tbuckley/cabot-search huggingface dataset:
Genomic features defining exonic variants that modulate splicing
Authors: Adam Woolfe, James C Mullikin, Laura Elnitski
Journal: Genome biology (2010)

Single point mutations at both synonymous and non-synonymous positions within exons can have severe effects on gene function through disruption of splicing. Predicting these mutations in silico purely from the genomic sequence is difficult due to an incomplete understanding of the multiple factors that may be responsible. In addition, little is known about which computational prediction approaches, such as those involving exonic splicing enhancers and exonic splicing silencers, are most informative.We assessed the features of single-nucleotide genomic variants verified to cause exon skipping and compared them to a large set of coding SNPs common in the human population, which are likely to have no effect on splicing. Our findings implicate a number of features important for their ability to discriminate splice-affecting variants, including the naturally occurring density of exonic splicing enhancers and exonic splicing silencers of the exon and intronic environment, extensive changes in the number of predicted exonic splicing enhancers and exonic splicing silencers, proximity to the splice junctions and evolutionary constraint of the region surrounding the variant. By extending this approach to additional datasets, we also identified relevant features of variants that cause increased exon inclusion and ectopic splice site activation.We identified a number of features that have statistically significant representation among exonic variants that modulate splicing. These analyses highlight putative mechanisms responsible for splicing outcome and emphasize the role of features important for exon definition. We developed a web-tool, Skippy, to score coding variants for these relevant splice-modulating features.
Microsatellite Instability, Mismatch Repair Deficiency, and <i>BRAF</i> Mutation in Treatment-Resistant Germ Cell Tumors
Authors: Friedemann Honecker, Hendrik Wermann, Frank Mayer, Ad J.M. Gillis, Hans Stoop, Ruud J.L.M. van Gurp, Karin Oechsle, Ewout Steyerberg, Jörg Th. Hartmann, Winand N.M. Dinjens, J. Wolter Oosterhuis, Carsten Bokemeyer, Leendert H.J. Looijenga
Journal: Journal of Clinical Oncology (2009)

Purpose Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown. Patients and Methods Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations. Results Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P &lt; .0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P &lt; .0001). BRAF mutations were highly correlated with MSI (P = .006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P = .017 and P = .008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P &lt; .001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P = .001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P = .068). Conclusion We report for the first time a correlation between a gene mutation—BRAF V600E—and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed.
Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse
Authors: Francis Giles, Norbert Vey, Daniel DeAngelo, Karen Seiter, Wendy Stock, Robert Stuart, Darinka Boskovic, Arnaud Pigneux, Martin Tallman, Joseph Brandwein, Jonathan Kell, Tadeusz Robak, Peter Staib, Xavier Thomas, Ann Cahill, Maher Albitar, Susan O'Brien
Journal: Blood (2009)
Randomized Study of Two Chemotherapy Regimens for Treatment of Low-Grade Glioma in Young Children: A Report From the Children's Oncology Group
Authors: Joann L. Ater, Tianni Zhou, Emiko Holmes, Claire M. Mazewski, Timothy N. Booth, David R. Freyer, Ken H. Lazarus, Roger J. Packer, Michael Prados, Richard Sposto, Gilbert Vezina, Jeffrey H. Wisoff, Ian F. Pollack
Journal: Journal of Clinical Oncology (2012)

PURPOSE Surgery is curative therapy for pediatric low-grade gliomas (LGGs) in areas of the brain amenable to complete resection. However, LGGs located in areas where complete resection is not possible can threaten both function and life. The purpose of this study was to compare two chemotherapy regimens for LGGs in children younger than age 10 years for whom radiotherapy was felt by the practitioner to pose a high risk of neurodevelopmental injury. PATIENTS AND METHODS Previously untreated children younger than age 10 years with progressive or residual LGGs were eligible. Children were randomly assigned to receive carboplatin and vincristine (CV) or thioguanine, procarbazine, lomustine, and vincristine (TPCV). Children with neurofibromatosis are reported separately. Results Of 274 randomly assigned patients who met eligibility requirements, 137 received CV and 137 received TPCV. The 5-year event-free survival (EFS) and overall survival (OS) rates for all eligible patients were 45% ± 3.2% and 86% ± 2.2%, respectively. The 5-year EFS rates were 39% ± 4% for CV and 52% ± 5% for TPCV (stratified log-rank test P = .10; cure model analysis P = .007). On multivariate analysis, factors independently predictive of worse EFS and OS were younger age and tumor size greater than 3 cm(2). Tumor location in the thalamus was also associated with poor OS. CONCLUSION The difference in EFS between the regimens did not reach significance on the basis of the stratified log-rank test. The 5-year EFS was higher for TPCV on the basis of the cure model analysis. Differences in toxicity may influence physician choice of regimens.
CYP2C19 Genotype and Proton Pump Inhibitors in Clopidogrel-Treated Patients
Authors: Michelle L. O'Donoghue
Journal: Circulation (2011)

