tbuckley/cabot-search huggingface dataset:
Detection of T790M, the Acquired Resistance <i>EGFR</i> Mutation, by Tumor Biopsy versus Noninvasive Blood-Based Analyses
Authors: Tilak K. Sundaresan, Lecia V. Sequist, John V. Heymach, Gregory J. Riely, Pasi A. Jänne, Walter H. Koch, James P. Sullivan, Douglas B. Fox, Robert Maher, Alona Muzikansky, Andrew Webb, Hai T. Tran, Uma Giri, Martin Fleisher, Helena A. Yu, Wen Wei, Bruce E. Johnson, Thomas A. Barber, John R. Walsh, Jeffrey A. Engelman, Shannon L. Stott, Ravi Kapur, Shyamala Maheswaran, Mehmet Toner, Daniel A. Haber
Journal: Clinical Cancer Research (2015)

Purpose: The T790M gatekeeper mutation in the EGFR is acquired by some EGFR-mutant non–small cell lung cancers (NSCLC) as they become resistant to selective tyrosine kinase inhibitors (TKI). As third-generation EGFR TKIs that overcome T790M-associated resistance become available, noninvasive approaches to T790M detection will become critical to guide management.Experimental Design: As part of a multi-institutional Stand-Up-To-Cancer collaboration, we performed an exploratory analysis of 40 patients with EGFR-mutant tumors progressing on EGFR TKI therapy. We compared the T790M genotype from tumor biopsies with analysis of simultaneously collected circulating tumor cells (CTC) and circulating tumor DNA (ctDNA).Results: T790M genotypes were successfully obtained in 30 (75%) tumor biopsies, 28 (70%) CTC samples, and 32 (80%) ctDNA samples. The resistance-associated mutation was detected in 47% to 50% of patients using each of the genotyping assays, with concordance among them ranging from 57% to 74%. Although CTC- and ctDNA-based genotyping were each unsuccessful in 20% to 30% of cases, the two assays together enabled genotyping in all patients with an available blood sample, and they identified the T790M mutation in 14 (35%) patients in whom the concurrent biopsy was negative or indeterminate.Conclusions: Discordant genotypes between tumor biopsy and blood-based analyses may result from technological differences, as well as sampling different tumor cell populations. The use of complementary approaches may provide the most complete assessment of each patient's cancer, which should be validated in predicting response to T790M-targeted inhibitors. Clin Cancer Res; 22(5); 1103–10. ©2015 AACR.
Plasma Total Cysteine as a Risk Factor for Vascular Disease
Authors: Lina El-Khairy, Per M. Ueland, Helga Refsum, Ian M. Graham, Stein E. Vollset
Journal: Circulation (2001)

Elevated plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. Although cysteine is structurally similar and metabolically linked to tHcy, its relation to the risk of cardiovascular disease has received little attention. We studied the relation between plasma total cysteine (tCys) levels and the risk of vascular disease in the coronary, cerebral, and peripheral vessels.This case-control study included 750 patients with vascular disease and 800 age- and sex-matched control subjects recruited from 19 centers in 9 European countries. Conventional risk factors for cardiovascular disease were recorded. In addition, plasma levels of tCys, tHcy, folate, B(6), B(12), and creatinine were measured. Overall, a U-shaped relationship was observed between tCys and risk of vascular disease. With the middle range of 250 to 275 micromol/L tCys used as the reference category, the adjusted risk of vascular disease at low (</=225 micromol/L) tCys levels was 2.1 (95% CI 1.2 to 3.6), and the risk at high (>300 micromol/L) tCys levels was 1.6 (95% CI 1.1 to 2.3). Different shapes of the dose-response relationship were seen for the 3 vascular disease categories. The relation with peripheral vascular and cerebrovascular disease was U-shaped, whereas a weak positive relation was observed with coronary heart disease.Our data show a significant U-shaped relationship between tCys and cardiovascular disease after adjustment for tHcy, creatinine, and other cardiovascular disease risk factors.
Dichotomal role of inhibition of p38 MAPK with SB 203580 in experimental colitis
Authors: T ten Hove
Journal: Gut (2002)

