tbuckley/cabot-search huggingface dataset:
Cell-centred meta-analysis reveals baseline predictors of anti-TNFα non-response in biopsy and blood of patients with IBD
Authors: Renaud Gaujoux, Elina Starosvetsky, Naama Maimon, Francesco Vallania, Haggai Bar-Yoseph, Sigal Pressman, Roni Weisshof, Idan Goren, Keren Rabinowitz, Matti Waterman, Henit Yanai, Iris Dotan, Edmond Sabo, Yehuda Chowers, Purvesh Khatri, Shai S Shen-Orr
Journal: Gut (2018)

Objective Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost–benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value. Design We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution—meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts. Results We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) –axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%. Conclusions Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.
Abstract 11118: Pre-procedural Blood Glucose is Associated with Acute Kidney Injury in Nondiabetics
Authors: Michael A Gaglia, Rebecca Torguson, Manuel A Gonzalez, Itsik Ben-Dor, Gabriel Maluenda, Sara D Collins, Asmir I Syed, Michael Mahmoudi, Kohei Wakabayashi, Loic Belle, Zhenyi Xue, William O Suddath, Kenneth M Kent, Lowell F Satler, Augusto D Pichard, Ron Waksman
Journal: Circulation (2010)

Introduction:  Diabetes mellitus is a risk factor for contrast-induced acute kidney injury (AKI), but the effect of hyperglycemia before percutaneous coronary intervention (PCI) is not well-described.   Hypothesis:  We hypothesized that elevated pre-procedure blood glucose would increase the risk of AKI, regardless of diabetes history.   Methods:  A total of 12392 patients undergoing PCI were retrospectively analyzed. The primary endpoint was the development of contrast-induced AKI, defined as an absolute creatinine increase ≥0.3 mg/dL or a relative increase ≥50%. Pre-procedure glucose was categorized as  140 mg/dL. Patients on chronic dialysis or presenting with shock were excluded. Multivariable logistic regression, stratified by history of diabetes mellitus, was performed to assess the independent effect of pre-PCI glucose upon AKI. This included the effect of specific therapies for diabetes and hypertension upon the risk of AKI.   Results:  423 patients (8.1%) with glucose  140 developed contrast-induced AKI (p 140 increased the risk of contrast-induced AKI in both diabetics (OR 1.36, 95% CI 1.02–1.81, p=0.04) and nondiabetics (OR 1.39, 95% CI 1.04–1.86, p=0.03; Table). Hypertension, lower creatinine clearance, and higher contrast volume increased the risk of AKI only in diabetics. Patients taking angiotensin receptor blockers, however, were less likely to suffer contrast-induced AKI in both groups.   Conclusions:  Elevated pre-procedural blood glucose increases the risk of contrast-induced AKI in both diabetic and nondiabetic patients.
Matrix metalloproteinase-related gene polymorphisms to predict efficacy of regorafenib in patients with metastatic colorectal cancer.
Authors: Mitsukuni Suenaga, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Yan Ning, Francesca Bergamo, Vittorina Zagonel, Daniele Rossini, Beatrice Borelli, Satoshi Okazaki, Martin D Berger, Yuji Miyamoto, Roel Gopez, Afsaneh Barzi, Toshiharu Yamaguchi, Fotios Loupakis, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