debate continues regarding the existence of an adverse interaction between proton pump inhibitors (PPIs) and clopidogrel.Concerns for a drug-drug interaction first emerged when experimental pharmacodynamic data indicated that omeprazole might diminish the in vitro antiplatelet effects of clopidogrel. 1,2These concerns were escalated when retrospective data from 2 large observational studies demonstrated that use of a PPI was associated with an increased risk of cardiovascular events for patients treated with clopidogrel. 3,4In response to these findings, the US Food and Drug Administration updated the drug's label to warn that the effectiveness of clopidogrel is reduced when administered in combination with omeprazole. 5However, these findings have since been disputed by a growing number of analyses from clinical trial populations that have failed to show an increased risk of adverse outcomes when PPIs are administered in combination with clopidogrel. 6 -8 Furthermore, the results of the only randomized clinical trial to address this issue demonstrated similar cardiovascular risk regardless of whether subjects were assigned to clopidogrel alone or in combination with omeprazole. 9
Mechanisms by which SGN-40, a Humanized Anti-CD40 Antibody, Induces Cytotoxicity in Human Multiple Myeloma Cells: Clinical Implications
Authors: Yu-Tzu Tai, Laurence P. Catley, Constantine S. Mitsiades, Renate Burger, Klaus Podar, Reshma Shringpaure, Teru Hideshima, Dharminder Chauhan, Makoto Hamasaki, Kenji Ishitsuka, Paul Richardson, Steven P. Treon, Nikhil C. Munshi, Kenneth C. Anderson
Journal: Cancer Research (2004)

Abstract CD40 is expressed on B-cell malignancies, including human multiple myeloma (MM) and a variety of carcinomas. We examined the potential therapeutic utility of SGN-40, the humanized anti-CD40 monoclonal antibody, for treating human MM using MM cell lines and patient MM cells (CD138++, CD40+). SGN-40 (0.01–100 μg/ml) induces modest cytotoxicity in MM cell lines and patient MM cells. In the presence of de novo protein synthesis inhibitor cycloheximide, SGN-40 significantly induced apoptosis in Dexamethasone (Dex)-sensitive MM.1S and Dex-resistant MM.1R cells and in patient MM cells. SGN-40-mediated cytotoxicity is associated with up-regulation of cytotoxic ligands of the tumor necrosis factor family (Fas/FasL, tumor necrosis factor-related apoptosis-inducing ligand, and tumor necrosis factor α). SGN-40 treatment also induces a down-regulation of CD40 dependent on an endocytic pathway. Consequently, pretreatment of MM cells with SGN-40 blocked sCD40L-mediated phosphatidylinositol 3′-kinase/AKT and nuclear factor κB activation. Importantly, pretreatment of MM.1S and MM.1R cells with SGN-40 inhibited proliferation triggered by interleukin 6 (IL-6) but not by insulin-like growth factor-I. In addition, SGN-40 pretreatment of MM.1S cells blocked the ability of IL-6 to protect against Dex-induced inhibition of DNA synthesis. This was associated with a 2–4-fold reduction of IL-6 receptor at protein and mRNA levels in SGN-40-treated MM.1S cells and patient MM cells. Taken together, these results provide the preclinical rationale for the evaluation of SGN-40 as a potential new therapy to improve patient outcome in MM.
Ambivalent role of pFAK-Y397 in serous ovarian cancer-a study of the OVCAD consortium
Authors: Stefanie Aust, Katharina Auer, Anna Bachmayr-Heyda, Carsten Denkert, Jalid Sehouli, Ioana Braicu, Sven Mahner, Sandrina Lambrechts, Ignace Vergote, Christoph Grimm, Reinhard Horvat, Dan Cacsire Castillo-Tong, Robert Zeillinger, Dietmar Pils
Journal: Molecular Cancer (2014)