Crohn's disease is characterised by a chronic relapsing inflammation of the bowel in which proinflammatory cytokines play an important perpetuating role. Mitogen activated protein kinase p38 (p38 MAPK) has been established as a major regulator of the inflammatory response, especially with regard to production of proinflammatory cytokines, but its role in inflammatory bowel disease is unexplored. In this paper we describe the effects of a specific p38 MAPK inhibitor, SB 203580, in trinitrobenzene sulphonic acid (TNBS) induced colitis in mice.SB 203580 had a dichotomal effect in TNBS mice. Weight loss of TNBS mice treated with SB 203580 was significantly worse and colon weight on sacrifice was significantly increased in MAPK inhibitor treated TNBS mice (229.2 mg and 289.1 mg, respectively). However, the total number of cells in the caudal lymph node decreased to 188.8 x 10(4) cells in SB 203580 treated TNBS mice compared with 334 x 10(4) cells in vehicle treated mice. CD3/CD28 double stimulated caudal lymph node cells of SB 203580 treated mice showed decreased interferon gamma production but increased tumour necrosis factor alpha production. The concentration of interleukin 12p70 in colon homogenates was significantly decreased in SB 203580 treated mice whereas concentrations of interleukin 12p40, tumour necrosis factor alpha, and interleukin 10 were similar in vehicle and SB 203580 treated TNBS mice.Our results reveal a dichotomy in p38 MAPK action during experimental colitis.
Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales
Authors: Ian Clark, Craig Atwood, Richard Bowen, Gilberto Paz-Filho, Bryce Vissel
Journal: Pharmacological Reviews (2012)

The evident limitations of the amyloid theory of the pathogenesis of Alzheimer9s disease are increasingly putting alternatives in the spotlight. We argue here that a number of independently developing approaches to therapy—including specific and nonspecific anti-tumor necrosis factor (TNF) agents, apolipoprotein E mimetics, leptin, intranasal insulin, the glucagon-like peptide-1 mimetics and glycogen synthase kinase-3 (GSK-3) antagonists—are all part of an interlocking chain of events. All these approaches inform us that inflammation and thence cerebral insulin resistance constitute the pathway on which to focus for a successful clinical outcome in treating this disease. The key link in this chain presently absent is a recognition by Alzheimer9s research community of the long-neglected history of TNF induction of insulin resistance. When this is incorporated into the bigger picture, it becomes evident that the interventions we discuss are not competing alternatives but equally valid approaches to correcting different parts of the same pathway to Alzheimer9s disease. These treatments can be expected to be at least additive, and conceivably synergistic, in effect. Thus the inflammation, insulin resistance, GSK-3, and mitochondrial dysfunction hypotheses are not opposing ideas but stages of the same fundamental, overarching, pathway of Alzheimer9s disease pathogenesis. The insight this provides into progenitor cells, including those involved in adult neurogenesis, is a key part of this approach. This pathway also has therapeutic implications for other circumstances in which brain TNF is pathologically increased, such as stroke, traumatic brain injury, and the infectious disease encephalopathies.
Impact of Cognitive Behavioral Therapy for Social Anxiety Disorder on the Neural Dynamics of Cognitive Reappraisal of Negative Self-beliefs
Authors: Philippe R Goldin, Michal Ziv, Hooria Jazaieri, Kevin Hahn, Richard Heimberg, James J Gross
Journal: JAMA Psychiatry (2013)

Cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) is thought to enhance cognitive reappraisal in patients with SAD. Such improvements should be evident in cognitive reappraisal-related prefrontal cortex responses.To determine whether CBT for SAD modifies cognitive reappraisal-related prefrontal cortex neural signal magnitude and timing when implementing cognitive reappraisal with negative self-beliefs. DESIGN Randomized clinical trial of CBT for SAD vs wait-list control group during a study that enrolled patients from 2007 to 2010.University psychology department.Seventy-five patients with generalized SAD randomly assigned to CBT or wait list.Sixteen sessions of individual CBT for SAD.Negative emotion ratings and functional magnetic resonance imaging blood oxygen-level dependent signal when reacting to and cognitively reappraising negative self-beliefs embedded in autobiographical social anxiety situations. RESULTS During reactivity trials, compared with wait list, CBT produced (1) greater reduction in negative emotion ratings and (2) greater blood oxygen-level dependent signal magnitude in the medial prefrontal cortex. During cognitive reappraisal trials, compared with wait list, CBT produced (3) greater reduction in negative emotion ratings, (4) greater blood oxygen level-dependent signal magnitude in the dorsolateral and dorsomedial prefrontal cortex, (5) earlier temporal onset of dorsomedial prefrontal cortex activity, and (6) greater dorsomedial prefrontal cortex-amygdala inverse functional connectivity.Modulation of cognitive reappraisal-related brain responses, timing, and functional connectivity may be important brain changes that contribute to the effectiveness of CBT for social anxiety. This study demonstrates that clinically applied neuroscience investigations can elucidate neurobiological mechanisms of change in psychiatric conditions.clinicaltrials.gov Identifier: NCT00380731.
Platinum versus platinum-combination chemotherapy in platinum-sensitive recurrent ovarian cancer: a meta-analysis using individual patient data
Authors: F.A. Raja, N. Counsell, N. Colombo, J. Pfisterer, A. du Bois, M.K. Parmar, I.B. Vergote, A. Gonzalez-Martin, D.S. Alberts, M. Plante, V. Torri, J.A. Ledermann
Journal: Annals of Oncology (2013)
Clinical measures of disease in adult non-CF bronchiectasis correlate with airway microbiota composition
Authors: Geraint B Rogers, Christopher J van der Gast, Leah Cuthbertson, Serena K Thomson, Kenneth D Bruce, Megan L Martin, David J Serisier
Journal: Thorax (2013)

Despite the potentially important roles for infection in adult non-cystic fibrosis (CF) bronchiectasis disease progression, the bacterial species present in the lower airways of these patients is poorly characterised.To provide a comprehensive cross-sectional analysis of bacterial content of lower airway samples from patients with non-CF bronchiectasis using culture-independent microbiology.Paired induced sputum and bronchoalveolar lavage samples, obtained from 41 adult patients with non-CF bronchiectasis, were analysed by 16S ribosomal RNA gene pyrosequencing. Assessment of species distribution and dispersal allowed 'core' and 'satellite' bacterial populations to be defined for this patient group. Microbiota characteristics correlated with clinical markers of disease.140 bacterial species were identified, including those associated with respiratory tract infections and opportunistic infections more generally. A group of core species, consisting of species detected frequently and in high abundance, was defined. Core species included those currently associated with infection in bronchiectasis, such as Pseudomonas aeruginosa, Haemophilus influenzae and Streptococcus pneumoniae, and many species that would be unlikely to be reported through standard diagnostic surveillance. These included members of the genera Veillonella, Prevotella and Neisseria. The comparative contribution of core and satellite groups suggested a low level of random species acquisition. Bacterial diversity was significantly positively correlated with forced expiratory volume in 1 s (FEV1) and bacterial community composition similarity correlated significantly with FEV1, neutrophil count and Leicester cough score.Characteristics of the lower airways microbiota of adult patients with non-CF bronchiectasis correlate significantly with clinical markers of disease severity.
Target-effector interaction in the human and murine natural killer system: specificity and xenogeneic reactivity of the solubilized natural killer-target structure complex and its loss in a somatic cell hybrid.
Authors: J C Roder, L Ahrlund-Richter, M Jondal
Journal: The Journal of Experimental Medicine (1979)

Preincubation of natural killer (NK) cells with electrophoresis purified proteins from a variety of NK-sensitive murine and human tumor cells specifically prevented subsequent binding to the intact, homologous target cell. The NK-target structures (NK-TS) consisted of some or all of four characteristic molecular species, tentatively assigned molecular weights of 140K, 160K, 190K, and 240K (+/-10K) based on electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gels. When these NK-TS molecules were compared in cross-inhibition assays, the large 240K molecule most often carried the unique NK specificity, whereas the smaller 140K molecules cross-reacted between YAC, 136-6 and X-63 in the mouse and between Molt-4 and K562 in the human. Mouse NK cells recognised a different spectrum of NK-TS molecules than human NK cells. The control of NK-TS expression was partially revealed in a cloned, somatic cell hybrid bwtween an NK sensitive (YAC-IR) and insensitive (A9HT) cell line. The hybrid did not express NK-TS and did not bind to NK cells which is in accordance with negative NK cytolytic results previously reported. Although unique specificities are carried by some of the multiple NK-TS protein molecules, cross-reactions were widespread. These observations taken together suggest that the NK cell is polyspecific and has some heterogeneity in the recognition structure although much less than would be expected of an antibody-combining site.
Sigmoid Diverticulitis
Authors: Arden M. Morris, Scott E. Regenbogen, Karin M. Hardiman, Samantha Hendren
Journal: JAMA (2014)

