable sigma-1 receptor affinity, suggesting that
this property differentiates clinically evaluated histamine H3 receptor
antagonists and may play a role in their efficacy. |
Which methods have been developed for extracting sequence variants from the literature? | TmVar and nala | MOTIVATION: The extraction of sequence variants from the literature remains an
important task. Existing methods primarily target standard (ST) mutation
mentions (e.g. 'E6V'), leaving relevant mentions natural language (NL) largely
untapped (e.g. 'glutamic acid was substituted by valine at residue 6').
RESULTS: We introduced three new corpora suggesting named-entity recognition
(NER) to be more challenging than anticipated: 28-77% of all articles contained
mentions only available in NL. Our new method nala captured NL and ST by
combining conditional random fields with word embedding features learned
unsupervised from the entire PubMed. In our hands, nala substantially
outperformed the state-of-the-art. For instance, we compared all unique mentions
in new discoveries correctly detected by any of three methods (SETH, tmVar, or
nala ). Neither SETH nor tmVar discovered anything missed by nala , while nala
uniquely tagged 33% mentions. For NL mentions the corresponding value shot up to
100% nala -only.
AVAILABILITY AND IMPLEMENTATION: Source code, API and corpora freely available
at: http://tagtog.net/-corpora/IDP4+ .
CONTACT: [email protected].
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online. |
Which molecules are targeted by defactinib? | PURPOSE: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. | Resistance to currently available targeted therapies significantly hampers the
survival of patients with prostate cancer with bone metastasis. Here we
demonstrate an important resistance mechanism initiated from tumor-induced bone.
Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed
that tumor cells resistant to cabozantinib, a Met and VEGFR-2 inhibitor, reside
in a "resistance niche" adjacent to prostate cancer-induced bone. We performed
secretome analysis of the conditioned medium from tumor-induced bone to identify
proteins (termed "osteocrines") found within this resistance niche. In
accordance with previous reports demonstrating that activation of integrin
signaling pathways confers therapeutic resistance, 27 of the 90 osteocrines
identified were integrin ligands. We found that following cabozantinib
treatment, only tumor cells positioned adjacent to the newly formed woven bone
remained viable and expressed high levels of pFAK-Y397 and pTalin-S425,
mediators of integrin signaling. Accordingly, treatment of C4-2B4 cells with
integrin ligands resulted in increased pFAK-Y397 expression and cell survival,
whereas targeting integrins with FAK inhibitors PF-562271 or defactinib
inhibited FAK phosphorylation and reduced the survival of PC3-mm2 cells.
Moreover, treatment of MDA-PCa-118b tumors with PF-562271 led to decreased tumor
growth, irrespective of initial tumor size. Finally, we show that upon treatment
cessation, the combination of PF-562271 and cabozantinib delayed tumor
recurrence in contrast to cabozantinib treatment alone. Our studies suggest that
identifying paracrine de novo resistance mechanisms may significantly contribute
to the generation of a broader set of potent therapeutic tools that act
combinatorially to inhibit metastatic prostate cancer. PURPOSE: VS-6063 (also known as defactinib or PF-04554878) is a
second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine
kinase-2. This phase 1 study evaluated the safety and tolerability,
pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with
advanced solid tumor maligcies in a first-in-Asian study setting.
METHODS: VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles
to cohorts of three subjects each with a standard 3 + 3 dose-escalation design
until disease progression or unacceptable toxicity. Blood samples for
pharmacokinetics were collected on Day 1 and 15. The assessments were performed
using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria
In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response.
RESULTS: Nine patients were treated across three dose levels (200-600 mg BID).
No dose-limiting toxicities were observed at any dose level. Most frequent
treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue,
decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort
experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK
analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of
400 mg BID was comparable with exposures previously reported in non-Japanese
subjects. Durable stable disease of approximately 24 weeks was confirmed in two
subjects (maligt mesothelioma and rectal cancer).
CONCLUSIONS: VS-6063 was well tolerated at all dose levels investigated in this
first-in-Asian study. These data support the administration of VS-6063 to
Japanese subjects at the RP2D in clinical trials involving solid tumor
maligcies. Squamous cell lung carcinoma (SCC) accounts for 30% of patients with NSCLC and
to date, no molecular targeted agents are approved for this type of tumor.
