tbuckley/cabot-search huggingface dataset:
Melatonin as a cardioprotective therapy following ST-segment elevation myocardial infarction: is it really promising? Reply
Authors: Derek J. Hausenloy, David Garcia-Dorado, Hans Erik Bøtker, Sean M. Davidson, James Downey, Felix B. Engel, Robert Jennings, Sandrine Lecour, Jonathan Leor, Rosalinda Madonna, Michel Ovize, Cinzia Perrino, Fabrice Prunier, Rainer Schulz, Joost P. G. Sluijter, Linda W. Van Laake, Jakob Vinten-Johansen, Derek M. Yellon, Kirsti Ytrehus, Gerd Heusch, Péter Ferdinandy
Journal: Cardiovascular Research (2017)
Abstract 156: Hydrogel Mattress, an in vitro Platform to Enhance Maturation and Evaluate Contractile Function of Individual hiPSC-CMs
Authors: Tromondae K Feaster, Charles H Williams, Adrian G Cadar, Young W Chun, Lili Wang, Nathan C Bloodworth, W. D Merryman, Chee C Lim, Bjorn C Knollmann, Charles C Hong
Journal: Circulation Research (2015)

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) have great potential as tools for human heart disease modeling and drug discovery. However, their contractile properties have not been routinely evaluated; as current methods are not accessible for most laboratories. We sought to develop a more efficient method to evaluate hiPSC-CM mechanical properties, at the single cell level. Individual hiPSC-CMs were cultured on a hydrogel based platform, termed the “hydrogel mattress,” and their cellular contractile properties evaluated using video-based edge detection. We found that hiPSC-CMs maintained on the mattress reproducibly exhibited robust cell shortening, in dramatic contrast to hiPSC-CMs maintained in a standard manner. We further found that contraction and peak cell shortening amplitude of hiPSC-CMs on mattress was comparable to that of freshly isolated adult ventricular mouse CM. Importantly, hiPSC-CMs maintained on the mattress exhibited several characteristics of a native CM, in terms of myocyte elongation, calcium handling and pharmacological response. Finally, using this platform, we could calculate the traction force generated by individual CMs. In summary, the Hydrogel mattress platform is a simple and reliable in vitro platform that not only enables the quantification of contractile performance of isolated hiPSC-CMs, but also enhances CM maturation. This flexible platform can be extended to in vitro disease modeling, drug discovery and cardiotoxicity testing.
Twinfilin 2a regulates platelet reactivity and turnover in mice
Authors: Simon Stritt, Sarah Beck, Isabelle C. Becker, Timo Vögtle, Markku Hakala, Katrin G. Heinze, Xiaoping Du, Markus Bender, Attila Braun, Pekka Lappalainen, Bernhard Nieswandt
Journal: Blood (2017)
ABC-04: A phase 1b trial of cisplatin, gemcitabine, and selumetinib in patients with advanced biliary tract cancer.
Authors: John A. Bridgewater, Sandy Beare, Lee Dymphna, Andre Lopes, Marian Duggan, Harpreet S Wasan, Juan W. Valle, Delyth McEntee, Marivic Ricamara, Ajithkumar Sukumaran
Journal: Journal of Clinical Oncology (2014)

4090 Background. Cisplatin + gemcitabine (CisGem) is a standard of care for advanced biliary tract cancer (ABC; Valle et al. 2010). Selumetinib (S; AZD6244, ARRY-142886) potently and selectively inhibits MEK1/2, an intracellular kinase (Adjei et al., 2008; Yeh et al., 2007), and has shown activity in ABC (Bekaii-Saab et al., 2009). The objective of the ABC-04 trial was to establish the recommended dose (RD) of S to give in combination with CisGem. Methods. Eligible patients (pts) were ≥ 18 years, had histology/cytology confirmed unresectable recurrent or metastatic biliary tract, gallbladder or ampullary carcinoma, WHO performance status 0-2, adequate major organ function. Pts may have had prior surgery, radiotherapy or adjuvant chemotherapy (CT), but no prior CisGem or CT for locally advanced or metastatic disease. Pts received cisplatin 25 mg/m2 plus gemcitabine 1000 mg/m2 intravenously on days 1 and 8 of a 21-day cycle. S capsules were taken daily. A dose de-escalation scheme was used to determine the RD of S. The first dose level was 75 mg bd. Pts were recruited in cohorts of 3 and assessed for dose limiting toxicity (DLT) during the first cycle of treatment. Pts received up to 8 cycles of CisGem and could receive S until disease progression. Results. Thirteen pts were recruited of whom 12 were evaluable for DLT (1 did not start treatment). All evaluable pts received the starting dose of 75 mg bd and only one patient experienced a DLT (ischaemic heart disease). Median number of days S taken (adjusted for the number of days of dose interruptions) was 167 (IQR: 75.5 to 311.5). Two pts remained on treatment at 14 and 19 months post registration. There were 3 temporary and 1 permanent interruptions of S in cycle 1. Eight pts had measurable disease (RECIST v1.1) and were evaluable for objective response: 3 had partial response and 5 stable disease. Toxicities related to S included oedema and rash; most were modest and manageable. Pharmacokinetic analysis did not show a significant interaction between gemcitabine and S. Conclusion. The RD of S when combined with CisGem is 75 mg bd. Translational studies are underway to determine any potential molecularly favoured subgroup. Clinical trial information: NCT01242605.
“Ethicolegal restrictions” restrict data sharing where it might help
Authors: Paul J Wicks
Journal: BMJ (2017)