692 Background: Matrix metalloproteinases (MMPs) are proteolytic enzyme for extracellular matrix and involved in regulation of tumor environment including angiogenesis. MMP-2 and MMP-9 were reported to be prognostic marker of anti-angiogenic therapy. We tested whether genetic polymorphisms in the MMP family predict clinical outcomes in patients with refractory mCRC receiving regorafenib. Methods: 228 patients with mCRC receiving regorafenib were included in this pooled analysis combining two different cohorts from Italy and Japan (median age, 62 years; male, 51.5%; median follow-up time, 26.2 months; Italian/Japanese, 150/79). Six single nucleotide polymorphisms (SNPs) of five genes in MMPs ( MMP2, MMP9, MMP14, TIMP2, CD44) were analyzed by PCR-based direct sequencing. Correlations between candidate SNPs and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank test. Disease control was compared by Fisher’s exact test. Multivariable analyses were conducted using the Cox proportional hazard regression model. Results: In univariate analysis, patients carrying the G/G variant in MMP2 rs1477017 had a significantly shorter OS compared to those with any A allele (4.4 vs. 7.8 months, HR 1.85, 95%CI: 1.13-3.03, P= 0.011). The findings were confirmed in multivariable analysis (HR 1.84, 95%CI: 1.11-3.07, P= 0.019). Although the frequency of the T/T variant in MMP9 rs2274755 was considerably low, the T/T variant was associated with shorter PFS and OS compared to any G allele in univariate analysis (1.7 vs. 2.1 months, HR 2.53, 95%CI: 1.17-5.46, P= 0.011; 3.9 vs. 7.6 months, HR 2.51, 95%CI: 1.11-5.72, P= 0.021) and multivariable analysis (HR 3.04, P= 0.009; HR 5.20, P&lt; 0.001). No significant interaction was shown between the SNPs and cohorts. Disease control was significantly infrequent in patients carrying the T/T variant in MMP9 rs2274755 ( P= 0.046). Conclusions: Our data suggest that MMPs network potentially mediates tumor angiogenesis responding to regorafenib. The MMP2 and MMP9 SNPs may predict efficacy of regorafenib in patients with refractory mCRC. However, this preliminary finding warrants further validation.
Seasonal temperature variability and emergency hospital admissions for respiratory diseases: a population-based cohort study
Authors: Shengzhi Sun, Francine Laden, Jaime E Hart, Hong Qiu, Yan Wang, Chit Ming Wong, Ruby Siu-yin Lee, Linwei Tian
Journal: Thorax (2018)

Background Climate change increases global mean temperature and changes short-term (eg, diurnal) and long-term (eg, intraseasonal) temperature variability. Numerous studies have shown that mean temperature and short-term temperature variability are both associated with increased respiratory morbidity or mortality. However, data on the impact of long-term temperature variability are sparse. Objective We aimed to assess the association of intraseasonal temperature variability with respiratory disease hospitalisations among elders. Methods We ascertained the first occurrence of emergency hospital admissions for respiratory diseases in a prospective Chinese elderly cohort of 66 820 older people (≥65 years) with 10–13 years of follow-up. We used an ordinary kriging method based on 22 weather monitoring stations in Hong Kong to spatially interpolate daily ambient temperature for each participant’s residential address. Seasonal temperature variability was defined as the SD of daily mean summer (June–August) or winter (December–February) temperatures. We applied Cox proportional hazards regression with time-varying exposure of seasonal temperature variability to respiratory admissions. Results During the follow-up time, we ascertained 12 689 cases of incident respiratory diseases, of which 6672 were pneumonia and 3075 were COPD. The HRs per 1°C increase in wintertime temperature variability were 1.20 (95% CI 1.08 to 1.32), 1.15 (1.01 to 1.31) and 1.41 (1.15 to 1.71) for total respiratory diseases, pneumonia and COPD, respectively. The associations were not statistically significant for summertime temperature variability. Conclusion Wintertime temperature variability was associated with higher risk of incident respiratory diseases.
Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma
Authors: Benjamin M Ellingson, Lauren E Abrey, Sarah J Nelson, Timothy J Kaufmann, Josep Garcia, Olivier Chinot, Frank Saran, Ryo Nishikawa, Roger Henriksson, Warren P Mason, Wolfgang Wick, Nicholas Butowski, Keith L Ligon, Elizabeth R Gerstner, Howard Colman, John de Groot, Susan Chang, Ingo Mellinghoff, Robert J Young, Brian M Alexander, Rivka Colen, Jennie W Taylor, Isabel Arrillaga-Romany, Arnav Mehta, Raymond Y Huang, Whitney B Pope, David Reardon, Tracy Batchelor, Michael Prados, Evanthia Galanis, Patrick Y Wen, Timothy F Cloughesy
Journal: Neuro-Oncology (2018)

