tbuckley/cabot-search huggingface dataset:
A phase I/II trial combining erlotinib with gamma secretase inhibitor RO4929097 in advanced non-small cell lung cancer (NSCLC).
Authors: Kathryn A. Gold, Lauren Averett Byers, You Hong Fan, Junya Fujimoto, Warner H Tse, J. Jack Lee, Sanjay Gupta, Ignacio Ivan Wistuba, David J. Stewart, Don Lynn Gibbons
Journal: Journal of Clinical Oncology (2013)

8104 Background: All NSCLC patients treated with erlotinib (E) eventually develop resistance. Both the epithelial-mesenchymal transition (EMT) and cancer stem cells may contribute to resistance to E. The Notch pathway plays a key role in maintaining stem cell viability and in EMT. Gamma secretase inhibitors such as RO4929097 (R) inhibit Notch activity by preventing cleavage of Notch to its active form. In this CTEP-sponsored study, primary endpoint of phase I was to determine maximum tolerated dose (MTD) of the combination of E and R; primary endpoint of phase II was response rate. Methods: Eligible pts had incurable NSCLC, measurable disease, ECOG PS 0-1, and adequate laboratory parameters. There were no limits on prior therapy. All pts were required to have a tumor biopsy. Patients received E PO daily on a continuous schedule and R PO daily on days 1-3, 8-10, and 14-17 of a 21 day cycle. Dose cohorts (E/R both in mg) were as follows: 100 /20, 150/20, 150/30, 150/45. Imaging was performed every 6 weeks. Patients could remain on therapy until progression. Results: 21 pts were enrolled between 9/2010 and 3/2012. 5 were not eligible and did not receive treatment. For the 16 treated pts: median age was 61 yrs (40-75), 7 (44%) were male, 14 (88%) had adenocarcinoma. All pts had received prior chemotherapy (1-8 regimens); 7 (44%) had prior E. 3 pts had known EGFR mutations; 2 pts had KRAS mutations. Time on therapy ranged from 20 to 248 days. Median PFS was 42 days. Pts with prior progression on E had a median PFS of 64 days. 1 pt (6%) had a partial response, 4 (19%) had stable disease at 6 weeks. Median overall survival is 6.5 months (1.3 to 24.5+ months). Observed dose-limiting toxicity was hypophosphatemia in 1 pt in 150/45 cohort. Other toxicities included rash, neuropathic pain and nausea. MTD was determined to be 150/45. The study was halted early, after completion of the phase I cohort, as production of R was discontinued by the manufacturer. 12 pts (75%) have adequate tumor tissue for analyses. Biomarker studies are pending. Conclusions: Combination of R and E is safe and feasible in pts with NSCLC. Though development of R has been discontinued, other drugs targeting the Notch pathway are in development (NCI R21CA153017). Clinical trial information: NCT01193881.
Abstract 19960: Human Cardiac Fibroblasts Increase SR-Dependency of Induced Pluripotent Stem Cell-Derived Cardiomyocyte Calcium Handling by Increasing SR Calcium Uptake and SERCA2a Expression via Direct Physical Contact
Authors: Christopher Kane, Priyanthi Dias, Julia Gorelik, Cesare M Terracciano
Journal: Circulation (2015)