Although Bally and colleagues’ study of myocardial infarction and non-steroidal anti-inflammatory drugs had a relatively large cohort (446 763), this represented only half of the potentially eligible studies identified through their literature search.1 Data from four studies could not be included for unspecified “ethicolegal restrictions.” Web appendix 1 says that these data included another …
Enzalutamide (E) versus abiraterone acetate (AA) in the treatment of metastatic, castration-resistant prostate cancer: Results of an indirect comparison with network meta-analysis.
Authors: Chiara Cherubini, Emanuela Bianchi, Fabrizio Drudi, Emiliano Tamburini, Manuela Fantini, Stefania Nicoletti, Lucia Stocchi, Mario Nicolini, Francesco Montanari, Lorenzo Gianni, Davide Tassinari
Journal: Journal of Clinical Oncology (2017)

e16519 Background: To compare efficacy and safety of E and AA in the treatment of metastatic, castration-resistant prostate cancer. Methods: Efficacy and safety of E and AA were compared using the data of the PREVAIL, AFFIRM, COU-AA-302 and COU-AA-301 trials. All the data extracted from the selected trials were reported ad Hazard Ratio (HR) or Odds Ratio (OR). Overall survival was assumed as index of efficacy, and was the primary end point of our analysis, all the side effects, grade III-IV side effects, serious side effects, side effects leading to treatment discontinuation or death were assumed as indexes of safety and were the secondary end points of our analysis. Overall survival was assessed both in the entire population and in the subgroups of patients chemotherapy-naïve or docetaxel-resistant. An alpha error of 5% was assumed as index of statistical significance. Results: The outcome of 5191 patients were reviewed. 1671 patients had been treated with E, 1339 with AA and 2181 with placebo. Comparing E vs AA no differences were observed for overall survival in the entire population (HR = 0.955, IC95% = 0.796-1.144, p = 0.616), overall survival in chemotherapy-naïve patients (HR = 0.947, IC95% = 0.723-1.24, p = 0.692), overall survival in docetaxel-resistant patients (HR = 0.961, IC95% = 0.753-1.228, p = 0.75), all side effects (OR = 0.414, IC95% = 0.054-3.196, p = 0.463), grade III-IV side effects (OR = 1.36, IC95% = 0.253-7.318, p = 0.72), serious side effects (OR = 0.742, IC95% = 0.137-4.006, p = 0.729), side effects leading to treatment discontinuation (OR = 0.743, IC95% = 0.132-4.193, p = 0.736), and side effects leading to death (OR = 0.572, IC95% = 0.089-3.657, p = 0.556). Conclusions: Although E and AA differ for pharmaceutical structure and mechanism of action, they seem to be comparable both for indication (pre- or post-docetaxel treatment in patients with metastatic, castration-resistant prostate cancer), and for efficacy or safety (in chemotherapy-naïve and docetaxel-resistant patients). It follows that compliance, patients characteristics and costs can play a role in the decision making process of clinical practice.
Misuse of suncare products: Toward a protocol for sunscreen application
Authors: N. Issachar, A. Nkengne, C. Bertin, C. Robert
Journal: Journal of Clinical Oncology (2009)

