tbuckley/cabot-search huggingface dataset:
An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors
Authors: Nicholas P. Tobin, Kristian Wennmalm, Linda S. Lindström, Theodoros Foukakis, Liqun He, Guillem Genové, Arne Östman, Göran Landberg, Christer Betsholtz, Jonas Bergh
Journal: Clinical Cancer Research (2016)

The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups.We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy.MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031).MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples. Clin Cancer Res; 22(10); 2417-26. ©2016 AACR.
Interferon-γ production by CMV-specific CD8+ T lymphocytes provides protection against cytomegalovirus reactivation in critically ill patients
Authors: Juan José Castón, Sara Cantisán, Francisco González-Gasca, Aurora Páez-Vega, Hasania Abdel-Hadi, Soledad Illescas, Gema Alonso, Julián Torre-Cisneros
Journal: Intensive Care Medicine (2015)
An uncomfortable hip exacerbated by exercise
Authors: Hao Chen
Journal: BMJ (2015)

A 41 year old woman presented to the hospital with gait disturbance. She had felt discomfort around her groin for several years, which was exacerbated recently after taking part in a square dance. On examination she had slight leg length discrepancy. A plain anteroposterior radiograph was taken of her pelvis⇓. What is the diagnosis?



This plain radiograph shows several radiographic signs that are characteristic of developmental dysplasia of the left hip.

### Discussion

This plain radiograph shows some characteristic radiographic signs indicative of developmental …
Abstract 15553: The Incidence of Emergency Department Visits for ST-Elevation Myocardial Infarction is Decreasing in the U.S
Authors: Michael J Ward, Sunil Kripalani, Yuwei Zhu, Alan B Storrow, Robert S Dittus, Frank E Harrell, Wesley H Self
Journal: Circulation (2014)

Introduction: The incidence and longitudinal trends of patients with ST-elevation myocardial infarction (STEMI) presenting to U.S. emergency departments (EDs) are currently unknown. Efforts to streamline door-to-balloon times by ED bypass, as well as greater use of effective treatments for cardiovascular disease, may decrease ED STEMI presentation. These estimates play an essential role in hospital resource allocation strategies.

Hypothesis: The incidence of STEMIs presenting to EDs is decreasing.

Methods: We conducted a descriptive epidemiological analysis of STEMI visits to EDs between 2006 through 2011 using the Nationwide Emergency Department Sample data which is the largest source of U.S. ED data. We included adult ED visits with an ICD-9CM diagnosis of STEMI and calculated incidence rates for STEMI ED visits using U.S. census population data. Incidence calculations were stratified by age group, geographic region, and year.

Results: From 2006-2011, there was a mean of 258,106 STEMIs presenting to EDs per year, declining from 300,466 in 2006 to 227,343 in 2011. Incidence of ED STEMI visits per 10,000 adults declined from 10.1 (95% CI 9.8,10.8) in 2006 to 7.3 (95% CI 6.8,7.8) in 2011. The Midwest had the highest rate at 10.0 (95% CI 9.2,10.8) and the West had the lowest with 6.6 (95% CI 6.1,7.0). The incidence of STEMI decreased for all age groups ( Figure ) and regions during the study period.

Conclusions: We report the first national estimates of STEMI presentation to U.S. EDs, which demonstrate decreasing incidence across all age groups and all geographic regions between 2006 and 2011.

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Abstract 13214: Prognostic Value of Venous Blood pH Levels in Patients Treated with Extracorporeal Cardiopulmonary Resuscitation after Cardiac Arrest Due to Cardiac Etiology
Authors: Harumi Hirose, Ken Nagao, kimio Kikushima, Kazuhiro Watanabe, Kei Nishikawa, Taketomo Soga, Masakazu Matsuzaki, Tsukasa Yagi
Journal: Circulation (2012)