<h3>Importance</h3> Diverticulitis is a common disease. Recent changes in understanding its natural history have substantially modified treatment paradigms. <h3>Objective</h3> To review the etiology and natural history of diverticulitis and recent changes in treatment guidelines. <h3>Evidence Review</h3> We searched the MEDLINE and Cochrane databases for English-language articles pertaining to diagnosis and management of diverticulitis published between January 1, 2000, and March 31, 2013. Search terms applied to 4 thematic topics:<i>pathophysiology</i>,<i>natural history</i>,<i>medical management</i>, and<i>indications for surgery</i>. We excluded small case series and articles based on data accrued prior to 2000. We hand searched the bibliographies of included studies, yielding a total of 186 articles for full review. We graded the level of evidence and classified recommendations by size of treatment effect, according to the guidelines from the American Heart Association Task Force on Practice Guidelines. <h3>Findings</h3> Eighty articles met criteria for analysis. The pathophysiology of diverticulitis is associated with altered gut motility, increased luminal pressure, and a disordered colonic microenvironment. Several studies examined histologic commonalities with inflammatory bowel disease and irritable bowel syndrome but were focused on associative rather than causal pathways. The natural history of uncomplicated diverticulitis is often benign. For example, in a cohort study of 2366 of 3165 patients hospitalized for acute diverticulitis and followed up for 8.9 years, only 13.3% of patients had a recurrence and 3.9%, a second recurrence. In contrast to what was previously thought, the risk of septic peritonitis is reduced and not increased with each recurrence. Patient-reported outcomes studies show 20% to 35% of patients managed nonoperatively progress to chronic abdominal pain compared with 5% to 25% of patients treated operatively. Randomized trials and cohort studies have shown that antibiotics and fiber were not as beneficial as previously thought and that mesalamine might be useful. Surgical therapy for chronic disease is not always warranted. <h3>Conclusions and Relevance</h3> Recent studies demonstrate a lesser role for aggressive antibiotic or surgical intervention for chronic or recurrent diverticulitis than was previously thought necessary.
Effects of a pseudoallergen‐free diet on chronic spontaneous urticaria: a prospective trial
Authors: M. Magerl, D. Pisarevskaja, R. Scheufele, T. Zuberbier, M. Maurer
Journal: Allergy (2009)

Abstract Background: Chronic spontaneous urticaria is a skin disorder that is difficult to manage and can last for years. ‘Pseudoallergens’ are substances that induce hypersensitive/intolerance reactions that are similar to true allergic reactions. They include food additives, vasoactive substances such as histamine, and some natural substances in fruits, vegetables and spices. Eliminating pseudoallergens from the diet can reduce symptom severity and improve patient quality of life. Aim: To assess the effects of a pseudoallergen‐free diet on disease activity and quality of life in patient’s chronic spontaneous urticaria. Methods: Study subjects had moderate or severe chronic spontaneous urticaria that had not responded adequately to treatment in primary care. For 3 weeks, subjects followed a pseudoallergen‐free diet. They kept a clinical diary, which recorded their wheal and pruritus severity each day, to yield a clinical rating of chronic spontaneous urticaria severity (the UAS4 score). The subjects also completed the DLQI, a validated quality‐of‐life instrument. Use of antihistamines and glucocorticoids was minimized, recorded, and analysed. Subjects were classified into nine response categories, according to the changes in symptom severity (UAS4), quality of life (DLQI) and medication usage. Results: From the 140 subjects, there were 20 (14%) strong responders and 19 (14%) partial responders. Additionally, there were nine (6%) subjects who made a substantial reduction in their medication without experiencing worse symptoms or quality of life. Conclusions: Altogether the pseudoallergen‐free diet is beneficial for one in three patients. The pseudoallergen‐free diet is a safe, healthy and cost‐free measure to identify patients with chronic spontaneous urticaria that will benefit from avoiding pseudoallergens.
Chemokine production by the BEAS-2B human bronchial epithelial cells: Differential regulation of eotaxin, IL-8, and RANTES by TH2- and TH1-derived cytokines
Authors: Takao Fujisawa, Yoshiko Kato, Jun Atsuta, Akihiko Terada, Kosei Iguchi, Hitoshi Kamiya, Hirokazu Yamada, Toshiharu Nakajima, Misato Miyamasu, Koichi Hirai
Journal: Journal of Allergy and Clinical Immunology (2000)
Determinants of Synonymous and Nonsynonymous Variability in Three Species of Drosophila
Authors: Penelope R. Haddrill, Kai Zeng, Brian Charlesworth
Journal: Molecular Biology and Evolution (2010)