Focal adhesion kinase (FAK) autophosphorylation seems to be a potential therapeutic target but little is known about the role and prognostic value of FAK and pFAK in epithelial ovarian cancer (EOC). Recently, we validated a gene signature classifying EOC patients into two subclasses and revealing genes of the focal adhesion pathway as significantly deregulated. FAK expression and pFAK-Y397 abundance were elucidated by immunohistochemistry and microarray analysis in 179 serous EOC patients. In particular the prognostic value of phosphorylated FAK (pFAK-Y397) and FAK in advanced stage EOC was investigated. Multiple Cox-regression analysis showed that high pFAK abundance was associated with improved overall survival (HR 0.54; p = 0.034). FAK was positive in a total of 92.2% (n = 165) and high pFAK abundance was found in 36.9% (n = 66). High pFAK abundance (36.9% ; n = 66) was associated with either nodal positivity and/or distant metastasis (p = 0.030). Whole genome gene expression data revealed a connection of the FAK-pFAK-Y397 axis and the mTOR-S6K1 pathway, shown to play a major role in carcinogenesis. The role of pFAK-Y397 remains controversial: although high pFAK-Y397 abundance is associated with distant and lymph node metastases, it is independently associated with improved overall survival.
Light-emitting diodes (LED) for domestic lighting: Any risks for the eye?
Authors: F. Behar-Cohen, C. Martinsons, F. Viénot, G. Zissis, A. Barlier-Salsi, J.P. Cesarini, O. Enouf, M. Garcia, S. Picaud, D. Attia
Journal: Progress in Retinal and Eye Research (2011)
Heart Disease in Children
Authors: G. A. Stephens
Journal: BMJ (1926)

HEART DISEASE IN CHILDREN.TMEDIcABRTou temperature of only 990, without constitutional disturbance, in marked contrast to the previous result, while the other test doses of the series were followed by no tempera- ture disturbance at all.This test was repeated twelve months later, with five-day intervals between the injections, instead of two as on the previous occasion (Chart 7).On this occasion likewise there was nothing approaching a reaction; a temperatur-e of 99.20 on June 3rd was on the fifth day after the first injection and previous to' the administration of tho second one.A temperature of 990 on June 10th was on the second day after the third injection, and neither of these, nor any of the other 31.8;9 J 3, 9 2I3t 4 61,0.~~~~fI ~~~~~~~~~~/I/UI 1 k -CHART 7.
Privacy and Confidentiality in the Publication of Pedigrees
Authors: Jeffrey R. Botkin, William M. McMahon, Ken R. Smith, Jean E. Nash
Journal: JAMA (1998)

Pedigree diagrams efficiently communicate family information to genetics investigators; however, the publication of pedigrees poses a risk to the privacy and confidentiality of individuals depicted in the diagrams. Two sets of authoritative guidelines have been published to protect the privacy and confidentiality of subjects, but the influence of these guidelines on publication practices for pedigrees is unknown.To determine the attitudes, practices, and experiences of investigators and journals with respect to privacy and confidentiality concerns in the publication of pedigrees.Investigators who have published pedigrees and editors of 26 biomedical journals were surveyed. Journals were reviewed for content in their "information for authors" sections and for documentation of informed consent in articles containing pedigrees.Practices regarding confidentiality and privacy reported by investigators and editors.Of 226 surveys sent to investigators, 177 were returned (78% response rate). Sixty-one investigators (36%) stated that family members were not informed that their pedigree would be published; 131 (78%) do not obtain informed consent specifically for pedigree publication and only 12 (28%) of the 43 who obtained consent obtained consent from all family members depicted. Thirty-two individuals (19%) reported having altered published pedigrees and 14 (45%) of 31 who had altered pedigrees stated that alterations were not disclosed to journals. Of the 14 journals that responded (54% response rate), only 3 reported written policies for managing potentially identifying information. Two journals reported having asked authors to alter pedigrees and 3 stated they had permitted alterations. A review of 5 genetics journals over a 2-year period revealed no documentation of consent for pedigree publication.Current practices in the publication of pedigrees do not conform with established recommendations and risk the privacy and confidentiality of subjects, often without informed consent. Attempts to address this problem through the alteration of data are being used, although this practice impairs the integrity of scientific communication.
Phylogenetic utility of the nuclear gene arginine decarboxylase: an example from Brassicaceae
Authors: G. L. Galloway, R. L. Malmberg, R. A. Price
Journal: Molecular Biology and Evolution (1998)