1548 Background: Increasing awareness of the UV-induced skin carcinogenesis has led to a significant demand for improved photo-protection both in UVB and UVA ranges. Sunscreen products are subjected to strict efficacy controls relying on standardized UV protection measurements and are widely recommended by oncologists and dermatologists in order to prevent skin cancers. However, sunscreen effectiveness depends not only on the quality of the product itself but also on the way people use it in real life. Misuse of suncare products might even lead to opposite deleterious effects. We conducted three successive studies in order to validate a sunscreen application protocol. Methods: Three studies were done on healthy volunteers who were asked to apply a sunscreen product as they usually do without any guidance or following a protocol of product application. Spontaneous application was evaluated in the first study (N = 17). Two application protocols were successively tested (N = 31) where both quantity of product and quality of sunscreen spreading were assessed (without and with the protocol) by three independent evaluators using photos taken under UVA light. Results: Spontaneous application of sunscreen resulted in an heterogeneous application of only 27% of the quantity recommended following COLIPA guidelines. Two application protocols giving practical informations concerning the quantity and the way to spread the product on each body anatomical sites were successively evaluated. Use of the application protocols improved both the quantity of suncare product and the homogeneity of product spreading with an highly significant improvement resulting from the use of the final and improved application protocol tested in the third study (p &lt; 0.02). Conclusions: The correct use of sunscreens is a public health issue about which the public still requires considerable education. We propose that, in addition to the usual photoprotection recommendations (i.e., clothing protection and avoidance of middle day exposure), population should be trained to use validated protocols for sunscreen application. [Table: see text]
Adenovirus-mediated transfer of siRNAs against MMP-2 mRNA results in impaired growth, invasion and migration of glioblastoma cells as well as inhibition of tumor-induced angiogenesis
Authors: Odysseas Kargiotis, Chandramu Chetty, Christopher Gondi, Sajani Lakka, Dzung Dinh, Meena Gujrati, Jasti Rao
Journal: Cancer Research (2007)

3080   Invasive tumors, including gliomas, utilize proteinases to break down extracellular matrix components and diffuse into adjacent tissues or migrate towards distant ones. In addition, proteinase activity is critical for tumor angiogenesis. Because levels of the proteinase Matrix Metalloproteinase-2 (MMP-2) are highly increased in gliomas, we studied the effect of downregulation of MMP-2 via adenovirus-mediated transfer of small interfering RNAs (siRNAs) in gliomas. Delivery of double-stranded small RNA molecules results in efficient, sequence-specific silencing of the targeted gene, which occurs at the post-transcriptional level. siRNAs against MMP-2 mRNA (Ad-SM2) significantly decreased MMP-2 activity and protein levels in the glioblastoma cell lines, U87 and U251, as shown by gelatin zymography and western blotting of conditioned media from cultured cells. MTT proliferation assay revealed impaired cell growth of the Ad-SM2-treated glioma cells. Moreover, infection of cells with the adenoviral construct inhibited cell invasion through matrigel and decreased migration from tumor spheroids. We also observed decreased VEGF protein levels as well as decreased tumor-induced angiogenesis  in vitro . In addition, the results of a dorsal skin-fold chamber assay in mice indicated the efficient inhibition of angiogenesis  in vivo . Finally, Ad-SM2 treatment triggered the cleavage of caspase 3 and DNA fragmentation in U87 and U251--both events are characteristic of apoptotic cell death. Thus, specific targeting of MMP-2 may provide an efficient approach in the development of new strategies to treat gliomas and improve the poor prognosis of these brain tumors.
Evaluation and Use of Epidemiological Evidence for Environmental Health Risk Assessment: WHO Guideline Document
Journal: Environmental Health Perspectives (2000)

Environmental health risk assessment is increasingly being used in the development of environmental health policies, public health decision making, the establishment of environmental regulations, and research planning.The credibility of risk assessment depends, to a large extent, on the strength of the scientific evidence on which it is based.It is, therefore, imperative that the processes and methods used to evaluate the evidence and estimate health risks are clear, explicit, and based on valid epidemiological theory and practice.Epidemiological Evidence for Environmental Health Risk Assessment is a World Health Organization (WHO) guideline document.The primary target audiences of the guidelines are expert review groups that WHO (or other organizations) might convene in the future to evaluate epidemiological evidence on the health effects of environmental factors.These guidelines identify a set of processes and general approaches to assess available epidemiological information in a clear, consistent, and explicit manner.The guidelines should also help in the evaluation of epidemiological studies with respect to their ability to support risk assessment and, consequently, risk management.Conducting expert reviews according to such explicit guidelines would make health risk assessment and subsequent risk management and risk communication processes more readily understood and likely to be accepted by policymakers and the public.It would also make the conclusions reached by reviews more readily acceptable as a basis for future WHO guidelines and other recommendations, and would provide a more rational basis for setting priorities for future research.
Erratum: Corrigendum: A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH
Authors: Henning Fenselau, John N Campbell, Anne M J Verstegen, Joseph C Madara, Jie Xu, Bhavik P Shah, Jon M Resch, Zongfang Yang, Yael Mandelblat-Cerf, Yoav Livneh, Bradford B Lowell
Journal: Nature Neuroscience (2017)
Benefits of preoperative jejunostomy tube in resectable esophageal cancer.
Authors: Adam Jeffrey Friedant, Brian G.A. Dalton, Tiffany A.P. Schatz, Karen Ruth, Stacey Su, Walter Joseph Scott
Journal: Journal of Clinical Oncology (2016)

