tbuckley/cabot-search huggingface dataset:
The Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 (Iressa) Suppresses c-Src and Pak1 Pathways and Invasiveness of Human Cancer Cells
Authors: Zhibo Yang, Rozita Bagheri-Yarmand, Rui-An Wang, Liana Adam, Vali Vassiliki Papadimitrakopoulou, Gary L. Clayman, Adel El-Naggar, Reuben Lotan, Christopher J. Barnes, Waun Ki Hong, Rakesh Kumar
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Abnormalities in the expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including those of the head and neck and breast. Accordingly, agents such as the EGFR tyrosine kinase inhibitor (EGFR-TKI) ZD1839 (Iressa) are promising, biologically based treatments that are in various stages of preclinical and clinical development. The process of tumor progression requires, among other steps, increased transformation, directional migration, and enhanced cell survival; this study explored the effect of ZD1839 on the stimulation of c-Src and p21-activated kinase 1 (Pak1), which are vital for transformation, directional motility, and cell survival of cancer cells. Experimental Design: We examined the effect of ZD1839 on biochemical and functional assays indicative of directional motility and cell survival, using human head and neck squamous cancer cells and breast cancer cells. Results: ZD1839 effectively inhibited c-Src activation and Pak1 activity in exponentially growing cancer cells. In addition, ZD1839 suppressed EGF-induced stimulation of EGFR autophosphorylation on Y1086 and Grb2-binding Y1068 sites, c-Src phosphorylation on Y215, and Pak1 activity. ZD1839 also blocked EGF-induced cytoskeleton remodeling, redistribution of activated EGFR, and in vitro invasiveness of cancer cells. Conclusions: These studies suggest that the EGFR-TKI ZD1839 may cause potent inhibition of the Pak1 and c-Src pathways and, therefore, have potential to affect the invasiveness of human cancer cells deregulated in these growth factor receptor pathways.
Fecal Incontinence in Adults
Authors: Arnold Wald
Journal: New England Journal of Medicine (2007)

A 53-year-old woman presents with a history of intermittent fecal incontinence. Physical activity often precipitates an episode, and she wears absorbent pads. She has occasional urinary incontinence when she coughs or sneezes. There is no history of gastrointestinal or rectal surgery and no neurologic symptoms. Examination reveals no perianal deformity or rectal prolapse. The tone of the anal canal is adequate, whereas contractions of the anal sphincter and puborectalis muscles are weak. When the patient bears down, there is no rectal prolapse, and perineal descent is approximately 2 cm. How should she be evaluated and treated?
One-Carbon Metabolism, Colorectal Carcinogenesis, Chemoprevention--with Caution
Authors: R. G. Ziegler, U. Lim
Journal: JNCI Journal of the National Cancer Institute (2007)

One-carbon metabolism comprises a network of integrated biochemical pathways that donate, and regenerate, the one-carbon moieties needed for physiologic processes. Efficient one-carbon metabolism is required for the biosynthesis of the purines, adenine and guanine, and the conversion of uridylate to thymidylate, which prevents the misincorporation of uracil into DNA ( 1 ). By donating a methyl group to homocysteine to create methionine, one-carbon metabolism also generates S -adenosylmethionine, the universal methyl donor, which is required for DNA methylation ( 1 ). Disruption of one-carbon metabolism can, therefore, interfere with DNA replication, DNA repair, and regulation of gene expression through methylation, each of which could promote carcinogenesis. One-carbon metabolism requires optimal activity of 25 or more enzymes, some of which depend on not only folate, a B vitamin, but also vitamins B-12, B-6, and B-2 (riboflavin) as coenzymes. Over the past 15 years, one-carbon metabolism has received increasing attention as a process whereby diet and genetic variation could modulate cancer risk. Based on the biochemistry, hypotheses were generated about the influence on cancer risk of folate and B-vitamin intake; folate and B-vitamin status; alcohol use, which interferes with folate bioavailability ( 2 ); and altered enzyme activity related to common genetic polymorphisms — hypotheses that could be tested in animal experiments, epidemiologic studies, and randomized clinical trials. In epidemiologic studies, low folate intake has been linked to increased risks of several cancers, including cancers of the breast, ovary, cervix, esophagus, stomach, pancreas, and lymphoid tissues, but the evidence is most extensive for colorectal cancer and its precursor, colorectal adenoma. In both men and women, low folate intake is associated with increased risk of colorectal adenoma and cancer in the majority of the epidemiologic studies ( 3 , 4 ). Serum and red blood cell folate have generally, although not always, been inversely associated with risk ( 3 ). Limited data suggest that intake of methionine, an essential source of one-carbon groups, may also be protective ( 3 ). High alcohol consumption, which interferes with folate utilization and other aspects of onecarbon metabolism (2), was associated with in creased risk, especially when folate intake was low ( 3 ). In rodent models, usually folate depletion enhanced and folate supplementation protected against the early stages of intestinal carcinogenesis ( 5 ). Although folate and methionine have received more attention as one-carbon donors in studies of chronic disease, choline and its metabolite betaine merit comparable consideration. Like 5-methyl tetrahydrofolate, choline, once oxidized to betaine, can transfer a one-carbon moiety to homocysteine to produce methionine and
Polymorphism of glutation-S-transferases T1 and M1 in chronic obstructive pulmonary disease
Authors: Svetlana Vakhrusheva, Vera Nevzorova, Tatyana Tilik, Evgeny Gilifanov, Marina Issaeva, Elena Samoilenko
Journal: European Respiratory Journal (2011)