In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS). Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS. A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status. Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.
Determinants of happiness and quality of life in patients with rheumatoid arthritis: a structural equation modelling approach
Authors: Eduardo José Ferreira Santos, Cátia Duarte, Ricardo J O Ferreira, Ana Margarida Pinto, Rinie Geenen, Jose A P da Silva
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> Besides increasing longevity, the ultimate goal of medical care is to improve patients' enjoyment of life, a concept akin to happiness. This study examined the determinants of happiness and quality of life (QoL) in patients with rheumatoid arthritis (RA). <h3>Methods</h3> In this observational, cross-sectional study, patients were assessed on disease activity, disease impact, personality, QoL and happiness. Structural equation modelling estimation was used to analyse the associations between these dimensions, pursuing three hypotheses: H<sub>1</sub>—disease activity and perceived impact of disease are negatively associated with overall QoL and happiness in patients with RA; H<sub>2</sub>—'positive' personality traits are related to happiness both directly and indirectly through perceived disease impact; H<sub>3</sub>—happiness has a mediating effect in the relation between impact of disease and QoL. <h3>Results</h3> Data from 213 patients were analysed. Results supported all driving hypotheses. Happiness was positively related to 'positive' personality and, to a lesser extent, negatively related to impact of disease. Impact of disease, in turn, was positively related to disease activity and mitigated by 'positive' personality traits. Impact of disease had a much stronger relation with QoL than with happiness. Happiness mitigated the negative effect of disease impact on QoL. <h3>Conclusion</h3> Optimisation of QoL and happiness of people with RA requires effective control of the disease process and also improvement of the disease impact domains. Personality seems to play a pivotal mediating role in these relations.
Taxes on alcohol, tobacco, and soft drinks are fair and produce health gains, review finds
Authors: Susan Mayor
Journal: BMJ (2018)

Taxes on alcohol, tobacco, and soft drinks offer a particularly effective strategy for reducing chronic disease among the poorest people in society who are disproportionately affected by unhealthy products, a review has found.1

Lawrence Summers, from Harvard University in Boston, USA, said in an accompanying editorial, “One of the most common arguments used to oppose taxing tobacco, alcohol or sugary beverages is the claim that such taxes are regressive—that it is unfair to make poorer people pay a larger share of their limited household incomes to consume these products than richer people.”2

He said …
Gefitinib as third-line re-challenge treatment in advanced NSCLC patients with EGFR activating mutation who benefited from first-line gefitinib treatment followed by second-line chemotherapy.
Authors: Yong Song, Yi-Long Wu, Lejie Cao, Jianhua Chen, Zhiyong Ma, Jiuwei Cui, Xin Ye, Jingyan Ding
Journal: Journal of Clinical Oncology (2017)

9035 Background: Several studies show that EGFR-mutant NSCLC patients (pts) gained response to EGFR-TKI treatment again after a TKI free interval. To date, no prospective evaluation of the clinical effects of EGFR-TKI re-challenge in EGFR-mutant NSCLC pts has been performed. Methods: This was a multicenter, open-label, single-arm, phase II study (CTONG1304, NCT01933347). Stage IIIB/IV NSCLC pts with EGFR exon 19del/L858R mutation, who previously benefited from first-line gefitinib treatment followed by second-line chemotherapy, took gefitinib 250mg/d until disease progression or death or intolerable toxicity occurred. Blood samples were dynamically collected for EGFRmutation testing using droplet digital PCR at every visit (from baseline to the end of gefitinib treatment). The primary objective was disease control rate (DCR) at week 8. Secondary objectives were objective response rate (ORR), progression free survival (PFS), and overall survival (OS). Results: From March 2014 to May 2016, 45 eligible pts were enrolled and 43 pts were included in the full analysis set (FAS) for efficacy analysis. Gefitinib re-challenge achieved DCR of 69.8%. ORR was 4.7%. Median PFS and OS were 4.4 and 8.0 months (m) respectively. T790M- subgroup at baseline had higher DCR, longer mPFS and mOS, compared with T790M+ subgroup. EGFRstatus changed significantly after gefitinib re-challenge. Conclusions: Gefitinib re-challenge was an effective option in EGFR-mutant NSCLC pts. T790M negativity is a potentially predictive efficacy biomarker for gefitinib re-challenge. Clinical trial information: NCT01933347. [Table: see text]
PLGA/β-TCP composite scaffold incorporating salvianolic acid B promotes bone fusion by angiogenesis and osteogenesis in a rat spinal fusion model
Authors: Sien Lin, Liao Cui, Guanghua Chen, Jianping Huang, Yanhua Yang, Kaijie Zou, Yuxiao Lai, Xinluan Wang, Liyi Zou, Tie Wu, Jack Chun Yiu Cheng, Gang Li, Bo Wei, Wayne Yuk Wai Lee
Journal: Biomaterials (2018)
Prevalence of Delusional Infestation—A Population-Based Study
Authors: John J. Kohorst, Christopher H. Bailey, Louise K. Andersen, Mark R. Pittelkow, Mark D. P. Davis
Journal: JAMA Dermatology (2018)