Background: Our previous study (Circ J 2012; 76) demonstrated that venous blood levels of ammonia and pH on emergency room (ER) arrival provided valuable information regarding neurological outcome ...
Alternatives to antibiotics—a pipeline portfolio review
Authors: Lloyd Czaplewski, Richard Bax, Martha Clokie, Mike Dawson, Heather Fairhead, Vincent A Fischetti, Simon Foster, Brendan F Gilmore, Robert E W Hancock, David Harper, Ian R Henderson, Kai Hilpert, Brian V Jones, Aras Kadioglu, David Knowles, Sigríður Ólafsdóttir, David Payne, Steve Projan, Sunil Shaunak, Jared Silverman, Christopher M Thomas, Trevor J Trust, Peter Warn, John H Rex
Journal: The Lancet Infectious Diseases (2016)
On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens
Authors: Amanda Shaine Janesick, Giorgio Dimastrogiovanni, Lenka Vanek, Christy Boulos, Raquel Chamorro-García, Weiyi Tang, Bruce Blumberg
Journal: Environmental Health Perspectives (2016)

Background:In ToxCast™ Phase I, the U.S. EPA commissioned screening of 320 pesticides, herbicides, fungicides, and other chemicals in a series of high-throughput assays. The agency also developed a toxicological prioritization tool, ToxPi, to facilitate using ToxCast™ assays to predict biological function.Objectives:We asked whether top-scoring PPARγ activators identified in ToxCast™ Phase I were genuine PPARγ activators and inducers of adipogenesis. Next, we identified ToxCast™ assays that should predict adipogenesis, developed an adipogenesis ToxPi, and asked how well the ToxPi predicted adipogenic activity.Methods:We used transient transfection to test the ability of ToxCast™ chemicals to modulate PPARγ and RXRα, and differentiation assays employing 3T3-L1 preadipocytes and mouse bone marrow-derived mesenchymal stem cells (mBMSCs) to evaluate the adipogenic capacity of ToxCast™ chemicals.Results:Only 5/21 of the top scoring ToxCast™ PPARγ activators were activators in our assays, 3 were PPARγ antagonists, the remainder were inactive. The bona fide PPARγ activators we identified induced adipogenesis in 3T3-L1 cells and mBMSCs. Only 7 of the 17 chemicals predicted to be active by the ToxPi promoted adipogenesis, 1 inhibited adipogenesis, and 2 of the 7 predicted negatives were also adipogenic. Of these 9 adipogenic chemicals, 3 activated PPARγ, and 1 activated RXRα.Conclusions:ToxCast™ PPARγ and RXRα assays do not correlate well with laboratory measurements of PPARγ and RXRα activity. The adipogenesis ToxPi performed poorly, perhaps due to the performance of ToxCast™ assays. We observed a modest predictive value of ToxCast™ for PPARγ and RXRα activation and adipogenesis and it is likely that many obesogenic chemicals remain to be identified.Citation:Janesick AS, Dimastrogiovanni G, Vanek L, Boulos C, Chamorro-García R, Tang W, Blumberg B. 2016. On the utility of ToxCast™ and ToxPi as methods for identifying new obesogens. Environ Health Perspect 124:1214–1226; http://dx.doi.org/10.1289/ehp.1510352
The TMPRSS6 Ala736 Val Polymorphism Is Associated With Decreased Hemoglobin and Iron Status In Females Undergoing Repeated Phlebotomy
Authors: Alan E. Mast, John C Langer, Walter Bialkowski, Simone Glynn, Tzong-Hae Lee, Joseph Kiss, Ritchard G. Cable, Michael Busch, Donald Brambilla
Journal: Blood (2013)
Phase II feasibility study of autologous vaccine (HSPPC-96) in patients with resectable lung cancer
Authors: G. Santis, N. N. Senzer, P. Champagne, L. Isakov, F. Teofilovici
Journal: Journal of Clinical Oncology (2008)