Chronic obstructive pulmonary disease (COPD) is the result of genetic factors and environmental conditions influence on a human organism. Glutation-S-transferases (GST) play significant role in cell resistance to oxidative stress, and in prevention of DNA damage from products of tobacco smoke.  80 patients have been examined. They were divided into two groups: 1 group - smoking persons without COPD; 2 group – smoking patients with I or II stages of COPD (2 subgroups). The control group consisted of healthy non-smoking persons.  In control group homozygous deletion of GSTT1 was found in 5% of patients. GSTT1 null-genotype has been revealed in 14.3% in first group and in 17.6% of cases in second group. Reliability of distinctions between groups was not received. However in comparison of the control group with subgroups of COPD patients statistically significant difference between frequency of GSTT1 null-genotype in control group and in II stage COPD patients had been received (χ 2  =10, p=0.02).  For smoking persons without COPD and patients with I stage of COPD OR equaled 1, and for smoking persons and II stage COPD patients OR was 1.5 that indicated on increased risk of illness with severe stage of COPD at presence of GSTT1 null-genotype. Also OR, identical to smokers without COPD and patients with COPD stage I, means equal risk of disease that was especially significant for smokers without COPD.  Frequency of GSTM1 null-genotype in all groups was equal (46.6, 46.4, 47% accordingly).  The results of our research demonstrate that null-genotype of GSTT1 could be recommended as a marker of chronic obstructive pulmonary disease fast progressing in smokers.
Comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis
Authors: Marc I. Chimowitz, Michael J. Lynn, Harriet Howlett-Smith, Barney J. Stern, Vicki S. Hertzberg, Michael R. Frankel, Steven R. Levine, Seemant Chaturvedi, Scott E. Kasner, Curtis G. Benesch, Cathy A. Sila, Tudor G. Jovin, Jose G. Romano
Journal: New England Journal of Medicine (2005)

Atherosclerotic intracranial arterial stenosis is an important cause of stroke. Warfarin is commonly used in preference to aspirin for this disorder, but these therapies have not been compared in a randomized trial.We randomly assigned patients with transient ischemic attack or stroke caused by angiographically verified 50 to 99 percent stenosis of a major intracranial artery to receive warfarin (target international normalized ratio, 2.0 to 3.0) or aspirin (1300 mg per day) in a double-blind, multicenter clinical trial. The primary end point was ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke.After 569 patients had undergone randomization, enrollment was stopped because of concerns about the safety of the patients who had been assigned to receive warfarin. During a mean follow-up period of 1.8 years, adverse events in the two groups included death (4.3 percent in the aspirin group vs. 9.7 percent in the warfarin group; hazard ratio for aspirin relative to warfarin, 0.46; 95 percent confidence interval, 0.23 to 0.90; P=0.02), major hemorrhage (3.2 percent vs. 8.3 percent, respectively; hazard ratio, 0.39; 95 percent confidence interval, 0.18 to 0.84; P=0.01), and myocardial infarction or sudden death (2.9 percent vs. 7.3 percent, respectively; hazard ratio, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.02). The rate of death from vascular causes was 3.2 percent in the aspirin group and 5.9 percent in the warfarin group (P=0.16); the rate of death from nonvascular causes was 1.1 percent and 3.8 percent, respectively (P=0.05). The primary end point occurred in 22.1 percent of the patients in the aspirin group and 21.8 percent of those in the warfarin group (hazard ratio, 1.04; 95 percent confidence interval, 0.73 to 1.48; P=0.83).Warfarin was associated with significantly higher rates of adverse events and provided no benefit over aspirin in this trial. Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis.
Coincidence of a Novel <i>KCNJ11</i> Missense Variant R365H With a Paternally Inherited 6q24 Duplication in a Patient With Transient Neonatal Diabetes
Authors: Juraj Staník, Mark Lethby, Sarah E. Flanagan, Daniela Gašperíková, Beata Milošovičová, Margaret Lever, Hilary Bullman, Lejla Zubcevic, Andrew T. Hattersley, Sian Ellard, Frances M. Ashcroft, Iwar Klimeš
Journal: Diabetes Care (2008)