Introduction: Cardiac fibroblasts can influence cardiomyocyte structure and function through direct physical interaction and/or by the secretion of soluble factors. Here we assess the relative importance of these different modalities of interaction in terms of their effects on cardiomyocyte electrophysiology. Methods: Ventricular fibroblasts from the explanted hearts of dilated cardiomyopathy (DCM) patients (n=4) were seeded directly onto a confluent monolayer of human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) at a ratio of 2:1 and cultured for 24 hours. iPS-CMs alone were used as control. Ca2+ transients and action potentials were recorded optically using fluo-4 AM and di-8-ANEPPS. Data are presented as percentage change from control where appropriate. Results: iPS-CM Ca2+ transient duration was significantly reduced by contact with fibroblasts (-8.4±2.2% n=12 p&lt;0.01). Sarcoplasmic reticulum (SR) Ca2+ uptake assessed by caffeine application was highly upregulated (2.07±0.12s-1 vs 0.63±0.07s-1 in control n=26, 23 p&lt;0.001), associated with a significant increase in SR Ca2+ content (F/F0: 3.74±0.11 vs 2.97±0.11 in control n=37, 32 p&lt;0.001) and SERCA2a protein expression (1.02±0.08 vs 0.55±0.01 n=3 p&lt;0.01). iPS-CMs in contact with fibroblasts displayed a greater dependence on SR uptake for Ca2+ extrusion than other mechanisms (SR/NCX/Slow: 60.7/31.9/7.4% vs 23.3/70.9/5.8% in control). Action potential duration (90%) was significantly prolonged in contact with fibroblasts (+18.8±2.5% n=22 p&lt;0.001 vs control). Screening of culture supernatants from the co-culture has identified the presence of a number of cytokines known to affect cardiomyocyte function including IL-6 (680pg/ml), MIF (1.16ng/ml), MCP-1 (1.25ng/ml) and TGF-β. (110pg/ml). Conclusions: DCM fibroblasts influence iPS-CM electrophysiology through different modalities; however physical contact with fibroblasts has effects not seen with soluble mediators alone. This contact-dependent shift towards greater SR-dependency represents a novel effect of fibroblasts on cardiomyocyte Ca2+ handling. Determining whether these effects are mediated through mechanical, electrical or paracrine signalling will be the focus of future work.
Anthropological and socioeconomic factors contributing to global antimicrobial resistance: a univariate and multivariable analysis
Authors: Peter Collignon, John J Beggs, Timothy R Walsh, Sumanth Gandra, Ramanan Laxminarayan
Journal: The Lancet Planetary Health (2018)

Understanding of the factors driving global antimicrobial resistance is limited. We analysed antimicrobial resistance and antibiotic consumption worldwide versus many potential contributing factors.Using three sources of data (ResistanceMap, the WHO 2014 report on antimicrobial resistance, and contemporary publications), we created two global indices of antimicrobial resistance for 103 countries using data from 2008 to 2014: Escherichia coli resistance-the global average prevalence of E coli bacteria that were resistant to third-generation cephalosporins and fluoroquinolones, and aggregate resistance-the combined average prevalence of E coli and Klebsiella spp resistant to third-generation cephalosporins, fluoroquinolones, and carbapenems, and meticillin-resistant Staphylococcus aureus. Antibiotic consumption data were obtained from the IQVIA MIDAS database. The World Bank DataBank was used to obtain data for governance, education, gross domestic product (GDP) per capita, health-care spending, and community infrastructure (eg, sanitation). A corruption index was derived using data from Transparency International. We examined associations between antimicrobial resistance and potential contributing factors using simple correlation for a univariate analysis and a logistic regression model for a multivariable analysis.In the univariate analysis, GDP per capita, education, infrastructure, public health-care spending, and antibiotic consumption were all inversely correlated with the two antimicrobial resistance indices, whereas higher temperatures, poorer governance, and the ratio of private to public health expenditure were positively correlated. In the multivariable regression analysis (confined to the 73 countries for which antibiotic consumption data were available) considering the effect of changes in indices on E coli resistance (R2 0·54) and aggregate resistance (R2 0·75), better infrastructure (p=0·014 and p=0·0052) and better governance (p=0·025 and p<0·0001) were associated with lower antimicrobial resistance indices. Antibiotic consumption was not significantly associated with either antimicrobial resistance index in the multivariable analysis (p=0·64 and p=0·070).Reduction of antibiotic consumption will not be sufficient to control antimicrobial resistance because contagion-the spread of resistant strains and resistance genes-seems to be the dominant contributing factor. Improving sanitation, increasing access to clean water, and ensuring good governance, as well as increasing public health-care expenditure and better regulating the private health sector are all necessary to reduce global antimicrobial resistance.None.
Peter Copeman: medical dermatologist who pioneered new classification of skin diseases
Authors: Penny Warren
Journal: BMJ (2018)

In 1958 the Lancet published “Treatment of Recurrent Styes” by Peter Copeman, a house surgeon in the eye department at St Thomas’ Hospital, London. It was the start of a distinguished career, but surprisingly not one in ophthalmology.

Colleagues in the fledgling dermatology department read the paper and persuaded Copeman to join them. In those days knowledge of dermatology was primitive, but today it is a highly competitive specialty, and Copeman’s career was instrumental in its transformation.

