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http://www.ncbi.nlm.nih.gov/pubmed/24821968 | 1. J Immunol. 2014 Jun 15;192(12):6062-70. doi: 10.4049/jimmunol.1303348. Epub
2014 May 12.
Essential role of Elmo1 in Dock2-dependent lymphocyte migration.
Stevenson C(1), de la Rosa G(1), Anderson CS(1), Murphy PS(1), Capece T(1), Kim
M(1), Elliott MR(2).
Author information:
(1)Department of Microbiology and Immunology, University of Rochester Medical
Center, Rochester, NY 14642; and David H. Smith Center for Vaccine Biology and
Imunology, University of Rochester Medical Center, Rochester, NY 14642.
(2)Department of Microbiology and Immunology, University of Rochester Medical
Center, Rochester, NY 14642; and David H. Smith Center for Vaccine Biology and
Imunology, University of Rochester Medical Center, Rochester, NY 14642
[email protected].
Elmo1 and Elmo2 are highly homologous cytoplasmic adaptor proteins that interact
with Dock family guanine nucleotide exchange factors to promote activation of
the small GTPase Rac. In T lymphocytes, Dock2 is essential for CCR7- and
CXCR4-dependent Rac activation and chemotaxis, but the role of Elmo proteins in
regulating Dock2 function in primary T cells is not known. In this article, we
show that endogenous Elmo1, but not Elmo2, interacts constitutively with Dock2
in mouse and human primary T cells. CD4(+) T cells from Elmo1(-/-) mice were
profoundly impaired in polarization, Rac activation, and chemotaxis in response
to CCR7 and CXCR4 stimulation. Transfection of full-length Elmo1, but not Elmo2
or a Dock2-binding mutant of Elmo1, rescued defective migration of Elmo1(-/-) T
cells. Interestingly, Dock2 protein levels were reduced by 4-fold in Elmo1(-/-)
lymphocytes despite normal levels of Dock2 mRNA. Dock2 polyubiquitination was
increased in Elmo1(-/-) T cells, and treatment with proteasome inhibitors
partially restored Dock2 levels in Elmo1(-/-) T cells. Finally, we show that
Dock2 is directly ubiquitinated in CD4(+) T cells and that Elmo1 expression in
heterologous cells inhibits ubiquitination of Dock2. Taken together, these
findings reveal a previously unknown, nonredundant role for Elmo1 in controlling
Dock2 levels and Dock2-dependent T cell migration in primary lymphocytes.
Inhibition of Dock2 has therapeutic potential as a means to control recruitment
of pathogenic lymphocytes in diseased tissues. This work provides valuable
insights into the molecular regulation of Dock2 by Elmo1 that can be used to
design improved inhibitors that target the Elmo-Dock-Rac signaling complex.
Copyright © 2014 by The American Association of Immunologists, Inc.
DOI: 10.4049/jimmunol.1303348
PMCID: PMC4127066
PMID: 24821968 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23827660 | 1. Environ Int. 2013 Sep;59:148-51. doi: 10.1016/j.envint.2013.06.008. Epub 2013
Jul 1.
Dietary cadmium exposure and kidney stone incidence: a population-based
prospective cohort study of men & women.
Thomas LD(1), Elinder CG, Tiselius HG, Wolk A, Akesson A.
Author information:
(1)Institute of Environmental Medicine, Unit of Nutritional Epidemiology,
Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden.
Cadmium exposure is associated with increased urinary calcium excretion.
Hypercalciuria is recognised as a major risk factor for kidney stone formation.
Increased prevalence of kidney stones among those occupationally exposed to
cadmium has previously been suggested. Food is the main source of cadmium
exposure in the general population with tobacco representing an important
additional source among smokers. We aimed to assess the association between
dietary cadmium exposure and kidney stone incidence in two large
population-based, prospective cohorts of men (Cohort of Swedish Men; COSM) and
women (The Swedish Mammography Cohort; SMC). Those with a history of kidney
stones were excluded. At baseline 1997, men (45-79yrs) and women (48 to 83yrs),
completed a self-administered questionnaire on diet and lifestyle. During
12years of follow-up, we ascertained 707 cases of kidney stones in men and 290
in women through linkage of the cohorts to the national inpatient and outpatient
registers. Individual dietary cadmium exposure was estimated using dietary data
and concentrations of cadmium in food. Hazard ratios (HR) were calculated using
the Cox proportional hazards regression models with adjustment for other risk
factors. Estimated dietary cadmium exposure was not associated with increased
kidney stone incidence among men HR 0.97 (95% confidence interval (CI):
0.77-1.23) or women HR 0.99 (95% CI: 0.89-1.43), comparing the highest tertile
with the lowest. In conclusion, our results do not support a strong association
between dietary cadmium and kidney stone risk at the exposure levels seen in the
general population.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.envint.2013.06.008
PMID: 23827660 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18371346 | 1. Cell Stem Cell. 2007 Aug 16;1(2):140-52. doi: 10.1016/j.stem.2007.07.017.
FoxO transcription factors and stem cell homeostasis: insights from the
hematopoietic system.
Tothova Z(1), Gilliland DG.
Author information:
(1)Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
[email protected]
The forkhead O (FoxO) family of transcription factors participates in diverse
physiologic processes, including induction of cell-cycle arrest, stress
resistance, differentiation, apoptosis, and metabolism. Several recent studies
indicate that FoxO-dependent signaling is required for long-term regenerative
potential of the hematopoietic stem cell (HSC) compartment through regulation of
HSC response to physiologic oxidative stress, quiescence, and survival. These
observations link FoxO function in mammalian systems with the evolutionarily
conserved role of FoxO in promotion of stress resistance and longevity in lower
phylogenetic systems. Furthermore, these findings have implications for aging in
higher organisms and in malignant stem cell biology, and suggest that FoxOs may
play an important role in the maintenance and integrity of stem cell
compartments in a broad spectrum of tissues.
DOI: 10.1016/j.stem.2007.07.017
PMID: 18371346 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19089153 | 1. J Appl Oral Sci. 2007 Aug;15(4):327-33. doi: 10.1590/s1678-77572007000400016.
Dental wear caused by association between bruxism and gastroesophageal reflux
disease: a rehabilitation report.
Machado NA(1), Fonseca RB, Branco CA, Barbosa GA, Fernandes Neto AJ, Soares CJ.
Author information:
(1)Dental School, Federal University of Uberlândia, Uberlândia, MG, Brazil.
Bruxism is a pathological activity of the stomatognathic system that involves
tooth grinding and clenching during parafunctional jaw movements. Clinical signs
of bruxism are mostly related to dental wear and muscular and joint discomforts,
but a large number of etiological factors can be listed, as local, systemic,
psychological and hereditary factors. The association between bruxism, feeding
and smoking habits and digestive disorders may lead to serious consequences to
dental and related structures, involving dental alterations (wear, fractures and
cracks), periodontal signs (gingival recession and tooth mobility) and
muscle-joint sensitivity, demanding a multidisciplinary treatment plan. This
paper presents a case report in which bruxism associated with acid feeding,
smoking habit and episodes of gastric reflow caused severe tooth wear and great
muscular discomfort with daily headache episodes. From the diagnosis, a
multidisciplinary treatment plan was established. The initial treatment approach
consisted of medical follow up with counseling on diet and smoking habits and
management of the gastric disorders. This was followed by the installation of an
interocclusal acrylic device in centric relation of occlusion (CRO) for
reestablishment of the occlusal stability, vertical dimension of occlusion,
anterior guides and return to normal muscle activity (90-day use approximately).
After remission of initial symptoms, oral rehabilitation was implemented in CRO
by means of full resin composite restorations and new interocclusal device for
protection of restorations. Satisfactory esthetics, improved function and
occlusal stability were obtained after oral rehabilitation. The patient has
attended annual follow-ups for the past 2 years. The multidisciplinary treatment
seems to be the key for a successful rehabilitation of severe cases of dental
wear involving the association of different health disorders.
DOI: 10.1590/s1678-77572007000400016
PMCID: PMC4327438
PMID: 19089153 |
http://www.ncbi.nlm.nih.gov/pubmed/16593484 | 1. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4100-4. doi:
10.1073/pnas.81.13.4100.
Isolation and characterization of a gene for a major light-harvesting
polypeptide from Cyanophora paradoxa.
Lemaux PG(1), Grossman A.
Author information:
(1)Department of Plant Biology, Carnegie Institution of Washington, 290 Panama
Street, Stanford, CA 94305.
Antibodies raised against mixtures of phycobilisome polypeptides from the
eukaryotic alga Cyanidium caldarium were used in an immunological screen to
detect expression of phycobiliprotein genes in an Escherichia coli library
containing segments of plastid (chloroplast, cyanelle) DNA from another
eukaryotic alga, Cyanophora paradoxa. The four candidate clones obtained were
mapped by restriction analysis and found to be overlapping. The clone with the
smallest insert (1.4 kilobases) was partially sequenced and a coding region
similar to the carboxyl terminus of the phycobiliprotein subunit
beta-phycocyanin was found. The coding region for the beta-phycocyanin gene in
C. paradoxa has been mapped to the small single copy region on the cyanelle
genome, and its orientation has been determined. A short probe unique to a
conserved chromophore binding site shared by at least two phycobiliprotein
subunits has now been generated from the carboxyl terminus of the
beta-phycocyanin gene. This probe may be useful in identifying specific
phycobiliprotein subunit genes, beta-phycocyanin, beta-phycoerythrocyanin, and
possibly beta-phycoerythrin, in other eukaryotic algae and in prokaryotic
cyanobacteria.
DOI: 10.1073/pnas.81.13.4100
PMCID: PMC345376
PMID: 16593484 |
http://www.ncbi.nlm.nih.gov/pubmed/21133188 | 1. Practitioner. 2010 Sep;254(1732):15-8, 2.
History central to diagnosing myasthenia gravis.
Spillane J(1), Kullmann D.
Author information:
(1)UCL Institute of Neurology, Queen Square, London.
Myasthenia gravis (MG) is caused by failure of chemical transmission at the
neuromuscular junction. It is an autoimmune disorder in which antibodies
interfere with neuromuscular transmission. It has a prevalence of around 20 per
100,000. The incidence is bimodal with a 2:1 female to male ratio in the younger
population and a reversed sex ratio over the age of 60. Around 15% of cases are
associated with a thymoma. MG presents with fatiguable painless muscle weakness.
Diplopia and ptosis are the most common presenting features. Around 80% of
patients presenting with ocular MG will subsequently develop more generalised
weakness. Respiratory muscle weakness is the most serious manifestation of MG
and can be fatal. A detailed history is the most valuable tool in the diagnosis
of MG. This should elicit the pattern of weakness, severity and diurnal
variation. Exacerbating factors including extremes of weather, emotional stress,
menstruation and intercurrent illness should be enquired about. No one
diagnostic test is 100% sensitive and patients who have negative antibodies and
normal neurophysiology may still have MG. Treatment should be directed at
ameliorating weakness with acetylcholinesterase blockers and modulating the
immune system. Pyridostigmine is the most widely used acetylcholinesterase
inhibitor. Most patients with generalised MG require immunomodulatory therapy
and prednisolone is generally used as the first-line agent. Despite the
availability of symptomatic and immunomodulatory treatment, up to 20% of
patients will experience a myasthenic crisis requiring admission for ventilatory
support at some stage.
PMID: 21133188 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16781064 | 1. Neurosci Lett. 2006 Aug 14;404(1-2):163-5. doi: 10.1016/j.neulet.2006.05.032.
Epub 2006 Jun 15.
Glucocerebrosidase mutations are not found in association with LRRK2 G2019S in
subjects with parkinsonism.
Eblan MJ(1), Scholz S, Stubblefield B, Gutti U, Goker-Alpan O, Hruska KS,
Singleton AB, Sidransky E.
Author information:
(1)Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, NIH,
Bethesda, MD 20892, USA.
Alteration G2019S in the leucine-rich repeat kinase 2 gene (LRRK2) has been
identified in several populations of patients with parkinsonism, including
Ashkenazi Jewish subjects with Parkinson disease. Mutations in
glucocerebrosidase (GBA), the enzyme deficient in Gaucher disease, are also
identified at an increased frequency among Parkinson probands, including those
of Ashkenazi Jewish ancestry. A Taqman Assay-by-Design SNP genotyping strategy
was utilized to establish whether G2019S was found in association with GBA
mutations. Among 37 subjects with parkinsonism who were heterozygous for a GBA
mutation, none carried G2019S. Furthermore, G2019S was not found in 18 patients
with Gaucher disease who developed parkinsonian manifestations and 11 other
Gaucher probands with parkinsonism in a first degree relative. Among 45 patients
with Gaucher disease without a history of parkinsonism, one G2019S carrier was
found. These findings suggest that GBA and LRRK2 mutations are discrete risk
factors for parkinsonism in both Ashkenazi Jewish and non-Jewish subjects.
DOI: 10.1016/j.neulet.2006.05.032
PMID: 16781064 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9659924 | 1. Mol Cell. 1998 Jan;1(2):277-87. doi: 10.1016/s1097-2765(00)80028-3.
Recruitment of CBP/p300 by the IFN beta enhanceosome is required for synergistic
activation of transcription.
Merika M(1), Williams AJ, Chen G, Collins T, Thanos D.
Author information:
(1)Department of Biochemistry and Molecular Biophysics, Columbia University, New
York, New York 10032, USA.
Transcriptional activation of the IFN beta gene in response to virus infection
requires the assembly of an enhanceosome, consisting of the transcriptional
activators NF-kappa B, IRF1, ATF2/c-Jun, and the architectural protein HMG I(Y).
The level of transcription generated by all of these activators is greater than
the sum of the levels generated by individual factors, a phenomenon designated
transcriptional synergy. We demonstrate that this synergy, in the context of the
enhanceosome, requires a new protein-protein interaction domain in the p65
subunit of NF-kappa B. Transcriptional synergy requires recruitment of the
CBP/p300 coactivator to the enhanceosome, via a new activating surface assembled
from the novel p65 domain and the activation domains of all of the activators.
Deletion, substitution, or rearrangement of any one of the activation domains in
the context of the enhanceosome decreases both recruitment of CBP and
transcriptional synergy.
DOI: 10.1016/s1097-2765(00)80028-3
PMID: 9659924 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16699448 | 1. Transplantation. 2006 May 15;81(9):1234-48. doi:
10.1097/01.tp.0000219703.39149.85.
Target of rapamycin inhibitors (sirolimus and everolimus) for primary
immunosuppression of kidney transplant recipients: a systematic review and
meta-analysis of randomized trials.
Webster AC(1), Lee VW, Chapman JR, Craig JC.
Author information:
(1)Cochrane Renal Group, Children's Hospital at Westmead, Westmead, and School
of Public Health, University of Sydney, Sydney, Australia.
[email protected]
BACKGROUND: Target of rapamycin inhibitors (TOR-I) have a novel mode of action
but uncertain clinical role. We performed a systematic review of randomized
trials where immunosuppressive regimens containing TOR-I were compared with
other regimens as initial therapy for kidney transplant recipients.
METHODS: Databases (inception, June 2005) and conference proceedings (1996-2005)
were searched. Two independent reviewers assessed trials for eligibility and
quality. Results at 1 year, are expressed as relative risk (RR), where values<1
favor TOR-I, or lower dose of TOR-I, and for continuous outcomes are expressed
as weighted mean difference (WMD), both expressed with 95% confidence intervals
(CI).
RESULTS: Thirty-three trials (142 reports) were included (27 trials of
sirolimus, 5 of everolimus, and 1 of head-to-head comparison). When TOR-I
replaced calcineurin inhibitors (CNI) (8 trials with 750 participants), there
was no difference in acute rejection (RR, 1.03; 95% CI, 0.74-1.44), but serum
creatinine was lower (WMD, -18.31 micromol/L; 95% CI, -30.96 to -5.67) and bone
marrow more suppressed (leukopenia: RR 2.02; 95% CI, 1.12-3.66;
thrombocytopenia: RR, 6.97; 95% CI, 2.97-16.36; and anaemia: RR, 1.67; 95% CI,
1.27-2.20). When TOR-I replaced antimetabolites (11 trials with 3966
participants), acute rejection and cytomegalovirus infection (CMV) were reduced
(RR, 0.84; 95% CI, 0.71-0.99; RR, 0.49; 95% CI, 0.37-0.65, respectively), but
hypercholesterolemia was increased (RR, 1.65; 95% CI, 1.32-2.06). When low- was
compared with high-dose TOR-I, with equal CNI dose (10 trials with 3,175
participants), rejection was increased (RR, 1.23; 95% CI, 1.06-1.43) but
calculated glomerular filtration rate (GFR) higher (WMD, 4.27 mL/min; 95% CI,
1.12-7.41), and when lower-dose TOR-I and standard-dose CNI were compared with
higher-dose TOR-I and reduced CNI, acute rejection was reduced (RR, 0.67; 95%
CI, 0.52-0.88), but calculated GFR was also reduced (WMD, -9.46 mL/min; 95% CI,
-12.16 to -6.76). There was no significant difference in mortality, graft loss,
or malignancy risk for TOR-I in any comparison.
CONCLUSIONS: TOR-I have been evaluated in four different primary
immunosuppressive algorithms: as replacement for CNI and antimetabolites, in
combination with CNI at low and high doses, and with a variable dose of CNI.
Generally, surrogate endpoints for graft survival favor TOR-I (lower risk of
acute rejection and higher GFR), and surrogate endpoints for patient outcomes
are worsened by TOR-I (bone marrow suppression and lipid disturbance). Long-term
hard-endpoint data from methodologically robust randomized trials are still
required.
DOI: 10.1097/01.tp.0000219703.39149.85
PMID: 16699448 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24110485 | 1. Annu Int Conf IEEE Eng Med Biol Soc. 2013;2013:3507-10. doi:
10.1109/EMBC.2013.6610298.
An ensemble rank learning approach for gene prioritization.
Lee PF, Soo VW.
Several different computational approaches have been developed to solve the gene
prioritization problem. We intend to use the ensemble boosting learning
techniques to combine variant computational approaches for gene prioritization
in order to improve the overall performance. In particular we add a heuristic
weighting function to the Rankboost algorithm according to: 1) the absolute
ranks generated by the adopted methods for a certain gene, and 2) the ranking
relationship between all gene-pairs from each prioritization result. We select
13 known prostate cancer genes in OMIM database as training set and protein
coding gene data in HGNC database as test set. We adopt the leave-one-out
strategy for the ensemble rank boosting learning. The experimental results show
that our ensemble learning approach outperforms the four gene-prioritization
methods in ToppGene suite in the ranking results of the 13 known genes in terms
of mean average precision, ROC and AUC measures.
DOI: 10.1109/EMBC.2013.6610298
PMID: 24110485 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7640201 | 1. Semin Dermatol. 1995 Jun;14(2):84-9. doi: 10.1016/s1085-5629(05)80002-1.
Bazex syndrome: acrokeratosis paraneoplastica.
Bolognia JL(1).
Author information:
(1)Department of Dermatology, Yale University School of Medicine, New Haven, CT
06520, USA.
The focus of this article is acrokeratosis paraneoplastica, one of two disorders
that have acquired the eponym Bazex syndrome. To date, all of the patients
reported in the literature have had an underlying neoplasm, most commonly
squamous cell carcinoma of the upper aerodigestive tract. In this review of 113
cases of acrokeratosis paraneoplastica (mean age, 61 years; 105 males, 8
females), the psoriasiform lesions preceded the diagnosis of the associated
malignancy in 73 (67%) of 109 patients, whereas the cutaneous manifestations
followed the diagnosis of the neoplasm in only 16 (15%) of 109; in the
remainder, the onset of the skin lesions and the diagnosis of the tumor occurred
simultaneously. Therefore, awareness of the cutaneous signs of Bazex syndrome is
of obvious importance to dermatologists. Evidence in favor of the paraneoplastic
nature of this disease is as follows: in 81 (93%) of 87 patients with adequate
clinical descriptions, the skin lesions either improved significantly (or
resolved) when the underlying neoplasm was treated or they remained unchanged in
the setting of persistent disease. Occasionally, the reappearance of skin
lesions has signaled a recurrence of the tumor.
DOI: 10.1016/s1085-5629(05)80002-1
PMID: 7640201 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21441944 | 1. Acta Pharmacol Sin. 2011 Apr;32(4):441-8. doi: 10.1038/aps.2010.226. Epub 2011
Mar 28.
Sildenafil and FDP-Sr attenuate diabetic cardiomyopathy by suppressing abnormal
expression of myocardial CASQ2, FKBP12.6, and SERCA2a in rats.
Cheng YS(1), Dai DZ, Ji H, Zhang Q, Dai Y.
Author information:
(1)The Faculty of Pharmacy, China Pharmaceutical University, Nanjing, China.
AIM: To study whether calcium-modulating proteins CASQ2, FKBP12.6 and SERCA2a
participate in diabetic cardiomyopathy, and whether the beneficial actions of
testosterone, sildenafil or fructose diphosphate Sr (FDP-Sr) in the treatment of
diabetic cardiomyopathy result from suppressing these molecules.
METHODS: Fifty male Sprague-Dawley (SD) rats were divided into five groups.
Except for the normal group (non-diabetic), the other four groups were injected
with streptozotocin (STZ, 60 mg/kg, ip) to induce diabetes. Four weeks after STZ
injection, the four groups received sildenafil (12 mg·kg(-1)·d(-1), ig, for 4
week), FDP-Sr (200 mg/kg, ig, for 4 week), testosterone propionate (4
mg·kg(-1)·d(-1), sc, for 4 week), or no treatment, respectively.
RESULTS: In the diabetic rats, blood glucose, free fatty acids, triglycerides,
total cholesterol, and low-density lipoprotein cholesterol (LDL-C) were
significantly increased, while high-density lipoprotein cholesterol (HDL-C) was
significantly reduced, as compared to the non-diabetic rats. Cardiac dysfunction
and myocardial hypertrophy of the diabetic rats were associated with increased
mRNA and protein expression of iNOS, OBRb, and PKCɛ, while expression of CASQ2,
SERCA2a, and FKBP12.6 was significantly down-regulated. Sildenafil and FDP-Sr,
but not testosterone, significantly attenuated the biomarker abnormalities,
without changing the metabolic abnormalities.
CONCLUSION: CASQ2, FKBP12.6 and SERCA2a were down-regulated in diabetic
cardiomyopathy. Sildenafil and FDP-Sr, but not testosterone, attenuated the
cardiac dysfunction in diabetic cardiomyopathy, without changing the metabolic
abnormalities, which may results from inhibiting oxidative and inflammatory
cytokines and improving calcium homeostasis.
DOI: 10.1038/aps.2010.226
PMCID: PMC4001973
PMID: 21441944 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12972430 | 1. J Biol Chem. 2003 Nov 21;278(47):46541-8. doi: 10.1074/jbc.M306381200. Epub
2003 Sep 12.
Cytoplasmic IkappaBalpha increases NF-kappaB-independent transcription through
binding to histone deacetylase (HDAC) 1 and HDAC3.
Viatour P(1), Legrand-Poels S, van Lint C, Warnier M, Merville MP, Gielen J,
Piette J, Bours V, Chariot A.
Author information:
(1)Laboratory of Medical Chemistry and Human Genetics, Center for Cellular and
Molecular Therapy, University of Liège, Sart-Tillman, 4000 Liège, Belgium.
IkappaBalpha is an inhibitory molecule that sequesters NF-kappaB dimers in the
cytoplasm of unstimulated cells. Upon stimulation, NF-kappaB moves to the
nucleus and induces the expression of a variety of genes including IkappaBalpha.
This newly synthesized IkappaBalpha also translocates to the nucleus, removes
activated NF-kappaB from its target genes, and brings it back to the cytoplasm
to terminate the phase of NF-kappaB activation. We show here that IkappaBalpha
enhances the transactivation potential of several homeodomain-containing
proteins such as HOXB7 and Pit-1 through a NF-kappaB-independent association
with histone deacetylase (HDAC) 1 and HDAC3 but not with HDAC2, -4, -5, and -6.