OBJECTIVE—Neonatal diabetes is a heterogeneous group of disorders with diabetes manifestation in the first 6 months of life. The most common etiology in permanent neonatal diabetes is mutations of the ATP-sensitive K+ channel subunits; in transient neonatal diabetes, chromosome 6q24 abnormalities are the most common cause. RESEARCH DESIGN AND METHODS—We report a sporadic case of diabetes without ketoacidosis diagnosed on the fourth day of life. RESULTS—Analysis of the KCNJ11 gene found a novel R365H mutation in the proband and her unaffected father. The functional analysis did not support pathogenicity of this variant. When the patient's diabetes remitted in the seventh month of life, the 6q24 region was analyzed and a paternally inherited duplication was identified. CONCLUSIONS—Our case reports a coincidental novel KCNJ11 variant in a patient with transient neonatal diabetes due to a 6q24 duplication, illustrating the difficulty in testing neonates before the clinical course of neonatal diabetes is known.
Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade
Authors: Evan J Lipson, Victor E Velculescu, Theresa S Pritchard, Mark Sausen, Drew M Pardoll, Suzanne L Topalian, Luis A Diaz
Journal: Journal for ImmunoTherapy of Cancer (2014)

Assessment of therapeutic activity of drugs blocking immune checkpoints such as CTLA-4 and PD-1/PD-L1 can be challenging, as tumors may seem to enlarge or appear anew before regressing, due to intratumoral inflammation. We assessed whether circulating tumor DNA (ctDNA) levels could serve as an early indicator of true changes in tumor burden in patients undergoing treatment with these agents.Tumors from 12 patients with metastatic melanoma undergoing treatment with checkpoint blocking drugs were analyzed for the presence of hotspot somatic mutations in BRAF, cKIT, NRAS, and TERT. Plasma was collected serially from each patient and levels of ctDNA were compared with radiologic and clinical outcomes. In 5 of 10 patients studied, mutations were detected in BRAF(1), NRAS(2), TERT(1) and ALK(1). Analysis of plasma from 4 of 5 patients identified mutations identical to those found in tumor specimens. Plasma ctDNA levels ranged from undetectable (<0.01%) to 5.5% of total circulating cell-free DNA. In 3 patients, increasing ctDNA levels correlated with progressive disease assessed by radiography. In one patient, ctDNA levels increased after undergoing a needle biopsy of a tumor deposit. In another patient, ctDNA levels increased initially as lymphadenopathy progressed by examination, but then became undetectable 3 weeks prior to clinical improvement.Levels of ctDNA correlated with clinical and radiologic outcomes, and, in one case, preceded eventual tumor regression. Further prospective analysis is required to assess the utility of ctDNA as an early biomarker of clinical outcomes in patients receiving immune checkpoint blocking drugs.
Measurement properties of the SenseWear armband in adults with chronic obstructive pulmonary disease
Authors: K. Hill, T. E. Dolmage, L. Woon, R. Goldstein, D. Brooks
Journal: Thorax (2010)