Copeman was born in London on 9 April 1932. When war broke out he spent school holidays with his family in Shaftesbury, where they were evacuated to. He enjoyed studying flowers and trees and learnt to imitate sounds such as a wild duck’s call.

In 1945 he went to Eton. He had a dry sense of humour and could take a joke against himself. A favourite story is how, as captain of the …
Mapping the<i>terra incognita</i>of economic cognition will require an experimental paradigm that incorporates context
Authors: Aaron D. Lightner, Edward H. Hagen
Journal: Behavioral and Brain Sciences (2018)

Abstract Researchers, including Boyer &amp; Petersen (B&amp;P), commonly use experimental economic studies to draw their conclusions. These studies conventionally strip away context and present participants only with abstract rules. Because context is a strictly necessary component of the decision-making process, it is not clear that inferences about high-level folk psychological concepts (e.g., rationality) can be drawn from decontextualized economic games.
Abstract 13920: SALL4 and YY1 Enhance Direct Cardiac Reprogramming in Chemically Defined Conditions
Authors: Weiming Chen, Jing Xuan Wong, Dan Liao, Huck-Hui Ng, Sik-Yin Foo Roger, Jianming Jiang
Journal: Circulation (2017)

Direct reprogramming of human fibroblasts into induced cardiomyocytes (iCMs) offers a great therapeutic approach for cardiovascular disease. Low efficiency of human iCMs generation is one of the ma...
Abstract 17234: Comparing the Efficacy of Primary Prevention Strategies in Doxorubicin-induced Cardiotoxicity using Echocardiography and High-Sensitivity Troponin T
Authors: Pimprapa Vejpongsa, Meng Chen, Dejka M Araujo, Mona R Massey, Jose Banchs, Sandra A Acholonu, Saamir A Hassan, Qing H Meng, Edward T Yeh
Journal: Circulation (2014)

Introduction: Detection of chemotherapy-induced cardiotoxicity has historically relied on clinical presentation and cardiac imaging measures. Recently, global longitudinal peak systolic strain (GLS) measures with speckle tracking echocardiography (STE) and high-sensitivity troponin T (hs-TnT) have been utilized to evaluate the development of cardiotoxicity. The increased sensitivity of these methods may allow us to differentiate the relative difference in efficacy amongst primary prevention strategies. Hypothesis: We tested the hypothesis that GLS or hs-TnT will differentiate the efficacy between dexrazoxane and continuous infusion of doxorubicin in preventing doxorubicin-induced cardiotoxicity. Methods: Twenty-three patients with newly diagnosed sarcoma were assigned to receive 72-hours doxorubicin infusion (13 patients) or doxorubicin + dexrazoxane injection (10 patients). hs-TnT was monitored before, at 24 and 72 hours of each chemotherapy cycle. All samples were assayed at the same time using hs-TnT (...
Medical Aspects of Transportation Aboard Commercial Aircraft
Journal: JAMA (1982)

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Abstract 15567: A Direct Factor Xa Inhibitor, Rivaroxaban, Attenuates Cardiac Hypertrophy and Fibrosis in Renin-overexpressing Hypertensive Mice
Authors: Masato Narita, Hiroaki Ichikawa, Yoshihiro Kimura, Maiko Senoo, Manabu Yonekura, Noritomo Narita, Kenji Hanada, Michiko Shimada, Makoto Tanaka, Tomohiro Osanai, Ken Okumura, Hirofumi Tomita
Journal: Circulation (2017)

Introduction: Rivaroxaban (Riv), a direct Xa inhibitor, has been used for the prevention of thromboembolic events. Recent study showed that Riv exerts an anti-inflammatory effect in addition to ant...
Abstract 18852: Myofilament Length Dependent Activation: Role of Titin
Authors: Younss AIT MOU, Karen H Hsu, Marion Greaser, Thomas C Irving, Pieter P deTombe
Journal: Circulation (2014)

