tbuckley/cabot-search huggingface dataset:
Abstract P318: Dietary Sodium to Potassium Ratio and Risk of Stroke in a Multi-ethnic Urban Dwelling Population: The Northern Manhattan Study
Authors: Sandino Cespedes, Joshua Z Willey, Ralph L Sacco, Clinton B Wright, Mitchell S Elkind, Hannah Gardener
Journal: Circulation (2016)

Background: There is growing evidence that an increase in dietary sodium increases morbidity and mortality from cardiovascular disease (CVD) at least in part via an increase in blood pressure (BP). Several researchers have identified an association of higher dietary potassium, seen with increased intake of fruits and vegetables, with lower BP. Moreover, there may be a potential interaction of sodium and potassium on CVD health, such that the relative levels of these variables may be more important than their absolute levels. The goal of this study was to determine the association of dietary sodium to potassium ratio (Na:K) with the risk of stroke and CVD in a multi-ethnic urban dwelling population. Methods: Stroke-free participants from the Northern Manhattan Study, a population-based cohort study of stroke incidence, were followed prospectively to assess incident stroke, myocardial infarction and vascular death. Baseline food-frequency questionnaires were analyzed for Sodium and Potassium intake based on self-reported food consumption using DIETSYS software (Block Dietary Data System: Dietsys+ analysis software, version 59, 1999). We examined the association of Na:K with incident stroke (ischemic and overall) as well as combined vascular events (CVE)(stroke, myocardial infarction and vascular death) using Cox-proportional Hazards models adjusting for age, sex, race/ethnicity, total daily calories, adherence to a Mediterranean-style diet, smoking, physical activity, BMI, diabetes, hypertension, and hypercholesterolemia. Results: 2570 participants had dietary data, (mean age 69 ± 10 years, 64% women, 21% white, 53% Hispanic, 24% black); the mean of the Na:K ratio intake was 1.22 with a standard deviation of 0.43. Over a mean follow-up time of 11.9 years (SD=5.4), 274 participants developed stroke (N=232 ischemic) and 745 had a vascular event overall. In adjusted models the Na:K intake ratio was associated with an increased risk for ischemic Stroke (HR=1.5, 95% CI: 1.2-2.0), all stroke (HR=1.5, 95% CI: 1.2-1.9) and CVE (HR=1.2, 95% CI: 1.0-1.4). These results were unchanged in models adjusting for sociodemographic variables only. Conclusions: Our findings suggest that Na:K intake may be an important predictor of the risk of ischemic stroke and overall CVE.
Polo-like Kinase 1 Inhibition as a Therapeutic Approach to Selectively Target BRCA1-Deficient Cancer Cells by Synthetic Lethality Induction
Authors: Sofía Carbajosa, María Florencia Pansa, Natalia S. Paviolo, Andrés M. Castellaro, Diego L. Andino, Ayelén D. Nigra, Iris Alejandra García, Ana C. Racca, Lucía Rodriguez-Berdini, Virginia Angiolini, Laura Guantay, Florencia Villafañez, María Belén Federico, María Celeste Rodríguez-Baili, Beatriz L. Caputto, Gerard Drewes, Kevin P. Madauss, Israel Gloger, Elmer Fernandez, Germán A. Gil, José Luis Bocco, Vanesa Gottifredi, Gastón Soria
Journal: Clinical Cancer Research (2019)