7584 Background: HSPPC-96 (Oncophage; also vitespen) is a novel, autologous, tumor-derived heat shock protein (gp96)-peptide complex vaccine that has shown signals of clinical activity in patients with several advanced malignancies. This trial is investigating the feasibility of deriving autologous HSPPC-96 from tumor tissue of patients with resectable non-small cell lung cancer (NSCLC). Methods: Fourteen eligible patients had American Joint Committee on Cancer stage Ib (n = 11), Iib (n = 2) or IIIa (n = 1) NSCLC; complete resection with no evidence of metastatic or residual disease; European Cooperative Oncology Group performance score of 0 or 1; and ≥9 g tumor tissue for vaccine production. For patients for whom vaccine could be made, HSPPC-96 was administered subcutaneously 6–8 w postsurgery once weekly x 4 w, then every 2 w until vaccine depletion. Treated patients were evaluated for disease status every 3 m for 3 y or until disease recurrence. The primary endpoint was vaccine production feasibility; secondary endpoints were recurrence-free survival (RFS), overall survival and safety. Results: The manufacturing success of HSPPC-96 for this indication was 100%. Vaccine yield was favorable, producing a sufficient vaccine for treatment, with a median of 58.5 vials per patient (n = 14). Ten patients have received ≥1 vaccine (n = 14) (median age: 68 y; 50% male, 50% female; stage Ib, n = 8; stage Iib, n = 2). The median number of injections received was 29 (range: 3–53). Three (30%) patients had ≥1 related treatment-emergent adverse event (TEAE), most relating to the injection itself. No related severe or serious TEAEs were reported. None of the patients received adjuvant chemotherapy or radiotherapy. (Although offered, adjuvant chemotherapy was declined by patients with stage Iib or IIIa disease included in this study.) To date, 3 (30%) patients have died and 7 (70%) remain in the tumor evaluation phase, with RFS ranging from 24 to 33 months. Conclusions: It is feasible to produce autologous HSPPC-96 for patients with resectable NSCLC. The vaccine appears well tolerated and shows encouraging signs of clinical activity to date in this patient population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Antigenics Antigenics Antigenics
RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway
Authors: Fatéméh Dubois, Maureen Keller, Olivier Calvayrac, Fabrice Soncin, Lily Hoa, Alexander Hergovich, Maria-Carla Parrini, Julien Mazières, Mélissa Vaisse-Lesteven, Jacques Camonis, Guénaëlle Levallet, Gérard Zalcman
Journal: Cancer Research (2016)

Inactivation of the tumor suppressor gene RASSF1A by promoter hypermethylation represents a key event underlying the initiation and progression of lung cancer. RASSF1A inactivation is also associated with poor prognosis and may promote metastatic spread. In this study, we investigated how RASSF1A inactivation conferred invasive phenotypes to human bronchial cells. RNAi-mediated silencing of RASSF1A induced epithelial-to-mesenchymal transition (EMT), fomenting a motile and invasive cellular phenotype in vitro and increased metastatic prowess in vivo. Mechanistic investigations revealed that RASSF1A blocked tumor growth by stimulating cofilin/PP2A-mediated dephosphorylation of the guanine nucleotide exchange factor GEF-H1, thereby stimulating its ability to activate the antimetastatic small GTPase RhoB. Furthermore, RASSF1A reduced nuclear accumulation of the Hippo pathway transcriptional cofactor Yes-associated protein (YAP), which was reinforced by RhoB activation. Collectively, our results indicated that RASSF1 acts to restrict EMT and invasion by indirectly controlling YAP nuclear shuttling and activation through a RhoB-regulated cytoskeletal remodeling process, with potential implications to delay the progression of RASSF1-hypermethylated lung tumors.
Exploring genomic alteration in pediatric cancer using ProteinPaint
Authors: Xin Zhou, Michael N Edmonson, Mark R Wilkinson, Aman Patel, Gang Wu, Yu Liu, Yongjin Li, Zhaojie Zhang, Michael C Rusch, Matthew Parker, Jared Becksfort, James R Downing, Jinghui Zhang
Journal: Nature Genetics (2015)
T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients
Authors: Yaxian Kong, Liuluan Zhu, Todd D. Schell, Jianhong Zhang, David F. Claxton, W. Christopher Ehmann, Witold B. Rybka, Melissa R. George, Hui Zeng, Hong Zheng
Journal: Clinical Cancer Research (2016)