e15574 Background: Standard treatment for locally advanced esophageal cancer includes neoadjuvant therapy followed by curative resection. Patients are at risk for malnutrition prior to and during neoadjuvant treatment. Therefore, these patients may derive benefit from preoperative jejunostomy tube (j-tube) placement. We hypothesize that usage of pre-operative j-tubes may be associated with better perioperative outcomes. Methods: A prospectively collected database at a single institution was retrospectively analyzed. Study period was from 2005 to 2015. Patients that underwent j-tube placement beforeinduction therapy prior to definitive resection for esophageal cancer were included in the analysis. Perioperative outcomes were compared between patients who adhered to recommended tube feeds during induction (users) and patients who did not adhere (non-users). P-values were calculated using Fisher’s exact test. Logistic regression was used to estimate odds ratios and confidence intervals. Multivariate analysis was performed controlling for age, clinical stage and open surgery. Results: During the study period, 94 patients received a j-tube prior to or during induction therapy for esophageal cancer. Seventy-three patients utilized tube feeds regularly during the induction phase while 21 patients did not. The groups did not differ significantly in dysphagia on presentation, post induction treatment performance status, or Charlson Comorbidity Index. Results for perioperative pneumonia are shown in Table 1. The trend toward lower rates of all complications also favored j-tube users (85.7% vs. 64.4%, p=0.1056). Conclusions: J-tube users had significantly decreased risk for pneumonia within 30 days of curative resection when compared to non-users. Use of j-tube nutrition preoperatively may decrease perioperative risk in esophagectomy patients. Perioperative pneumonia: Users vs non-users. Effect Odds Ratio Estimates OR 95% CI P-value Model 1, Univariate J-tube (user vs non- user) J-tube user vs non-user 0.24 0.06 0.91 0.036 Model 2, Adjusted J-tube (user vs non- user) J-tube user vs non-user 0.11 0.02 0.62 0.013 Sex (M vs F) 3.26 0.27 39.86 0.355 log (LOS) 1.95 0.68 5.58 0.213 Wound Infection (Y vs N) 30.74 3.05 309.57 0.004
A Longitudinal Analysis of the Influence of the Neighborhood Environment on Recreational Walking within the Neighborhood: Results from RESIDE
Authors: Hayley Christian, Matthew Knuiman, Mark Divitini, Sarah Foster, Paula Hooper, Bryan Boruff, Fiona Bull, Billie Giles-Corti
Journal: Environmental Health Perspectives (2017)

There is limited longitudinal evidence confirming the role of neighborhood environment attributes in encouraging people to walk more or if active people simply choose to live in activity-friendly neighborhoods. Natural experiments of policy changes to create more walkable communities provide stronger evidence for a causal effect of neighborhood environments on residents' walking.We aimed to investigate longitudinal associations between objective and perceived neighborhood environment measures and neighborhood recreational walking.We analyzed longitudinal data collected over 8 yr (four surveys) from the RESIDential Environments (RESIDE) Study (Perth, Australia, 2003-2012). At each time point, participants reported the frequency and total minutes of recreational walking/week within their neighborhood and neighborhood environment perceptions. Objective measures of the neighborhood environment were generated using a Geographic Information System (GIS).Local recreational walking was influenced by objectively measured access to a medium-/large-size park, beach access, and higher street connectivity, which was reduced when adjusted for neighborhood perceptions. In adjusted models, positive perceptions of access to a park and beach, higher street connectivity, neighborhood esthetics, and safety from crime were independent determinants of increased neighborhood recreational walking. Local recreational walking increased by 9 min/wk (12% increase in frequency) for each additional perceived neighborhood attribute present.Our findings provide urban planners and policy makers with stronger causal evidence of the positive impact of well-connected neighborhoods and access to local parks of varying sizes on local residents' recreational walking and health. https://doi.org/10.1289/EHP823.
Gender bias: Underdiagnosing hereditary cancer in men with prostate cancer.
Authors: Lauren Bowling, Patrick Reineke, Rachel E. McFarland, Shuwei Li, Emily Dalton, Jill S Dolinsky
Journal: Journal of Clinical Oncology (2016)