However, recent studies have revealed several oncogenic mutations in SCC
patients, including an alteration of the PI3K/AKT pathway, i.e. PI3K point
mutations and amplification, AKT mutations and loss or reduced PTEN expression.
Prompted by our observation of a correlation between PTEN loss and FAK
phosphorylation in a cohort of patients with stage IV SCC, we evaluated the
relevance of PTEN loss in cancer progression as well as the efficacy of a new
combined treatment with the pan PI3K inhibitor buparlisip and the FAK inhibitor
defactinib. An increase in AKT and FAK phosphorylation, associated with
increased proliferation and invasiveness, paralleled by the acquisition of
mesenchymal markers, and overexpression of the oncomir miR-21 were observed in
SKMES-1-derived cell clones with a stable reduction of PTEN. Notably, the
combined treatment induced a synergistic inhibition of cell proliferation, and a
significant reduction in cell migration and invasion only in cells with reduced
PTEN. The molecular mechanisms underlying these findings were unraveled using a
specific RTK array that showed a reduction in phosphorylation of key kinases
such as JNK, GSK-3 α/β, and AMPK-α2, due to the concomitant decrease in AKT and
FAK activation. In conclusion, the combination of buparlisib and defactinib was
effective against cells with reduced PTEN and warrants further studies as a
novel therapeutic strategy for stage IV SCC patients with loss of PTEN
expression. A sensitive, specific, selective and rapid LC-ESI-MS/MS method has been
developed and validated for the quantification of defactinib in mice plasma
using 13C3,15N-tofacitinib as an internal standard (I.S.). Sample preparation
was accomplished through a liquid-liquid extraction process. Baseline
chromatographic resolution of defactinib and the I.S. was achieved on an
Atlantis dC18 column using an isocratic mobile phase comprising 0.2% formic acid
in water and acetonitrile (25:75, v/v) delivered at a flow rate of 0.5mL/min.
Defactinib and the I.S. eluted at ∼1.59 and 0.99min, respectively. The total
chromatographic run time was 2.50min. A linear response function was established
in the concentration range of 0.13-106 ng/mL. Method validation was performed as
per regulatory guidelines and the results met the acceptance criteria. The
intra- and inter-day accuracy and precision were in the range of 5.57-13.3 and
8.63-12.1%, respectively. Defactinib was found to be stable under various
stability conditions. This novel method has been applied to a pharmacokinetic
study in mice. BACKGROUND: Docetaxel, the standard chemotherapy for metastatic
castration-resistant prostate cancer (CRPC) also enhances the survival of
patients with metastatic castration-sensitive prostate cancer (CSPC) when
combined with androgen-deprivation therapy. Focal Adhesion Kinase (FAK)
activation is a mediator of docetaxel resistance in prostate cancer cells. The
aim of this study was to investigate the effect of the second generation FAK
inhibitor VS-6063 on docetaxel efficacy in pre-clinical CRPC and CSPC models.
METHODS: Docetaxel-resistant CRPC cells, mice with PC3 xenografts, and ex vivo
cultures of patient-derived primary prostate tumors were treated with VS-6063
and/or docetaxel, or vehicle control. Cell counting, immunoblotting, and
immunohistochemistry techniques were used to evaluate the treatment effects.
RESULTS: Docetaxel and VS-6063 co-treatment caused a greater decrease in the
viability of docetaxel-resistant CRPC cells, and a greater inhibition in PC3
xenograft growth compared to either monotherapy. FAK expression in human primary
prostate cancer was positively associated with advanced tumor stage.
Patient-derived prostate tumor explants cultured with both docetaxel and VS-6063
displayed a higher percentage of apoptosis in cancer cells, than monotherapy
treatment.