T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a recently identified T-cell coinhibitory receptor. In this study, we aimed to determine the clinical impact of TIGIT in patients with acute myelogenous leukemia (AML) and dissect the role of TIGIT in the pathogenesis of leukemia progression.TIGIT expression on T cells from peripheral blood collected from patients with AML was examined by flow cytometry. The correlation of TIGIT expression to clinical outcomes, including rate of complete remission and relapse post-allogeneic stem cell transplantation (alloSCT) in AML patients, was analyzed. Phenotypic and functional study (cytokine release, proliferation, killing, and apoptosis) of TIGIT-expressing T cells were performed. Using siRNA to silence TIGIT, we further elucidated the regulatory role of TIGIT in the T-cell immune response by dissecting the effect of TIGIT knockdown on cytokine release and apoptosis of T cells from AML patients.TIGIT expression on CD8(+) T cells is elevated in AML patients and high-TIGIT correlates with primary refractory disease and leukemia relapse post-alloSCT. TIGIT(+) CD8(+) T cells display phenotypic features of exhaustion and exhibit functional impairment manifested by low production of cytokines and high susceptibility to apoptosis. Importantly, their functional defects are reversed by TIGIT knockdown.TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in AML. Our study suggests that blockade of TIGIT to restore T-cell function and antitumor immunity may represent a novel effective leukemia therapeutic. Clin Cancer Res; 22(12); 3057-66. ©2016 AACR.
Sexual violence in the United States and the role of season
Authors: R P Michael, D Zumpe
Journal: American Journal of Psychiatry (1983)

An analysis by the cosinor method of over 50,000 rapes in 16 different locations in the United States revealed statistically significant annual rhythms in 14 locations, with maxima in the summer. Changes in numbers of rapes and assaults showed similar seasonal patterns, suggesting that rape comprised a subcategory of aggressive behavior. In contrast, there was a virtual absence of seasonal changes in numbers of murders. A close relation emerged between assaults and rapes, on the one hand, and temperature, on the other, in different geographical locations. The authors hypothesize that human violence, just like aggression in nonhuman primates, is influenced by exteroceptive environmental factors.
Urinary incontinence in adult bronchiectasis patients: Common but treatable
Authors: Jonathan Miller, Hilary Tedd, Jackie Rees, Anthony DeSoyza
Journal: European Respiratory Journal (2012)

Background: Patients suffering from urinary incontinence (UI) often avoid seeking medical attention, due to embarrassment, consequently remaining untreated. UI negatively impacts of quality of life, psychological health and relationships. In patients with non-CF bronchiectasis, it may also reduce adherence to chest physiotherapy. UK Physiotherapy Guidelines (2009) suggets screening for UI in patients with non-CF bronchiectasis.  Methods: Screening at new specialist bronchiectasis clinic for symptoms of UI, with referral onto Continence specialist services.  Results: Of the initial 116 patient referred to the bronchiectasis service, 76 were female. 55% of female patients had UI (UI-Br). 87.5% of UI-Br patients reported symptoms for over 5 years, with 40% of patients describing symptoms of over 10 years duration. 37% reported UI as having a terrible impact on quality of life. Patients were assessed by a Continence Nurse Consultant. A personalised UI management plan was formulated, including education on pelvic floor strengthening, urge suppression and voiding techniques. Other techniques used included bladder retraining (40%) and toilet rescheduling (40%). Over 60% of patients have been discharged by the Continence Service, following symptom improvement.  Conclusions: In asking about UI, in line with UK guidelines, we identified symptomatic patients and referred them onto an appropriate specialist service. We identified a high prevalence of UI in female patients with non-CF bronchiectasis. Patients suffered symptoms for a prolonged period with a significant impact on quality of life. Through appropriate specialist input, these distressing symptoms have been improved in the majority of our patient group.
DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated With Chromatin States
Authors: Haodong Chen, Luz D. Orozco, Jessica Wang, Christoph D. Rau, Liudmilla Rubbi, Shuxun Ren, Yibin Wang, Matteo Pellegrini, Aldons J. Lusis, Thomas M. Vondriska
Journal: Circulation Research (2016)