without LGBT-specific dermatologic concerns (or parents of children with dermatologic concerns); in line with AAMC recommendations, those cases can sensitize students to general issues of LGBT-related cultural competency (for example, appropriate use of pronouns and other terminology). 5Per AAMC recommendations, to ensure that medical students are achieving relevant competencies through the online curriculum and other sources, medical student evaluations should include LGBT-related content in examination questions, evaluation scenarios, and patient scenarios. 5Graduate and continuing medical education in dermatology should also include LGBT health-related content to help dermatologists provide appropriate care to LGBT persons.
Atorvastatin in Combination With Narrowband UV-B in Adult Patients With Active Vitiligo
Authors: Sophie Nguyen, Sai Yee Chuah, Eric Fontas, Abdallah Khemis, Anjali Jhingan, Steven Tien Guan Thng, Thierry Passeron
Journal: JAMA Dermatology (2018)

Studies have reported the anti-inflammatory, immunomodulatory, and antioxidant effects of statins.Targeting motif chemokine CXCL10 using antibodies has been shown to prevent the depigmentation in the vitiligo mouse model. 1 In the same model, simvastatin was effective in the regression of vitiligo. 2Simvastatin has also been shown to protect melanocytes from oxidative stress by activating nuclear factor (erythroid-derived 2)-like 2, 3 and atorvastatin can reduce plasma levels of CXCL10 in patients with Crohn disease. 4Therefore, there is a rationale for using statins to halt the progression of active vitiligo.
AIDA Selectively Mediates Downregulation of Fat Synthesis Enzymes by ERAD to Retard Intestinal Fat Absorption and Prevent Obesity
Authors: Hui Luo, Ming Jiang, Guili Lian, Qing Liu, Meng Shi, Terytty Yang Li, Lintao Song, Jing Ye, Ying He, Luming Yao, Cixiong Zhang, Zhi-Zhong Lin, Chen-Song Zhang, Tong-Jin Zhao, Wei-Ping Jia, Peng Li, Shu-Yong Lin, Sheng-Cai Lin
Journal: Cell Metabolism (2018)
Air Pollution and Glucose Metabolism: An Analysis in Non-Diabetic Participants of the Heinz Nixdorf Recall Study
Authors: Sarah A. Lucht, Frauke Hennig, Clara Matthiessen, Simone Ohlwein, Andrea Icks, Susanne Moebus, Karl-Heinz Jöckel, Hermann Jakobs, Barbara Hoffmann
Journal: Environmental Health Perspectives (2018)

