tbuckley/cabot-search huggingface dataset:
Author Correction: Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition
Authors: Kerrin S. Small, Marijana Todorčević, Mete Civelek, Julia S. El-Sayed Moustafa, Xiao Wang, Michelle M. Simon, Juan Fernandez-Tajes, Anubha Mahajan, Momoko Horikoshi, Alison Hugill, Craig A. Glastonbury, Lydia Quaye, Matt J. Neville, Siddharth Sethi, Marianne Yon, Calvin Pan, Nam Che, Ana Vinuela, Pei-Chien Tsai, Abhishek Nag, Alfonso Buil, Gudmar Thorleifsson, Avanthi Raghavan, Qiurong Ding, Andrew P. Morris, Jordana T. Bell, Unnur Thorsteinsdottir, Kari Stefansson, Markku Laakso, Ingrid Dahlman, Peter Arner, Anna L. Gloyn, Kiran Musunuru, Aldons J. Lusis, Roger D. Cox, Fredrik Karpe, Mark I. McCarthy
Journal: Nature Genetics (2018)
Abstract 5056: HPV, HIV and male gender as major risk factors for anal neoplastic transformation in African Americans
Authors: Hassan Brim, Ali Afsari, Nazli Atefi, Nicole Retland, Muneer Abbas, Tammey Naab, Babak Shokrani, Adeyinka O. Laiyemo, Edward L. Lee, Seyed M. Nouraie, Hassan Ashktorab
Journal: Cancer Research (2018)

Abstract Background: Human Papilloma Virus (HPV) is the most common sexually transmitted infectious agent. The incidence HPV-related anal cancers increased among HIV infected people. Aim: To assess risk factors of anal lesions among African Americans in an inner city hospital. Methods: We reviewed medical records of 370 African-Americans with anal lesions at Howard University Hospital from Jan. 2007 to Dec. 2015. Demographic, clinical and pathological data including; HPV, HIV, HCV (hepatitis C virus), diabetes mellitus (DM), hypertension (HTN) and body mass index (BMI) were collected. Statistical analysis was performed using Chi-square and Student's t-test. Results: 276 (75%) patients were male, with median age of 44 years and BMI of 25.8 kg/m2. The frequency of condyloma, high grade dysplasia, squamous cell carcinoma (SCC) and adenocarcinoma was 191 (52%), 26 (7%), 31 (8%) and 8 (2%), respectively. The frequency of HPV, HIV, and HCV was 231 (68%), 147 (43%) and 42 (12%), respectively. HPV and HIV were risk factors for condyloma and dysplasia (P&amp;lt;0.05). Forty two percent of patients had diabetes (DM) and hypertension (HTN). Conclusion: Our results shows that majority of patients with condyloma are male and young with HPV and HIV infection. A clinical utility of HPV as risk factor may be use for prediction of anal lesions. Citation Format: Hassan Brim, Ali Afsari, Nazli Atefi, Nicole Retland, Muneer Abbas, Tammey Naab, Babak Shokrani, Adeyinka O. Laiyemo, Edward L. Lee, Seyed M. Nouraie, Hassan Ashktorab. HPV, HIV and male gender as major risk factors for anal neoplastic transformation in African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5056.
Abstract P112: Peripheral Arterial Disease and Carotid Atherosclerosis among Middle-aged Women Living in Chiapas, Mexico: Preliminary Results
Authors: EduardoOrtiz-Panozo, MartinLajous, ElsaYunes-Díaz, NatalyMercado, AndreaLuviano, FernandoFlores-Silva, VidalDircio-Delgado, CarlosCantu-Brito, AndresCatzin-Kuhlmann, RuyLópez-Ridaura
Journal: Circulation (2013)

Background: Mexico is undergoing a fast-paced epidemiological and nutritional transition. Evaluating the presence of early cardiovascular disease and understanding risk factors leading to it in this context may provide insight on prevention strategies for the growing burden of this disease in developing countries. Methods and Results: We evaluated subclinical cardiovascular disease in 443 women aged ≥40 years in an urban and a rural site in Chiapas, Mexico. All women were participants in the ongoing ESMaestras cohort, a prospective study of 116,683 Mexican female teachers, which started in 2006-2008. In September 2012, an evaluation of subclinical cardiovascular disease was undertaken in a sub-cohort of 2,000 ESMaestras participants. We present preliminary results from this initial effort. Women were invited to a clinical site where ankle-brachial index (ABI) were measured by previously standardized personnel using the automated VaSera VS-1000 sphyngmomanometer. Carotid intima-media thickness (IMT) was as...
Mitochondrial Uncoupling Protein 1 Expressed in the Heart of Transgenic Mice Protects Against Ischemic-Reperfusion Damage
Authors: JacquelineHoerter, Maria-del-MarGonzalez-Barroso, ElodieCouplan, PhilippeMateo, ChantalGelly, Anne-MarieCassard-Doulcier, PhilippeDiolez, FredericBouillaud
Journal: Circulation (2004)