Arginine decarboxylase (ADC) is an important enzyme in the production of putrescine and polyamines in plants. It is encoded by a single or low-copy nuclear gene that lacks introns in sequences studied to date. The rate of Adc amino acid sequence evolution is similar to that of ndhF for the angiosperm family studied. Highly conserved regions provide several target sites for PCR priming and sequencing and aid in nucleotide and amino acid sequence alignment across a range of taxonomic levels, while a variable region provides an increased number of potentially informative characters relative to ndhF for the taxa surveyed. The utility of the Adc gene in plant molecular systematic studies is demonstrated by analysis of its partial nucleotide sequences obtained from 13 representatives of Brassicaceae and 3 outgroup taxa, 2 from the mustard oil clade (order Capparales) and 1 from the related order Malvales. Two copies of the Adc gene, Adc1 and Adc2, are found in all members of the Brassicaceae studied to data except the basal genus Aethionema. The resulting Adc gene tree provides robust phylogenetic data regarding relationships within the complex mustard family, as well as independent support for proposed tribal realignments based on other molecular data sets such as those from chloroplast DNA.
Inhibition of Four-and-a-Half LIM Domain Protein-2 Increases Survival, Migratory Capacity, and Paracrine Function of Human Early Outgrowth Cells Through Activation of the Sphingosine Kinase-1 Pathway
Authors: Talin Ebrahimian, Omar Arfa, Stefania Simeone, Catherine A. Lemarié, Stéphanie Lehoux, Sven Wassmann
Journal: Circulation Research (2013)

Rationale: Inhibition of four-and-a-half LIM domain protein-2 (FHL2) attenuates atherosclerotic lesion formation and increases endothelial cell migration. Early outgrowth cells (EOCs) contribute substantially to endothelial repair. Objective: We investigated the role of FHL2 in the regulation of EOCs. Methods and Results: Human EOCs were cultured from peripheral blood. FHL2 knockdown in EOCs by siRNA resulted in increased EOC numbers and reduced apoptosis, as indicated by decreased cleaved caspase-III and reduced Bax/Bcl-2 expression ratio. This was mediated through increased phosphorylation and membrane translocation of sphingosine kinase-1, increased sphingosine-1-phosphate levels, and Akt phosphorylation. FHL2 knockdown increased stromal cell–derived factor-1–induced EOC migration through upregulation of αv/β3, αv/β5, and β2 integrins, associated with increased cortactin expression. Reduced apoptosis, increased EOC migration, and cortactin upregulation by FHL2 siRNA were prevented by CAY10621, the sphingosine kinase-1 inhibitor, and the sphingosine-1-phosphate receptor-1/-3 antagonist VPC23019. These findings were confirmed using spleen-derived EOCs from FHL2 −/− mice. Apoptosis was decreased and migration increased in endothelial cells exposed to the conditioned medium of FHL2 −/− versus wild-type (WT) EOCs. These paracrine effects were abolished by VPC23019. Importantly, reendothelialization after focal carotid endothelial injury in WT mice was significantly increased after intravenous injection of FHL2 −/− versus WT EOCs. Conclusions: Our findings suggest that FHL2 negatively regulates EOC survival, migration, and paracrine function. FHL2 inhibition in EOCs reduces apoptosis and enhances survival and migratory capacity of both EOCs and surrounding endothelial cells by activation of the sphingosine kinase-1/sphingosine-1-phosphate pathway, resulting in improvement of endothelial regeneration.
A 46-year-old female with dyspnoea, stridor and chronic cough
Authors: N. Maimon, T. Marras, D. Hwang, N. Paul, S. Keshavjee, C. K. N. Chan
Journal: European Respiratory Journal (2006)