The cellular basis of the Frank-Starling mechanism is sarcomere length (SL) modulation of myofilament Ca 2+ sensitivity (LDA). The molecular mechanism(s) that underlie LDA are unknown, but recent evidence has implicated the giant protein titin as possible sarcomeric strain sensor responsible for LDA by an, as of yet unidentified, signal transduction pathway. Accordingly, the aim of the present study was to elucidate the impact of SL (from slack=2.0 μm to stretch=2.4 μm) on LDA and sarcomere structure in isolated rat myocardium from either wild-type (WT) or mutant (HM) rats expressing a giant splice isoform of titin. At stretch, WT muscles showed reduced increase in passive tension (-20%) and twitch force (-58%); also, LDA was significantly blunted at the myofilament level. Time-resolved small angle x-ray diffraction of intact twitching muscles during diastole revealed at stretch a significant increase in intensity and spacing of: myosin M2 (+121% &amp; +0.4%) and troponin T3 (+174% &amp; +1.0%); Myosin binding protein C (MyoBPC) also trended to increase (C1%C2). These SL dependent changes in sarcomere structure were absent in HM muscles. Cross-bridge radial spacing (layer line analysis) was significantly reduced at stretch in WT (-8.0%); in HM muscles radial spacing was further, but similarly reduced at both slack and stretch (~-20%). Equatorial spacings and intensity ratios were similar between WT and HM at both slack and stretch. Electron density reconstruction revealed, only in WT, increased mass in both thick and thin filament, and the appearance of an as of yet unidentified moiety spanning the space between the thick and thin filaments at stretch. These results were independently confirmed in skinned myocyte fragments in which endogenous TnC was replaced with fluorescently labelled TnC. Conclusion: Stretch induces structural changes in both thick and thin filaments mediated by titin strain. Moreover, MyoBPC may interact with actin to mediate LDA.
Инсулинорезистентность, ее роль в развитии неалкогольной жировой болезни печени у больных с метаболическим синдромом, пути коррекции
Authors: G.A. Anokhina, V.V. Kharchenko, I.A Korulya, I.A. Yakubovskaya
Journal: GASTROENTEROLOGY (2014)

В статье приведены данные о роли печени в углеводном и липидном обмене, описаны особенности метаболизма глюкозы в условиях инсулинорезистентности и роль глюкокиназного пути поступления глюкозы в гепатоцит. Освещены результаты экспериментальных и клинических исследований влияния биотина на обмен глюкозы, липидов, аминокислот и возможности его использования в лечении больных неалкогольной жировой болезнью печени.
Impact of peritoneal carcinomatosis on clinical outcomes of patients receiving self-expandable metal stents for malignant colorectal obstruction
Authors: Jae Park, Kwangwon Rhee, Jin Yoon, Soo Park, Joo Kim, Jie-Hyun Kim, Young Youn, Tae Kim, Hyojin Park, Won Kim, Jae Cheon
Journal: Endoscopy (2018)

Abstract Background Peritoneal carcinomatosis can influence clinical outcomes of patients receiving self-expandable metal stents (SEMS) for malignant colorectal obstruction, but data regarding this issue are sparse. We analyzed the clinical outcomes of post-SEMS insertion for malignant colorectal obstruction based on carcinomatosis status. Methods Stent- and patient-related clinical outcomes were compared for carcinomatosis status in a retrospective review involving 323 consecutive patients (colorectal cancer 198 patients; extracolonic malignancy 125 patients) who underwent palliative SEMS placement for malignant colorectal obstruction from January 2005 to March 2012. Severity of carcinomatosis was classified as mild, moderate, or severe. Results Carcinomatosis was observed in 190 patients (58.8 %). The rates of technical (84.7 vs. 94.7 %; P = 0.005) and clinical (73.2 vs. 83.5 %; P = 0.03) success were lower in patients with vs. without carcinomatosis. Rates of early (2.1 % vs. 3.0 %; P = 0.72) and delayed (1.6 % vs. 6.0 %; P = 0.08) perforation and stent failure (27.9 % vs. 26.3 %; P = 0.75) showed no difference. Technical and clinical success rates were significantly different based on the severity of carcinomatosis (technical success rate: mild 90.7 %, moderate 97.4 %, severe 76.3 %, P = 0.003; clinical success rate: mild 83.3 %, moderate 82.1 %, severe 63.9 %, P = 0.01). In multivariate analysis, severe carcinomatosis was identified as an independent factor related to technical (odds ratio [OR] 0.18, 95 % confidence interval [CI] 0.06 – 0.56) and clinical (OR 0.33, 95 %CI 0.15 – 0.74) success. Conclusions Peritoneal carcinomatosis was associated with decreased technical and clinical success rates in patients receiving SEMS for malignant colorectal obstruction. Moreover, the presence of severe carcinomatosis was an independent factor determining these clinical outcomes.
The challenge of ageing populations and patient frailty: can primary care adapt?
Authors: David Reeves, Stephen Pye, Darren M Ashcroft, Andrew Clegg, Evangelos Kontopantelis, Tom Blakeman, Harm van Marwijk
Journal: BMJ (2018)