IkappaBalpha bound both HDAC proteins through its ankyrin repeats, and this
interaction was disrupted by p65. Immunofluorescence experiments demonstrated
further that IkappaBalpha acts by partially redirecting HDAC3 to the cytoplasm.
At the same time, an IkappaBalpha mutant, which lacked a functional nuclear
localization sequence, interacted very efficiently with HDAC1 and -3 and
intensively enhanced the transactivation potential of Pit-1. Our results support
the hypothesis that the NF-kappaB inhibitor IkappaBalpha regulates the
transcriptional activity of homeodomain-containing proteins positively through
cytoplasmic sequestration of HDAC1 and HDAC3, a mechanism that would assign a
new and unexpected role to IkappaBalpha.
DOI: 10.1074/jbc.M306381200
PMID: 12972430 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22260327 | 1. Growth Factors. 2012 Apr;30(2):107-16. doi: 10.3109/08977194.2011.649918. Epub
2012 Jan 20.
EGFR ligands exhibit functional differences in models of paracrine and autocrine
signaling.
Wilson KJ(1), Mill C, Lambert S, Buchman J, Wilson TR, Hernandez-Gordillo V,
Gallo RM, Ades LM, Settleman J, Riese DJ 2nd.
Author information:
(1)Purdue University College of Pharmacy, Purdue University Center for Cancer
Research, West Lafayette, IN 47907-2064, USA.
Epidermal growth factor (EGF) family peptides are ligands for the EGF receptor
(EGFR). Here, we elucidate functional differences among EGFR ligands and
mechanisms underlying these distinctions. In 32D/EGFR myeloid and MCF10A breast
cells, soluble amphiregulin (AR), transforming growth factor alpha (TGFα),
neuregulin 2 beta, and epigen stimulate greater EGFR coupling to cell
proliferation and DNA synthesis than do EGF, betacellulin, heparin-binding
EGF-like growth factor, and epiregulin. EGF competitively antagonizes AR,
indicating that its functional differences reflect dissimilar intrinsic activity
at EGFR. EGF stimulates much greater phosphorylation of EGFR Tyr1045 than does
AR. Moreover, the EGFR Y1045F mutation and z-cbl dominant-negative mutant of the
c-cbl ubiquitin ligase potentiate the effect of EGF but not of AR. Both EGF and
AR stimulate phosphorylation of EGFR Tyr992. However, the EGFR Y992F mutation
and phospholipase C gamma inhibitor U73122 reduce the effect of AR much more
than that of EGF. Expression of TGFα in 32D/EGFR cells causes greater EGFR
coupling to cell proliferation than does expression of EGF. Moreover, expression
of EGF in 32D/EGFR cells causes these cells to be largely refractory to
stimulation with soluble EGF. Thus, EGFR ligands are functionally distinct in
models of paracrine and autocrine signaling and EGFR coupling to biological
responses may be specified by competition among functionally distinct EGFR
ligands.
DOI: 10.3109/08977194.2011.649918
PMCID: PMC3962550
PMID: 22260327 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Interest: The authors report no
conflicts of interest. The authors alone are responsible for the content and
writing of the paper. |
http://www.ncbi.nlm.nih.gov/pubmed/15605531 | 1. Ann Ital Chir. 2004 May-Jun;75(3):379-84; discussion 385.
[Intestinal endometriosis: an obscure cause of cyclic rectal bleeding].
[Article in Italian]
Sciumè C(1), Geraci G, Pisello F, Li Volsi F, Facella T, Modica G.
Author information:
(1)Università degli Studi di Palermo, Dipartimento di Chirurgia Generale,
d'Urgenza e dei Trapianti d'Organo, Unità Operativa di Chirurgia Generale ad
indirizzo Toracico. [email protected]
OBJECTIVE: Authors report their experience about a case of intestinal
endometriosis that lead cyclic and recurrent rectal bleeding in a fertile-age
woman.
DESIGN: Report of 1 case with multidisciplinary approach and surgical treatment.
Surgical effectiveness evaluation and 2 years follow-up. Brief review on the
recent literature and the diagnostic and therapeutic implications.
SETTING: Section of General and Thoracic Surgery, Department of General Surgery,
Emergency and Organ Transplantation, Policlinico "Paolo Giaccone", Palermo.
INTERVENTION: After correct and sure diagnosis, the patient was submitted to
sigmoid segmental resection with radical and curative intention.
RESULTS: Complete recovery. Follow-up (24 months) negative.
CONCLUSIONS: Diagnosis of endometriosis should be considered in women with
recurrent monthly abdominal pain and bowel symptoms, especially if accompanied
by gynaecologic complaints, even because the significant symptoms overlap with
the irritable bowel syndrome (IBS) and makes the differentiation extremely
difficult. Treatment of GI endometriosis is best approached in collaboration
between gynaecologist experienced and intestinal surgeon. The high accuracy and
low complications suggested that EUS-FNA was effective for the correct
histologic diagnosis of intestinal endometriosis.
PMID: 15605531 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2315439 | 1. Psychopharmacology (Berl). 1990;100(3):426-32. doi: 10.1007/BF02244618.
Effects of nalmefene on feeding in humans. Dissociation of hunger and
palatability.
Yeomans MR(1), Wright P, Macleod HA, Critchley JA.
Author information:
(1)Department of Psychology, University of Edinburgh, UK.
Effects of nalmefene on eating were investigated in two groups of ten male
volunteers, in a double-blind placebo-controlled study. The nalmefene treated
group ate 22% less, both in terms of absolute weight and caloric intake, of a
standardised buffet-meal than did the placebo group. No differences in
subjective ratings of hunger or satiety were found between the groups,
suggesting that the reduced feeding was not a consequence of any change in
motivation to eat. When analysed by nutrient content, nalmefene was found to
reduce fat and protein, but not carbohydrate, intakes. Analyses of intakes of
individual foods showed a differential effect of nalmefene on foods rated as
highly palatable. Thus the apparent nutrient specificity of nalmefene appeared
to be an indirect consequence of its effect on palatability. Nalmefene also
caused slight increases in self-rated alertness, and decreases in ratings of
tiredness and elation, although it was thought unlikely that these accounted for
observed changes in eating behaviour. No other side-effects were detected, and
performance on a choice reaction time task was unaffected. These results add
weight to suggestions that endogenous opioids are involved in reward-related
aspects of feeding associated with food palatability.
DOI: 10.1007/BF02244618
PMID: 2315439 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19074899 | 1. Cancer Res. 2008 Dec 15;68(24):10307-14. doi: 10.1158/0008-5472.CAN-08-1954.
MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic
target in human epithelial ovarian cancer.
Yang N(1), Kaur S, Volinia S, Greshock J, Lassus H, Hasegawa K, Liang S, Leminen
A, Deng S, Smith L, Johnstone CN, Chen XM, Liu CG, Huang Q, Katsaros D, Calin
GA, Weber BL, Bützow R, Croce CM, Coukos G, Zhang L.
Author information:
(1)Center for Research on Early Detection and Cure of Ovarian Cancer, University
of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
MicroRNAs (miRNA) are approximately 22-nucleotide noncoding RNAs that negatively
regulate protein-coding gene expression in a sequence-specific manner via
translational inhibition or mRNA degradation. Our recent studies showed that
miRNAs exhibit genomic alterations at a high frequency and their expression is
remarkably deregulated in ovarian cancer, strongly suggesting that miRNAs are
involved in the initiation and progression of this disease. In the present
study, we performed miRNA microarray to identify the miRNAs associated with
chemotherapy response in ovarian cancer and found that let-7i expression was
significantly reduced in chemotherapy-resistant patients (n = 69, P = 0.003).
This result was further validated by stem-loop real-time reverse
transcription-PCR (n = 62, P = 0.015). Both loss-of-function (by synthetic
let-7i inhibitor) and gain-of-function (by retroviral overexpression of let-7i)
studies showed that reduced let-7i expression significantly increased the
resistance of ovarian and breast cancer cells to the chemotherapy drug,
cis-platinum. Finally, using miRNA microarray, we found that decreased let-7i
expression was significantly associated with the shorter progression-free
survival of patients with late-stage ovarian cancer (n = 72, P = 0.042). This
finding was further validated in the same sample set by stem-loop real-time
reverse transcription-PCR (n = 62, P = 0.001) and in an independent sample set
by in situ hybridization (n = 53, P = 0.049). Taken together, our results
strongly suggest that let-7i might be used as a therapeutic target to modulate
platinum-based chemotherapy and as a biomarker to predict chemotherapy response
and survival in patients with ovarian cancer.
DOI: 10.1158/0008-5472.CAN-08-1954
PMCID: PMC2762326
PMID: 19074899 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure of Potential Conflicts of Interest:
No potential conflicts of interest were disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/8075508 | 1. Reprod Toxicol. 1994 May-Jun;8(3):203-5. doi: 10.1016/0890-6238(94)90003-5.
Maternal carbamazepine and infant spina bifida.
Källén AJ(1).
Author information:
(1)Department of Embryology, University of Lund, Sweden.
Women with epilepsy giving birth during 1973 to 1991 were identified by record
linkage of Swedish health registries. Among 3,625 identified infants, 9 had
spina bifida. A nested case-control study was performed, comparing drugs used in
early pregnancy in the 9 cases and in 18 controls, matched for year of delivery,
maternal age, and parity. Six of the spina bifida mothers had used carbamazepine
and two had used valproic acid. Among the controls, 5 women used carbamazepine
and one valproic acid. There is an apparent excess risk for spina bifida after
use of either of these two drugs, but it is not statistically significant when
the analysis is restricted to drug-using women. The findings support earlier
reports in the literature of an association between carbamazepine and spina
bifida.
DOI: 10.1016/0890-6238(94)90003-5
PMID: 8075508 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18056425 | 1. Genes Dev. 2007 Dec 1;21(23):3135-48. doi: 10.1101/gad.1597707.
Mechanism of mRNA deadenylation: evidence for a molecular interplay between
translation termination factor eRF3 and mRNA deadenylases.
Funakoshi Y(1), Doi Y, Hosoda N, Uchida N, Osawa M, Shimada I, Tsujimoto M,
Suzuki T, Katada T, Hoshino S.
Author information:
(1)Department of Biological Chemistry, Graduate School of Pharmaceutical
Sciences, Nagoya City University, Nagoya 467-8603, Japan.
In eukaryotes, shortening of the 3'-poly(A) tail is the rate-limiting step in
the degradation of most mRNAs, and two major mRNA deadenylase
complexes--Caf1-Ccr4 and Pan2-Pan3--play central roles in this process, referred
to as deadenylation. However, the molecular mechanism triggering deadenylation
remains elusive. Previously, we demonstrated that eukaryotic releasing factor
eRF3 mediates deadenylation and decay of mRNA in a manner coupled to translation
termination. Here, we report the mechanism of mRNA deadenylation. The
eRF3-mediated deadenylation is catalyzed by both Caf1-Ccr4 and Pan2-Pan3.
Interestingly, translation termination complexes eRF1-eRF3, Pan2-Pan3, and
Caf1-Ccr4 competitively interact with polyadenylate-binding protein PABPC1. In
each complex, eRF3, Pan3, and Tob, respectively, mediate PABPC1 binding, and a
combination of a PAM2 motif and a PABC domain is commonly utilized for their
contacts. A translation-dependent exchange of eRF1-eRF3 for the deadenylase
occurs on PABPC1. Consequently, PABPC1 binding leads to the activation of
Pan2-Pan3 and Caf1-Ccr4. From these results, we suggest a mechanism of mRNA
deadenylation by Pan2-Pan3 and Caf1-Ccr4 in cooperation with eRF3 and PABPC1.
DOI: 10.1101/gad.1597707
PMCID: PMC2081979
PMID: 18056425 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12437507 | 1. Expert Opin Investig Drugs. 2002 Nov;11(11):1615-22. doi:
10.1517/13543784.11.11.1615.
Treprostinil therapy for pulmonary artery hypertension.
Horn EM(1), Barst RJ.
Author information:
(1)Departments of Medicine and Pediatrics, New York Presbyterian Pulmonary
Hypertension Center, New York, NY, USA. [email protected]
Pulmonary artery hypertension is a life-threatening disease characterised by a
pulmonary vasculopathy and progressive right ventricular failure. Major advances
were made with the development of continuous intravenous epoprostenol (Flolan
trade mark ) as a treatment modality. Nevertheless, it is far from ideal as
treatment for this disease. Subcutaneous treprostinil has been FDA approved for
the treatment of New York Heart Association Functional Class II - IV pulmonary
artery hypertension. It is a longer acting subcutaneous prostacyclin analogue
that offers an additional mode of therapy for this disease. A discussion of the
pharmacology of this prostacyclin analogue as compared to its related compounds,
the clinical studies which led to its approval, a review of some additional
basic studies and the practical use of this drug in the treatment modalities for
precapillary pulmonary artery hypertension in 2002 in light of other available
therapies is discussed.
DOI: 10.1517/13543784.11.11.1615
PMID: 12437507 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24489866 | 1. PLoS One. 2014 Jan 29;9(1):e87185. doi: 10.1371/journal.pone.0087185.
eCollection 2014.
Long-term oral administration of hop flower extracts mitigates Alzheimer
phenotypes in mice.
Sasaoka N(1), Sakamoto M(1), Kanemori S(1), Kan M(1), Tsukano C(2), Takemoto
Y(2), Kakizuka A(1).
Author information:
(1)Laboratory of Functional Biology, Kyoto University Graduate School of
Biostudies, Sakyo-ku, Kyoto, Japan.
(2)Department of Organic Chemistry, Kyoto University Graduate School of
Pharmaceutical Sciences, Sakyo-ku, Kyoto, Japan.
Coincident with the expanding population of aged people, the incidence of
Alzheimer disease (AD) is rapidly increasing in most advanced countries. At
present, no effective prophylactics are available. Among several pathological
mechanisms proposed for AD, the "amyloid hypothesis" has been most widely
accepted, in which accumulation or deposition of Aβ is considered to be the
initial event. Thus, prevention of Aβ production would be an ideal strategy for
the treatment or prevention of AD. Aβ is produced via the proteolytic cleavage
of its precursor protein, APP (amyloid precursor protein), by two different
enzymes, β and γ-secretases. Indeed, inhibitors against either or both enzymes
have been developed and tested for clinical efficacy. Based on the "amyloid
hypothesis", we developed a luciferase-based screening method to monitor
γ-secretase activity, screened more than 1,600 plant extracts, most of which
have long been used in Chinese medicine, and observed that Hop extracts
significantly inhibit Aβ production in cultured cells. A major component of the
inhibitory activity was purified, and its chemical identity was determined by
NMR to be Garcinielliptone HC. In vivo, oral administration of Hop extracts to
AD model mice decreased Aβ depositions in the cerebral cortex of the parietal
lobe, hippocampus, and artery walls (amyloid angiopathy) in the brains. In a
Morris water maze test, AD model mice that had daily consumed Hop extracts in
their drinking water showed significant mitigation of memory impairment at ages
of 9 and 12 months. Moreover, in the open field test oral administration of Hop
extracts also prevented an emotional disturbance that appeared in the AD mice at
18 months. Despite lifelong consumption of Hop extracts, no deleterious side
effects were observed at any age. These results support the "amyloid
hypothesis", and indicate that Hop extract is a promising candidate for an
effective prophylactic for AD.
DOI: 10.1371/journal.pone.0087185
PMCID: PMC3906130
PMID: 24489866 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: In relation to this
manuscript, Kyoto University applied for a domestic (Japanese) patent (Tokugan
2011-19043), and Norio Sasaoka, Megumi Sakamoto, Shoko Kanemori, Chihiro
Tsukano, Yoshiji Takemoto, and Akira Kakizuka were inventors of the applied
patent. Michiru Kan has no competing interests. This does not alter the authors'
adherence to PLOS ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/15226378 | 1. J Cell Sci. 2004 Jul 15;117(Pt 16):3547-59. doi: 10.1242/jcs.01231. Epub 2004
Jun 29.
Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the
helicase Chl1 and the polymerase-alpha-associated protein Ctf4 is essential for
chromatid disjunction during meiosis II.
Petronczki M(1), Chwalla B, Siomos MF, Yokobayashi S, Helmhart W, Deutschbauer
AM, Davis RW, Watanabe Y, Nasmyth K.
Author information:
(1)Research Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna,
Austria.
Cohesion between sister chromatids mediated by a multisubunit complex called
cohesin is established during DNA replication and is essential for the orderly
segregation of chromatids during anaphase. In budding yeast, a specialized
replication factor C called RF-C(Ctf18/Dcc1/Ctf8) and the
DNA-polymerase-alpha-associated protein Ctf4 are required to maintain
sister-chromatid cohesion in cells arrested for long periods in mitosis. We show
here that CTF8, CTF4 and a helicase encoded by CHL1 are required for efficient
sister chromatid cohesion in unperturbed mitotic cells, and provide evidence
that Chl1 functions during S-phase. We also show that, in contrast to mitosis,
RF-C(Ctf18/Dcc1/Cft8), Ctf4 and Chl1 are essential for chromosome segregation
during meiosis and for the viability of meiotic products. Our finding that cells
deleted for CTF8, CTF4 or CHL1 undergo massive meiosis II non-disjunction
suggests that the second meiotic division is particularly sensitive to cohesion
defects. Using a functional as well as a cytological assay, we demonstrate that
CTF8, CHL1 and CTF4 are essential for cohesion between sister centromeres during
meiosis but dispensable for cohesin's association with centromeric DNA. Our
finding that mutants in fission yeast ctf18 and dcc1 have similar defects
suggests that the involvement of the alternative RF-C(Ctf18/Dcc1/Ctf8) complex
in sister chromatid cohesion might be highly conserved.
DOI: 10.1242/jcs.01231
PMID: 15226378 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24556663 | 1. J Pharmacol Exp Ther. 2014 May;349(2):209-20. doi: 10.1124/jpet.113.208223.
Epub 2014 Feb 20.
Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor
nintedanib in experimental models of lung fibrosis.
Wollin L(1), Maillet I, Quesniaux V, Holweg A, Ryffel B.
Author information:
(1)Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany (L.W., A.H.);
UMR7355, INEM, CNRS and University of Orleans, Orleans, France (I.M., V.Q.,
B.R.); and IIDMM, University of Cape Town, Cape Town, Republic of South Africa
(B.R.).
The tyrosine kinase inhibitor nintedanib (BIBF 1120) is in clinical development
for the treatment of idiopathic pulmonary fibrosis. To explore its mode of
action, nintedanib was tested in human lung fibroblasts and mouse models of lung
fibrosis. Human lung fibroblasts expressing platelet-derived growth factor
(PDGF) receptor-α and -β were stimulated with platelet-derived growth factor BB
(homodimer) (PDGF-BB). Receptor activation was assessed by autophosphorylation
and cell proliferation by bromodeoxyuridine incorporation. Transforming growth
factor β (TGFβ)-induced fibroblast to myofibroblast transformation was
determined by α-smooth muscle actin (αSMA) mRNA analysis. Lung fibrosis was
induced in mice by intratracheal bleomycin or silica particle administration.
Nintedanib was administered every day by gavage at 30, 60, or 100 mg/kg.
Preventive nintedanib treatment regimen started on the day that bleomycin was
administered. Therapeutic treatment regimen started at various times after the
induction of lung fibrosis. Bleomycin caused increased macrophages and
lymphocytes in the bronchoalveolar lavage (BAL) and elevated interleukin-1β
(IL-1β), tissue inhibitor of metalloproteinase-1 (TIMP-1), and collagen in lung
tissue. Histology revealed chronic inflammation and fibrosis. Silica-induced
lung pathology additionally showed elevated BAL neutrophils, keratinocyte
chemoattractant (KC) levels, and granuloma formation. Nintedanib inhibited PDGF
receptor activation, fibroblast proliferation, and fibroblast to myofibroblast
transformation. Nintedanib significantly reduced BAL lymphocytes and neutrophils
but not macrophages. Furthermore, interleukin-1β, KC, TIMP-1, and lung collagen
were significantly reduced. Histologic analysis showed significantly diminished
lung inflammation, granuloma formation, and fibrosis. The therapeutic effect was
dependent on treatment start and duration. Nintedanib inhibited receptor
tyrosine kinase activation and the proliferation and transformation of human
lung fibroblasts and showed antifibrotic and anti-inflammatory activity in two
animal models of pulmonary fibrosis. These results suggest that nintedanib may
impact the progressive course of fibrotic lung diseases such as idiopathic
pulmonary fibrosis.
DOI: 10.1124/jpet.113.208223
PMID: 24556663 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23830905 | 1. Neuroscience. 2013 Oct 10;250:8-19. doi: 10.1016/j.neuroscience.2013.06.049.
Epub 2013 Jul 2.
Increased lysosomal biogenesis in activated microglia and exacerbated neuronal
damage after traumatic brain injury in progranulin-deficient mice.
Tanaka Y(1), Matsuwaki T, Yamanouchi K, Nishihara M.
Author information:
(1)Department of Veterinary Physiology, Graduate School of Agricultural and Life
Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Progranulin (PGRN) is known to play a role in the pathogenesis of
neurodegenerative diseases. Recently, it has been demonstrated that patients
with the homozygous mutation in the GRN gene present with neuronal ceroid
lipofuscinosis, and there is growing evidence that PGRN is related to lysosomal
function. In the present study, we investigated the possible role of PGRN in the
lysosomes of activated microglia in the cerebral cortex after traumatic brain
injury (TBI). We showed that the mouse GRN gene has two possible coordinated
lysosomal expression and regulation (CLEAR) sequences that bind to transcription
factor EB (TFEB), a master regulator of lysosomal genes. PGRN was colocalized
with Lamp1, a lysosomal marker, and Lamp1-positive areas in GRN-deficient (KO)
mice were significantly expanded compared with wild-type (WT) mice after TBI.
Expression of all the lysosome-related genes examined in KO mice was
significantly higher than that in WT mice. The number of activated microglia
with TFEB localized to the nucleus was also significantly increased in KO as
compared with WT mice. Since the TFEB translocation is regulated by the
mammalian target of rapamycin complex 1 (mTORC1) activity in the lysosome, we
compared ribosomal S6 kinase 1 (S6K1) phosphorylation that reflects mTORC1
activity. S6K1 phosphorylation in KO mice was significantly lower than that in
WT mice. In addition, the number of nissl-positive and fluoro-jade B-positive
cells around the injury was significantly decreased and increased, respectively,
in KO as compared with WT mice. These results suggest that PGRN localized in the
lysosome is involved in the activation of mTORC1, and its deficiency leads to
increased TFEB nuclear translocation with a resultant increase in lysosomal
biogenesis in activated microglia and exacerbated neuronal damage in the
cerebral cortex after TBI.
Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.neuroscience.2013.06.049
PMID: 23830905 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17578162 | 1. Vnitr Lek. 2007 Apr;53(4):333-7.
[Long-term experience with trerpostinil infusion treatment in patients with
pulmonary arterial hypertension in the Czech Republic].
[Article in Czech]
Jansa P(1), Ambroz D, Maresová J, Jelínková L, Polácek P, Palecek T, Aschermann
M, Linhart A.
Author information:
(1)Centrum pro plicní hypertenzi II. interní kliniky kardiologie a angiologie 1.
lékarské fakulty UK a VFN Praha. [email protected]
INTRODUCTION: Pulmonary arterial hypertension (PAH) is a serious primary illness
of the pulmonary arterioles, characterised by progressive precapillary pulmonary
hypertension. The conventional therapy for this condition is so-called specific
pharmacotherapy, which addresses the key mechanisms in the pathophysiology of
the illness, making use of drugs from the prostanoid group, endothelin receptor
antagonists and phosphodiesterase inhibitors. Treprostinil is a stable analogue
of prostacyclin, which can be administered subcutaneously, intravenously or by
inhalation.