We estimated the intensity of selection on preferred codons in Drosophila pseudoobscura and D. miranda at X-linked and autosomal loci, using a published data set on sequence variability at 67 loci, by means of an improved method that takes account of demographic effects. We found evidence for stronger selection at X-linked loci, consistent with their higher levels of codon usage bias. The estimates of the strength of selection and mutational bias in favor of unpreferred codons were similar to those found in other species, after taking into account the fact that D. pseudoobscura showed evidence for a recent expansion in population size. We examined correlates of synonymous and nonsynonymous diversity in these species and found no evidence for effects of recurrent selective sweeps on nonsynonymous mutations, which is probably because this set of genes have much higher than average levels of selective constraints. There was evidence for correlated effects of levels of selective constraints on protein sequences and on codon usage, as expected under models of selection for translational accuracy. Our analysis of a published data set on D. melanogaster provided evidence for the effects of selective sweeps of nonsynonymous mutations on linked synonymous diversity, but only in the subset of loci that experienced the highest rates of nonsynonymous substitutions (about one-quarter of the total) and not at more slowly evolving loci. Our correlational analysis of this data set suggested that both selective constraints on protein sequences and recurrent selective sweeps affect the overall level of codon usage.
Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study
Authors: C. Y. Lu, F. Zhang, M. D. Lakoma, J. M. Madden, D. Rusinak, R. B. Penfold, G. Simon, B. K. Ahmedani, G. Clarke, E. M. Hunkeler, B. Waitzfelder, A. Owen-Smith, M. A. Raebel, R. Rossom, K. J. Coleman, L. A. Copeland, S. B. Soumerai
Journal: BMJ (2014)

<b>Objective</b> To investigate if the widely publicized warnings in 2003 from the US Food and Drug Administration about a possible increased risk of suicidality with antidepressant use in young people were associated with changes in antidepressant use, suicide attempts, and completed suicides among young people. <b>Design</b> Quasi-experimental study assessing changes in outcomes after the warnings, controlling for pre-existing trends. <b>Setting</b> Automated healthcare claims data (2000-10) derived from the virtual data warehouse of 11 health plans in the US Mental Health Research Network. <b>Participants</b> Study cohorts included adolescents (around 1.1 million), young adults (around 1.4 million), and adults (around 5 million). <b>Main outcome measures</b> Rates of antidepressant dispensings, psychotropic drug poisonings (a validated proxy for suicide attempts), and completed suicides. <b>Results</b> Trends in antidepressant use and poisonings changed abruptly after the warnings. In the second year after the warnings, relative changes in antidepressant use were −31.0% (95% confidence interval −33.0% to −29.0%) among adolescents, −24.3% (−25.4% to −23.2%) among young adults, and −14.5% (−16.0% to −12.9%) among adults. These reflected absolute reductions of 696, 1216, and 1621 dispensings per 100 000 people among adolescents, young adults, and adults, respectively. Simultaneously, there were significant, relative increases in psychotropic drug poisonings in adolescents (21.7%, 95% confidence interval 4.9% to 38.5%) and young adults (33.7%, 26.9% to 40.4%) but not among adults (5.2%, −6.5% to 16.9%). These reflected absolute increases of 2 and 4 poisonings per 100 000 people among adolescents and young adults, respectively (approximately 77 additional poisonings in our cohort of 2.5 million young people). Completed suicides did not change for any age group. <b>Conclusions</b> Safety warnings about antidepressants and widespread media coverage decreased antidepressant use, and there were simultaneous increases in suicide attempts among young people. It is essential to monitor and reduce possible unintended consequences of FDA warnings and media reporting.