CONCLUSIONS: Our findings suggest that co-administration of the FAK inhibitor,
VS-6063, with docetaxel represents a potential therapeutic strategy to overcome
docetaxel resistance in prostate cancer. Enzymatic inhibition has proven to be a successful modality for the development
of many small-molecule drugs. In recent years, small-molecule-induced protein
degradation has emerged as an orthogonal therapeutic strategy that has the
potential to expand the druggable target space. Focal adhesion kinase (Fak) is a
key player in tumor invasion and metastasis, acting simultaneously as a kinase
and a scaffold for several signaling proteins. While previous efforts to
modulate Fak activity were limited to kinase inhibitors with low success in
clinical studies, protein degradation offers a possibility to simultaneously
block Fak's kinase signaling and scaffolding capabilities. Here, we report the
development of a selective and potent Fak degrader, PROTAC-3, which outperforms
a clinical candidate, defactinib, with respect to Fak activation as well as
Fak-mediated cell migration and invasion. These results underline the potential
that PROTACs offer in expanding the druggable space and controlling protein
functions that are not easily addressed by traditional small-molecule
therapeutics. |
What is Chrysophanol? | Chrysophanol is an anthraquinone compound, which exhibits anticancer effects on certain types of cancer cells | Chrysophanol is an anthraquinone compound, mainly isolated from rhubarb, with
anti-cancer effects on some types of cancer cells. However, effects of
chrysophanol on human choriocarcinoma cells are not known. Therefore, the
objective of this study was to determine effects of chrysophanol on
choriocarcinoma cells (JAR and JEG-3) and identify signal transduction cascades
activated by chrysophanol. Results of present study, showed that chrysophanol
decreased cell viability and induced apoptosis of JEG-3, but not JAR cells, in a
dose-dependent manner. Chrysophanol also increased oxidative stress in JEG-3
cells by inducing ROS generation followed by mitochondrial dysfunction including
depolarization of mitochondrial inner membrane potential. Western blot analysis
revealed that ERK1/2, P90RSK, AKT, and P70S6K were increased significantly in
JEG-3 cells by chrysophanol. Next, we investigated chrysophanol-mediated effects
on proliferation of JEG-3 cells using pharmacological inhibitors of PI3K/AKT
(LY294002) and ERK1/2 (U0126). Inhibition of AKT and ERK1/2 prevented
chrysophanol-induced stimulation of proliferation of JEG-3 cells. In addition,
the phosphorylation of AKT and ERK1/2 was suppressed by LY294002 and U0126 in
JEG-3 cells treated with chrysophanol, whereas, the AKT protein was activated by
pre-treatment of JEG-3 cells with U0126. Furthermore, we compared therapeutic
effects of chrysophanol with cisplatin and paclitaxel which are conventional
salvage regimens for choriocarcinoma. Our results verified that chrysophanol has
synergistic effects with traditional therapy to increase apoptosis of JEG-3
cells. Collectively, these results indicate that chrysophanol is a potential
effective chometherapeutic agent for treatment of choriocarcinoma therapy, and
minimizing side effects of conventional treatment regimens. J. Cell. Physiol.
232: 331-339, 2017. © 2016 Wiley Periodicals, Inc. Sepsis is a life-threatening disease. Inflammation is a major concomitant
symptom of sepsis Chrysophanol, an anthraquinone derivative isolated from the
rhizomes of rheumpalmatum, has been reported to have a protective effect against
lipopolysaccharide(LPS)-induced inflammation. However, the underlying molecular
mechanisms are not well understood. The aim of this study was to explore the
effect and mechanism of chrysophanol on lipopolysaccharide (LPS)-induced
anti-inflammatory effect of RAW264.7 cells and its involved potential mechanism.
The mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin
(IL)-1β and inducible nitric oxide synthase (iNOS), nuclear factor kappa B
(NF-κB) and PPAR-γ were measured by qRT-PCR and western blotting, the production
of TNF-α, IL-1β was evaluated by ELISA. Then, the phosphorylation of NF-κB p65
was also detected by western blotting. And NF-κB p65 promoter activity was
analyzed by the Dual-Luciferase reporter assay system as well. Meanwhile, PPAR-γ
inhibitor GW9662 was performed to knockdown PPAR-γ expression in cells. Our data
revealed that LPS induced the up-regulation of TNF-α, IL-1β, iNOS and NF-κB p65,
the down-regulation of PPAR-γ were substantially suppressed by chrysophanol in
RAW264.7 cells. Furthermore, our data also figured out that these effects of
chrysophanol were largely abrogated by PPAR-γ inhibitor GW9662. Taken together,
our results indicated that LPS-induced inflammation was potently compromised by
chrysophanol very likely through the PPAR-γ-dependent inactivation of NF-κB in
RAW264.7 cells. Patients with diabetes mellitus are easy to experience diabetic encephalopathy
(DE) and other cognition dysfunction, whereas the neural alterations in