PATIENT SAMPLE AND METHOD: In the centre for pulmonary hypertension in the
Second Internal Clinic of Cardiology and Angiology of 1st Faculty of Medicine,
Charles University, and the General Teaching Hospital in Prague, 22 patients
with PAH (idiopathic PAH, familial PAH, PAH associated with congenital heart
disease and PAH associated with systemic connective tissue disease) were treated
with trerpostinil, 18 patients with a continuous subcutaneous infusion and 4
patients with a continuous intravenous infusion. The indicators followed were
the distance reached in a 6-minute walking test, functional capacity assessed by
NYHA classification and mortality.
RESULTS: The patients for whom treprostinil treatment was indicated had an
average pressure in the right atrium of 11.9 +/- 4.2 mm Hg, average pressure in
the pulmonary artery of 56.8 +/- 10.7 mm Hg, a cardiac index of 1.78 +/- 0.25
l/min/m2 and a total pulmonary resistance of 16.26 +/- 4.48 WU. 15 patients were
functionally NYHA III and 7 patients were NYHA IV. The average distance achieved
in a 6-minute walk test before the start of treatment was 326 +/- 83 m. When
treated with gradually increasing doses of treprostinil the distance achieved in
the 6-minute walk test improved. After 6 months, the group that received
subcutaneous treatment had extended their distance to 359 m, after 12 months it
was 393 m, after 24 months 447 m and after 36 months 494 m. After 6 months, the
group that received intravenous treatment had extended their distance to 473 m,
which increased to 451 m after 12 months and 489 m after 24 months. Functional
capacity also improved. In total 5 patients were unable to tolerate the
subcutaneous infusion, of whom 3 were placed on intravenous treprostinil and 2
on oral bosentan. 7 of the patients died in the period examined (31.8%).
CONCLUSION: Treprostinil improves symptoms and hemodynamics for PAH patients and
reduces mortality.
PMID: 17578162 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12897129 | 1. Mol Cell Biol. 2003 Aug;23(16):5540-55. doi: 10.1128/MCB.23.16.5540-5555.2003.
deltaNp73 facilitates cell immortalization and cooperates with oncogenic Ras in
cellular transformation in vivo.
Petrenko O(1), Zaika A, Moll UM.
Author information:
(1)Department of Pathology, Stony Brook University, Stony Brook, New York 11794,
USA.
TP73, despite significant homology to TP53, is not a classic tumor suppressor
gene, since it exhibits upregulation of nonmutated products in human tumors and
lacks a tumor phenotype in p73-deficient mice. We recently reported that an
N-terminally truncated isoform, DeltaNp73, is upregulated in breast and
gynecological cancers. We further showed that DeltaNp73 is a potent
transdominant inhibitor of wild-type p53 and TAp73 in cultured human tumor cells
by efficiently counteracting their target gene transactivations, apoptosis, and
growth suppression functions (A. I. Zaika et al., J. Exp. Med. 6:765-780, 2002).
Although these data strongly suggest oncogenic properties of DeltaNp73, this can
only be directly shown in primary cells. We report here that DeltaNp73 confers
resistance to spontaneous replicative senescence of primary mouse embryo
fibroblasts (MEFs) and immortalizes MEFs at a 1,000-fold-higher frequency than
occurs spontaneously. DeltaNp73 cooperates with cMyc and E1A in promoting
primary cell proliferation and colony formation and compromises p53-dependent
MEF apoptosis. Importantly, DeltaNp73 rescues Ras-induced senescence. Moreover,
DeltaNp73 cooperates with oncogenic Ras in transforming primary fibroblasts in
vitro and in inducing MEF-derived fibrosarcomas in vivo in nude mice. Wild-type
p53 is likely a major target of DeltaNp73 inhibition in primary fibroblasts
since deletion of p53 or its requisite upstream activator ARF abrogates the
growth-promoting effect of DeltaNp73. Taken together, DeltaNp73 behaves as an
oncogene that targets p53 that might explain why DeltaNp73 upregulation may be
selected for during tumorigenesis of human cancers.
DOI: 10.1128/MCB.23.16.5540-5555.2003
PMCID: PMC166317
PMID: 12897129 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19842203 | 1. Am J Med Genet A. 2009 Nov;149A(11):2527-31. doi: 10.1002/ajmg.a.33067.
Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American
cohort: a suggested approach to molecular diagnostics.
Saunders CJ(1), Zhao W, Ardinger HH.
Author information:
(1)Department of Pathology and Laboratory Medicine, The Children's Mercy
Hospitals and Clinics, Kansas City, Missouri 64108, USA. [email protected]
Mowat-Wilson syndrome is a genetic condition characterized by a recognizable
facial phenotype in addition to moderate to severe cognitive disability with
severe speech impairment and variable multiple congenital anomalies. The
anomalies may include Hirschsprung disease, heart defects, structural eye
anomalies including microphthalmia, agenesis of the corpus callosum, and
urogenital anomalies. Microcephaly, seizure disorder and constipation are
common. All typical cases result from haploinsufficiency of the ZEB2 (also known
as ZFHX1B or SIP-1) gene, with over 100 distinct mutations now described.
Approximately 80% of patients have a nonsense or frameshift mutation detectable
by sequencing, with the rest having gross deletions necessitating a dosage
sensitive assay. Here we report on the results of comprehensive molecular
testing for 27 patients testing positive for MWS. Twenty-one patients had a
nonsense, frameshift, or splice site mutation identified by sequencing; 14 of
which localized to exon 8 and 17 of which are novel. Six patients had deletions
in the ZEB2 gene, including two novel partial gene deletions. This report, the
first such analysis in North American patients, adds to the growing list of both
novel pathogenic mutations associated with MWS, as well as other variants in the
ZEB2 gene. In addition, we suggest an economical testing strategy.
Copyright 2009 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.33067
PMID: 19842203 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21497181 | 1. Neuroscience. 2011 Sep 15;191:101-6. doi: 10.1016/j.neuroscience.2011.04.013.
Epub 2011 Apr 14.
Progesterone in the treatment of acute traumatic brain injury: a clinical
perspective and update.
Stein DG(1).
Author information:
(1)Brain Research Laboratory, Department of Emergency Medicine, Emory
University, 1365 B Clifton Road NE, Suite 5100, Atlanta, GA 30322, USA.
[email protected]
Despite decades of laboratory research and clinical trials, a safe and effective
treatment for traumatic brain injury has yet to reach clinical practice. The
failure is due in part to the prevalence of a reductionist philosophy and
research praxis that targets a single receptor mechanism, gene, or brain locus.
This approach fails to account for the fact that traumatic brain injury is a
very complex disease caused by a cascade of systemic toxic events in the brain
and throughout the body. Attention is now turning to pleiotropic drugs that act
on multiple genomic, proteomic, and metabolic pathways to enhance morphological
and functional outcomes after brain injury. Of the agents now in clinical trial,
the neurosteroid progesterone appears to hold considerable promise. Many still
assume that progesterone is "just a female hormone" with limited, if any,
neuroprotective properties, but this view is outdated. This review will survey
the evidence that progesterone has salient pleiotropic properties as a
neuroprotective agent in a variety of central nervous system injury models. This
article is part of a Special Issue entitled: Neuroactive Steroids: Focus on
Human Brain.
Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.neuroscience.2011.04.013
PMID: 21497181 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8876687 | 1. Mutat Res. 1996 Oct 25;357(1-2):115-21. doi: 10.1016/0027-5107(96)00091-7.
Effect of hydroxyurea and normal plasma on DNA synthesis in lymphocytes from
Fanconi anemia patients.
Frias S(1), Gómez L, Molina B, Rojas E, Ostrosky-Wegman P, Carnevale A.
Author information:
(1)Genetics Department, Instituto Nacional de Pediatría, México D.F., Mexico.
Fanconi anemia (FA) is characterized at the cellular level by a high frequency
of spontaneous chromosomal aberrations; crosslinking agents cause an abnormal
increase in the frequency of chromosomal damage, and semiconservative DNA
synthesis is severely inhibited. Deoxyribonucleotides are needed in both
semiconservative and repair DNA synthesis. To investigate the involvement of
deoxyribonucleotide pools in the inhibition of DNA synthesis in FA, we evaluated
the effect on FA lymphocytes of hydroxyurea (HU), an inhibitor of ribonucleotide
reductase which is known to alter the intracellular levels of
deoxyribonucleotides. To achieve this goal, lymphocyte cultures of 4 FA patients
and 4 normal individuals were used. Cultures were treated with HU and/or
mitomycin C and normal human plasma. All cultures were processed to detect the
number of DNA synthesizing nuclei by autoradiography. Scoring of 2000 nuclei for
each kind of culture every 6 h in the last 24 h of incubation showed that, in
long incubation periods, DNA synthesis in FA is largely inhibited by HU and this
hypersensitivity may be partially decreased by addition of normal human plasma.
It is known that recovery from damage induced by HU involves several enzymes
such as flavin oxido-reductase, superoxide dismutase and catalase which are
involved in the production or scavenging of O2 radicals; FA cells are deficient
in the detoxification of oxygen and this could explain the response of FA cells
to HU.
DOI: 10.1016/0027-5107(96)00091-7
PMID: 8876687 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17962579 | 1. J Appl Physiol (1985). 2008 Jan;104(1):178-85. doi:
10.1152/japplphysiol.00643.2007. Epub 2007 Oct 25.
Thyroid hormone (T3) rapidly activates p38 and AMPK in skeletal muscle in vivo.
Irrcher I(1), Walkinshaw DR, Sheehan TE, Hood DA.
Author information:
(1)Department of Biology, York University, Toronto, Ontario, Canada.
Thyroid hormone (T(3)) regulates the function of many tissues within the body.
The effects of T(3) have largely been attributed to the modulation of thyroid
hormone receptor-dependent gene transcription. However, nongenomic actions of
T(3) via the initiation of signaling events are emerging in a number of cell
types. This study investigated the ability of short-term T(3) treatment to
phosphorylate and, therefore, activate signaling proteins in rat tissues in
vivo. The kinases investigated included p38, AMP-activated protein kinase
(AMPK), and extracellular signal-regulated kinase (ERK) 1/2. Following 2 h of
T(3) treatment, p38 and AMPK phosphorylation was increased in both the
slow-twitch soleus and the fast-twitch plantaris muscles. In contrast, ERK1/2
was not activated in either muscle type. Neither p38 nor AMPK was affected in
heart. However, AMPK activation was decreased by T(3) in liver. ERK1/2
activation was decreased by T(3) in heart, but increased in liver. Possible
downstream consequences of T(3)-induced kinase phosphorylation were investigated
by measuring cAMP response element binding protein (CREB) and thyroid hormone
receptor DNA binding, as well as peroxisome proliferator-activated
receptor-alpha coactivator-1 mRNA levels. Protein DNA binding to the cAMP or
thyroid hormone response elements was unaltered by T(3). However, peroxisome
proliferator-activated receptor-alpha coactivator-1 mRNA expression was
increased following 12 h of T(3) treatment in soleus. These data are the first
to characterize the effects of T(3) treatment on kinase phosphorylation in vivo.
We show that T(3) rapidly modifies kinase activity in a tissue-specific fashion.
Moreover, the T(3)-induced phosphorylation of p38 and AMPK in both slow- and
fast-twitch skeletal muscles suggests that these events may be important in
mediating hormone-induced increases in mitochondrial biogenesis in skeletal
muscle.
DOI: 10.1152/japplphysiol.00643.2007
PMID: 17962579 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23448446 | 1. Curr Pharm Des. 2013;19(34):6156-85. doi: 10.2174/1381612811319340010.
Epigenetic and disease targets by polyphenols.
Pan MH(1), Lai CS, Wu JC, Ho CT.
Author information:
(1)Department of Food Science, Rutgers University, 65 Dudley Road, New
Brunswick, NJ 08901, USA. [email protected].
An epigenetic change is defined as an alteration in gene expression that does
not involve a change in the DNA sequence. Epigenetic modifications, including
DNA methylation, histone modification (acetylation, methylation and
phosphorylation) and miRNA, are critical for regulating developmental events.
However, aberrant epigenetic mechanisms may lead to pathological consequences
such as cardiovascular disease (CAD), neurodegenerative disease, obesity,
metabolic disorder, bone and skeletal diseases and various cancers. Given that
epigenetic modifications are heritable and reversible, in contrast to genetic
changes, they have been identified as promising targets for disease prevention
strategies. Over the past few decades, polyphenols, which are widely present in
foods such as fruits and vegetables, have been shown to exhibit a broad spectrum
of biological activities for human health. Polyphenols reverse adverse
epigenetic regulation by altering DNA methylation and histone modification, and
they modulate microRNA expression or directly interact with enzymes that result
in the reactivation of silenced tumor suppressor genes or the inactivation of
oncogenes. Therefore, dietary polyphenol- targeted epigenetics becomes an
attractive approach for disease prevention and intervention. In this review, we
summarize the current knowledge and underlying mechanisms of the most common
dietary polyphenols and their influence on major epigenetic mechanisms
associated with disease intervention.
DOI: 10.2174/1381612811319340010
PMID: 23448446 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21656899 | 1. Birth Defects Res A Clin Mol Teratol. 2011 Sep;91(9):842-7. doi:
10.1002/bdra.20837. Epub 2011 Jun 8.
Semaphorin 3A expression in the colon of Hirschsprung disease.
Wang LL(1), Fan Y, Zhou FH, Li H, Zhang Y, Miao JN, Gu H, Huang TC, Yuan ZW.
Author information:
(1)Key Laboratory of Health Ministry for Congenital Malformation, Shengjing
Hospital, China Medical University, Shenyang.
BACKGROUND: Hirschsprung disease (HSCR) is a congenital disorder characterized
by an absence of intrinsic ganglion cells in the nerve plexuses of the lower
colon. The Semaphorin 3A (SEMA3A) gene is involved in the migration of enteric
neural precursors (ENPs). To analyze the function of SEMA3A in HSCR, the SEMA3A
expression in different colon segments in HSCR was examined.
METHODS: The expression levels of SEMA3A in both ganglionic and aganglionic
colon tissues of 32 patients with HSCR and in colon tissue of 5 newborn
unaffected individuals were examined by real-time RT-PCR, Western-blot, and
immunohistology.
RESULTS: Comparison of SEMA3A expression levels between ganglionic and
aganglionic tissues in HSCR revealed upregulation of SEMA3A expression in 43.75%
(14/32) of the aganglionic colons. SEMA3A was expressed in the ganglion cells of
the myenteric plexus, submucosa, as well as in the longitudinal and circular
muscle layer of the normal colon of both unaffected newborns and patients with
HSCR. In the aganglionic segment of patients with HSCR, SEMA3A was highly
expressed in the circular muscle layer and was also detected in the submucosa
and in the longitudinal muscles layer. The fluorescence intensity of SEMA3A in
the circular muscle layer in the aganglionic segment was much higher than that
in ganglionic segment (p < .001).
CONCLUSION: SEMA3A expression was upregulated in the aganglionic smooth muscle
layer of the colon in some patients with HSCR and our data suggest that
increased SEMA3A expression may be a risk factor for HSCR pathology in a subset
of patients.
Copyright © 2011 Wiley-Liss, Inc.
DOI: 10.1002/bdra.20837
PMID: 21656899 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23836287 | 1. Tumour Biol. 2013 Dec;34(6):3501-8. doi: 10.1007/s13277-013-0928-3. Epub 2013
Jul 9.
MiRNA expression signature for potentially predicting the prognosis of ovarian
serous carcinoma.
Yu X(1), Zhang X, Bi T, Ding Y, Zhao J, Wang C, Jia T, Han D, Guo G, Wang B,
Jiang J, Cui S.
Author information:
(1)Department of Histology and Embryology, Dalian Medical University, No 9
LvShun South Road-W, 116044, Dalian, China.
One of the best prognostic predictors for patients with epithelial ovarian
cancer is the Federation of Obstetrics and Gynecology (FIGO) stage at diagnosis.
Advanced-stage ovarian serous carcinoma (OSC) generally have poor prognosis. The
goal of this study is to develop and validate a miRNA expression profile that
can differentiate the OSC at early and advanced stages and study its correlation
with the prognosis of OSC. To identify a unique microRNA (miRNA) pattern
associated with the progression of OSC at early and advanced stages, a miRNA
microarray was performed using Chinese tumor bank specimens of patients with OSC
stage I or III in a retrospective analysis. The expression of four dysregulated
miRNAs was validated using quantitative real-time polymerase chain reaction
(qRT-PCR) in an external cohort of 51 cases of OSC samples at stages I and III.
Kaplan-Meier analysis was performed to analyze the correlation between the
expression of some miRNAs and prognosis. Of the 768 miRNAs analyzed in the
microarray, 26 miRNAs were significantly either up- or downregulated, with at
least a 2-fold difference, in OSC stage I compared with stage III. The qRT-PCR
results showed that miR-510, miR-509-5p, and miR-508-3p were significantly
downregulated and that miR-483-5p was upregulated in stage III OSC compared with
stage I, which was consistent with the microarray results. Kaplan-Meier analysis
showed low miR-510 expression, low miR-509-5p expression, and advanced FIGO
stage, and chemotherapy resistance were significantly associated with poorer
overall survival (P < 0.05). Our results suggest that miRNAs may play a role in
the progression of OSC, and miR-510 and miR-509-5p may be considered
novel-candidate clinical biomarkers for predicting OSC outcome.
DOI: 10.1007/s13277-013-0928-3
PMID: 23836287 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25801169 | 1. Mol Cell. 2015 Apr 16;58(2):362-70. doi: 10.1016/j.molcel.2015.02.014. Epub
2015 Mar 19.
Convergence of developmental and oncogenic signaling pathways at transcriptional
super-enhancers.
Hnisz D(1), Schuijers J(1), Lin CY(2), Weintraub AS(3), Abraham BJ(1), Lee
TI(1), Bradner JE(2), Young RA(4).
Author information:
(1)Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge,
MA 02142, USA.
(2)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
02115, USA.
(3)Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge,
MA 02142, USA; Department of Biology, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA.
(4)Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge,
MA 02142, USA; Department of Biology, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA. Electronic address: [email protected].
Comment in
Cancer Discov. 2015 May;5(5):OF11. doi: 10.1158/2159-8290.CD-RW2015-056.
Super-enhancers and stretch enhancers (SEs) drive expression of genes that play
prominent roles in normal and disease cells, but the functional importance of
these clustered enhancer elements is poorly understood, so it is not clear why
genes key to cell identity have evolved regulation by such elements. Here, we
show that SEs consist of functional constituent units that concentrate multiple
developmental signaling pathways at key pluripotency genes in embryonic stem
cells and confer enhanced responsiveness to signaling of their associated genes.
Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we
show that these genes are especially sensitive to perturbation of oncogenic
signaling pathways. Super-enhancers thus provide a platform for signaling
pathways to regulate genes that control cell identity during development and
tumorigenesis.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2015.02.014
PMCID: PMC4402134
PMID: 25801169 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23729230 | 1. Int J Cancer. 2013 Dec 1;133(11):2587-95. doi: 10.1002/ijc.28295. Epub 2013
Jun 21.
TACE-dependent TGFα shedding drives triple-negative breast cancer cell invasion.
Giricz O(1), Calvo V, Peterson EA, Abouzeid CM, Kenny PA.
Author information:
(1)Department of Developmental & Molecular Biology, Albert Einstein College of
Medicine, Bronx, NY.
The epidermal growth factor receptor (EGFR) is frequently expressed in
triple-negative breast cancer (TNBC) and is a marker of poor prognosis in this
patient population. Because activating mutations in this kinase are very rare
events in breast cancer, we screened breast tumor gene expression profiles to
examine the distribution of EGFR ligand expression. Of the six known EGFR
ligands, transforming growth factor alpha (TGFα) was expressed more highly in
triple-negative breast tumors than in tumors of other subtypes. TGFα is
synthesized as a transmembrane precursor requiring tumor necrosis factor alpha
converting enzyme (TACE)/ADAM17-dependent proteolytic release to activate its
receptor. In our study, we show that an inhibitor of this proteolytic release
blocks invasion, migration and colony formation by several TNBC cell lines. Each
of the effects of the drug was reversed upon expression of a soluble TGFα mutant
that does not require TACE activity, implicating this growth factor as a key
metalloproteinase substrate for these phenotypes. Together, these data
demonstrate that TACE-dependent TGFα shedding is a key process driving EGFR
activation and subsequent proliferation and invasion in TNBC cell lines.
Copyright © 2013 UICC.
DOI: 10.1002/ijc.28295
PMCID: PMC3966141
PMID: 23729230 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25280590 | 1. Transfus Med Rev. 2014 Oct;28(4):187-97. doi: 10.1016/j.tmrv.2014.08.004. Epub
2014 Sep 3.
A mechanistic approach to the diagnosis and management of atypical hemolytic
uremic syndrome.
Tsai HM(1).
Author information:
(1)iMAH Hematology Associates, New Hyde Park, NY; EDA Hospital, Kaohsiung,
Taiwan. Electronic address: [email protected].
Until recently, atypical hemolytic uremic syndrome (aHUS), conventionally
defined in the pediatric literature as a syndrome of the triad of renal failure,
microangiopathic hemolytic anemia, and thrombocytopenia without a prodrome of
hemorrhagic diarrhea, has received little attention in adult practice because
the patients are commonly given the diagnosis of thrombotic thrombocytopenic
purpura (TTP) or TTP/HUS and treated as TTP with plasma exchange, augmented in
refractory cases with rituximab and sometimes even splenectomy. Molecular
studies have shown that the regulation of the alternative complement pathway is
defective in many patients with conventionally defined aHUS. With this new
knowledge and the findings of ADAMTS13 autoinhibitors or mutations in TTP, it is
time to redefine aHUS as a disorder with propensity to the development of
thrombotic microangiopathy due to defective regulation of the alternative
complement pathway and TTP as a disorder with propensity to arteriolar and
capillary thrombosis due to ADAMTS13 deficiency. This new definition provides a
clear distinction of aHUS from TTP, encompasses patients without all 3
components of the triad, and provides the rationale for management with
anticomplement therapy.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.tmrv.2014.08.004
PMID: 25280590 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16289269 | 1. Cell Calcium. 2006 Feb;39(2):131-42. doi: 10.1016/j.ceca.2005.10.004. Epub
2005 Nov 9.
Overexpression of junctin causes adaptive changes in cardiac myocyte Ca(2+)
signaling.
Kirchhefer U(1), Hanske G, Jones LR, Justus I, Kaestner L, Lipp P, Schmitz W,
Neumann J.
Author information:
(1)Institut für Pharmakologie und Toxikologie, Westfälische
Wilhelms-Universität, Domagkstr. 12, 48149 Münster, Germany.
In cardiac muscle, junctin forms a quaternary protein complex with the ryanodine
receptor (RyR), calsequestrin, and triadin 1 at the luminal face of the
junctional sarcoplasmic reticulum (jSR). By binding directly the RyR and
calsequestrin, junctin may mediate the Ca(2+)-dependent regulatory interactions
between both proteins. To gain more insight into the underlying mechanisms of
impaired contractile relaxation in transgenic mice with cardiac-specific
overexpression of junctin (TG), we studied cellular Ca(2+) handling in these
mice. We found that the SR Ca(2+) load was reduced by 22% in cardiomyocytes from
TG mice. Consistent with this, the frequency of Ca(2+) sparks was diminished by
32%. The decay of spontaneous Ca(2+) sparks was prolonged by 117% in TG. This
finding was associated with a lower Na(+)-Ca(2+) exchanger (NCX) protein
expression (by 67%) and a higher basal RyR phosphorylation at Ser(2809) (by 64%)
in TG. The shortening- and Delta[Ca](i)-frequency relationships (0.5-4 Hz) were
flat in TG compared to wild-type (WT) which exhibited a positive staircase for
both parameters. Furthermore, increasing stimulation frequencies hastened the
time of relaxation and the decay of [Ca](i) by a higher percentage in TG. We
conclude that the impaired relaxation in TG may result from a reduced NCX
expression and/or a higher SR Ca(2+) leak. The altered shortening-frequency
relationship in TG seems to be a consequence of an impaired
excitation-contraction coupling with depressed SR Ca(2+) release at higher rates
of stimulation. Our data suggest that the more prominent frequency-dependent
hastening of relaxation in TG results from a stimulation of SR Ca(2+) transport
reflected by corresponding changes of [Ca](i).