Background— Mitochondrial respiration is the main source of energy in aerobic animal cells and is adapted to the energy demand by respiratory coupling. Uncoupling proteins (UCPs) perturb respiratory coupling by inducing a proton leak through the mitochondrial inner membrane. Although this could lead to deleterious energy waste, it may prevent the production of oxygen radicals when the rate of phosphorylation of ADP into ATP is low, whereas oxygen and substrate availability to mitochondria is high. The latter conditions are encountered during cardiac reperfusion after ischemia and are highly relevant to heart infarction. Methods and Results— Heart function of 6 transgenic mice expressing high amounts of UCP1 and of 6 littermate controls was compared in isolated perfused hearts in normoxia, after 40-minute global ischemia, and on reperfusion. In normoxia, oxygen consumption, contractility (quantified as the rate-pressure product), and their relationship (energetic yield) were similar in controls and transge...
Abstract 4513: Notch inhibitors relieve growth suppression by TGF-β and promote growth and metastasis of triple-negative breast cancers
Authors: Pothana Saikumar, Prajjal K. Singha, Srilakshmi Pandeswara, Manjeri A. Venkatachalam
Journal: Cancer Research (2018)

Abstract The paradoxical behavior of Notch1 and transforming growth factor-beta (TGF-β) is puzzling as they were shown to have both tumor-suppressive and tumor-promoting activities. We addressed the interaction between these two signaling pathways in cancer development and progression in a systematic way. Towards this goal, we utilized primary human mammary epithelial cells (HMEC) and various triple-negative breast cancer (TNBC) cells and examined the molecular crosstalk between TGF-β1 and Notch signaling pathways using biochemical, molecular and cell biology techniques. First, we observed lower expression of Notch1 in most of the TNBC cells compared to normal cells. Most of these TNBC cells also overexpressed TMEPAI (transmembrane prostate androgen induced), which we previously showed switches TGF-β from tumor-suppressive to a tumor-promoting role in breast cancer. Surprisingly, treatment of TNBC with Notch inhibitors increased their growth rate both in the absence and presence of TGF-β, while Notch inhibitors relieved normal cells from TGF-β mediated growth suppression. Both normal and TNBC cells showed increased growth in the presence of Notch inhibitors with decreased TGF-β signaling activity. In fact, normal cells that express very low levels of TMEPAI both at mRNA and protein levels, overexpressed TMEPAI in presence of various Notch inhibitors, suggesting that Notch1 negatively regulates TMEPAI expression. Correspondingly, knockdown of TMEPAI in TNBC cell lines showed increased expression of Notch1 and Jagged 1, suggesting a negative regulation of Notch1 by TMEPAI. In fact, TMEPAI, which binds to E3 ligases, promoted increased turnover of Notch1. In contrast to notch inhibitors, overexpression of active Notch1 in MDA-MB-231 cells inhibited tumor cell growth both in vitro and in vivo. Our results clearly suggest that a crosstalk between TGF-β and Notch1 signaling exists through TMEPAI. Importantly, these studies should be taken into consideration while contemplating the use of Notch inhibitors in triple-negative breast cancer therapy. Citation Format: Pothana Saikumar, Prajjal K. Singha, Srilakshmi Pandeswara, Manjeri A. Venkatachalam. Notch inhibitors relieve growth suppression by TGF-β and promote growth and metastasis of triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4513.
Novel Cardiac Apoptotic Pathway
Authors: Wei-QiTan, Jian-XunWang, Zhi-QiangLin, Yan-RuiLi, YuLin, Pei-FengLi
Journal: Circulation (2008)