<h3>Rationale</h3> The SenseWear armband (SAB) is designed to measure energy expenditure (EE). In people with chronic obstructive pulmonary disease (COPD), EE estimated using the SAB (EE<sub>SAB</sub>) is a popular outcome measure. However, a detailed analysis of the measurement properties of the SAB in COPD is lacking. <h3>Objective</h3> To examine the sensitivity of EE<sub>SAB</sub>, agreement between EE<sub>SAB</sub> and EE measured via indirect calorimetry (EE<sub>IC</sub>), and its repeatability in COPD. <h3>Methods</h3> 26 people with COPD (forced expiratory volume in 1 s (FEV<sub>1</sub>)=49±18% predicted; 15 males) spent 6 min in five standardised tasks that comprised supine, sitting, standing and two walking speeds. A subgroup (n=12) walked using a rollator. Throughout each task, measurements of EE<sub>SAB</sub> and EE<sub>IC</sub> were collected. The protocol was repeated on a second day. <h3>Results</h3> EE<sub>SAB</sub> increased between standing and slow walking (2.4, metabolic equivalents (METs) 95% CI 2.2 to 2.7) as well as slow and fast walking (0.5 METs, 95% CI 0.3 to 0.7). Considering all tasks together, the difference between EE<sub>SAB</sub> and EE<sub>IC</sub> was −0.2 METs (p=0.21) with a limit of agreement of 1.3 METs. The difference between days in EE<sub>SAB</sub> was 0.0 METs with a coefficient of repeatability of 0.4 METs. Rollator use increased the variability in EE<sub>SAB</sub>, compromising its repeatability and agreement with EE<sub>IC</sub>. <h3>Conclusions</h3> EE<sub>SAB</sub> was sensitive to small but important changes. There was fair agreement between EE<sub>SAB</sub> and EE<sub>IC</sub>, and measurements of EE<sub>SAB</sub> were repeatable. These observations suggest that the SAB is useful for the evaluation of EE in patients with COPD who walk without a rollator.
Direct Activation of Bax Protein for Cancer Therapy
Authors: Zhiqing Liu, Ye Ding, Na Ye, Christopher Wild, Haiying Chen, Jia Zhou
Journal: Medicinal Research Reviews (2015)

Bax, a central cell death regulator, is an indispensable gateway to mitochondrial dysfunction and a major proapoptotic member of the B-cell lymphoma 2 (Bcl-2) family proteins that control apoptosis in normal and cancer cells. Dysfunction of apoptosis renders the cancer cell resistant to treatment as well as promotes tumorigenesis. Bax activation induces mitochondrial membrane permeabilization, thereby leading to the release of apoptotic factor cytochrome c and consequently cancer cell death. A number of drugs in clinical use are known to indirectly activate Bax. Intriguingly, recent efforts demonstrate that Bax can serve as a promising direct target for small-molecule drug discovery. Several direct Bax activators have been identified to hold promise for cancer therapy with the advantages of specificity and the potential of overcoming chemo- and radioresistance. Further investigation of this new class of drug candidates will be needed to advance them into the clinic as a novel means to treat cancer.
Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes
Authors: Benjamin J Schiller, Rajas Chodankar, Lisa C Watson, Michael R Stallcup, Keith R Yamamoto
Journal: Genome biology (2014)

Abstract Background Glucocorticoid receptor (GR) is a hormone-activated, DNA-binding transcriptional regulatory factor that controls inflammation, metabolism, stress responses, and other physiological processes. In vitro , GR binds as an inverted dimer to a motif consisting of two imperfectly palindromic 6 bp half sites separated by 3 bp spacers. In vivo , GR employs different patterns of functional surfaces of GR to regulate different target genes. The relationships between GR genomic binding and functional surface utilization have not been defined. Results We find that A477T, a GR mutant that disrupts the dimerization interface, differs from wild-type GRα in binding and regulation of target genes. Genomic regions strongly occupied by A477T are enriched for a novel half site motif. In vitro , GRα binds half sites as a monomer. Through the overlap between GRα- and A477T-bound regions, we identify GRα-bound regions containing only half sites. We further identify GR target genes linked with half sites and not with the full motif. Conclusions Genomic regions bound by GR differ in underlying DNA sequence motifs and in the GR functional surfaces employed for regulation. Identification of GR binding regions that selectively utilize particular GR surfaces may discriminate sub-motifs, including the half site motif, that favor those surfaces. This approach may contribute to predictive models for GR activity and therapy.
One Allele's Loss Is Another's Gain: Alterations of <i>NKX2–8</i> in Non–Small Cell Lung Cancer
Authors: Joel W. Neal, Alice T. Shaw
Journal: Clinical Cancer Research (2010)