DOI: 10.1016/j.ceca.2005.10.004
PMID: 16289269 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24985919 | 1. BMC Infect Dis. 2014 Jul 1;14:357. doi: 10.1186/1471-2334-14-357.
Characterisation of inflammatory response, coagulation, and radiological
findings in Katayama fever: a report of three cases at the Medical University of
Vienna, Austria.
Lagler H, Ay C, Waneck F, Gattringer R, Graninger W, Ramharter M(1).
Author information:
(1)Department of Medicine I, Division of Infectious Diseases and Tropical
Medicine, Medical University of Vienna, Währinger Gürtel 18-20, Vienna 1090,
Austria. [email protected].
BACKGROUND: Katayama fever is an acute clinical condition characterised by high
fever, dry cough and general malaise occurring during early Schistosoma spp.
infection. It is predominantly reported in travellers from non-endemic regions.
Whereas the immunological response to Schistosoma infection is well
characterised, alterations in inflammatory markers and coagulation in response
to acute infection are poorly understood.
METHODS: Here we report the clinical, laboratory and radiological
characteristics of three returning travellers with Katayama fever. Inflammatory
markers and coagulation status were assessed repeatedly during follow-up to
characterise the host response to infection. Radiographic findings were
correlated with clinical and laboratory markers.
RESULTS: Clinical symptoms were suggestive of a significant inflammatory
response in all patients including high fever (>39°C), cough, and general
malaise. Classical inflammatory markers including blood sedimentation rate,
C-reactive protein, and serum amyloid A were only moderately elevated. Marked
eosinophilia (33-42% of white blood cells) was observed and persisted despite
anti-inflammatory and anthelminthic treatment for up to 32 weeks. Analysis of
blood coagulation markers indicated increased coagulability reflected by
elevated D-dimer values (0.57-1.17 μg/ml) and high thrombin generating
potentials (peak thrombin activity: 311-384 nM). One patient showed particularly
high levels of microparticle-associated tissue factor activity at initial
presentation (1.64 pg/ml). Multiple pulmonary and hepatic opacities demonstrated
by computed tomography (CT) scanning were associated with raised inflammatory
markers in one patient.
CONCLUSIONS: The characterisation of the inflammatory response, blood
coagulation parameters and radiological findings in three patients adds to our
current understanding of Katayama fever and serves as a starting point for
further systematic investigations of the pathophysiology of this acute
helminthic infection.
DOI: 10.1186/1471-2334-14-357
PMCID: PMC4085376
PMID: 24985919 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21772710 | 1. J Anaesthesiol Clin Pharmacol. 2011 Apr;27(2):293-4. doi:
10.4103/0970-9185.81853.
Cerebral autosomal dominant arteriopathy with subcortical infarct and
leukoencephalopathy: A rare syndrome raising anesthetic concerns!
Singh GP(1), Mahajan C, Prabhakar H, Bindra A.
Author information:
(1)Department of Neuroanaesthesiology, All India Institute of Medical Sciences,
New Delhi - 110 029, India.
DOI: 10.4103/0970-9185.81853
PMCID: PMC3127329
PMID: 21772710 |
http://www.ncbi.nlm.nih.gov/pubmed/22193623 | 1. Mol Biol Rep. 2012 May;39(5):5561-7. doi: 10.1007/s11033-011-1360-7. Epub 2011
Dec 23.
Associations between matrilin-1 gene polymorphisms and adolescent idiopathic
scoliosis curve patterns in a Korean population.
Bae JW(1), Cho CH, Min WK, Kim UK.
Author information:
(1)Department of Biology, College of Natural Sciences, Kyungpook National
University, Daegu, 702-701, Korea.
Erratum in
Mol Biol Rep. 2012 Sep;39(9):9275.
Adolescent idiopathic scoliosis (AIS) is a complex disorder with an unclear
etiology and pathogenesis. In previous studies, genome-wide linkage and genetic
association analyses have been carried out to find genetic factors linked with
AIS. In this study, we examined whether the susceptibility to AIS is associated
with MATN1 gene polymorphisms in a Korean population, which included 166
individuals with AIS and 126 controls. We found that there were no statistically
significant associations between any of the MATN1-linked allele or genotype
frequencies between AIS and controls. However, statistically significant
associations were found at single nucleotide polymorphism (SNP) rs1065755 when
comparing the curve patterns of AIS with the controls. The A allele of SNP
rs1065755 was associated with a higher risk of AIS than the allele G in the
genotype-phenotype (curve pattern) analysis (P = 0.029). In addition, the
frequency of the A allele of SNP rs1065755 in AIS with double major curves was
higher than in controls (P = 0.021, ORs = 2.56 within 95% CI = 1.12-5.83).
Additionally, among the predicted common haplotypes, the frequency of the
haplotype GATT (31.3%) in AIS with double major curves was higher than in
controls (15.2%) (P = 0.024, ORs = 2.54 within 95% CI = 1.11-5.84). We conclude
that the A allele of SNP rs1065755 in the MATN1 gene is associated with AIS.
DOI: 10.1007/s11033-011-1360-7
PMID: 22193623 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23042258 | 1. Ther Drug Monit. 2012 Dec;34(6):607-14. doi: 10.1097/FTD.0b013e31826d07ea.
Prenatal exposure to selective serotonin reuptake inhibitors and infant outcome.
Malm H(1).
Author information:
(1)Teratology Information, HUSLAB and Helsinki University Central Hospital,
Helsinki, Finland. [email protected]
BACKGROUND: The selective serotonin reuptake inhibitors are prescribed
increasingly also during pregnancy. Although a number of studies have assessed
their safety, data concerning congenital malformations and adverse perinatal
outcome are conflicting.
METHODS: Literature search in PubMed until March 31, 2012, including original
research articles, meta-analyses, and reviews.
RESULTS: Fluoxetine and paroxetine use in early pregnancy has been associated
with a small increased risk for specific cardiovascular malformations in some
studies, fluoxetine with ventricular septal defects and paroxetine with right
ventricular outflow tract defects. The observed absolute risk for these specific
malformations is small. Data on preterm birth, low birth weight, and being small
for gestational age have been conflicting; and mother's underlying depression is
obviously an important confounder. Respiratory distress and neonatal adaptation
problems are common in prenatally exposed infants, and an increased risk for
persistent pulmonary hypertension of the newborn has been observed in several
studies. Although several studies have not confirmed an increased risk for
adverse neurodevelopment, a recent study observed an increased risk for autism
spectrum disorders in prenatally exposed offspring.
CONCLUSIONS: Causality cannot be confirmed in observational study settings.
However, parallel results in individual studies regarding the cardiac
malformations and pulmonary hypertension of the newborn, together with an
existing biologically plausible mechanism behind these events may support
causality. Considering the important role of serotonin in central nervous system
development, more studies are needed to assess the possible adverse effects on
long-term neurodevelopment.
DOI: 10.1097/FTD.0b013e31826d07ea
PMID: 23042258 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9664695 | 1. J Mol Evol. 1998 Jul;47(1):42-51. doi: 10.1007/pl00006361.
Variation of microsatellite size homoplasy across electromorphs, loci, and
populations in three invertebrate species.
Viard F(1), Franck P, Dubois MP, Estoup A, Jarne P.
Author information:
(1)Institut des Sciences de l'Evolution, Université Montpellier II, France.
[email protected]
Size homoplasy was analyzed at microsatellite loci by sequencing electromorphs,
that is, variants of the same size (base pairs). This study was conducted using
five interrupted and/or compound loci in three invertebrate species, the honey
bee Apis mellifera, the bumble bee Bombus terrestris, and the freshwater snail
Bulinus truncatus. The 15 electromorphs sequenced turned out to hide 31 alleles
(i.e., variants identical in sequence). Variation in the amount of size
homoplasy was detected among electromorphs and loci. From one to seven alleles
were detected per electromorph, and one locus did not show any size homoplasy in
both bee species. The amount of size homoplasy was related to the sequencing
effort, since the number of alleles was correlated with the number of copies of
electromorphs sequenced, but also with the molecular structure of the core
sequence at each locus. Size homoplasy within populations was detected only
three times, meaning that size homoplasy was detected mostly among populations.
We analyzed population structure, estimating Fst and a genetic distance, based
on either electromorphs or alleles. Whereas little difference was found in A.
mellifera, uncovering size homoplasy led to a more marked population structure
in B. terrestris and B. truncatus. We also showed in A. mellifera that the
detection of size homoplasy may alter phylogenetic reconstructions.
DOI: 10.1007/pl00006361
PMID: 9664695 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22077640 | 1. J Cutan Pathol. 2012 Mar;39(3):366-71. doi: 10.1111/j.1600-0560.2011.01813.x.
Epub 2011 Nov 12.
Brooke-Spiegler syndrome: report of two cases not associated with a mutation in
the CYLD and PTCH tumor-suppressor genes.
Ponti G(1), Nasti S, Losi L, Pastorino L, Pollio A, Benassi L, Giudice S,
Bertazzoni G, Veratti E, Azzoni P, Bianchi Scarrà G, Seidenari S.
Author information:
(1)Division of Dermatology, Department of Internal Medicine, University of
Modena and Reggio Emilia, Modena, Italy. [email protected]
Brooke-Spiegler syndrome represents an autosomal dominant disease characterized
by the occurrence of multiple cylindromas, trichoepitheliomas and (sporadically)
spiroadenomas. Patients with Brooke-Spiegler syndrome are also at risk of
developing tumors of the major and minor salivary glands. Patients with
Brooke-Spiegler syndrome have various mutations in the CYLD gene, a
tumor-suppressor gene located on chromosome 16q. To date, 68 unique CYLD
mutations have been identified. We describe two families with Brooke-Spiegler
syndrome, one with familial cylindromatosis and one with multiple familial
trichoepithelioma, which showed wide inter-family phenotypic variability.
Analysis of germline mutations of the CYLD and PTCH genes was performed using
peripheral blood. In addition, formalin-fixed paraffin-embedded tumor samples
were analyzed for PTCH somatic mutations and cylindroma cell cultures were
obtained directly from patients for further growth and analysis. Clinically, the
major features of Brooke-Spiegler syndrome include the presence of heterogeneous
skin tumors and wide inter- and intra-familial phenotypic variability.
Histopathologically, both cylindromas and trichoepitheliomas were found in
affected individuals. Mutations or loss of heterozygosity was not found in CYLD
and PTCH genes. In CYLD and PTCH mutation-negative patients, other genes may be
affected and further studies are needed to clarify whether these patients may be
affected by de novo germline mutations.
Copyright © 2011 John Wiley & Sons A/S.
DOI: 10.1111/j.1600-0560.2011.01813.x
PMID: 22077640 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24323361 | 1. J Mol Neurosci. 2014 Jan;52(1):28-36. doi: 10.1007/s12031-013-0193-3. Epub
2013 Dec 10.
Influence of terminal differentiation and PACAP on the cytokine, chemokine, and
growth factor secretion of mammary epithelial cells.
Csanaky K(1), Doppler W, Tamas A, Kovacs K, Toth G, Reglodi D.
Author information:
(1)Department of Anatomy, PTE-MTA "Lendulet" PACAP Research Team, University of
Pecs, Szigeti ut 12, Pecs, 7624, Hungary.
Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with
trophic and cytoprotective effects, has been shown to affect cell survival,
proliferation, and also differentiation of various cell types. The high PACAP
level in the milk and its changes during lactation suggest a possible effect of
PACAP on the differentiation of mammary epithelial cells. Mammary cell
differentiation is regulated by hormones, growth factors, cytokines/chemokines,
and angiogenic proteins. In this study, differentiation was hormonally induced
by lactogenic hormones in confluent cultures of HC11 mouse mammary epithelial
cells. We investigated the effect of PACAP on mammary cell differentiation as
well as release of cytokines, chemokines, and growth factors. Differentiation
was assessed by expression analysis of the milk protein β-casein.
Differentiation significantly decreased the secretion of interferon gammainduced
protein (IP)-10, "regulated upon activation normal T cell expressed and
presumably secreted" (RANTES), insulin-like growth factor-binding protein
(IGFBP)-3 and the epidermal growth factor receptor (EGFR) ligands, such as
epidermal growth factor (EGF) and amphiregulin (AREG). The changes in the levels
of IP-10 and RANTES may be relevant for the alterations in homing of T cells and
B cells at different stages of mammary gland development, while the changes of
the EGFR ligands may facilitate the switch from proliferative to lactating
stage. PACAP did not modulate the expression of β-casein or the activity of
hormone-induced pathways as determined by the analysis of phosphorylation of
Akt, STAT5, and p38 MAPK. However, PACAP decreased the release of EGF and AREG
from non-differentiated cells. This may influence the extracellular
signal-related transactivation of EGFR in the non-differentiated mammary
epithelium and is considered to have an impact on the modulation of oncogenic
EGFR signaling in breast cancer.
DOI: 10.1007/s12031-013-0193-3
PMID: 24323361 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23832984 | 1. Brain Nerve. 2013 Jul;65(7):811-23.
[Pathomechanisms and treatment of CADASIL].
[Article in Japanese]
Mizuno T(1).
Author information:
(1)Department of Neurology, Kyoto Prefectual University of Medicine, Japan.
The pathomechanisms of cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) are still under debate. Granular
osmiophilic material (GOM), which accumulates around the basement membrane, and
the extracellular domain of NOTCH3 (NECD) in the vessel are key molecules that
contributes to the destruction of smooth muscle cells in CADASIL. In addition,
GOM and NECD may be related to the dysfunction of cerebral small vessels in
patients with CADASIL. In this review, the role of the accumulation of these
abnormal proteins in the cerebral small vessels, and the pathomechanism from
white matter lesions, microbleeds, and lacunar infarctions to vascular dementia
are discussed. We diagnosed 63 CADASIL cases and identified 3 features that were
common to Japanese cases. First, the ages of onset of clinical symptoms other
than migraine were widely distributed; the age of onset of symptoms was greater
than 60 years in more than 20% of the cases. Second, 65% of the Japanese CADASIL
cases had stroke risk factors, such as hypertension, hyperlipidemia, or smoking.
Third, in 20% of the cases, there was no family history of stroke. Therefore,
new diagnostic criteria for Japanese patients with CADASIL were proposed on the
basis of these clinical features in order to avoid missing cases of CADASIL. The
criteria are useful for screening candidates of CADASIL, even in cases with
elderly onset, stroke risk factors, and obscure family history.
PMID: 23832984 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22388002 | 1. J Cardiovasc Pharmacol Ther. 2012 Sep;17(3):237-47. doi:
10.1177/1074248412436608. Epub 2012 Mar 2.
Dabigatran: comparison to warfarin, pathway to approval, and practical
guidelines for use.
Iyer V(1), Singh HS, Reiffel JA.
Author information:
(1)Department of Medicine, Division of Cardiology, Columbia University Medical
Center, NY 10032, USA.
Atrial fibrillation (AF) affects more than 3 million Americans and is expected
to reach epidemic proportions as the US population ages. The presence of AF
increases lifetime stroke risk nearly 5-fold. Conventionally, patients at
moderate or high risk of stroke have been prescribed antiplatelet agents or
vitamin K antagonists to reduce the risk, but each has significant limitations.
Accordingly, the development of new oral anticoagulants (direct thrombin
inhibitors [DTIs] and factor Xa inhibitors) has attracted significant interest.
The DTI dabigatran etexilate was recently shown to provide superior risk
reduction to warfarin for stroke and systemic embolism for patients with
nonvalvular AF and recently gained US Food and Drug Administration approval for
this indication. Dabigatran etexilate is the first new agent for this indication
in the United States in more than 50 years. Herein, we outline the options for
stroke prevention in AF in the new oral anticoagulant era. The efficacy and
practical obstacles surrounding the use of warfarin are summarized. We then
review the mechanism of action, efficacy, and safety of dabigatran-including
clinically relevant pharmacokinetics. Practical issues of initiation, conversion
of anticoagulant therapy, and recommendations for dabigatran use in patients at
high risk of bleeding and other special populations are discussed. We conclude
by proposing a role for dabigatran in the armamentarium of drugs available for
the management of stroke risk in AF.
DOI: 10.1177/1074248412436608
PMID: 22388002 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21845054 | 1. Ther Clin Risk Manag. 2011;7:313-23. doi: 10.2147/TCRM.S14015. Epub 2011 Jul
22.
Current and emerging treatments for the management of myasthenia gravis.
Sathasivam S(1).
Author information:
(1)The Walton Centre NHS Foundation Trust, Lower Lane, Liverpool, UK.
Myasthenia gravis is an autoimmune neuromuscular disorder. There are several
treatment options, including symptomatic treatment (acetylcholinesterase
inhibitors), short-term immunosuppression (corticosteroids), long-term
immunosuppression (azathioprine, cyclosporine, cyclophosphamide, methotrexate,
mycophenolate mofetil, rituximab, tacrolimus), rapid acting short-term
immunomodulation (intravenous immunoglobulin, plasma exchange), and long-term
immunomodulation (thymectomy). This review explores in detail these different
treatment options. Potential future treatments are also discussed.
DOI: 10.2147/TCRM.S14015
PMCID: PMC3150477
PMID: 21845054 |
http://www.ncbi.nlm.nih.gov/pubmed/20132664 | 1. Hematology. 2010 Feb;15(1):58-62. doi: 10.1179/102453310X12583347009531.
Clinical, genetic and cytogenetic study of Fanconi anemia in an Indian
population.
Korgaonkar S(1), Ghosh K, Vundinti BR.
Author information:
(1)Department of Cytogenetics, National Institute of Immunohaematology, Parel,
Mumbai, India.
Fanconi anemia (FA) is a rare autosomal recessive genetic disease, associated
with congenital anomalies and a predisposition to cancers. FA patients exhibit
spontaneous chromosome breakage and FA cells are sensitive to DNA interstrand
crosslink agents and expresses high frequency of chromosome breakage. Recently
13 genes have been shown to be involved with the FA phenotype. We have carried
out a detailed study in clinically diagnosed FA patients in an Indian
population. Thirty three patients were clinically diagnosed with FA and had
aplastic anemia and bleeding abnormalities. The genetic analysis revealed a
significantly (P<0.0001) high frequency (36.4%) of parental consanguinity in FA
patients compared to controls (3.33%). Chromosomal analysis revealed spontaneous
chromosome breakage in 63.64% FA patients. The mitomycin C and diepoxybutane
induced cultures showed a significantly (P<0.001) high frequency of chromosome
breakage and radial formation compared to controls. Among 33 patients, nine
(27.27%) patients developed malignancies and chromosomal abnormalities were
detected in five (55.5%) patients bone marrow cells including monosomy 5 and 7,
trisomy 10, der(1q) and inv(7). Cytogenetic investigation is important in
aplastic anemia to rule out FA. The clinical presentation and the associated
high frequency of consanguinity in FA, and the molecular analysis are
complementary in the study of an Indian population.
DOI: 10.1179/102453310X12583347009531
PMID: 20132664 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21856302 | 1. FEBS Lett. 2011 Oct 3;585(19):3011-4. doi: 10.1016/j.febslet.2011.08.018. Epub
2011 Aug 17.
The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27
methylation states.
Wigle TJ(1), Knutson SK, Jin L, Kuntz KW, Pollock RM, Richon VM, Copeland RA,
Scott MP.
Author information:
(1)Epizyme, Inc., 325 Vassar St., Cambridge, MA 02139, USA. [email protected]
Mutations at tyrosine 641 (Y641F, Y641N, Y641S and Y641H) in the SET domain of
EZH2 have been identified in patients with certain subtypes of non-Hodgkin
lymphoma (NHL). These mutations were shown to change the substrate specificity
of EZH2 for various methylation states of lysine 27 on histone H3 (H3K27). An
additional mutation at EZH2 Y641 to cysteine (Y641C) was also found in one
patient with NHL and in SKM-1 cells derived from a patient with myelodisplastic
syndrome (MDS). The Y641C mutation has been reported to dramatically reduce
enzymatic activity. Here, we demonstrate that while the Y641C mutation ablates
enzymatic activity against unmethylated and monomethylated H3K27, it is superior
to wild-type in catalyzing the formation of trimethylated H3K27 from the
dimethylated precursor.
Copyright © 2011 Federation of European Biochemical Societies. Published by
Elsevier B.V. All rights reserved.
DOI: 10.1016/j.febslet.2011.08.018
PMID: 21856302 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14673105 | 1. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15428-33. doi:
10.1073/pnas.2136809100. Epub 2003 Dec 12.
Genome evolution reveals biochemical networks and functional modules.
von Mering C(1), Zdobnov EM, Tsoka S, Ciccarelli FD, Pereira-Leal JB, Ouzounis
CA, Bork P.
Author information:
(1)European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg,
Germany.
The analysis of completely sequenced genomes uncovers an astonishing variability
between species in terms of gene content and order. During genome history, the
genes are frequently rear-ranged, duplicated, lost, or transferred horizontally
between genomes. These events appear to be stochastic, yet they are under
selective constraints resulting from the functional interactions between genes.
These genomic constraints form the basis for a variety of techniques that employ
systematic genome comparisons to predict functional associations among genes.
The most powerful techniques to date are based on conserved gene neighborhood,
gene fusion events, and common phylogenetic distributions of gene families. Here
we show that these techniques, if integrated quantitatively and applied to a
sufficiently large number of genomes, have reached a resolution which allows the
characterization of function at a higher level than that of the individual gene:
global modularity becomes detectable in a functional protein network. In
Escherichia coli, the predicted modules can be bench-marked by comparison to
known metabolic pathways. We found as many as 74% of the known metabolic enzymes
clustering together in modules, with an average pathway specificity of at least
84%. The modules extend beyond metabolism, and have led to hundreds of reliable
functional predictions both at the protein and pathway level. The results
indicate that modularity in protein networks is intrinsically encoded in
present-day genomes.
DOI: 10.1073/pnas.2136809100
PMCID: PMC307584
PMID: 14673105 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21875659 | 1. Hear Res. 2011 Dec;282(1-2):184-95. doi: 10.1016/j.heares.2011.08.005. Epub
2011 Aug 23.
Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in
a mouse model of CHARGE syndrome.
Hurd EA(1), Adams ME, Layman WS, Swiderski DL, Beyer LA, Halsey KE, Benson JM,
Gong TW, Dolan DF, Raphael Y, Martin DM.
Author information:
(1)Department of Pediatrics, 3520A MSRB I, University of Michigan, Ann Arbor, MI
48109-5652, USA. [email protected]
Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7
(CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes
vestibular dysfunction and hearing loss. Mice with heterozygous Chd7 mutations
exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis, and
are an excellent model of CHARGE syndrome. Here we characterized Chd7 expression
in mature middle and inner ears, analyzed morphological features of mutant ears
and tested whether Chd7 mutant mice have altered responses to noise exposure and
correlated those responses to inner and middle ear structure. We found that Chd7
is highly expressed in mature inner and outer hair cells, spiral ganglion
neurons, vestibular sensory epithelia and middle ear ossicles. There were no
obvious defects in individual hair cell morphology by prestin immunostaining or
scanning electron microscopy, and cochlear innervation appeared normal in
Chd7(Gt)(/+) mice. Hearing thresholds by auditory brainstem response (ABR)
testing were elevated at 4 and 16 kHz in Chd7(Gt)(/+) mice, and there were
reduced distortion product otoacoustic emissions (DPOAE). Exposure of
Chd7(Gt)(/+) mice to broadband noise resulted in variable degrees of hair cell
loss which inversely correlated with severity of stapedial defects. The degrees
of hair cell loss and threshold shifts after noise exposure were more severe in
wild type mice than in mutants. Together, these data indicate that Chd7(Gt)(/+)
mice have combined conductive and sensorineural hearing loss, correlating with
changes in both middle and inner ears.