Only a small portion of the known heritability of cardiovascular diseases, such as heart failure, can be explained based on single-gene mutations. Chromatin structure and regulation provide a substrate through which genetic differences in noncoding regions may affect cellular function and response to disease, but the mechanisms are unknown.We conducted genome-wide measurements of DNA methylation in different strains of mice that are susceptible and resistant to isoproterenol-induced dysfunction to test the hypothesis that this epigenetic mark may play a causal role in the development of heart failure.BALB/cJ and BUB/BnJ mice, determined to be susceptible and resistant to isoproterenol-induced heart failure, respectively, were administered the drug for 3 weeks via osmotic minipump. Reduced representational bisulfite sequencing was then used to compare the differences between the cardiac DNA methylomes in the basal state between strains and then after isoproterenol treatment. Single-base resolution DNA methylation measurements were obtained and revealed a bimodal distribution of methylation in the heart, enriched in lone intergenic CpGs and depleted from CpG islands around genes. Isoproterenol induced global decreases in methylation in both strains; however, the basal methylation pattern between strains shows striking differences that may be predictive of disease progression before environmental stress. The global correlation between promoter methylation and gene expression (as measured by microarray) was modest and revealed itself only with focused analyses of transcription start site and gene body regions (in contrast to when gene methylation was examined in toto). Modules of comethylated genes displayed correlation with other protein-based epigenetic marks, supporting the hypothesis that chromatin modifications act in a combinatorial manner to specify transcriptional phenotypes in the heart.This study provides the first single-base resolution map of the mammalian cardiac DNA methylome and the first case-control analysis of the changes in DNA methylation with heart failure. The findings demonstrate marked genetic differences in DNA methylation that are associated with disease progression.
Reconsidering the Resources Needed for Multiple Casualty Events
Authors: Eric M. Campion, Catherine Juillard, M. Margaret Knudson, Rochelle Dicker, Mitchell J. Cohen, Robert Mackersie, Andre R. Campbell, Rachael A. Callcut
Journal: JAMA Surgery (2016)

To date, a substantial portion of multiple casualty incident literature has focused exclusively on prehospital and emergency department resources needed for optimal disaster response. Thus, inpatient resources required to care for individuals injured in multiple casualty events are not well described.To highlight the resources beyond initial emergency department triage needed for multiple casualty events, using one of the largest commercial aviation disasters in modern US history as a case study.Prospective case series of injured individuals treated at an urban level I trauma center following the crash of Asiana Airlines flight 214 on July 6, 2013. This analysis was conducted between June 1, 2014, and December 1, 2015.Commercial jetliner crash.Medical records, imaging data, nursing overtime, blood bank records, and trauma registry data were analyzed. Disaster logs, patient injuries, and blood product data were prospectively collected during the incident.Among 307 people aboard the flight, 192 were injured; 63 of the injured patients were initially evaluated at San Francisco General Hospital and Trauma Center (the highest number at any of the receiving medical facilities; age range, 4-74 years [23 were aged <17 years and 3 were aged >60 years]; median injury severity score of 19 admitted patients, 9 [range, 9-45]), including the highest number of critically injured patients (10 of 12). Despite the high impact of the crash, only 3 persons (<1%) died, including 1 in-hospital death. Among the 63 patients, 32 (50.8%) underwent a computed tomographic imaging study, with imaging of the abdomen and pelvis being the most common. Sixteen of the 32 patients undergoing computed tomography (50.0%) had a positive finding on at least 1 scan. Nineteen patients had major injuries and required admission, with 5 taken directly from the emergency department to the operating room. The most frequent injury was spinal fracture (13 patients). In the first 48 hours, 15 operations were performed and 117 total units of blood products were transfused. A total of 370 nursing overtime hours were required to treat the injured patients on the day of the event.Proper disaster preparedness requires attention to hospital-level needs beyond initial emergency department triage. The Asiana Airlines flight 214 crash highlights the need to plan for high use of advanced imaging, blood products, operating room availability, nursing resources, and management of inpatient hospital beds.