Background— Apoptosis repressor with caspase recruitment domain (ARC) is abundantly expressed in cardiomyocytes. Protein kinase CK2 can phosphorylate ARC at threonine-149, thereby enabling ARC to antagonize apoptosis. ARC phosphorylation occurs in a constitutive manner. Nevertheless, cardiomyocytes still undergo apoptosis that is related to cardiac diseases such as myocardial infarction and heart failure. Whether the occurrence of apoptosis is related to the loss of protection by ARC under pathological conditions remains unknown. Methods and Results— ARC phosphorylation levels are decreased in cardiomyocytes treated with isoproterenol or aldosterone. We explored the molecular mechanism by which ARC phosphorylation levels are decreased. Our results reveal that either direct incubation or coexpression with calcineurin leads to a decrease in ARC phosphorylation levels. Inhibition of calcineurin can attenuate the reduction in ARC phosphorylation levels on treatment with isoproterenol or aldosterone. These dat...
Abstract 2912: CRISPR-Cas9: A tool for rapid target discovery and validation
Authors: Ceri M. Wiggins, David Walter, Paul Russell, Clare Sheridan, Chantelle Hudson, Joanne Yarker, Carlos le Sage, Nicola McCarthy, Jonathan D. Moore
Journal: Cancer Research (2018)

Abstract Genetic perturbations mediated by CRISPR-Cas9 are transforming the drug discovery process. In the hunt for novel drug targets, researchers finally have a screening tool with sufficient penetrance and power to identify new interactions, followed by a rapid gene editing technology to streamline validation approaches. At Horizon Discovery, we have now initiated more than 250 CRISPR-Cas9 knockout (KO) screens, including a significant effort to identify novel synthetic lethal interactions in colon and lung cancer genotypes. These screens have identified a reassuring number of known essential interactions, such as MDM2 and PPMID in TP53 wild type cancer cell lines. These results provide confidence in the ability of these screens to also discover novel targets that should make it through the validation process. Indeed, we have discovered novel targets for selective ablation of TP53 mutant colon cancers, several of which are strongly supported by the literature. In FBXW7 mutant colon cancers, CRISPR-Cas9 KO screens identified a set of potential novel druggable targets in addition to MCL1 - a known substrate of FBXW7, which showed a strong dependency in FBXW7 mutant lines. An important step in triaging primary hits ahead of extensive validation work has been secondary screens that target functional domains with high density sgRNA tiling. They allow more targets to be examined than would be feasible by any arrayed approach. Data from such screens, which test tens to hundreds of guides in unison, not only increases hit calling power, but can also yield information regarding important domains and mechanism of action. This was evident in the FBXW7 secondary screen data, where guides targeting the key functional BH domains of MCL1 proved to be the most effective. This information can be used to prioritise individual targets for further validation, using techniques that include an inducible CRISPR-Cas9 system to assess the effect of individual guides in an arrayed format on cell proliferation and survival, and CRISPRi. These data exemplify how CRISPR-Cas9 can enable the discovery of a new, more robust generation of drug and antibody targets. Citation Format: Ceri M. Wiggins, David Walter, Paul Russell, Clare Sheridan, Chantelle Hudson, Joanne Yarker, Carlos le Sage, Nicola McCarthy, Jonathan D. Moore. CRISPR-Cas9: A tool for rapid target discovery and validation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2912.
Abstract 11029: Netrin-1 Alleviates Post-Resuscitation Myocardial Dysfunction in a Rat Model of Cardiac Arrest
Authors: Lu Yin, Shen Zhao, JoongBum Moon, Peng Sun, Jiangang Wang, Haifang Yu, Ziren Tang, Xiaobo Wu, Xiaobo Wu, Jena Cahoon, Wanchun Tang
Journal: Circulation (2015)

Introduction: Post-resuscitation myocardial dysfunction has been recognized as one of the major causes of fatal outcomes after initial successful cardiopulmonary resuscitation (CPR). Previous research demonstrated that Netrin-1 improved post ischemic injury cardiac function via preservation of mitochondrial integrity. In the present study, we investigated the role of netrin-1 after cardiac arrest. Hypothesis: We hypothesized that the netrin-1 alleviated post-resuscitation myocardial dysfunction in a rat model of cardiac arrest. Methods: A total of sixteen male Sprague-Dawley rats (450-550 g) were randomized to two groups as follows: (1) Control group (C group); (2) Netrin-1 group (N group). Ventricular fibrillation was induced and untreated for 8 mins followed by 8 mins of CPR. Netrin-1 or saline were given at the onset of precordial compression. Ejection fraction (EF) was measured by echocardiography at baseline, 1,2,3 and 4 hours after ROSC. Results: Eight rats were resuscitated in the netrin-1 group and 7 rats were resuscitated in the saline group. In both groups, EF decreased after resuscitation when compared to the baseline (#p &lt; 0.05). In the netrin-1 group, EF decreased from ( 68.1±3.4)% at baseline to (51.1±5.0)% at 1 hour post-resuscitation. In the saline group, EF decreased from (67.7±2.1)% at baseline to (44.5±5.3)% at 1 hr post-resuscitation. EF was better in the netrin-1 group than in the saline group at 2, 3 and 4 hours post-resuscitation (*p &lt; 0.05) ( Figure 1). Conclusion: Netrin-1 alleviates post-resuscitation myocardial dysfunction in a rat model of cardiac arrest.
Abstract 2034: Traf2-and Nck-interacting kinase (TNIK) inhibitor, NCB-0846, suppresses TGF-β1-induced epithelial-mesenchymal transition in lung cancer
Authors: Teppei Sugano, Mari Masuda, Yuko Uno, Naoko Goto, Masahiro Seike, Masaaki Sawa, Akihiko Gemma, Tesshi Yamada
Journal: Cancer Research (2018)