A 46-yr-old female presented to the chest clinic with chronic dry cough and increasing dyspnoea on exertion. The patient's symptoms had deteriorated over the past 15 months and, at presentation, the patient developed dyspnoea after only 50 yards of walking. She had experienced multiple emergency department visits and frequent admissions to the hospital because of breathing difficulties. Also, during the last year, she experienced recurrent respiratory infections with a frequency of one to two infections per month. The patient received a diagnosis of bronchial asthma and was treated with short courses of systemic steroids, multiple inhalers and courses of antibiotics; resulting in only mild and temporary improvement in her symptoms. Pulmonary function tests (PFTs) 15 months earlier had shown a forced expiratory volume in one second (FEV1) of 1.5 L (84% predicted).

The patient's past medical history was unremarkable. Specifically, there was no history of childhood asthma or frequent infections. She was an ex-smoker with 15 pack-yrs. Family history, environmental allergies and occupational exposures were all unremarkable. At presentation her medications included salmeterol-fluticasone inhaler, tiotropium, montelukast, prednisone 30 mg daily and pantoprazole.

The patient appeared well with a blood pressure of 130/80 mmHg, heart rate of 80·min-1 and regular, respiratory rate of 18·min-1. Her saturation on room air was at 95%. Head and neck examination did not demonstrate lymphadenopathy or signs of chondral inflammation. Her cardiovascular examination revealed a normal jugular vein pulse with normal heart sounds and no pedal oedema. Respiratory examination demonstrated absence of clubbing and no evidence of wheezing or crackle. However, forced expiration produced an audible stridor sound.

Spirometry demonstrated a forced vital capacity (FVC) of 1.7 L (75% pred), FEV1 0.65 L (25% pred), and FEV1/FVC 35%. A flow/volume curve is shown in figure 1⇓. Diffusing …
<i>In Vitro</i> and <i>In Vivo</i> Selective Antitumor Activity of a Novel Orally Bioavailable Proteasome Inhibitor MLN9708 against Multiple Myeloma Cells
Authors: Dharminder Chauhan, Ze Tian, Bin Zhou, Deborah Kuhn, Robert Orlowski, Noopur Raje, Paul Richardson, Kenneth C. Anderson
Journal: Clinical Cancer Research (2011)

The success of bortezomib therapy for treatment of multiple myeloma (MM) led to the development of structurally and pharmacologically distinct novel proteasome inhibitors. In the present study, we evaluated the efficacy of one such novel orally bioactive proteasome inhibitor MLN9708/MLN2238 in MM using well-established in vitro and in vivo models.MM cell lines, primary patient cells, and the human MM xenograft animal model were used to study the antitumor activity of MN2238.Treatment of MM cells with MLN2238 predominantly inhibits chymotrypsin-like activity of the proteasome and induces accumulation of ubiquitinated proteins. MLN2238 inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies without affecting the viability of normal cells. In animal tumor model studies, MLN2238 is well tolerated and inhibits tumor growth with significantly reduced tumor recurrence. A head-to-head analysis of MLN2238 versus bortezomib showed a significantly longer survival time in mice treated with MLN2238 than mice receiving bortezomib. Immununostaining of MM tumors from MLN2238-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Mechanistic studies showed that MLN2238-triggered apoptosis is associated with activation of caspase-3, caspase-8, and caspase-9; increase in p53, p21, NOXA, PUMA, and E2F; induction of endoplasmic reticulum (ER) stress response proteins Bip, phospho-eIF2-α, and CHOP; and inhibition of nuclear factor kappa B. Finally, combining MLN2238 with lenalidomide, histone deacetylase inhibitor suberoylanilide hydroxamic acid, or dexamethasone triggers synergistic anti-MM activity.Our preclinical study supports clinical evaluation of MLN9708, alone or in combination, as a potential MM therapy.