Copyright © 2011 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.heares.2011.08.005
PMCID: PMC3230679
PMID: 21875659 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22056965 | 1. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):298-304. doi:
10.1136/jnnp-2011-300826. Epub 2011 Nov 5.
Long term lymphocyte reconstitution after alemtuzumab treatment of multiple
sclerosis.
Hill-Cawthorne GA(1), Button T, Tuohy O, Jones JL, May K, Somerfield J, Green A,
Giovannoni G, Compston DA, Fahey MT, Coles AJ.
Author information:
(1)Department of Neurology, University of Cambridge, Cambridge, UK.
BACKGROUND: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has
demonstrated superior efficacy over interferon β-1a for relapsing-remitting
multiple sclerosis (MS), and is currently under investigation in phase 3 trials.
One unresolved issue is the duration and significance of the lymphopenia
induced. The long term effects on lymphocyte reconstitution of a single course,
and the consequences that this has on disability, morbidity, mortality and
autoimmunity, were examined.
METHODS: The lymphocyte reconstitution (n=36; 384 person years) and crude safety
data (n=37; 447 person years) are reported for the first patients with
progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was
expressed as a geometric mean or, when a non-negligible number of individuals
failed to recover, as a median using survival analysis.
RESULTS: Geometric mean recovery time (GMRT) of total lymphocyte counts to the
lower limit of the normal range (LLN; ≥1.0×10(9) cells/l) was 12.7 months (95%
CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10(9)/l) was 7.1 months
(95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10(9) cells/l) and
CD4 lymphocytes (LLN ≥0.4×10(9) cells/l) were 20 months and 35 months,
respectively. However, CD8 and CD4 counts recovered to baseline levels in only
30% and 21% of patients, respectively. No infective safety concerns arose during
447 person years of follow-up.
CONCLUSIONS: Lymphocyte counts recovered to LLN after a single course of
alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets),
but usually did not recover to baseline values. However, this long lasting
lymphopenia in patients with a previously normal immune system was not
associated with an increased risk of serious opportunistic infection.
DOI: 10.1136/jnnp-2011-300826
PMID: 22056965 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17325244 | 1. Circulation. 2007 Mar 13;115(10):1244-51. doi:
10.1161/CIRCULATIONAHA.106.646778. Epub 2007 Feb 26.
Prevalence of desmin mutations in dilated cardiomyopathy.
Taylor MR(1), Slavov D, Ku L, Di Lenarda A, Sinagra G, Carniel E, Haubold K,
Boucek MM, Ferguson D, Graw SL, Zhu X, Cavanaugh J, Sucharov CC, Long CS,
Bristow MR, Lavori P, Mestroni L; Familial Cardiomyopathy Registry; BEST
(Beta-Blocker Evaluation of Survival Trial) DNA Bank.
Author information:
(1)University of Colorado at Denver and Health Sciences Center, Denver, Colo,
USA. [email protected]
BACKGROUND: Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal
muscle disease caused by mutations in the desmin (DES) gene. Mutations in the
central 2B domain of DES cause skeletal muscle disease that typically precedes
cardiac involvement. However, the prevalence of DES mutations in dilated
cardiomyopathy (DCM) without skeletal muscle disease is not known.
METHODS AND RESULTS: Denaturing high-performance liquid chromatography was used
to screen DES for mutations in 116 DCM families from the Familial Dilated
Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker
Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13
and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects
on cytoskeletal desmin network architecture were analyzed with confocal
microscopy. Five novel missense DES mutations, including the first localized to
the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection
of DES mutations in the 2B domain severely disrupted the fine intracytoplasmic
staining of desmin, causing clumping of the desmin protein. A tail domain
mutation (Val459Ile) showed milder effects on desmin cytoplasmic network
formation and appears to be a low-penetrant mutation restricted to black
subjects.
CONCLUSIONS: The prevalence of DES mutations in DCM is between 1% and 2%, and
mutations in the 1A helical domain, as well as the 2B rod domain, are capable of
causing a DCM phenotype. The lack of severe disruption of cytoskeletal desmin
network formation seen with mutations in the 1A and tail domains suggests that
dysfunction of seemingly intact desmin networks is sufficient to cause DCM.
DOI: 10.1161/CIRCULATIONAHA.106.646778
PMID: 17325244 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19299048 | 1. Rev Med Interne. 2009 May;30(5):416-24. doi: 10.1016/j.revmed.2008.12.022.
Epub 2009 Mar 18.
[Targeted therapies and their indications in solid neoplasias].
[Article in French]
Dreyer C(1), Raymond E, Faivre S.
Author information:
(1)Service inter-hospitalier de cancérologie Bichat-Beaujon, hôpital Beaujon,
92118 Clichy cedex, France.
Targeted therapies are widely used in cancer because of their effectiveness,
even in tumours that are resistant to conventional chemotherapy such as kidney
or hepatocellular carcinomas. There are different families classified according
to their mode of action. The antiangiogenics block tumor angiogenesis by acting
on VEGF or its receptor. The main molecules are bevacizumab, sunitinib, and
sorafinib. HER inhibitors work by blocking these receptors, which control
different signaling intracellular pathways, and include an inhibitor of HER2,
trastuzumab, and various inhibitors of HER1, or EGFR, including cetuximab,
erlotinib, and gefitinib. Inhibitors of KIT, a membrane receptor, are mainly
represented by imatinib, an inhibitor of tyrosine kinase. Finally, mTOR
inhibitors act on the signaling pathway PI3K/AKT/mTOR, and key molecules are
temsirolimus, everolimus, and deforolimus.
DOI: 10.1016/j.revmed.2008.12.022
PMID: 19299048 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24065914 | 1. Front Hum Neurosci. 2013 Sep 19;7:606. doi: 10.3389/fnhum.2013.00606.
eCollection 2013.
A "bottom-up" approach to aetiological research in autism spectrum disorders.
Unwin LM(1), Maybery MT, Wray JA, Whitehouse AJ.
Author information:
(1)School of Psychology, The University of Western Australia , Perth, WA ,
Australia ; Telethon Institute for Child Health Research, Centre for Child
Health Research, The University of Western Australia , Perth, WA , Australia.
Autism spectrum disorders (ASD) are currently diagnosed in the presence of
impairments in social interaction and communication, and a restricted range of
activities and interests. However, there is considerable variability in the
behaviors of different individuals with an ASD diagnosis. The heterogeneity
spans the entire range of IQ and language abilities, as well as other
behavioral, communicative, and social functions. While any psychiatric condition
is likely to incorporate a degree of heterogeneity, the variability in the
nature and severity of behaviors observed in ASD is thought to exceed that of
other disorders. The current paper aims to provide a model for future research
into ASD subgroups. In doing so, we examined whether two proposed risk factors -
low birth weight (LBW), and in utero exposure to selective serotonin reuptake
inhibitors (SSRIs) - are associated with greater behavioral homogeneity. Using
data from the Western Australian Autism Biological Registry, this study found
that LBW and maternal SSRI use during pregnancy were associated with greater
sleep disturbances and a greater number of gastrointestinal complaints in
children with ASD, respectively. The findings from this "proof of principle"
paper provide support for this "bottom-up" approach as a feasible method for
creating homogenous groups.
DOI: 10.3389/fnhum.2013.00606
PMCID: PMC3777013
PMID: 24065914 |
http://www.ncbi.nlm.nih.gov/pubmed/20649511 | 1. Recent Pat Cardiovasc Drug Discov. 2010 Nov;5(3):156-61. doi:
10.2174/157489010793351962.
MicroRNA-21 as therapeutic target in cancer and cardiovascular disease.
Bonci D(1).
Author information:
(1)Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore
Sanità, Rome, Italy. [email protected]
MicroRNAs (miRNAs) are a broad class of small non-coding RNAs that control
expression of complementary target messenger RNAs. Dysregulation of miRNAs has
been described in various disease states including cancer and cardiac disease. A
particular miRNA that was consistently reported to be upregulated in both cancer
and various forms of cardiovascular diseases is miR-21. MiR-21 exerts oncogenic
activity and therefore is considered as an oncomir. In the cardiovascular system
miR-21 is enriched in fibroblasts and contributes to the development of fibrosis
and heart failure. MiR-21 therefore emerges as an interesting candidate for the
development of therapeutic strategies against many forms of cancer as well as
heart diseases. Indeed, treatment with anti-miR-21 oligonucleotides reduced
breast cancer growth. Inhibition of miR-21 by synthetic miRNA antagonists
(antagomirs) improved heart function in a cardiac disease model. The same
beneficial effects were observed in miR-21 knockout mice subjected to
pressure-overload of the left ventricle underlining the key role of miR-21 as a
therapeutic target. We here overview the current patent situation about the
therapeutic use of miR-21 modulation in cancer and cardiovascular disease.
DOI: 10.2174/157489010793351962
PMID: 20649511 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22707570 | 1. Genome Res. 2012 Dec;22(12):2529-40. doi: 10.1101/gr.140475.112. Epub 2012 Jun
15.
Long noncoding RNAs in C. elegans.
Nam JW(1), Bartel DP.
Author information:
(1)Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142,
USA.
Thousands of long noncoding RNAs (lncRNAs) have been found in vertebrate
animals, a few of which have known biological roles. To better understand the
genomics and features of lncRNAs in invertebrates, we used available RNA-seq,
poly(A)-site, and ribosome-mapping data to identify lncRNAs of Caenorhabditis
elegans. We found 170 long intervening ncRNAs (lincRNAs), which had single- or
multiexonic structures that did not overlap protein-coding transcripts, and
about sixty antisense lncRNAs (ancRNAs), which were complementary to
protein-coding transcripts. Compared to protein-coding genes, the lncRNA genes
tended to be expressed in a stage-dependent manner. Approximately 25% of the
newly identified lincRNAs showed little signal for sequence conservation and
mapped antisense to clusters of endogenous siRNAs, as would be expected if they
serve as templates and targets for these siRNAs. The other 75% tended to be more
conserved and included lincRNAs with intriguing expression and sequence features
associating them with processes such as dauer formation, male identity, sperm
formation, and interaction with sperm-specific mRNAs. Our study provides a
glimpse into the lncRNA content of a nonvertebrate animal and a resource for
future studies of lncRNA function.
DOI: 10.1101/gr.140475.112
PMCID: PMC3514682
PMID: 22707570 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24613036 | 1. Cancer Treat Rev. 2014 Jul;40(6):750-9. doi: 10.1016/j.ctrv.2014.02.003. Epub
2014 Feb 24.
Crosstalk between hedgehog and other signaling pathways as a basis for
combination therapies in cancer.
Brechbiel J(1), Miller-Moslin K(2), Adjei AA(3).
Author information:
(1)Articulate Science, 300 American Metro Boulevard, Suite 132, Hamilton, NJ
08619, USA. Electronic address: [email protected].
(2)Articulate Science, 300 American Metro Boulevard, Suite 132, Hamilton, NJ
08619, USA. Electronic address: [email protected].
(3)Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Electronic address: [email protected].
The hedgehog (Hh) pathway is aberrantly activated in a number of tumors. In
medulloblastoma, basal cell carcinoma, and rhabdomyosarcoma, mutations in Hh
pathway genes lead to ligand-independent pathway activation. In many other tumor
types, ligand-dependent activation of Hh signaling is potentiated through
crosstalk with other critical molecular signaling pathways. Among such pathways,
RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch are of particular interest
because agents that selectively inhibit these pathways are available and can be
readily combined with agents such as vismodegib, sonidegib (LDE225), and
BMS-833923, which target smoothened-a key Hh pathway regulator. Numerous
preclinical studies have revealed the ways in which Hh intersects with each of
these pathways, and combination therapies have resulted in improved antitumor
efficacy and survival in animal models. Hh also plays an important role in
hematopoiesis and in the maintenance of BCR-ABL-driven leukemic stem cells.
Thus, combined inhibition of the Hh pathway and BCR-ABL has emerged as a
promising potential therapeutic strategy in chronic myeloid leukemia (CML). A
number of clinical trials evaluating combinations of Hh inhibitors with other
targeted agents are now underway in CML and a variety of solid tumors. This
review highlights these trials and summarizes preclinical evidence of crosstalk
between Hh and four other actionable pathways-RAS/RAF/MEK/ERK, PI3K/AKT/mTOR,
EGFR, and Notch-as well as the role of Hh in the maintenance of BCR-ABL-driven
leukemic stem cells.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ctrv.2014.02.003
PMID: 24613036 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24711702 | 1. Ther Clin Risk Manag. 2014 Mar 22;10:197-205. doi: 10.2147/TCRM.S30159.
eCollection 2014.
Rivaroxaban as an oral anticoagulant for stroke prevention in atrial
fibrillation.
Turpie AG(1).
Author information:
(1)Department of Medicine, McMaster University, Hamilton, ONT, Canada.
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the developed
world and is associated with a fivefold increase in the risk of stroke,
accounting for up to 15% of strokes in the general population. The European
Society of Cardiology now recommends direct oral anticoagulants, such as
rivaroxaban, apixaban, and dabigatran, in preference to vitamin K antagonist
therapy for the prevention of stroke in patients with A F. This review focuses
on the direct Factor Xa inhibitor rivaroxaban, summarizing the properties that
make rivaroxaban appropriate for anticoagulant therapy in this indication
(including its predictable pharmacokinetic and pharmacodynamic profile and
once-daily dosing regimen) and describing data from the Phase III ROCKET AF
trial, which showed once-daily rivaroxaban to be noninferior to warfarin for the
prevention of stroke in patients with nonvalvular AF. In this trial, similar
rates of major and nonmajor clinically relevant bleeding were observed; however,
when compared with warfarin, rivaroxaban was associated with clinically
significant reductions in intracranial and fatal bleeding. On the basis of these
results, rivaroxaban was approved in both the United States and the European
Union for the prevention of stroke and systemic embolism in patients with
nonvalvular AF. Subanalyses of ROCKET AF data showed rivaroxaban to have
consistent efficacy and safety across a wide range of patients, and studies to
confirm these results in real-world settings are underway. This review also
describes practical considerations for treatment with rivaroxaban in clinical
practice (including dose reductions in specific high-risk patients, eg, those
with renal impairment), recommendations for the transition from vitamin K
antagonists to rivaroxaban, the management of bleeding events, and the
measurement of rivaroxaban exposure.
DOI: 10.2147/TCRM.S30159
PMCID: PMC3968084
PMID: 24711702 |
http://www.ncbi.nlm.nih.gov/pubmed/10343261 | 1. J Thorac Cardiovasc Surg. 1999 Jun;117(6):1128-34. doi:
10.1016/s0022-5223(99)70249-7.
A randomized double-blind study of the effect of triiodothyronine on cardiac
function and morbidity after coronary bypass surgery.
Mullis-Jansson SL(1), Argenziano M, Corwin S, Homma S, Weinberg AD, Williams M,
Rose EA, Smith CR.
Author information:
(1)Departments of Anesthesiology, Surgery,and Medicine, Columbia University
College of Physicians and Surgeons, New York, NY, USA.
BACKGROUND: Although triiodothyronine deficiency has been described after
cardiopulmonary bypass, data supporting its use have been conflicting. A
double-blind, randomized, placebo-controlled study was undertaken to further
define the effect of triiodothyronine on hemodynamics and outcome after coronary
artery bypass grafting.
METHODS: A total of 170 patients undergoing elective coronary artery bypass
grafting were enrolled and completed the study from November 1996 through March
1998. On removal of the aortic crossclamp, patients were randomized to receive
either intravenous triiodothyronine (0.4 microgram/kg bolus plus 0.1
microgram/kg infusion administered over a 6-hour period, n = 81) or placebo (n =
89). Outcome variables included hemodynamic profile and inotropic drug/pressor
requirements at several time points (mean +/- standard error of the mean),
perioperative morbidity (arrhythmia/ischemia/infarction), and mortality.
RESULTS: Despite similar baseline characteristics, patients randomized to
triiodothyronine had a higher cardiac index and lower inotropic requirements
after the operation. Subjects receiving triiodothyronine demonstrated a
significantly lower incidence of postoperative myocardial ischemia (4% vs 18%, P
=.007) and pacemaker dependence (14% vs 25%, P =.013). Seven patients in the
placebo group required postoperative mechanical assistance (intra-aortic balloon
pump, n = 4; left ventricular assist device, n = 3), compared with none in the
triiodothyronine group (P =.01). There were 2 deaths in the placebo group and no
deaths in the triiodothyronine group.
CONCLUSIONS: Parenteral triiodothyronine given after crossclamp removal during
elective coronary artery bypass grafting significantly improved postoperative
ventricular function, reduced the need for treatment with inotropic agents and
mechanical devices, and decreased the incidence of myocardial ischemia. The
incidence of atrial fibrillation was slightly decreased, and the need for
postoperative pacemaker support was reduced.
DOI: 10.1016/s0022-5223(99)70249-7
PMID: 10343261 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22955974 | 1. Genome Res. 2012 Sep;22(9):1616-25. doi: 10.1101/gr.134445.111.
Deep sequencing of subcellular RNA fractions shows splicing to be predominantly
co-transcriptional in the human genome but inefficient for lncRNAs.
Tilgner H(1), Knowles DG, Johnson R, Davis CA, Chakrabortty S, Djebali S, Curado
J, Snyder M, Gingeras TR, Guigó R.
Author information:
(1)Centre for Genomic Regulation and UPF, E-08003, Barcelona, Catalonia, Spain.
Splicing remains an incompletely understood process. Recent findings suggest
that chromatin structure participates in its regulation. Here, we analyze the
RNA from subcellular fractions obtained through RNA-seq in the cell line K562.
We show that in the human genome, splicing occurs predominantly during
transcription. We introduce the coSI measure, based on RNA-seq reads mapping to
exon junctions and borders, to assess the degree of splicing completion around
internal exons. We show that, as expected, splicing is almost fully completed in
cytosolic polyA+ RNA. In chromatin-associated RNA (which includes the RNA that
is being transcribed), for 5.6% of exons, the removal of the surrounding introns
is fully completed, compared with 0.3% of exons for which no intron-removal has
occurred. The remaining exons exist as a mixture of spliced and fewer unspliced
molecules, with a median coSI of 0.75. Thus, most RNAs undergo splicing while
being transcribed: "co-transcriptional splicing." Consistent with
co-transcriptional spliceosome assembly and splicing, we have found significant
enrichment of spliceosomal snRNAs in chromatin-associated RNA compared with
other cellular RNA fractions and other nonspliceosomal snRNAs. CoSI scores
decrease along the gene, pointing to a "first transcribed, first spliced" rule,
yet more downstream exons carry other characteristics, favoring rapid,
co-transcriptional intron removal. Exons with low coSI values, that is, in the
process of being spliced, are enriched with chromatin marks, consistent with a
role for chromatin in splicing during transcription. For alternative exons and
long noncoding RNAs, splicing tends to occur later, and the latter might remain
unspliced in some cases.
DOI: 10.1101/gr.134445.111
PMCID: PMC3431479
PMID: 22955974 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18190825 | 1. Urol Oncol. 2008 Jan-Feb;26(1):17-24. doi: 10.1016/j.urolonc.2006.08.021. Epub
2007 Oct 22.
Tissue microarray based analysis of prognostic markers in invasive bladder
cancer: much effort to no avail?
Liedberg F(1), Anderson H, Chebil G, Gudjonsson S, Höglund M, Lindgren D,
Lundberg LM, Lövgren K, Fernö M, Månsson W.
Author information:
(1)Department of Urology, Lund University Hospital, Lund, Sweden.
[email protected]
PURPOSE: To evaluate altered protein expression with tissue microarray
methodology for 15 different markers with potential prognostic significance in
invasive bladder cancer.
MATERIALS AND METHODS: Invasive tumor was sampled with the tissue-arraying
instrument in 133 consecutive patients who underwent radical cystectomy, and at
least 3, 0.6-mm tissue cores were obtained. With immunohistochemistry, the
expressions of TP53, RB1, CDKN1A (p21), MKI67 (Ki67), PTGS2 (Cox-2), CTNNA1
(alpha-catenin), CTNNB1 (beta-catenin), AKT, PTEN, RHOA, RHOC, STAT1, VEGFC,
EGFR, and ERBB2 (HER2) were quantified, and correlations were made with tumor
grade, pathologic stage, lymph node status, and disease-specific survival.
RESULTS: Decreased immunohistochemical expression of CTNNA1 and of PTEN
correlated with higher pathologic tumor stages (P = 0.01 and P = 0.01,
respectively), whereas increased AKT1 and ERBB2 correlated with lower pathologic
tumor stages (P = 0.01 and P = 0.03, respectively). Increased RHOA expression
was more common in grade 3 than in grade 2 tumors (P = 0.016). There were no
other correlations among the 15 factors studied and pathologic stage, lymph node
status, or tumor grade. No association was found between bladder cancer death
and altered marker status for any of the markers studied.
CONCLUSIONS: Currently, there are reasons to have a skeptical attitude toward
the value of tissue microarray based immunohistochemistry as a method for
evaluating prognostic markers in invasive bladder cancer. In this study, 15
antibodies were tested but were found to be of little clinical value. Whether
this negative finding is related to the group of patients or factors studied, or
the methodology is unclear.
DOI: 10.1016/j.urolonc.2006.08.021
PMID: 18190825 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10790203 | 1. Hum Mutat. 2000;15(5):418-29. doi:
10.1002/(SICI)1098-1004(200005)15:5<418::AID-HUMU3>3.0.CO;2-2.
RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing
gel systems.
Hofstra RM(1), Wu Y, Stulp RP, Elfferich P, Osinga J, Maas SM, Siderius L,
Brooks AS, vd Ende JJ, Heydendael VM, Severijnen RS, Bax KM, Meijers C, Buys CH.
Author information:
(1)Department of Medical Genetics, University of Groningen, Groningen, The
Netherlands. [email protected]
Hirschsprung disease (HSCR) is a congenital disorder characterised by intestinal
obstruction due to an absence of intramural ganglia along variable lengths of
the intestine. RET is the major gene involved in HSCR. Mutations in the GDNF
gene, and encoding one of the RET ligands, either alone or in combination with
RET mutations, can also cause HSCR, as can mutations in four other genes (EDN3,
EDNRB, ECE1, and SOX10). The rare mutations in the latter four genes, however,
are more or less restricted to HSCR associated with specific phenotypes. We have
developed a novel comprehensive mutation detection system to analyse all but
three amplicons of the RET and GDNF genes, based on denaturing gradient gel
electrophoresis. We make use of two urea-formamide gradients on top of each
other, allowing mutation detection over a broad range of melting temperatures.
For the three remaining (GC-rich) PCR fragments we use a combination of DGGE and
constant denaturing gel electrophoresis (CDGE). These two dual gel systems
substantially facilitate mutation scanning of RET and GDNF, and may also serve
as a model to develop mutation detection systems for other disease genes. In a
screening of 95 HSCR patients, RET mutations were found in nine out of 17
familial cases (53%), all containing long segment HSCR. In 11 of 78 sporadic
cases (14%), none had long segment HSCR. Only one GDNF mutation was found, in a
sporadic case.
Copyright 2000 Wiley-Liss, Inc.
DOI: 10.1002/(SICI)1098-1004(200005)15:5<418::AID-HUMU3>3.0.CO;2-2
PMID: 10790203 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21572014 | 1. Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H459-68. doi:
10.1152/ajpheart.00054.2011. Epub 2011 May 13.
Metformin improves cardiac function in a nondiabetic rat model of post-MI heart
failure.