1545 Background: Men and women are equally likely to carry mutations in hereditary cancer genes and both have elevated cancer risks. Despite this, over 96% of patients undergoing hereditary cancer multi-gene panel testing (MGPT) are women. Prostate cancer (PC) is associated with mutations in CHEK2, ATM, BRCA1 and BRCA2 (BRCA),and National Comprehensive Cancer Network (NCCN) recommendations for early screening exist for mutation carriers. We sought to describe the mutation spectrum and MGPT uptake in men with PC as compared to women with breast cancer (BC). Methods: Test results were reviewed for PC patients undergoing MGPT (Jun 2013 – Sep 2015) for BRCA and 3-47 other genes. Clinical history was obtained from ordering providers. Results: 14.2% (51/360) of PC probands carried at least one mutation across 14 genes, compared to 7.9% of women with BC (p = 7.076E-5; 95% CI 1.40 - 2.62). BRCA mutations made up 39% of PC positives (20/51). BRCA2 mutations accounted for 29% of positives and were found in 4.1% of PC probands. Consistent with findings among women with BC, other commonly mutated genes included ATM (2.5%) and CHEK2(1.9%). The median age at PC diagnosis was 60 for mutation-positive and negative men. The median time from PC diagnosis to MGPT was 6 years, compared to 1 year for female BC. 92% of mutation-positive men met NCCN hereditary breast and ovarian cancer syndrome (HBOC) criteria at the time of testing. Over 68% (35/51) of positives had multiple primary cancers, with PC followed by a related cancer in 85.7% (30/35). Of these, 86% (26/30) met NCCN HBOC criteria at their PC diagnosis, as 46/51 had relevant family history, yet testing was not initiated until another HBOC cancer developed. Conclusions: In this cohort of men with PC, MGPT identified mutations in hereditary cancer genes at rates higher than females with BC undergoing the same panels. Although PC plus a family history of HBOC-related cancer meets NCCN criteria for testing, most MGPT-positive men were not tested until developing a subsequent HBOC cancer. Revisions to NCCN guidelines (2012-present) do increasingly recognize the contribution of PC to risk for HBOC; however, increased awareness among clinicians is needed to identify otherwise unrecognized male mutation carriers.
Novel germline risk loci in familial melanoma (FM).
Authors: Esther Kazlow, Robert Ferguson, Danny Simpson, Carlos N. Martinez, Matjaz Vogelsang, Una Moran, Yesung Lee, Iman Osman, David Polsky, Tomas Kirchhoff
Journal: Journal of Clinical Oncology (2017)

1535 Background: While about 10% of cutaneous melanoma (CM) clusters in families, known high-risk loci explain not more than 40% of expected inherited risk. Besides the most frequently mutated genes in FM (e.g. CDKN2A), it is estimated that the remaining 60% of FM susceptibility is due to the interaction of environment with specific pools of rare known loci and yet unknown high-risk genes. In our study, we report the discoveries of novel germline genetic risk factors in FM in a recently developed FM cohort at New York University Langone Medical Center (NYULMC) consisting of CM and multiple primary melanomas (MPM) of Ashkenazi Jewish (AJ) and non-AJ European ancestries. Methods: As part of an ongoing ascertainment of FM at NYULMC, we assessed the status of CDKN2A mutations using Sanger sequencing, examining the coding regions of 47 AJ FM families and 81 non-AJ FM kindreds. In high-risk mutation-negative families, we applied whole-exome sequencing (WXS) and an innovative hot-spot mutational analysis of non-coding regions to identify novel high-risk loci associated with FM susceptibility. Results: We found that frequencies of CDKN2A deleterious mutations in our FM cohort (13%) are comparable with observations from previous studies. We have also identified a specific CDKN2A coding mutation in FM kindreds of AJ ancestry, which is particularly interesting as CDKN2A mutations in AJ cohorts have been sparsely reported in prior studies. The WXS/targeted non-coding sequencing of mutation-negative families identified putatively deleterious mutations in regulatory regions in the vicinity of several novel loci, including SMAD4 and PAX8, co-segregating in FM kindreds. Conclusions: Our unique FM ascertainment, including &gt; 50% AJ kindreds, provides an excellent platform for mapping high-risk genetic susceptibility in FM. Novel deleterious mutations identified in non-coding regulatory regions of SMAD4 and PAX8 genes, some with increased frequency in AJ families, suggest a need for a more thorough investigation of the non-coding genome using a founder FM population, as we propose here. As our ongoing ascertainment expands, we are pursuing validation of our observations through comprehensive sequencing efforts.