Abstract Epithelial mesenchymal transition (EMT) has been implicated in cancer cell migration, invasion, and metastasis. Transforming growth factor-β (TGF-β) signal was known to be an essential EMT promotor. Development of therapeutics for targeting EMT through the TGF-β signal may be beneficial for the management of cancer metastasis. Recently, we found that a Traf2- and Nck-interacting kinase (TNIK) inhibitor, named NCB-0846, was capable of attenuating tumor-initiating cells among human colorectal cancer (1, 2). The cross link between EMT and cancer stemness has been revealed in several studies. Therefore we evaluated whether this small-molecule compound could have efficacy to inhibit TGF-β-induced EMT. NCB-0846 reduced the expression of mesenchymal markers (Vimentin and N-cadherin) and upregulated the expression of epithelial marker E-cadherin in A549 and H2228 cells. NCB-0846 suppressed the phosphorylation and nuclear translocation of Smad proteins and also inhibited migration, invasion, and metastasis. NCB-0846 inhibited TGF-β1-induced EMT through the down-regulation of TGFBR1 in mRNA levels. MiR-186-5p and miR-320 family were identified as candidate miRNAs that could target TGFBR1 and inhibited TGFBR1 protein expression.NCB-0846 might be a novel therapeutics drugs that targets the invasion and metastasis through inhibiting TGF-β-induced EMT in lung cancer. 1. Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacology &amp; therapeutics. 2015;156:1-9. Epub 2015/11/07.2. Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, Kukimoto-Niino M, et al. TNIK inhibition abrogates colorectal cancer stemness. Nature communications. 2016;7:12586. Epub 2016/08/27. Citation Format: Teppei Sugano, Mari Masuda, Yuko Uno, Naoko Goto, Masahiro Seike, Masaaki Sawa, Akihiko Gemma, Tesshi Yamada. Traf2-and Nck-interacting kinase (TNIK) inhibitor, NCB-0846, suppresses TGF-β1-induced epithelial-mesenchymal transition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2034.
Low-Energy Cardioversion of Spontaneous Atrial Fibrillation
Authors: SamuelLévy, PhilippeRicard, MaxGueunoun, FlorenceYapo, JacquesTrigano, ChadiaMansouri, FranckPaganelli
Journal: Circulation (1997)

Background Recent studies have suggested that induced atrial fibrillation (AF) could be successfully terminated by using a two-catheter electrode system and low energy (<400 V). This study evaluated the efficacy and safety of low-energy cardioversion in spontaneous chronic and paroxysmal AF. Methods and Results Forty-two consecutive patients with spontaneous AF underwent low-energy electrical cardioversion. AF was chronic (≥1 month) with a mean duration of 9±19 months in 28 patients (group I) or paroxysmal with a history of recurrent attacks and a mean duration of the present episode of 7±16 days in 14 patients (group II). An underlying heart disease was present in 28 patients. A 3/3-ms biphasic shock was delivered between catheters positioned in the right atrium and the coronary sinus in 32 patients. In 10 patients, the left pulmonary artery branch was used. The catheters were connected to a custom external defibrillator. The shocks were synchronized to the R wave. Following a test shock of 60 V, the ene...
Abstract 5342: Somatic bi-allelic loss of TSC genes in eosinophilic solid and cystic renal cell carcinoma (ESC RCC)
Authors: Nicole D. Lee, Pankaj Vats, Xuhong Cao, Fengyun Su, Robert Lonigro, Kumpati Premkumar, Kiril Trpkov, Jesse K. McKenney, Rohit Mehra, Saravana M. Dhanasekaran, Arul M. Chinnaiyan
Journal: Cancer Research (2018)