Yin M(1), van der Horst IC, van Melle JP, Qian C, van Gilst WH, Silljé HH, de
Boer RA.
Author information:
(1)University Medical Center Groningen, Thorax Center, Department of Cardiology,
University of Groningen, The Netherlands.
Metformin is the first choice drug for the treatment of patients with diabetes,
but its use is debated in patients with advanced cardiorenal disease.
Epidemiological data suggest that metformin may reduce cardiac events, in
patients both with and without heart failure. Experimental evidence suggests
that metformin reduces cardiac ischemia-reperfusion injury. It is unknown
whether metformin improves cardiac function (remodeling) in a long-term post-MI
remodeling model. We therefore studied male, nondiabetic, Sprague-Dawley rats
that were subjected to either myocardial infarction (MI) or sham operation.
Animals were randomly allocated to treatment with normal water or
metformin-containing water (250 mg·kg(-1)·day(-1)). At baseline, 6 wk, and 12
wk, metabolic parameters were analyzed and oral glucose tolerance tests (OGTT)
were performed. Echocardiography and hemodynamic parameters were assessed 12 wk
after MI. In the MI model, infarct size was significantly smaller after 12-wk
metformin treatment (29.6 ± 3.2 vs. 38.0 ± 2.2%, P < 0.05). Moreover, metformin
resulted in less left ventricular dilatation (6.0 ± 0.4 vs. 7.6 ± 0.6 mm, P <
0.05) and preservation of left ventricular ejection fraction (65.8 ± 3.7% vs.
48.6 ± 5.6%, P < 0.05) compared with MI control. The improved cardiac function
was associated with decreased atrial natriuretic peptide mRNA levels in the
metformin-treated group (50% reduction compared with MI, P < 0.05). Insulin
resistance did not occur during cardiac remodeling (as indicated by normal OGTT)
and fasting glucose levels and the pattern of the OGTT were not affected by
metformin. Molecular analyses suggested that altered AMP kinase phosphorylation
status and low insulin levels mediate the salutary effects of metformin.
Altogether our results indicate that metformin may have potential to attenuate
heart failure development after myocardial infarction, in the absence of
diabetes and independent of systemic glucose levels.
DOI: 10.1152/ajpheart.00054.2011
PMID: 21572014 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19327580 | 1. Hematol Oncol Clin North Am. 2009 Apr;23(2):215-31. doi:
10.1016/j.hoc.2009.01.003.
Dyskeratosis congenita.
Savage SA(1), Alter BP.
Author information:
(1)Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics,
National Cancer Institute, National Institutes of Health, 6120 Executive
Boulevard, Rockville, MD 20852, USA. [email protected]
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome
characterized clinically by the triad of abnormal nails, reticular skin
pigmentation, and oral leukoplakia, and is associated with high risk of
developing aplastic anemia, myelodysplastic syndrome, leukemia, and solid
tumors. Patients have very short germline telomeres, and approximately half have
mutations in one of six genes encoding proteins that maintain telomere function.
Accurate diagnosis of DC is critical to ensure proper clinical management,
because patients who have DC and bone marrow failure do not respond to
immunosuppressive therapy and may have increased morbidity and mortality
associated with hematopoietic stem cell transplantation.
DOI: 10.1016/j.hoc.2009.01.003
PMCID: PMC2702847
PMID: 19327580 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20434785 | 1. Trends Biotechnol. 2010 Jun;28(6):281-90. doi: 10.1016/j.tibtech.2010.03.002.
Epub 2010 Apr 29.
Single cell analysis: the new frontier in 'omics'.
Wang D(1), Bodovitz S.
Author information:
(1)Lawrence Berkeley National Laboratory, Berkeley, California, USA.
[email protected]
Cellular heterogeneity that arises from stochastic expression of genes, proteins
and metabolites is a fundamental principle of cell biology, but single cell
analysis has been beyond the capability of 'omics' technology. This is rapidly
changing with the recent examples of single cell genomics, transcriptomics,
proteomics and metabolomics. The rate of change is expected to accelerate owing
to emerging technologies that range from micro/nanofluidics to microfabricated
interfaces for mass spectrometry to third- and fourth-generation automated DNA
sequencers. As described in this review, single cell analysis is the new
frontier in omics, and single cell omics has the potential to transform systems
biology through new discoveries derived from cellular heterogeneity.
DOI: 10.1016/j.tibtech.2010.03.002
PMCID: PMC2876223
PMID: 20434785 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17674627 | 1. IEEE Trans Inf Technol Biomed. 2007 Jul;11(4):443-9. doi:
10.1109/titb.2007.894335.
Segmentation and classification of dot and non-dot-like fluorescence in situ
hybridization signals for automated detection of cytogenetic abnormalities.
Lerner B(1), Koushnir L, Yeshaya J.
Author information:
(1)Department of Electrical and Computer Engineering, Ben-Gurion University,
Beer Sheva 84105, Israel. [email protected]
Signal segmentation and classification of fluorescence in situ hybridization
(FISH) images are essential for the detection of cytogenetic abnormalities.
Since current methods are limited to dot-like signal analysis, we propose a
methodology for segmentation and classification of dot and non-dot-like signals.
First, nuclei are segmented from their background and from each other in order
to associate signals with specific isolated nuclei. Second, subsignals composing
non-dot-like signals are detected and clustered to signals. Features are
measured to the signals and a subset of these features is selected representing
the signals to a multiclass classifier. Classification using a naive Bayesian
classifier (NBC) or a multilayer perceptron is accomplished. When applied to a
FISH image database, dot and non-dot-like signals were segmented almost
perfectly and then classified with accuracy of approximately 80% by either of
the classifiers.
DOI: 10.1109/titb.2007.894335
PMID: 17674627 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24316116 | 1. Spine J. 2014 Jun 1;14(6):e29-35. doi: 10.1016/j.spinee.2013.11.046. Epub 2013
Dec 6.
Vertebral compression fractures in patients under treatment with denosumab: a
contraindication for percutaneous vertebroplasty?
Mattei TA(1), Mendel E(2), Bourekas EC(3).
Author information:
(1)Department of Neurological Surgery, The Ohio State University Wexner Medical
Center/The James Cancer Center, 410 W 10th Ave., N1037 Doan Hall, Columbus, OH
43210, USA. Electronic address: [email protected].
(2)Department of Neurological Surgery, The Ohio State University Wexner Medical
Center/The James Cancer Center, 410 W 10th Ave., N1037 Doan Hall, Columbus, OH
43210, USA.
(3)Department of Neurological Surgery, The Ohio State University Wexner Medical
Center/The James Cancer Center, 410 W 10th Ave., N1037 Doan Hall, Columbus, OH
43210, USA; Department of Radiology, The Ohio State University Wexner Medical
Center, 487 Faculty Office Tower, 395 W. 12th Ave., Columbus, OH 43210, USA;
Department of Neurology, The Ohio State University Wexner Medical Center, 487
Faculty Office Tower, 395 W. 12th Ave., Columbus, OH 43210, USA.
BACKGROUND CONTEXT: Denosumab (XGeva) is a receptor activator of nuclear
factor-κB ligand (RANKL)-antibody that was approved by the Food and Drug
Administration (FDA) in 2010 for the prevention of skeletal fractures in
patients with bone metastases from solid tumors. Although there is a widespread
use of such drug in patients under risk of pathological fractures, the
compatibility of denosumab therapy with percutaneous vertebroplasty (an
interventional procedure commonly used for pain control in such population) has
not yet been established.
PURPOSE: To present the serial imaging findings and technical report of an
attempted percutaneous vertebroplasty in a patient with refractory pain and a
lytic pathological vertebral fracture related to small cell lung cancer spinal
metastasis and who was actively under medical treatment with denosumab.
STUDY DESIGN: Retrospective review and case report.
METHODS: The authors present the imaging findings and technical report of an
attempted percutaneous vertebroplasty in the only patient found to be actively
under treatment with denosumab after a retrospective review of the databank of
patients with pathological fractures referred to the Department of Radiology of
the Ohio State University for percutaneous vertebroplasty (a total sample of 20
patients) since the FDA approval of denosumab (November 2010) until June 2013 (a
30-month period).
RESULTS: Although the computed tomography scan of the thoracic spine, performed
6 weeks after the initiation of the treatment with denosumab, presented a
remarkable remodeling of the previously lytic vertebral lesion (which became
markedly sclerotic in appearance), the clinical response in terms of pain
improvement was not satisfactory. At the time of the percutaneous vertebroplasty
(which was indicated for pain control), after advancing the 11-gauge needle
through the pedicle with extreme difficulty, the needle repeatedly deviated
laterally and, despite several attempts, it was not possible to penetrate the
vertebral body and perform the cement injection.
CONCLUSIONS: This is the first report of the technical peculiarities of
percutaneous vertebroplasty in patients under medical treatment with denosumab.
According to our experience, because of its RANKL-mediated effects on
osteoclasts activity, denosumab has been shown to induce a fast and marked
sclerotic response on vertebral bodies that may not be accompanied by a
satisfactory improvement in pain control (especially in patients with mechanical
type of pain) and which may actually prevent the successful performance of
percutaneous vertebroplasty. Therefore, it is of paramount importance that
future studies evaluating patients with vertebral fractures under treatment with
denosumab include long-term pain outcome measures. Additionally, further
investigation is warranted to determine the optimal order of treatment and the
best timeframe for combining percutaneous vertebroplasty and denosumab therapy
in patients presenting with acute vertebral compression fractures and refractory
axial pain.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.spinee.2013.11.046
PMID: 24316116 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21173160 | 1. Mol Cell Biol. 2011 Mar;31(5):1098-108. doi: 10.1128/MCB.01279-10. Epub 2010
Dec 20.
TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic
and oxidative stressor.
Dewey CM(1), Cenik B, Sephton CF, Dries DR, Mayer P 3rd, Good SK, Johnson BA,
Herz J, Yu G.
Author information:
(1)Department of Neuroscience, University of Texas Southwestern Medical Center,
6000 Harry Hines Blvd., Dallas, TX 75390-9111, USA.
TDP-43, or TAR DNA-binding protein 43, is a pathological marker of a spectrum of
neurodegenerative disorders, including amyotrophic lateral sclerosis and
frontotemporal lobar degeneration with ubiquitin-positive inclusions. TDP-43 is
an RNA/DNA-binding protein implicated in transcriptional and posttranscriptional
regulation. Recent work also suggests that TDP-43 associates with cytoplasmic
stress granules, which are transient structures that form in response to stress.
In this study, we establish sorbitol as a novel physiological stressor that
directs TDP-43 to stress granules in Hek293T cells and primary cultured glia. We
quantify the association of TDP-43 with stress granules over time and show that
stress granule association and size are dependent on the glycine-rich region of
TDP-43, which harbors the majority of pathogenic mutations. Moreover, we
establish that cells harboring wild-type and mutant TDP-43 have distinct stress
responses: mutant TDP-43 forms significantly larger stress granules, and is
incorporated into stress granules earlier, than wild-type TDP-43; in striking
contrast, wild-type TDP-43 forms more stress granules over time, but the granule
size remains relatively unchanged. We propose that mutant TDP-43 alters stress
granule dynamics, which may contribute to the progression of TDP-43
proteinopathies.
DOI: 10.1128/MCB.01279-10
PMCID: PMC3067820
PMID: 21173160 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11076767 | 1. Development. 2000 Dec;127(24):5475-85. doi: 10.1242/dev.127.24.5475.
Papilin in development; a pericellular protein with a homology to the ADAMTS
metalloproteinases.
Kramerova IA(1), Kawaguchi N, Fessler LI, Nelson RE, Chen Y, Kramerov AA,
Kusche-Gullberg M, Kramer JM, Ackley BD, Sieron AL, Prockop DJ, Fessler JH.
Author information:
(1)MCD Biology Department and Molecular Biology Institute, University of
California at Los Angeles, CA 90095, USA.
Papilin is an extracellular matrix glycoprotein that we have found to be
involved in, (1) thin matrix layers during gastrulation, (2) matrix associated
with wandering, phagocytic hemocytes, (3) basement membranes and (4)
space-filling matrix during Drosophila development. Determination of its cDNA
sequence led to the identification of Caenorhabditis and mammalian papilins. A
distinctly conserved 'papilin cassette' of domains at the amino-end of papilins
is also the carboxyl-end of the ADAMTS subgroup of secreted, matrix-associated
metalloproteinases; this cassette contains one thrombospondin type 1 (TSR)
domain, a specific cysteine-rich domain and several partial TSR domains. In
vitro, papilin non-competitively inhibits procollagen N-proteinase, an ADAMTS
metalloproteinase. Inhibiting papilin synthesis in Drosophila or Caenorhabditis
causes defective cell arrangements and embryonic death. Ectopic expression of
papilin in Drosophila causes lethal abnormalities in muscle, Malpighian tubule
and trachea formation. We suggest that papilin influences cell rearrangements
and may modulate metalloproteinases during organogenesis.
DOI: 10.1242/dev.127.24.5475
PMID: 11076767 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21995290 | 1. BMC Med Genet. 2011 Oct 13;12:138. doi: 10.1186/1471-2350-12-138.
Comprehensive analysis of RET common and rare variants in a series of Spanish
Hirschsprung patients confirms a synergistic effect of both kinds of events.
Núñez-Torres R(1), Fernández RM, Acosta MJ, Enguix-Riego Mdel V, Marbá M, Carlos
de Agustín J, Castaño L, Antiñolo G, Borrego S.
Author information:
(1)Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal,
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del
Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
BACKGROUND: RET is the major gene associated to Hirschsprung disease (HSCR) with
differential contributions of its rare and common, coding and noncoding
mutations to the multifactorial nature of this pathology. In the present study,
we have performed a comprehensive study of our HSCR series evaluating the
involvement of both RET rare variants (RVs) and common variants (CVs) in the
context of the disease.
METHODS: RET mutational screening was performed by dHPLC and direct sequencing
for the identification of RVs. In addition Taqman technology was applied for the
genotyping of 3 RET CVs previously associated to HSCR, including a variant lying
in an enhancer domain within RET intron 1 (rs2435357). Statistical analyses were
performed using the SPSS v.17.0 to analyze the distribution of the variants.
RESULTS: Our results confirm the strongest association to HSCR for the
"enhancer" variant, and demonstrate a significantly higher impact of it in male
versus female patients. Integration of the RET RVs and CVs analysis showed that
in 91.66% of cases with both kinds of mutational events, the enhancer allele is
in trans with the allele bearing the RET RV.
CONCLUSIONS: A gender effect exists on both the transmission and distribution of
rare coding and common HSCR causing mutations. In addition, these RET CVs and
RVs seem to act in a synergistic way leading to HSCR phenotype.
DOI: 10.1186/1471-2350-12-138
PMCID: PMC3210088
PMID: 21995290 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24834120 | 1. Ecancermedicalscience. 2014 May 2;8:425. doi: 10.3332/ecancer.2014.425.
eCollection 2014.
Information perception, wishes, and satisfaction in ambulatory cancer patients
under active treatment: patient-reported outcomes with QLQ-INFO25.
Pinto AC(1), Ferreira-Santos F(2), Lago LD(3), de Azambuja E(1), Pimentel FL(4),
Piccart-Gebhart M(3), Razavi D(5).
Author information:
(1)Medicine Department, Medical Oncology Unit, Institut Jules Bordet, Université
Libre de Bruxelles, Boulevard de Waterloo, 121 (7 Floor), 1000 Brussels, Belgium
; Br.E.A.S.T. Data Centre, Institut Jules Bordet, Brussels 1000, Belgium.
(2)Laboratory of Neuropsychophysiology, Faculty of Psychology and Education
Sciences, University of Porto, Porto 4200-135, Portugal ; Developmental
Cognitive Neuroscience Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
(3)Medicine Department, Medical Oncology Unit, Institut Jules Bordet, Université
Libre de Bruxelles, Boulevard de Waterloo, 121 (7 Floor), 1000 Brussels,
Belgium.
(4)Health Sciences, University of Aveiro, Aveiro 3810-193, Portugal.
(5)Psychosomatic and Psycho-Oncology Research Unit, Université Libre de
Bruxelles, Brussels 1050, Belgium ; Psycho-Oncology Clinic, Institut Jules
Bordet, Université Libre de Bruxelles, Brussels 1000, Belgium.
BACKGROUND: Information is vital to cancer patients. Physician-patient
communication in oncology presents specific challenges. The aim of this study
was to evaluate self-reported information of cancer patients in ambulatory care
at a comprehensive cancer centre and examine its possible association with
patients' demographic and clinical characteristics.
PATIENTS AND METHODS: This study included adult patients with solid tumours
undergoing chemotherapy at the Institute Jules Bordet's Day Hospital over a
ten-day period. EORTC QLQ-C30 and QLQ-INFO25 questionnaires were administered.
Demographic and clinical data were collected. Descriptive and inferential
statistics were used.
RESULTS: 101 (99%) fully completed the questionnaires. They were mostly Belgian
(74.3%), female (78.2%), with a mean age of 56.9 ± 12.8 years. The most frequent
tumour was breast cancer (58.4%). Patients were well-informed about the disease
and treatments, but presented unmet information domains. The Jules Bordet
patients desired more information on treatment side effects, long-term outcome,
nutrition, and recurrence symptoms. Patients on clinical trials reported having
received less information about their disease and less written information than
patients outside clinical trials. Higher information levels were associated with
higher quality of life (QoL) scores and higher patient satisfaction.
CONCLUSION: Patients were satisfied with the information they received and this
correlated with higher QoL, but they still expressed unmet information wishes.
Additional studies are required to investigate the quality of the information
received by patients enrolled in clinical trials.
DOI: 10.3332/ecancer.2014.425
PMCID: PMC4019460
PMID: 24834120 |
http://www.ncbi.nlm.nih.gov/pubmed/16567358 | 1. Rheumatology (Oxford). 2006 Jun;45(6):669-75. doi:
10.1093/rheumatology/kel065. Epub 2006 Mar 27.
Synovial fibroblasts: key players in rheumatoid arthritis.
Huber LC(1), Distler O, Tarner I, Gay RE, Gay S, Pap T.
Author information:
(1)Center of Experimental Rheumatology, University Hospital Zurich,
Gloriastrasse 23CH-8091 Zürich, Switzerland. [email protected]
Rheumatoid arthritis (RA) is a chronic autoimmune-disease of unknown origin that
primarily affects the joints and ultimately leads to their destruction. The
involvement of immune cells is a general hallmark of autoimmune-related
disorders. In this regard, macrophages, T cells and their respective cytokines
play a pivotal role in RA. However, the notion that RA is a primarily
T-cell-dependent disease has been strongly challenged during recent years.
Rather, it has been understood that resident, fibroblast-like cells contribute
significantly to the perpetuation of disease, and that they may even play a role
in its initiation. These rheumatoid arthritis synovial fibroblasts (RASFs)
constitute a quite unique cell type that distinguishes RA from other
inflammatory conditions of the joints. A number of studies have demonstrated
that RASFs show alterations in morphology and behaviour, including molecular
changes in signalling cascades, apoptosis responses and in the expression of
adhesion molecules as well as matrix-degrading enzymes. These changes appear to
reflect a stable activation of RASFs, which occurs independently of continuous
exogenous stimulation. As a consequence, RASFs are no longer considered passive
bystanders but active players in the complex intercellular network of RA.
DOI: 10.1093/rheumatology/kel065
PMID: 16567358 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23091002 | 1. Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18372-7. doi:
10.1073/pnas.1210903109. Epub 2012 Oct 22.
Structural insight into HIV-1 capsid recognition by rhesus TRIM5α.
Yang H(1), Ji X, Zhao G, Ning J, Zhao Q, Aiken C, Gronenborn AM, Zhang P, Xiong
Y.
Author information:
(1)Department of Molecular Biophysics and Biochemistry, Yale University, New
Haven, CT 06520, USA.
Tripartite motif protein isoform 5 alpha (TRIM5α) is a potent antiviral protein
that restricts infection by HIV-1 and other retroviruses. TRIM5α recognizes the
lattice of the retrovirus capsid through its B30.2 (PRY/SPRY) domain in a
species-specific manner. Upon binding, TRIM5α induces premature disassembly of
the viral capsid and activates the downstream innate immune response. We have
determined the crystal structure of the rhesus TRIM5α PRY/SPRY domain that
reveals essential features for capsid binding. Combined cryo-electron microscopy
and biochemical data show that the monomeric rhesus TRIM5α PRY/SPRY, but not the
human TRIM5α PRY/SPRY, can bind to HIV-1 capsid protein assemblies without
causing disruption of the capsid. This suggests that the PRY/SPRY domain alone
constitutes an important pattern-sensing component of TRIM5α that is capable of
interacting with viral capsids of different curvatures. Our results provide
molecular insights into the mechanisms of TRIM5α-mediated retroviral
restriction.
DOI: 10.1073/pnas.1210903109
PMCID: PMC3494900
PMID: 23091002 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/12962492 | 1. Biochemistry. 2003 Sep 16;42(36):10674-82. doi: 10.1021/bi034708c.
Phosphorylation by cAMP-dependent protein kinase modulates the structural
coupling between the transmembrane and cytosolic domains of phospholamban.
Li J(1), Bigelow DJ, Squier TC.
Author information:
(1)School of Molecular Biosciences, Washington State University Tri-Cities,
Richland, Washington 99352, USA.
We have used frequency-domain fluorescence spectroscopy to investigate the
structural linkage between the transmembrane and cytosolic domains of the
regulatory protein phospholamban (PLB). Using an engineered PLB having a single
cysteine (Cys(24)) derivatized with the fluorophore N-(1-pyrenyl)maleimide
(PMal), we have used fluorescence resonance energy transfer (FRET) to measure
the average spatial separation and conformational heterogeneity between PMal
bound to Cys(24) in the transmembrane domain and Tyr(6) in the cytosolic domain
near the amino terminus of PLB. In these measurements, PMal serves as a FRET
donor, and Tyr(6) serves as a FRET acceptor following its nitration by
tetranitromethane. The native structure of PLB is retained following
site-directed mutagenesis and chemical modification, as indicated by the ability
of the derivatized PLB to fully regulate the Ca-ATPase following their
co-reconstitution. To assess how phosphorylation modulates the structure of PLB
itself, FRET measurements were made following reconstitution of PLB in membrane
vesicles made from extracted sarcoplasmic reticulum membrane lipids. We find
that the cytosolic domain of PLB assumes a wide range of conformations relative
to the transmembrane sequence, consistent with other structural data indicating
the presence of a flexible hinge region between the transmembrane and cytosolic
domains of PLB. Phosphorylation of Ser(16) by PKA results in a 3 A decrease in
the spatial separation between PMal at Cys(24) and nitroTyr(6) and an almost
2-fold decrease in conformational heterogeneity, suggesting a stabilization of
the hinge region of PLB possibly through an electrostatic linkage between
phosphoSer(16) and Arg(13) that promotes a coil-to-helix transition. This
structural transition has the potential to function as a conformational switch,
since inhibition of the Ca-ATPase requires disruption of the secondary structure
of PLB in the vicinity of the hinge element to permit association with the
nucleotide binding domain at a site located approximately 50 A above the
membrane surface. Following phosphorylation, the stabilization of the helical
content in the hinge domain will disrupt this inhibitory interaction by reducing
the maximal dimension of the cytosolic domain of PLB. Thus, stabilization of the
structure of PLB following phosphorylation of Ser(16) is part of a switching
mechanism, which functions to alter binding interactions between PLB and the
nucleotide binding domain of the Ca-ATPase that modulates enzyme inhibition.
DOI: 10.1021/bi034708c
PMID: 12962492 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20615966 | 1. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):12877-82. doi:
10.1073/pnas.0911828107. Epub 2010 Jul 6.
Differential control of TAp73 and DeltaNp73 protein stability by the ring finger
ubiquitin ligase PIR2.
Sayan BS(1), Yang AL, Conforti F, Tucci P, Piro MC, Browne GJ, Agostini M,
Bernardini S, Knight RA, Mak TW, Melino G.