Background: Despite the importance of understanding the connection between air pollution exposure and diabetes, studies investigating links between air pollution and glucose metabolism in nondiabetic adults are limited. Objective: We aimed to estimate the association of medium-term air pollution exposures with blood glucose and glycated hemoglobin A1c (HbA1c) among nondiabetics. Methods: This study included observations from nondiabetic participants (nobs=7,108) of the population-based Heinz Nixdorf Recall study at baseline (2000–2003) and follow-up examination (2006–2008). Daily fine particulate matter (aerodynamic diameter≤2.5 μm, PM2.5; aerodynamic diameter≤10 μm, PM10), accumulation mode particle number (PNAM), and nitrogen dioxide (NO2) exposures were estimated at participants' residences using the spatiotemporal European Air Pollution Dispersion (EURAD) chemistry transport model. We evaluated the associations between medium-term air pollution exposures (28- and 91-d means) and glucose metabolism measures using mixed linear regression and adjusting for season, meteorology, and personal characteristics. A range of other exposure windows (1-, 2-, 3-, 7-, 14-, 45-, 60-, 75-, 105-, 120-, and 182-d means) were also evaluated to identify potentially relevant biological windows. Results: We observed positive associations between PM2.5 and PNAM exposures and blood glucose levels [e.g., 28-d PM2.5: 0.91mg/dL (95% CI: 0.38, 1.44) per 5.7 μg/m3]. PM2.5, PM10, and PNAM exposures were positively associated with HbA1c [e.g., 91-d PM2.5: 0.07p.p. (95% CI: 0.04, 0.10) per 4.0 μg/m3]. Mean exposures during longer exposure windows (75- to 105-d) were most strongly associated with HbA1c, whereas 7- to 45-d exposures were most strongly associated with blood glucose. NO2 exposure was not associated with blood glucose or with HbA1c. Conclusions: Medium-term PM and PNAM exposures were positively associated with glucose measures in nondiabetic adults. These findings indicate that reducing ambient air pollution levels may decrease the risk of diabetes. https://doi.org/10.1289/EHP2561
SOX11 augments BCR signaling to drive MCL-like tumor development
Authors: Pei-Yu Kuo, Shashidhar S. Jatiani, Adeeb H. Rahman, Donna Edwards, Zewei Jiang, Katya Ahr, Deepak Perumal, Violetta V. Leshchenko, Joshua Brody, Rita Shaknovich, B. Hilda Ye, Samir Parekh
Journal: Blood (2018)
KEYNOTE-059 cohort 1: Pembrolizumab (Pembro) monotherapy in previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer in patients (Pts) with PD-L1+ tumors—Asian subgroup analysis.
Authors: Kei Muro, Charles S. Fuchs, Raymond Woo-Jun Jang, Taroh Satoh, Manuela Machado, Weijing Sun, Shadia Ibrahim Jalal, Manish A. Shah, Jean-Philippe Metges, Marcelo Garrido, Talia Golan, Mario Mandala, Zev A. Wainberg, Daniel V.T. Catenacci, Yung-Jue Bang, Jianxin Lin, Jia Lu, Harry H. Yoon, Toshihiko Doi
Journal: Journal of Clinical Oncology (2018)

723 Background: The US FDA approved pembro for treating pts with 1) recurrent locally advanced or metastatic G/GEJ adenocarcinoma, whose disease has progressed on or after ≥2 prior therapies and whose tumors express PD-L1 (combined positive score [CPS] ≥1), and 2) unresectable or metastatic, microsatellite instability-high (MSI-H) solid tumors that have progressed after prior therapy and who have no fitting options. We report Asian subgroup analyses from cohort 1 of KEYNOTE-059 (NCT02335411), a global, phase 2 study in advanced G/GEJ cancer. Methods: Eligible pts had measurable recurrent or metastatic G/GEJ adenocarcinoma whose disease has progressed on ≥2 prior chemotherapy regimens. Pts received pembro 200 mg Q3W up to 2 y. PD-L1+ tumors had a CPS ≥1. Primary end points were ORR (RECIST 1.1, by central review) and safety. Results: Cohort 1 enrolled 259 pts; 57% had PD-L1+ tumors. MSI status was evaluable in 174 tumor samples; of these, 7 were MSI-H. At data cutoff (4/21/2017), median (range) follow-up was 6 mo (1-25). Overall ORR was 12% (95% CI, 8-17) and median (range) DOR was 14 mo (2-19+). PFS 6-mo rate was 15% and OS 6-mo rate was 46%. In pts with PD-L1+ tumors, ORR was 16% (95% CI, 11-23) and median (range) DOR was 14 mo (3+-19+). In pts with PD-L1+ tumors, PFS 6-mo rate was 20% and OS 6-mo rate was 50%. In pts with MSI-H tumors, ORR was 57% (95% CI, 18-90) and median (range) DOR was not reached (5-14+ mo). In cohort 1, 41 pts were Asian and 218 pts were non-Asian. PD-L1+ tumors occurred in 42% of Asian pts and 60% of non-Asian pts. ORR was 12% (95% CI, 2-36) in Asian pts with PD-L1+ tumors and 17% (95% CI, 11-24) in non-Asian pts with PD-L1+ tumors. One of 7 pts with MSI-H tumors was Asian; this pt had CR. Grade 3-5 treatment-related AEs occurred in 17% and 18% of Asian and non-Asian pts, similar to the overall cohort. Conclusions: Pembro showed durable clinical benefit in previously treated pts with advanced G/GEJ cancer, especially those with PD-L1+ or MSI-H tumors. Safety and efficacy were similar in Asian and non-Asian pts. These findings highlight pembro as a standard treatment option in Asian and non-Asian pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.