Abstract Renal cell carcinoma (RCC) subtypes with overlapping histomorphologic features pose diagnostic challenges. For instance, a unique category of sporadic renal tumors with eosinophilic cytoplasm and solid and cystic growth pattern (ESC RCC) may mimic a RCC subtype usually encountered in patients with germline aberrations of tuberous sclerosis complex (TSC) genes (TSC RCC). Here, we used next-generation sequencing (NGS) technology to interrogate the clinicopathologic and molecular profiles of ESC RCC tumors. Mutational and copy number analysis of NGS data from ESC RCC tumors revealed a somatic bi-allelic loss of TSC family genes, specifically TSC1 or TSC2, in six out of seven profiled cases. However, the corresponding background kidney showed only wild type alleles, thus excluding any germline involvement and differentiating ESC RCC from TSC RCC. Furthermore, bi-allelic loss of the TSC genes occurred in a mutually exclusively manner in this cohort. Our study clarifies the molecular identity of ESC RCC, and can thus guide future therapeutic strategies and provide a basis for the revision of current RCC classification. Citation Format: Nicole D. Lee, Pankaj Vats, Xuhong Cao, Fengyun Su, Robert Lonigro, Kumpati Premkumar, Kiril Trpkov, Jesse K. McKenney, Rohit Mehra, Saravana M. Dhanasekaran, Arul M. Chinnaiyan. Somatic bi-allelic loss of TSC genes in eosinophilic solid and cystic renal cell carcinoma (ESC RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5342.
Abstract 294: The Effect of 1-Shock Protocol using Biphasic Defibrillators for Treatment of Out-of-Hospital Shockable Cardiac Arrest
Authors: TsukasaYagi, KenNagao, EizoTachibana, KeiNishikawa, NaohiroYonemoto, ShinichiShirai, MorimasaTakayama, HiroshiNonogi, TakeshiKimura
Journal: Circulation (2012)

BACKGROUND In recent guidelines for electrical therapy of cardiopulmonary resuscitation (CPR), there was insufficient evidence to recommend any specific biphasic waveform. When defibrillation is required, a single shock should be provided with immediate resumption of chest compressions after the shock (1-shock protocol). We investigated the effect of 1-shock protocol using biphasic defibrillators. METHODS From the data of the All-Japan Utstein Registry, a prospective, nationwide, population-based registry of out-of-hospital cardiac arrest, we extracted the patients who were persons 18 years of age or older with bystander-witnessed shockable cardiac arrest due to cardiac etiology in the years 2005 (the 3-shock protocol era), and 2008, 2009 and 2010 (the 1-shock protocol era). The study patients were divided into 4 groups according to the two shock protocols and the two AED waveforms. The primary endpoint was 30-day favorable neurological outcome after shockable arrest. RESULTS Of the 17,297 patients who me...
A Visit to the Emergency Department With Neck and Shoulder Pain
Authors: Manu Kaushik, Sunu Philip, Ramachandra Kolachalam
Journal: JAMA Surgery (2018)

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Changes in Intra-Abdominal Visceral Fat and Serum Leptin Levels in Patients With Obstructive Sleep Apnea Syndrome Following Nasal Continuous Positive Airway Pressure Therapy
Authors: KazuoChin, KouichiShimizu, TakayaNakamura, NoboruNarai, HiroakiMasuzaki, YoshihiroOgawa, MichiakiMishima, TakashiNakamura, KazuwaNakao, MotoharuOhi
Journal: Circulation (1999)

Background—Obstructive sleep apnea syndrome (OSAS) is a common disorder in obese subjects. Visceral fat accumulation (VFA) is a better predictor of coronary heart disease than body mass index. Leptin is a hormone involved in the control of body weight and fat distribution. The effect of nasal continuous positive airway pressure (NCPAP) treatment on VFA and serum leptin levels in OSAS patients has not been known. Methods and Results—VFA and subcutaneous fat accumulation (SFA) were assessed by CT before and after NCPAP treatment in 22 OSAS patients (mean apnea and hypopnea index >50 episodes/h). Serum leptin levels of another 21 OSAS patients were measured before and after 3 to 4 days of NCPAP to gain insight into the mechanism by which NCPAP affects fat distribution. VFA and SFA decreased significantly after 6 months of NCPAP treatment (236±16 to 182±14cm2, P=0.0003 and 215±21 to 189±18 cm2, P=0.003, respectively). VFA decreased significantly in the body weight reduction group (n=9, P<0.01) and the no body...