Author information:
(1)Medical Research Council, Toxicology Unit, Leicester University, Leicester
LE1 9HN, United Kingdom.
p73 is a p53-related transcription factor with fundamental roles in development
and tumor suppression. Transcription from two different promoters on the p73
gene results in generation of transcriptionally active TAp73 isoforms and
dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic
functions. Therefore, the relative ratio of each isoform is an important
determinant of the cell fate. Proteasomal degradation of p73 is mediated by
polyubiquitination-dependent and -independent processes both of which appear,
thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. Here, we
describe the characterization of another transcriptional target of TAp73; a ring
finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2
was initially identified a p53-induced gene (p53RFP), low abundance of PIR2
transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice
and comparison of PIR2 mRNA and protein levels following TAp73 or p53
overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although
PIR2 expression was induced by DNA damage, its expression did not alter
apoptotic response or cell cycle profile per se. However, coexpression of PIR2
with TAp73 or DeltaNp73 resulted in an increase of the TA/DeltaNp73 ratio, due
to preferential degradation of DeltaNp73. Finally, PIR2 was able to relieve the
inhibitory effect of DeltaNp73 on TAp73 induced apoptosis following DNA damage.
These results suggest that PIR2, by being induced by TAp73 and degrading
DeltaNp73, differentially regulates TAp73/DeltaNp73 stability, and, hence, it
may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.
DOI: 10.1073/pnas.0911828107
PMCID: PMC2919933
PMID: 20615966 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/26261848 | 1. Drugs Today (Barc). 2015 Jun;51(6):345-56. doi: 10.1358/dot.2015.51.6.2336331.
Nintedanib in idiopathic pulmonary fibrosis.
Woodcock HV(1), Maher TM(2).
Author information:
(1)Centre for Injury and Tissue Repair, University College London, London, UK.
(2)Centre for Injury and Tissue Repair, University College London; NIHR
Respiratory Biomedical Research Unit, Royal Brompton Hospital; Fibrosis Research
Group, National Heart and Lung Institute, Imperial College, London, UK.
[email protected].
Idiopathic pulmonary fibrosis (IPF) conveys a median survival of 3 years and
until recently has lacked effective therapies. Nintedanib, an orally available,
small-molecule tyrosine kinase inhibitor with selectivity for vascular
endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and
fibroblast growth factor (FGF) receptors has recently been shown, in two pivotal
phase III studies, to effectively slow IPF disease progression. Consequently,
nintedanib was given accelerated approval by the FDA in October 2014 for the
treatment of IPF. This monograph explores the preclinical rationale for the
antifibrotic role of nintedanib and provides an overview of the available data
on pharmacokinetics, efficacy and safety.
Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.
DOI: 10.1358/dot.2015.51.6.2336331
PMID: 26261848 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17130378 | 1. Tob Control. 2006 Dec;15(6):481-4. doi: 10.1136/tc.2006.016097.
An uncontrolled trial of cytisine (Tabex) for smoking cessation.
Zatonski W(1), Cedzynska M, Tutka P, West R.
Author information:
(1)Department of Epidemiology & Cancer Prevention, The M Skłodowska-Curie
Memorial Cancer Center & Institute of Oncology, Warsaw, Poland.
[email protected]
OBJECTIVES: Cytisine (Tabex) has been licensed in Eastern Europe as an aid to
smoking cessation for 40 years. Cytisine is a partial agonist with high affinity
binding to the alpha4beta2 nicotinic acetylcholine receptor believed to be
central to the rewarding effect of nicotine. There is insufficient information
on effectiveness to warrant licensing by modern standards. To assess whether
full-scale controlled trials are warranted, this study sought to obtain an
estimate of the 12-month continuous abstinence rates of smokers using cytisine
with minimal behavioural support.
DESIGN: An uncontrolled, open-label trial.
SETTING: A smokers' clinic in an oncology centre in Warsaw, Poland.
SUBJECTS: 436 consecutive attendees of the smokers' clinic of whom 191 were
male. The mean dependence score (Fagerstrom Test for Nicotine Dependence) was
6.1.
INTERVENTION: The standard regimen of Tabex (cytisine) was used, involving 25
days of treatment with minimal behavioural support.
MAIN OUTCOME MEASURE: Self-reported continuous abstinence for 12 months; with
abstinence verified by carbon monoxide at the final follow up (after 12 months).
RESULTS: 60 participants (13.8% of the total sample) were abstinent for 12
months. Of the 315 subjects, who had taken the drug, 49 (15.5%) stopped cytisine
because of adverse effects (mostly gastric disturbances and nausea), although
they were not serious. The frequency of the minor adverse effects, primarily
gastric disturbance, was similar to that observed in previous studies with the
drug.
CONCLUSIONS: The long-term abstinence rates were similar to those observed in
smokers receiving nicotine replacement therapy. Full-scale randomised trials of
cytisine (Tabex), conducted to the standards required by regulatory authorities,
are warranted.
DOI: 10.1136/tc.2006.016097
PMCID: PMC2563682
PMID: 17130378 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: none declared by WZ, MC and
PT. RW has undertaken research and consultancy for companies that develop and
manufacture smoking cessation medications. He is part funded by Cancer Research
UK |
http://www.ncbi.nlm.nih.gov/pubmed/7407830 | 1. Cell Tissue Res. 1980;208(2):183-96. doi: 10.1007/BF00234869.
The caveolae in rabbit sinus node and atrium.
Masson-Pévet M, Gros D, Besselsen E.
Caveolae or membrane vesicles are commonly observed in smooth and skeletal
muscle as well as in working heart muscle. Using sections of fixed tissue and
replicas of freeze-cleaved material, we show in this study that caveolae are
also very numerous in sinus node cells of the rabbit, and to a lesser degree, in
the atrial cells. Caveolae increase the plasma membrane surface area by 115% in
the leading sinus node, and by 56% in the atrial cells. In these two cell types,
the membrane of the caveolae contains four times fewer intramembranous particles
than the rest of the plasma membrane, and this difference applies to both PF and
EF faces. The role of the caveolae is still unclear, but it does not seem that
they have a pinocytotic function.
DOI: 10.1007/BF00234869
PMID: 7407830 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24039610 | 1. PLoS Genet. 2013;9(9):e1003777. doi: 10.1371/journal.pgen.1003777. Epub 2013
Sep 5.
Cell-type specific features of circular RNA expression.
Salzman J(1), Chen RE, Olsen MN, Wang PL, Brown PO.
Author information:
(1)Department of Biochemistry, Stanford University School of Medicine, Stanford,
California, United States of America.
Erratum in
PLoS Genet. 2013 Dec;9(12).
doi:10.1371/annotation/f782282b-eefa-4c8d-985c-b1484e845855.
Thousands of loci in the human and mouse genomes give rise to circular RNA
transcripts; at many of these loci, the predominant RNA isoform is a circle.
Using an improved computational approach for circular RNA identification, we
found widespread circular RNA expression in Drosophila melanogaster and estimate
that in humans, circular RNA may account for 1% as many molecules as poly(A)
RNA. Analysis of data from the ENCODE consortium revealed that the repertoire of
genes expressing circular RNA, the ratio of circular to linear transcripts for
each gene, and even the pattern of splice isoforms of circular RNAs from each
gene were cell-type specific. These results suggest that biogenesis of circular
RNA is an integral, conserved, and regulated feature of the gene expression
program.
DOI: 10.1371/journal.pgen.1003777
PMCID: PMC3764148
PMID: 24039610 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/8577251 | 1. Mol Microbiol. 1995 Jun;16(6):1171-81. doi:
10.1111/j.1365-2958.1995.tb02340.x.
The atxA gene product activates transcription of the anthrax toxin genes and is
essential for virulence.
Dai Z(1), Sirard JC, Mock M, Koehler TM.
Author information:
(1)Department of Microbiology and Molecular Genetics, Medical School, University
of Texas, Houston 77030, USA.
Bacillus anthracis plasmid pXO1 carries the structural genes for the three
anthrax toxin proteins, cya (edema factor), lef (lethal factor), and pag
(protective antigen). Expression of the toxin genes by B. anthracis is enhanced
during growth under elevated levels of CO2. This CO2 effect is observed only in
the presence of another pXO1 gene, atxA, which encodes a transactivator of
anthrax toxin synthesis. Here we show that transcription of atxA does not appear
to differ in cells grown in 5% CO2 compared with cells grown in air. Using a new
efficient method for gene replacement in B. anthracis, we constructed an
atxA-null mutant in which the atxA-coding sequence on pXO1 is replaced with an
omega km-2 cassette. Transcription of all three toxin genes is decreased in the
absence of atxA. The pag gene possesses two apparent transcription start sites,
P1 and P2; only transcripts with 5' ends mapping to P1 are decreased in the
atxA-null mutant. Deletion analysis of the pag promoter region indicates that
the 111 bp region upstream of the P1 site is sufficient for atxA-mediated
activation of this transcript. The cya and lef genes each have one apparent
start site for transcription. Transcripts with 5' ends mapping to these sites
are not detected in the atxA-null mutant. The atxA-null mutant is avirulent in
mice. Moreover, the antibody response to all three toxin proteins is decreased
significantly in atxA-null mutant-infected mice. These data suggest that the
atxA gene product also regulates toxin gene expression during infection.
DOI: 10.1111/j.1365-2958.1995.tb02340.x
PMID: 8577251 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24418890 | 1. RNA Biol. 2013 Nov;10(11):1661-9. doi: 10.4161/rna.26851.
Screening of small molecules affecting mammalian P-body assembly uncovers links
with diverse intracellular processes and organelle physiology.
Martínez JP(1), Pérez-Vilaró G(2), Muthukumar Y(3), Scheller N(2), Hirsch T(3),
Diestel R(3), Steinmetz H(4), Jansen R(4), Frank R(3), Sasse F(3), Meyerhans
A(5), Díez J(2).
Author information:
(1)Infection Biology Group; Department of Experimental and Health Sciences;
Universitat Pompeu Fabra; Barcelona, Spain.
(2)Molecular Virology Group; Department of Experimental and Health Sciences;
Universitat Pompeu Fabra; Barcelona, Spain.
(3)Department of Chemical Biology; Helmholtz Centre for Infection Research;
Braunschweig, Germany.
(4)Department of Microbial Drugs; Helmholtz Centre for Infection Research;
Braunschweig, Germany.
(5)Infection Biology Group; Department of Experimental and Health Sciences;
Universitat Pompeu Fabra; Barcelona, Spain; Institució Catalana de Recerca i
Estudis Avançats (ICREA); Barcelona, Spain.
Processing bodies (P-bodies) are cytoplasmatic mRNP granules containing
non-translating mRNAs and proteins from the mRNA decay and silencing
machineries. The mechanism of P-body assembly has been typically addressed by
depleting P-body components. Here we apply a complementary approach and
establish an automated cell-based assay platform to screen for molecules
affecting P-body assembly. From a unique library of compounds derived from
myxobacteria, 30 specifically inhibited P-body assembly. Gephyronic acid A (GA),
a eukaryotic protein synthesis inhibitor, showed the strongest effect. GA also
inhibited, under stress conditions, phosphorylation of eIF2α and stress granule
formation. Other hits uncovered interesting novel links between P-body assembly,
lipid metabolism, and internal organelle physiology. The obtained results
provide a chemical toolbox to manipulate P-body assembly and function.
DOI: 10.4161/rna.26851
PMCID: PMC3907476
PMID: 24418890 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23038625 | 1. Eur J Endocrinol. 2012 Dec 10;168(1):9-13. doi: 10.1530/EJE-12-0457. Print
2013 Jan.
Germline mutations of AIP gene in somatotropinomas resistant to somatostatin
analogues.
Oriola J(1), Lucas T, Halperin I, Mora M, Perales MJ, Alvarez-Escolá C, Paz de
MN, Díaz Soto G, Salinas I, Julián MT, Olaizola I, Bernabeu I, Marazuela M,
Puig-Domingo M.
Author information:
(1)Hospital Universitari Germans Trias i Pujol, Carretera de Canyet, Badalona,
Spain.
OBJECTIVE: Most cases of familial isolated pituitary adenomas with mutated aryl
hydrocarbon receptor-interacting protein (AIP:HGNC:358) gene develop
somatotropinomas. They are characterised by an aggressive clinical phenotype
including early age at diagnosis, large tumours and frequent invasiveness. There
is little information on AIP gene mutations' prevalence in isolated
somatotropinomas characterised by poor response to somatostatin analogue
treatment. The aim of this study was to investigate the prevalence of AIP
mutations in non-familial cases of somatotropinomas with poor response to
conventional treatment.
DESIGN AND METHODS: Fifty patients with acromegaly (22 males/28 females, age
51±18 years) and 60 controls were included in this study performed at eight
University Hospitals in Spain. None had family history of pituitary adenomas or
other endocrine tumors. All patients failed to respond to conventional treatment
including surgery and somatostatin analogues. Some patients received adjuvant
radiotherapy and most cases required pegvisomant (PEG) treatment for
normalisation of IGF1. AIP analysis was performed in DNA extracted from
peripheral leucocytes, using standardised PCR protocol in which the coding
regions of exons 1, 2, 3, 4, 5 and 6 were amplified. Possible
deletions/duplications were studied using multiplex ligation-dependent probe
amplification.
RESULTS: SEQUENCE CHANGES OF POTENTIAL DIFFERENT SIGNIFICANCE THAT COULD BE
CONSIDERED AS MUTATIONS OR VARIATIONS OF UNKNOWN SIGNIFICANCE (VUS) OF THE AIP
GENE WERE FOUND IN FOUR PATIENTS (8%). IN TWO CASES, TWO DIFFERENT MUTATIONS
PREVIOUSLY DESCRIBED WERE FOUND: p.Arg9Gln and p.Phe269Phe. Two other VUS were
also found: c.787+24C>T in intron 5 and c.100-18C>T in intron 1. Age at
diagnosis ranged from 21 to 50 years old, and in all patients, the tumor was a
macroadenoma depicting IGF1 normalisation under PEG treatment.
CONCLUSIONS: AIP germline mutations show a low, but non-negligible, prevalence
in non-familial acromegaly patients with tumors resistant to treatment with
somatostatin analogues.
DOI: 10.1530/EJE-12-0457
PMID: 23038625 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20477251 | 1. Expert Rev Respir Med. 2008 Apr;2(2):235-43. doi: 10.1586/17476348.2.2.235.
Role of antibiotics in the management of chronic obstructive pulmonary disease.
Black PN(1).
Author information:
(1)Department of Pharmacology & Clinical Pharmacology, Faculty of Medical and
Health Sciences, University of Auckland, Private Bag 92019, Auckland, New
Zealand. [email protected]
Exacerbations of chronic obstructive pulmonary disease (COPD) are an important
cause of morbidity and healthcare expenditure. In hospitalized patients,
antibiotics decrease treatment failure and reduce mortality. There is also
evidence for the effectiveness of antibiotics in treating COPD exacerbations in
the community, but this is most convincing in patients with severe airflow
obstruction and there is uncertainty regarding the value of antibiotics in
patients with mild airflow obstruction. Treatment with antibiotics is usually
recommended for patients who have an increase in sputum volume, sputum purulence
and breathlessness, but the most important determinant of bacterial infection
appears to be purulence. There is some evidence to suggest that the decision to
use antibiotics can be guided by the use of procalcitonin, although this needs
to be confirmed in further studies. Newer broad-spectrum antibiotics may be more
effective than older antibiotics but, because of concerns regarding antibiotic
resistance, it may be appropriate to reserve them for patients at highest risk
of treatment failure. A number of studies suggest that antibiotic courses of 5
days in duration may be as effective as those for 7 days or more in patients
with mild-to-moderate exacerbations of COPD. Guidelines do not recommend the use
of prophylactic antibiotics in COPD but there is preliminary evidence to suggest
that they may reduce the number of exacerbations. Until the full results of
these studies are published, it will not be clear if they should be used.
DOI: 10.1586/17476348.2.2.235
PMID: 20477251 |
http://www.ncbi.nlm.nih.gov/pubmed/21680987 | 1. Postgrad Med. 2011 Jul;123(4):38-45. doi: 10.3810/pgm.2011.07.2302.
A new approach to glucose control in type 2 diabetes: the role of kidney
sodium-glucose co-transporter 2 inhibition.
Basile J(1).
Author information:
(1)Seinsheimer Cardiovascular Health Program, Medical University of South
Carolina, Ralph H. Johnson VA Medical Center, Charleston, SC 29403, USA.
[email protected]
Hyperglycemia is a defining characteristic of type 2 diabetes mellitus and is a
major risk factor associated with the development of many microvascular
complications. There are numerous therapies currently available to treat
hyperglycemia, but glycemic control rates remain poor. One potential reason is
the decline in ß-cell function over time, which decreases the effectiveness of
therapies that rely on insulin action. The kidney occupies a central position in
the control of glucose homeostasis by its role in gluconeogenesis and by
regulating glucose excretion. Under normal conditions, glucose filtered by the
kidney is virtually totally reabsorbed in the proximal tubule by the
sodium-glucose co-transporter 2 (SGLT2). Inhibition of SGLT2 is an attractive,
insulin-independent target for increasing glucose excretion in the setting of
hyperglycemia. A number of SGLT2 inhibitors have been synthesized, and results
from preclinical studies have shown that they increase glucose excretion and
normalize plasma glucose in diabetic models. Initial clinical data are promising
and suggest that SGLT2 inhibitors may be a new therapeutic option for treating
type 2 diabetes mellitus.
DOI: 10.3810/pgm.2011.07.2302
PMID: 21680987 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17332013 | 1. Nucleic Acids Res. 2007;35(6):1885-96. doi: 10.1093/nar/gkm085. Epub 2007 Mar
1.
Studies on the function of the riboregulator 6S RNA from E. coli: RNA polymerase
binding, inhibition of in vitro transcription and synthesis of RNA-directed de
novo transcripts.
Gildehaus N(1), Neusser T, Wurm R, Wagner R.
Author information:
(1)Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf,
Düsseldorf, Germany.
Escherichia coli 6S RNA represents a non-coding RNA (ncRNA), which, based on the
conserved secondary structure and previous functional studies, had been
suggested to interfere with transcription. Selective inhibition of sigma-70
holoenzymes, preferentially at extended -10 promoters, but not
stationary-phase-specific transcription was described, suggesting a direct role
of 6S RNA in the transition from exponential to stationary phase. To elucidate
the underlying mechanism, we have analysed 6S RNA interactions with different
forms of RNA polymerase by gel retardation and crosslinking. Preferred binding
of 6S RNA to Esigma(70) was confirmed, however weaker binding to Esigma(38) was
also observed. The crosslinking analysis revealed direct contact between a
central 6S RNA sequence element and the beta/beta' and sigma subunits. Promoter
complex formation and in vitro transcription analysis with exponential- and
stationary-phase-specific promoters and the corresponding holoenzymes
demonstrated that 6S RNA interferes with transcription initiation but does not
generally distinguish between exponential- and stationary-phase-specific
promoters. Moreover, we show for the first time that 6S RNA acts as a template
for the transcription of defined RNA molecules in the absence of DNA. In
conclusion, this study reveals new aspects of 6S RNA function.
DOI: 10.1093/nar/gkm085
PMCID: PMC1874619
PMID: 17332013 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26035255 | 1. N Engl J Med. 2015 Aug 13;373(7):621-31. doi: 10.1056/NEJMoa1505654. Epub 2015
Jun 2.
Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma.
Lonial S(1), Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I,
Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M,
Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL,
Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson
KC, Richardson P; ELOQUENT-2 Investigators.
Author information:
(1)From Winship Cancer Institute, Emory University School of Medicine, Atlanta
(S.L.); National and Kapodistrian University of Athens, Athens (M.D.); A.O.U.
San Giovanni Battista di Torino-Ospedale Molinette, Turin, Italy (A.P.); QEII
Health Science Center and Dalhousie University, Halifax, NS (D.W.), Cross Cancer
Institute and University of Alberta, Edmonton (A.B.), and Princess Margaret
Cancer Centre, Toronto (D.R.) - all in Canada; Silesian Medical University,
Katowice (S.G.), and Medical University of Lublin, Lublin (A.W.-C.) - both in
Poland; Charles University Hospital, Prague, Czech Republic (I.S.); University
Hospital, Nantes, France (P.M.); Complejo Asistencial Universitario de
Salamanca-Instituto de Investigación Biomédica de Salamanca, Salamanca
(M.-V.M.), and Clinica Universidad de Navarra-Centro de Investigación Médica
Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona (J.S.-M.) -
both in Spain; Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, and
Tel Aviv University, Ramat Aviv - both in Israel (H.M.); Ankara University,
Ankara, Turkey (M.B.); Alfred Health-Monash University, Melbourne, VIC,
Australia (A. Spencer); Barts and the London NHS Trust, London (H.O.);
University of Texas M.D. Anderson Cancer Center, Houston (R.Z.O.); Kyoto
Prefectural University of Medicine, Kyoto (M.T.), and Nishigunma National
Hospital, Shibukawa (M.M.) - both in Japan; Universitätsklinikum der Technische
Universität, Dresden (C.R.), and Universitätsklinikum Würzburg, Würzburg (H.E.)
- both in Germany; Zeikenhuis Netwerk Antwerpen (ZNA) Stuivenberg, Antwerp,
Belgium (K.L.W.); AbbVie Biotherapeutics, Redwood City, CA (A. Singhal);
Bristol-Myers Squibb, Princeton, NJ (J.K.), Wallingford, CT (E.B.), and
Braine-l'Alleud, Belgium (V.P.); and Dana-Farber Cancer Institute, Boston
(K.C.A., P.R.).
BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting
signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in
combination with lenalidomide and dexamethasone in a phase 1b-2 study in
patients with relapsed or refractory multiple myeloma.
METHODS: In this phase 3 study, we randomly assigned patients to receive either
elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or
lenalidomide and dexamethasone alone (control group). Coprimary end points were
progression-free survival and the overall response rate. Final results for the
coprimary end points are reported on the basis of a planned interim analysis of
progression-free survival.
RESULTS: Overall, 321 patients were assigned to the elotuzumab group and 325 to
the control group. After a median follow-up of 24.5 months, the rate of
progression-free survival at 1 year in the elotuzumab group was 68%, as compared
with 57% in the control group; at 2 years, the rates were 41% and 27%,
respectively. Median progression-free survival in the elotuzumab group was 19.4
months, versus 14.9 months in the control group (hazard ratio for progression or
death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85;
P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66%
in the control group (P<0.001). Common grade 3 or 4 adverse events in the two
groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion
reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1
or 2 in 29 patients.
CONCLUSIONS: Patients with relapsed or refractory multiple myeloma who received
a combination of elotuzumab, lenalidomide, and dexamethasone had a significant
relative reduction of 30% in the risk of disease progression or death. (Funded
by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2
ClinicalTrials.gov number, NCT01239797.).
DOI: 10.1056/NEJMoa1505654
PMID: 26035255 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19404190 | 1. Am J Phys Med Rehabil. 2009 Jul;88(7):525-32. doi:
10.1097/PHM.0b013e3181a5ade3.
Effects of amantadine in children with impaired consciousness caused by acquired
brain injury: a pilot study.
McMahon MA(1), Vargus-Adams JN, Michaud LJ, Bean J.
Author information:
(1)Division of Pediatric Rehabilitation, Department of Physical Medicine and
Rehabilitation, University of Cincinnati School of Medicine and Cincinnati
Children's Hospital Medical Center, Cincinnati, Ohio, USA.
OBJECTIVE: To conduct a pilot study of amantadine in children with impaired
consciousness caused by acquired brain injury, to establish design feasibility,
and to assess the effect on level of arousal and consciousness.