Large-scale genetic changes such as loss or gain of chromosomes are important drivers of solid tumor carcinogenesis. Recent technological advances in genomic profiling have allowed quantitative detection of gene copy numbers, leading to identification of the 14q13.3 gene locus as functionally important in non-small cell lung cancers.
Autologous Culture-Modified Mononuclear Cells Confer Vascular Protection After Arterial Injury
Authors: Rajiv Gulati, Dragan Jevremovic, Timothy E. Peterson, Tyra A. Witt, Laurel S. Kleppe, Cheryl S. Mueske, Amir Lerman, Richard G. Vile, Robert D. Simari
Journal: Circulation (2003)

Background— Bone marrow–derived cells have been shown to contribute to endothelial replacement after vascular injury. In vitro culture of peripheral blood mononuclear cells produces cells with phenotypic characteristics of endothelium. To test the hypothesis that delivery of autologous culture-modified mononuclear cells (CMMCs) to injured arteries could attenuate the vascular response to injury, a rabbit model was studied. Methods and Results— Rabbit peripheral blood mononuclear cells were cultured in endothelial growth media for 7 to 12 days, yielding highly proliferative cells with distinct endothelial phenotype (expressing CD31 and endothelial nitric oxide synthase and capable of acetylated LDL uptake). A rabbit model of balloon carotid injury was used to evaluate the effect of day 7 CMMC delivery on vascular responses. Animals underwent balloon injury and immediate delivery of autologous CMMCs or buffered saline by 20 minutes of local dwelling. Fluorescence-labeled CMMCs were detected in all vessel layers 4 weeks after delivery. Colonies of cells that localized to the lumen and stained for endothelial markers were also identified. Local CMMC administration at the time of balloon injury accelerated reendothelialization at 4 weeks compared with saline ( P &lt;0.05). Moreover, CMMC delivery markedly improved endothelium-dependent vasoreactivity at 4 weeks compared with saline ( P &lt;0.005). Finally, CMMC treatment reduced neointimal formation by 55% at 4 weeks ( P &lt;0.05). Conclusions— These data demonstrate that delivery of CMMCs to balloon-injured arteries is associated with accelerated reendothelialization, enhanced endothelium-dependent vasoreactivity, and reduced neointimal formation. Thus, delivery of autologous CMMCs represents a novel vasculoprotective approach to attenuate the response to acute vascular injury.
Purifying Selection on Splice-Related Motifs, Not Expression Level nor RNA Folding, Explains Nearly All Constraint on Human lincRNAs
Authors: Andreas Schüler, Avazeh T. Ghanbarian, Laurence D. Hurst
Journal: Molecular Biology and Evolution (2014)

There are two strong and equally important predictors of rates of human protein evolution: The amount the gene is expressed and the proportion of exonic sequence devoted to control splicing, mediated largely by selection on exonic splice enhancer (ESE) motifs. Is the same true for noncoding RNAs, known to be under very weak purifying selection? Prior evidence suggests that selection at splice sites in long intergenic noncoding RNAs (lincRNAs) is important. We now report multiple lines of evidence indicating that the great majority of purifying selection operating on lincRNAs in humans is splice related. Splice-related parameters explain much of the between-gene variation in evolutionary rate in humans. Expression rate is not a relevant predictor, although expression breadth is weakly so. In contrast to protein-coding RNAs, we observe no relationship between evolutionary rate and lincRNA stability. As in protein-coding genes, ESEs are especially abundant near splice junctions and evolve slower than non-ESE sequence equidistant from boundaries. Nearly all constraint in lincRNAs is at exon ends (N.B. the same is not witnessed in Drosophila). Although we cannot definitely answer the question as to why splice-related selection is so important, we find no evidence that splicing might enable the nonsense-mediated decay pathway to capture transcripts incorrectly processed by ribosomes. We find evidence consistent with the notion that splicing modifies the underlying chromatin through recruitment of splice-coupled chromatin modifiers, such as CHD1, which in turn might modulate neighbor gene activity. We conclude that most selection on human lincRNAs is splice mediated and suggest that the possibility of splice–chromatin coupling is worthy of further scrutiny.