The challenge of ageing populations and frail people: can primary care adapt? StandfirstHealth care systems worldwide are having to adapt to ageing populations and increasing numbers of older people with frailty with complex health and social needs, and in the UK primary care is at the frontline of policy attempts to meet this challenge, but achieving the goal of making frailty an integral part of primary care practice is not without considerable challenges.
Mitochondrial DNA Variation Dictates Expressivity and Progression of Nuclear DNA Mutations Causing Cardiomyopathy
Authors: Meagan J. McManus, Martin Picard, Hsiao-Wen Chen, Hans J. De Haas, Prasanth Potluri, Jeremy Leipzig, Atif Towheed, Alessia Angelin, Partho Sengupta, Ryan M. Morrow, Brett A. Kauffman, Marc Vermulst, Jagat Narula, Douglas C. Wallace
Journal: Cell Metabolism (2018)
Mutations and karyotype predict treatment response in myelodysplastic syndromes
Authors: Dame Idossa, Terra L. Lasho, Christy M. Finke, Rhett P. Ketterling, Mrinal M. Patnaik, Animesh Pardanani, Naseema Gangat, Ayalew Tefferi
Journal: American Journal of Hematology (2018)

We examined the influence of mutations and karyotype on conventional treatment response, specifically hematological improvement in anemia, in primary myelodysplastic syndromes (MDS). Cytogenetic and next generation sequencing (NGS)-derived mutation information was available in 357 patients (median age 74 years; 70% males); the revised international prognostic scoring system risk distribution was very high in 11%, high 15%, intermediate 17%, low 40% and very low 16%. At least one mutation was detected in 81% of patients; most frequent were SF3B1 (32%), ASXL1 (27%), TET2 (24%) and U2AF1 (15%). At median follow-up of 24 months, treatment with hypomethylating agents (HMAs) was documented in 121 (34%) patients, lenalidomide (LEN) in 55 (15%), and erythropoiesis stimulating agents (ESAs) in 136 (38%). ASXL1 mutations adversely affected response to HMAs (27% vs 48%; P = 0.02) and LEN (9% vs 43%; P = 0.04), but not ESAs (P = 0.6). LEN response was also adversely affected by U2AF1 mutations (0% vs 42%; P = 0.02) and high risk karyotype (0% vs 41% in intermediate vs 47% in low risk; P = 0.01). Patients with SF3B1 mutations were more likely to respond to LEN (56% vs 27%; P = 0.04). Contrary to previous reports, we found no association between TET2 mutations and HMA treatment response (40% vs 41%; P = 0.9), even in the absence of ASXL1 mutations (P = 0.4).We conclude that ASXL1 mutations in MDS predict inferior response to treatment with both HMAs and LEN; response to LEN was also compromised by U2AF1 mutations and high risk karyotype; SF3B1 mutations identified patients likely to respond to LEN.
If we build it, who will come? The case for attention to equity in healthy community design
Authors: Meridith Sones, Daniel Fuller, Yan Kestens, Meghan Winters
Journal: British Journal of Sports Medicine (2018)

The health and economic burden of physical inactivity is substantial and showing few signs of decline despite increased attention in policy agendas globally.1 To address this pandemic, we need to look beyond the health sector and reimagine our environments into places that get us moving more, and sitting less. Governments are investing in active transportation and sustainable development projects in light of their health, economic and environmental promise. But who stands to benefit from these investments, and in what context?

Physical inactivity is socially distributed, varying by socioeconomic status, gender, age, education and ethnicity.2 This trend is global and consequential; a recent study using smartphone data from over 700 000 people across 111 countries showed that inequities in physical activity are a better predictor of obesity prevalence than average physical activity.3 The built environment has the potential to either mitigate or exacerbate health inequities. Vulnerable populations often live in built environments lacking access to amenities that promote active mobility, such as transit and recreational facilities.4 In addition to supporting physical activity, designing safe environments that increase the active transportation of underserved groups may …