DESIGN: Randomized, double-blind, placebo-controlled crossover trial. Seven
subjects (mean age, 12.7 yrs) with an acquired brain injury (mean duration, 6
wks) were randomized to receive either 3 wks of placebo or amantadine, followed
by a 1-wk washout period and then 3 wks of the other agent. Main outcome
measures were the Coma/Near-Coma Scale and Coma Recovery Scale-Revised, each
done three times per week. Subjective evaluations of change in arousal and
consciousness by the parent and physician were done weekly.
RESULTS: Five subjects completed the study. There was no significant difference
in the slopes of recovery during either arm for the Coma/Near-Coma Scale (P =
0.24) or the Coma Recovery Scale-Revised (P = 0.28), although improvements in
consciousness were noted by the physician during weeks when amantadine was given
(P = 0.02).
CONCLUSIONS: This study suggests that amantadine facilitates recovery of
consciousness in pediatric acquired brain injury and provides important
information necessary to design future more definitive studies.
DOI: 10.1097/PHM.0b013e3181a5ade3
PMID: 19404190 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9556633 | 1. J Biol Chem. 1998 May 1;273(18):11378-83. doi: 10.1074/jbc.273.18.11378.
Novel mutations of the endothelin B receptor gene in patients with
Hirschsprung's disease and their characterization.
Tanaka H(1), Moroi K, Iwai J, Takahashi H, Ohnuma N, Hori S, Takimoto M,
Nishiyama M, Masaki T, Yanagisawa M, Sekiya S, Kimura S.
Author information:
(1)Department of Obstetrics and Gynecology, Chiba University School of Medicine,
Chiba, Japan.
Hirschsprung's disease (HSCR) is a congenital intestinal disease, characterized
by the absence of ganglion cells in the distal portion of the intestinal tract.
Recently, three susceptibility genes have been identified in HSCR, namely the
RET protooncogene, the endothelin B (ETB) receptor gene (EDNRB), and the
endothelin-3 (ET-3) gene (EDN3). To investigate whether mutations in EDNRB could
be related with HSCR in non-inbred populations in Japan, we examined alterations
of the gene in 31 isolated patients. Three novel mutations were detected as
follows: two transversions, A to T and C to A at nucleotides 311 (N104I) and
1170 (S390R), respectively, and a transition, T to C at nucleotide 325 (C109R).
To analyze functions of these mutant receptors, they were expressed in Chinese
hamster ovary cells. S390R mutation did not change the binding affinities but
caused the decreases in the ligand-induced increment of intracellular calcium
and in the inhibition of adenylyl cyclase activity, showing the impairment of
the intracellular signaling. C109R receptors were proved to be localized near
the nuclei as an unusual 44-kDa protein with the extremely low affinity to
endothelin-1 (ET-1) and not to be translocated into the plasma membrane. On the
other hand, N104I receptors showed almost the same binding affinities and
functional properties as those of the wild type. Therefore, we conclude that
S390R and C109R mutations could cause HSCR but that N104I mutation might be
polymorphous.
DOI: 10.1074/jbc.273.18.11378
PMID: 9556633 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22041710 | 1. Endocr Relat Cancer. 2011 Dec 1;18(6):R253-76. doi: 10.1530/ERC-11-0170. Print
2011 Dec.
Genetics and clinical characteristics of hereditary pheochromocytomas and
paragangliomas.
Welander J(1), Söderkvist P, Gimm O.
Author information:
(1)Department of Clinical and Experimental Medicine, Faculty of Health Sciences,
Linköping University, 58185 Linköping, Sweden.
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine
tumors of the adrenal glands and the sympathetic and parasympathetic
paraganglia. They can occur sporadically or as a part of different hereditary
tumor syndromes. About 30% of PCCs and PGLs are currently believed to be caused
by germline mutations and several novel susceptibility genes have recently been
discovered. The clinical presentation, including localization, malignant
potential, and age of onset, varies depending on the genetic background of the
tumors. By reviewing more than 1700 reported cases of hereditary PCC and PGL, a
thorough summary of the genetics and clinical features of these tumors is given,
both as part of the classical syndromes such as multiple endocrine neoplasia
type 2 (MEN2), von Hippel-Lindau disease, neurofibromatosis type 1, and
succinate dehydrogenase-related PCC-PGL and within syndromes associated with a
smaller fraction of PCCs/PGLs, such as Carney triad, Carney-Stratakis syndrome,
and MEN1. The review also covers the most recently discovered susceptibility
genes including KIF1Bβ, EGLN1/PHD2, SDHAF2, TMEM127, SDHA, and MAX, as well as a
comparison with the sporadic form. Further, the latest advances in elucidating
the cellular pathways involved in PCC and PGL development are discussed in
detail. Finally, an algorithm for genetic testing in patients with PCC and PGL
is proposed.
DOI: 10.1530/ERC-11-0170
PMID: 22041710 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16537902 | 1. Mol Cell Biol. 2006 Apr;26(7):2560-9. doi: 10.1128/MCB.26.7.2560-2569.2006.
Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and
are enriched in facultative heterochromatin.
Bernstein E(1), Duncan EM, Masui O, Gil J, Heard E, Allis CD.
Author information:
(1)Laboratory of Chromatin Biology, The Rockefeller University, 1230 York Ave.,
New York, New York 10021, USA.
The chromodomain (CD) of the Drosophila Polycomb protein exhibits preferential
binding affinity for histone H3 when trimethylated at lysine 27. Here we have
investigated the five mouse Polycomb homologs known as Cbx2, Cbx4, Cbx6, Cbx7,
and Cbx8. Despite a high degree of conservation, the Cbx chromodomains display
significant differences in binding preferences. Not all CDs bind preferentially
to K27me3; rather, some display affinity towards both histone H3 trimethylated
at K9 and H3K27me3, and one CD prefers K9me3. Cbx7, in particular, displays
strong affinity for both H3K9me3 and H3K27me3 and is developmentally regulated
in its association with chromatin. Cbx7 associates with facultative
heterochromatin and, more specifically, is enriched on the inactive X
chromosome. Finally, we find that, in vitro, the chromodomain of Cbx7 can bind
RNA and that, in vivo, the interaction of Cbx7 with chromatin, and the inactive
X chromosome in particular, depends partly on its association with RNA. We
propose that the capacity of this mouse Polycomb homolog to associate with the
inactive X chromosome, or any other region of chromatin, depends not only on its
chromodomain but also on the combination of histone modifications and RNA
molecules present at its target sites.
DOI: 10.1128/MCB.26.7.2560-2569.2006
PMCID: PMC1430336
PMID: 16537902 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18977757 | 1. J Biol Chem. 2009 Jan 2;284(1):404-413. doi: 10.1074/jbc.M807027200. Epub 2008
Oct 31.
Transcriptional activation in yeast in response to copper deficiency involves
copper-zinc superoxide dismutase.
Wood LK(1), Thiele DJ(2).
Author information:
(1)Department of Pharmacology and Cancer Biology, Duke University Medical
Center, Durham, North Carolina 27710.
(2)Department of Pharmacology and Cancer Biology, Duke University Medical
Center, Durham, North Carolina 27710. Electronic address:
[email protected].
Copper is an essential trace element, yet excess copper can lead to membrane
damage, protein oxidation, and DNA cleavage. To balance the need for copper with
the necessity to prevent accumulation to toxic levels, cells have evolved
sophisticated mechanisms to regulate copper acquisition, distribution, and
storage. In Saccharomyces cerevisiae, transcriptional responses to copper
deficiency are mediated by the copper-responsive transcription factor Mac1.
Although Mac1 activates the transcription of genes involved in high affinity
copper uptake during periods of deficiency, little is known about the mechanisms
by which Mac1 senses or responds to reduced copper availability. Here we show
that the copper-dependent enzyme Sod1 (Cu,Zn-superoxide dismutase) and its
intracellular copper chaperone Ccs1 function in the activation of Mac1 in
response to an external copper deficiency. Genetic ablation of either CCS1 or
SOD1 results in a severe defect in the ability of yeast cells to activate the
transcription of Mac1 target genes. The catalytic activity of Sod1 is essential
for Mac1 activation and promotes a regulated increase in binding of Mac1 to
copper response elements in the promoter regions of genomic Mac1 target genes.
Although there is precedent for additional roles of Sod1 beyond protection of
the cell from oxygen radicals, the involvement of this protein in
copper-responsive transcriptional regulation has not previously been observed.
Given the presence of both Sod1 and copper-responsive transcription factors in
higher eukaryotes, these studies may yield important insights into how copper
deficiency is sensed and appropriate cellular responses are coordinated.
DOI: 10.1074/jbc.M807027200
PMCID: PMC2610518
PMID: 18977757 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20202189 | 1. BMC Genomics. 2010 Mar 4;11:151. doi: 10.1186/1471-2164-11-151.
Promiscuity of enhancer, coding and non-coding transcription functions in
ultraconserved elements.
Licastro D(1), Gennarino VA, Petrera F, Sanges R, Banfi S, Stupka E.
Author information:
(1)Telethon Institute of Genetics and Medicine (TIGEM), via Pietro Castellino
111, 80131 Napoli, Italy.
BACKGROUND: Ultraconserved elements (UCEs) are highly constrained elements of
mammalian genomes, whose functional role has not been completely elucidated yet.
Previous studies have shown that some of them act as enhancers in mouse, while
some others are expressed in both normal and cancer-derived human tissues. Only
one UCE element so far was shown to present these two functions concomitantly,
as had been observed in other isolated instances of single, non ultraconserved
enhancer elements.
RESULTS: We used a custom microarray to assess the levels of UCE transcription
during mouse development and integrated these data with published microarray and
next-generation sequencing datasets as well as with newly produced PCR
validation experiments. We show that a large fraction of non-exonic UCEs is
transcribed across all developmental stages examined from only one DNA strand.
Although the nature of these transcripts remains a mistery, our meta-analysis of
RNA-Seq datasets indicates that they are unlikely to be short RNAs and that some
of them might encode nuclear transcripts. In the majority of cases this function
overlaps with the already established enhancer function of these elements during
mouse development. Utilizing several next-generation sequencing datasets, we
were further able to show that the level of expression observed in non-exonic
UCEs is significantly higher than in random regions of the genome and that this
is also seen in other regions which act as enhancers.
CONCLUSION: Our data shows that the concurrent presence of enhancer and
transcript function in non-exonic UCE elements is more widespread than
previously shown. Moreover through our own experiments as well as the use of
next-generation sequencing datasets, we were able to show that the RNAs encoded
by non-exonic UCEs are likely to be long RNAs transcribed from only one DNA
strand.
DOI: 10.1186/1471-2164-11-151
PMCID: PMC2847969
PMID: 20202189 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19363520 | 1. Oncogene. 2009 May 14;28(19):2024-33. doi: 10.1038/onc.2009.59. Epub 2009 Apr
13.
Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma.
Lau LM(1), Wolter JK, Lau JT, Cheng LS, Smith KM, Hansford LM, Zhang L, Baruchel
S, Robinson F, Irwin MS.
Author information:
(1)Hospital for Sick Children, University of Toronto, Ontario, Canada.
p73 encodes multiple functionally distinct isoforms. Proapoptotic TAp73 isoforms
contain a transactivation (TA) domain, and like p53, have tumor suppressor
properties and are activated by chemotherapies to induce cell death. In
contrast, antiapoptotic DeltaNp73 isoforms lack the TA domain and are
dominant-negative inhibitors of p53 and TAp73. DeltaNp73 proteins are
overexpressed in a variety of tumors including neuroblastoma. Thus,
identification of drugs that upregulate TAp73 and/or downregulate DeltaNp73
represents a potential therapeutic strategy. Here, we report that cyclooxygenase
(COX) inhibitors induce apoptosis independent of p53, and differentially
modulate endogenous p73 isoforms in neuroblastoma and other tumors. COX
inhibitor-mediated apoptosis is associated with the induction of TAp73beta and
its target genes. COX inhibitors also downregulate the alternative-spliced
DeltaNp73(AS) isoforms, Deltaexon2 and Deltaexon2/3. Furthermore, forced
expression of DeltaNp73(AS) results in diminished apoptosis in response to the
selective COX-2 inhibitor celecoxib. Celecoxib-mediated downregulation of
DeltaNp73(AS) is associated with decreased E2F1 levels and diminished E2F1
activation of the p73 promoter. These results provide the first evidence that
COX inhibitors differentially modulate p73 isoforms leading to enhanced
apoptosis, and support the potential use of COX inhibitors as novel regulators
of p73 to enhance chemosensitivity in tumors with deregulated E2F1 and in those
with wild-type (wt) or mutant p53.
DOI: 10.1038/onc.2009.59
PMID: 19363520 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9287354 | 1. J Biol Chem. 1997 Sep 12;272(37):23389-97. doi: 10.1074/jbc.272.37.23389.
Complex formation between junctin, triadin, calsequestrin, and the ryanodine
receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane.
Zhang L(1), Kelley J, Schmeisser G, Kobayashi YM, Jones LR.
Author information:
(1)Department of Medicine and the Krannert Institute of Cardiology, Indiana
University School of Medicine, Indianapolis, Indiana 46202, USA.
Several key proteins have been localized to junctional sarcoplasmic reticulum
which are important for Ca2+ release. These include the ryanodine receptor,
triadin, and calsequestrin, which may associate into a stable complex at the
junctional membrane. We recently purified and cloned a fourth component of this
complex, junctin, which exhibits homology with triadin and is the major
125I-calsequestrin-binding protein detected in cardiac sarcoplasmic reticulum
vesicles (Jones, L. R., Zhang, L., Sanborn, K., Jorgensen, A. O., and Kelley, J.
(1995) J. Biol. Chem. 270, 30787-30796). In the present study, we have examined
the binding interactions between the cardiac forms of these four proteins with
emphasis placed on the role of junctin. By a combination of approaches including
calsequestrin-affinity chromatography, filter overlay, immunoprecipitation
assays, and fusion protein binding analyses, we find that junctin binds directly
to calsequestrin, triadin, and the ryanodine receptor. This binding interaction
is localized to the lumenal domain of junctin, which is highly enriched in
charged amino acids organized into "KEKE" motifs. KEKE repeats are also found in
the common lumenal domain of triadin, which likewise is capable of binding to
calsequestrin and the ryanodine receptor (Guo, W., and Campbell, K. P. (1995) J.
Biol. Chem. 270, 9027-9030). It appears that junctin and triadin interact
directly in the junctional sarcoplasmic reticulum membrane and stabilize a
complex that anchors calsequestrin to the ryanodine receptor. Taken together,
these results suggest that junctin, calsequestrin, triadin, and the ryanodine
receptor form a quaternary complex that may be required for normal operation of
Ca2+ release.
DOI: 10.1074/jbc.272.37.23389
PMID: 9287354 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18393531 | 1. Anal Chem. 2008 May 15;80(10):3751-6. doi: 10.1021/ac702072c. Epub 2008 Apr 8.
Quantitative analysis of HIV-1 protease inhibitors in cell lysates using
MALDI-FTICR mass spectrometry.
van Kampen JJ(1), Burgers PC, de Groot R, Osterhaus AD, Reedijk ML, Verschuren
EJ, Gruters RA, Luider TM.
Author information:
(1)Department of Neurology, Laboratory of Neuro-Oncology and Clinical and Cancer
Proteomics, Erasmus MC, Rotterdam, The Netherlands.
In this report we explore the use of MALDI-FTICR mass spectrometry for the
quantitative analysis of five HIV-1 protease inhibitors in cell lysates.
2,5-Dihydroxybenzoic acid (DHB) was used as the matrix. From a quantitative
perspective, DHB is usually a poor matrix due to its poor shot-to-shot and poor
spot-to-spot reproducibilities. We found that the quantitative precisions
improved significantly when DMSO (dimethylsulfoxide) was added to the matrix
solution. For lopinavir and ritonavir, currently the most frequently prescribed
HIV-1 protease inhibitors, the signal-to-noise ratios improved significantly
when potassium iodide was added to the matrix solution. The mean quantitative
precisions, expressed as % relative standard deviation, were 6.4% for
saquinavir, 7.3% for lopinavir, 8.5% for ritonavir, 11.1% for indinavir, and
7.2% for nelfinavir. The mean quantitative accuracies, expressed as % deviation,
were 4.5% for saquinavir, 6.0% for lopinavir, 5.9% for ritonavir, 6.6% for
indinavir, and 8.0% for nelfinavir. The concentrations measured for the
individual quality control samples were all within 85-117% of the theoretical
concentrations. The lower limits of quantification in cell lysates were 4
fmol/microL for saquinavir, 16 fmol/microL for lopinavir, 31 fmol/microL for
ritonavir, and 100 fmol/microL for indinavir and nelfinavir. The mean mass
accuracies for the protease inhibitors were 0.28 ppm using external calibration.
Our results show that MALDI-FTICR mass spectrometry can be successfully used for
precise, accurate, and selective quantitative analyses of HIV-1 protease
inhibitors in cell lysates. In addition, the lower limits of quantification
obtained allow clinical applications of the technique.
DOI: 10.1021/ac702072c
PMID: 18393531 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8204006 | 1. Arch Pathol Lab Med. 1994 Jun;118(6):608-15.
Comparison of Ewing's sarcoma of bone and peripheral neuroepithelioma. An
immunocytochemical and ultrastructural analysis of two primitive neuroectodermal
neoplasms.
Navarro S(1), Cavazzana AO, Llombart-Bosch A, Triche TJ.
Author information:
(1)Department of Pathology, Universidad de Valencia, Spain.
Comment in
Arch Pathol Lab Med. 1995 Nov;119(11):992.
Arch Pathol Lab Med. 1994 Jun;118(6):606-7.
Ewing's sarcoma of bone (ESB) and peripheral neuroepithelioma (PN) are
frequently considered to be different tumors. Some researchers have suggested
that PN is morphologically a neuroectodermal Ewing's sarcoma. We sought to
determine the extent of neuroectodermal features in conventional ESB on direct
patient material (25 cases) and to compare these tumors with a similar group of
readily diagnosed PNs (10 cases). Light microscopic, ultrastructural, and
immunophenotypic parameters were assessed and compared for both groups. The
avidin-biotin complex method was used. All tumors were antigenically intact
since all stained for vimentin or at least one marker. Neuroectodermal antigens
(neuron-specific enolase, Leu-7 [HNK-1], neurofilament 200 kd, and S100) were
found in nine of 10 cases of PN and in 17 of 25 cases of ESB. In ESB, an
atypical light microscopic appearance correlated with the presence of
neuroectodermal features in most cases, but neuroectodermal phenotype was more
frequent (68%) than morphological evidence of neuroectodermal differentiation
(36%). These data support the concept that ESB and PN are both peripheral
primitive neuroectodermal neoplasms, differing only in extent of neuroectodermal
phenotype and morphological differentiation.
PMID: 8204006 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22540167 | 1. Expert Rev Pharmacoecon Outcomes Res. 2012 Aug;12(4):425-37. doi:
10.1586/erp.12.31. Epub 2012 Apr 27.
Health-economic review of zoledronic acid for the management of skeletal-related
events in bone-metastatic prostate cancer.
Carter JA(1), Botteman MF.
Author information:
(1)Pharmerit North America LLC, Bethesda, MD 20814, USA.
Zoledronic acid is the only bisphosphonate approved for the prevention or delay
of skeletal-related events in patients with bone metastases secondary to
prostate cancer. Recently, the US FDA and the EMA approved denosumab (a fully
human monoclonal antibody) to treat skeletal-related events in bone-metastatic
prostate cancer. This article summarizes the cost-effectiveness literature
pertaining to these two agents when used in the prevention of skeletal-related
events secondary to malignancy. Zoledronic acid (and denosumab in comparison
with zoledronic acid) have been found to be cost effective and cost ineffective
depending on the analytical perspective and model parameters.
DOI: 10.1586/erp.12.31
PMID: 22540167 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18713579 | 1. Curr Neurol Neurosci Rep. 2008 Sep;8(5):419-26. doi:
10.1007/s11910-008-0065-3.
Monoclonal antibody treatments for multiple sclerosis.
Rose JW(1), Foley J, Carlson N.
Author information:
(1)Neurovirology Research Laboratory, VA Salt Lake City Health Care System;
Department of Neurology, University of Utah Neurovirology Research Laboratory,
Salt Lake City, UT 84148, USA. [email protected]
Monoclonal antibodies (MAbs) may have great potential as therapies for
autoimmune diseases. Their development as treatments for multiple sclerosis (MS)
is promising. Partially effective immunomodulatory therapies have been helpful
for many MS patients; however, for patients failing these immunomodulatory
treatments, MAbs are an important new treatment option. Currently, MAbs are
approved by the US Food and Drug Administration for treatment of many
conditions, including autoimmune diseases. Four MAbs that have been investigated
as potential treatments for MS are reviewed in this article. Of these MAbs,
natalizumab is approved for treatment of MS. The other three MAbs (alemtuzumab,
rituximab, and daclizumab) are all promising therapies in development for
treatment of MS. Adverse effects are relatively mild for these MAbs; however,
care in administration and management of these agents is emphasized. Overall,
these MAb therapies have great promise in the treatment of MS.
DOI: 10.1007/s11910-008-0065-3
PMID: 18713579 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21470540 | 1. Can Urol Assoc J. 2011 Apr;5(2):120-33. doi: 10.5489/cuaj.10160.
Emerging novel therapies in the treatment of castrate-resistant prostate cancer.
Abdulla A(1), Kapoor A.
Author information:
(1)McMaster Institute of Urology, Division of Urology, Department of Surgery
McMaster University, Hamilton, ON.
The treatment options for patients with castration-resistant prostate cancer
(CRPC), until very recently, only included docetaxel. In the past 10 months,
newly Federal Drug Administration (FDA) approved agents in the United States
have shown survival benefit for patients with CRPC. This review takes a closer
look at these newer agents: sipuleucel-T (immune therapy) and cabazi-taxel
(cytotoxic therapy). We also review the evidence supporting the FDA's approval
of denosumab (bone-targeted therapy) as a treatment option for men with CRPC and
bony metastases. Newer agents currently being investigated in phase III clinical
trials for their potential role in metastatic CRPC are also reviewed. These
agents include abiraterone (hormonal therapy), TAK-700 (hormonal therapy),
MDV3100 (hormonal therapy), ipilimumab (immune therapy), zibotentan
(endothelin-A receptor antagonist) and dasatinib (tyrosine kinase inhibitor). As
ongoing studies using all the aforementioned agents continue to evolve, our
understanding of how and where these agents fit into the treatment paradigm for
patients with CRPC will become clearer.
Les options thérapeutiques des patients atteints d’un cancer de la prostate
résistant à la castration (CPRC), jusqu’à tout récemment, ne comprenaient que le
docetaxel. Au cours des 10 derniers mois, de nouveaux agents approuvés par la
Food and Drug Administration (FDA) des États-Unis ont montré un avantage lié à
la survie chez les patients atteints d’un CPRC. Nous examinons ici plus
étroitement ces nouveaux agents : le sipuleucel-T (immunothérapie) et le
cabazitaxel (traitement cytotoxique). Nous passons aussi en revue les données
étayant l’approbation par la FDA du dénosumab (traitement ciblant les cellules
osseuses) comme option thérapeutique chez les hommes atteints d’un cancer de la
prostate résistant à la castration avec métastases osseuses. Les nouveaux agents
en cours d’études cliniques de phase III en raison de leur rôle potentiel dans
le traitement du CPRC métastatique sont aussi examinés. Ces agents incluent
l’abiratérone (hormonothérapie), le TAK-700 (hormonothérapie), le MDV3100
(hormonothérapie), l’ipilimumab (immunothérapie), le zibotentan (antagoniste des
récepteurs de l’endothéline-A) et le dasatinib (inhibiteur de la
tyrosine-kinase). À mesure que les études en cours sur ces agents continuent de
progresser, notre compréhension du rôle et de l’usage de ces agents dans le
paradigme thérapeutique des patients atteints de CPRC s’approfondira.
DOI: 10.5489/cuaj.10160
PMCID: PMC3104424
PMID: 21470540 |