developing this disease are unknown yet. Chrysophanol (CHR) is one of
traditional Chinese medicine which was reported to show protective effects in
cognition dysfunction and inflammatory in previously studies. In this current
study, whether CHR protects learning and memory dysfunctions induced by diabetes
disease or not and underlying mechanisms were studied. DE model was induced by
streptozotocin (STZ, i.p.) in ICR mice. CHR was administrated 3 days after STZ
treated mice which was confirmed with diabetes for consecutive 6 days. Learning
and memory function was tested by Morris water maze after the CHR injection. The
morphology of neuronal cells in hippocampus CA3 region was stained by
HE-staining. ELISA and Western blot assay were used to determine the levels of
pro-inflammation cytokines (IL-1β, IL-4, IL-6, TNF-α) in hippocampus. Here, we
demonstrated that mice harboring diabetes mellitus induced by STZ exhibit high
blood glucose, learning and memory deficits detected by Morris water maze
behavior tests. Application with CHR right after developing diabetes disease
rescues partial blood sugar increasing, learning and memory deficits. The data
also indicated that the death rate of neurons and the number of astrocytes in
hippocampus CA3 region was significantly improved in diabetic mice. Moreover,
the underlying mechanisms of CHR's protective effect are likely associated with
anti-inflammation by downregulating the expression of pro-inflammation cytokines
(IL-1β, IL-4, IL-6, TNF-α) in hippocampus and inhibiting the over-activation of
astrocytes in hippocampus CA3 region. Therefore, application with CHR
contributes to the learning and memory deficits induced by diabetes disease via
inhibitory expressions of inflammatory in hippocampus region. Chrysophanol, a major anthraquinone component occurring in many traditional
Chinese herbs, is accepted as important active component with various
pharmacological actions such as antibacterial and anticancer activity. Previous
studies demonstrated that exposure to chrysophanol induced cytotoxicity, but the
mechanisms of the toxic effects remain unknown. In the present metabolism study,
three oxidative metabolites (M1-M3, aloe-emodine, 7-hydroxychrysophanol, and
2-hydroxychrysophanol) and five GSH conjugates (M4-M8) were detected in rat and
human liver microsomal incubations of chrysophanol supplemented with GSH, and
the formation of the metabolites was NADPH dependent except M4 and M5. M4 and M5
were directly derived from parent compound chrysophanol, M6 arose from M2, and
M7 and M8 resulted from the oxidation of M4 and M5. Metabolites M5 and M6 were
also observed in bile of rats after exposure to chrysophanol, M1-M3 and one NAC
conjugate (M9) were detected in urine of rats administrated chrysophanol, and
urinary metabolite M9 originated from the degradation of biliary GSH conjugation
M6. Recombit P450 enzyme incubation and microsome inhibition studies
demonstrated that P450 1A2 was the primary enzyme responsible for the metabolic
activation of chrysophanol and that P450 2B6 and P450 3A4 also participated in
the generation of the oxidative metabolites. These findings helped us to
understand the mechanisms of chrysophanol-induced cytotoxicity. |
What is the percentage of individuals at risk of dominant medically actionable disease? | 1 in 38 individuals at risk of a dominant medically actionable disease. | Clinical genomic sequencing can identify pathogenic variants unrelated to the
initial clinical question, but of medical relevance to the patients and their
families. With ongoing discussions on the utility of disclosing or searching for
such variants, it is of crucial importance to obtain unbiased insight in the
prevalence of these incidental or secondary findings, in order to better weigh
potential risks and benefits. Previous studies have reported a broad range of
secondary findings ranging from 1 to 9%, merely attributable to differences in
study design, cohorts tested, sequence technology used and genes analyzed. Here,
we analyzed WES data of 1640 anonymized healthy Dutch individuals to establish
the frequency of medically actionable disease alleles in an outbred population
of European descent. Our study shows that 1 in 38 healthy individuals (2.7%) has
a (likely) pathogenic variant in one of 59 medically actionable domit disease
genes for which the American College of Medical Genetics and Genomics (ACMG)
recommends disclosure. Additionally, we identified 36 individuals (2.2%) to be a
carrier of a recessive pathogenic disease allele. Whereas these frequencies of
secondary findings are in line with what has been reported in the East-Asian
population, the pathogenic variants are differently distributed across the 59
ACMG genes. Our results contribute to the debate on genetic risk factor
screening in healthy individuals and the discussion whether the potential
benefits of this knowledge and related preventive options, outweigh the risk of
the emotional impact of the test result and possible stigmatization. |