BRCA1 and BRCA2 deficiencies are widespread drivers of human cancers that await the development of targeted therapies. We aimed to identify novel synthetic lethal relationships with therapeutic potential using BRCA-deficient isogenic backgrounds.We developed a phenotypic screening technology to simultaneously search for synthetic lethal (SL) interactions in BRCA1- and BRCA2-deficient contexts. For validation, we developed chimeric spheroids and a dual-tumor xenograft model that allowed the confirmation of SL induction with the concomitant evaluation of undesired cytotoxicity on BRCA-proficient cells. To extend our results using clinical data, we performed retrospective analysis on The Cancer Genome Atlas (TCGA) breast cancer database.The screening of a kinase inhibitors library revealed that Polo-like kinase 1 (PLK1) inhibition triggers strong SL induction in BRCA1-deficient cells. Mechanistically, we found no connection between the SL induced by PLK1 inhibition and PARP inhibitors. Instead, we uncovered that BRCA1 downregulation and PLK1 inhibition lead to aberrant mitotic phenotypes with altered centrosomal duplication and cytokinesis, which severely reduced the clonogenic potential of these cells. The penetrance of PLK1/BRCA1 SL interaction was validated using several isogenic and nonisogenic cellular models, chimeric spheroids, and mice xenografts. Moreover, bioinformatic analysis revealed high-PLK1 expression in BRCA1-deficient tumors, a phenotype that was consistently recapitulated by inducing BRCA1 deficiency in multiple cell lines as well as in BRCA1-mutant cells.We uncovered an unforeseen addiction of BRCA1-deficient cancer cells to PLK1 expression, which provides a new means to exploit the therapeutic potential of PLK1 inhibitors in clinical trials, by generating stratification schemes that consider this molecular trait in patient cohorts.
Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS
Authors: Shoko Edogawa, Adam L Edwinson, Stephanie A Peters, Lakshmikanth L Chikkamenahalli, Wendy Sundt, Sara Graves, Sakteesh V Gurunathan, Margaret Breen-Lyles, Stephen Johnson, Roy Dyer, Rondell Graham, Jun Chen, Purna Kashyap, Gianrico Farrugia, Madhusudan Grover
Journal: Gut (2019)

Objective The intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS. Design 39 patients with IBS and 25 healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states. Results Patients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (&gt;95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota. Conclusion A subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function.
Outcomes of distal femoral fractures treated with minimally invasive plate osteosynthesis versus open reduction internal fixation with combined locking plate and interfragmentary screws
Authors: Sheng-Hao Wang, Chia-Chun Wu, William T. Li, Hsain-Chung Shen, Leou-Chyr Lin, Ru-Yu Pan
Journal: International Journal of Surgery (2019)
Abstract 20348: Cholesterol Burden After a First Coronary Event is Related to Outcome
Authors: Francois Schiele, Romain Chopard, Oussama Daou, Marion Chatot, Fiona Ecarnot, Marc Badoz, Nicolas Meneveau
Journal: Circulation (2017)

Introduction: In patients under statins after a coronary event, the lower the LDL-cholesterol (LDL-C), the lower the risk of progression of the disease. The “secondary LDL-C burden”,can be calculated as the product of LDL-C by the duration of exposition after the first event. Hypothesis: We aimed to determine the impact of secondary LDL-C burden in the number of recurrent events Methods: Over 17 years, from a single center prospective registry patients (pts) with more than 3 coronary angiographies (CA) indicated for a clinical event were selected. Patients with recurrent events related to restenosis or stent thrombosis were excluded. Pts were categorized according to the angiographic progression of coronary disease (i.e. significant change versus previous CA or appearance of new lesion) into 4 groups (0, 1, 2 or >2 progressions).The secondary LDL-C burden was calculated after the first event and during the FU as Σ (LDL-C x years) for each LDL-C level recorded during the follow-up (FU). To adjust for the d...
Abstract 11174: Diagnosis and Prognosis Using the V-index in Patients With Symptoms Suggestive of Acute Myocardial Infarction
Authors: Roger Abächerli, Raphael Twerenbold, Jasper Boeddinghaus, Thomas Nestelberger, Roberto Sassi, Luca Minardi, Stefan Osswald, Christian Mueller
Journal: Circulation (2016)

Introduction: The V-index is an ECG marker quantifying the spatial heterogeneity of ventricular repolarization. We prospectively investigated the diagnostic and prognostic value of the V-index in patients with symptoms suggestive of acute myocardial infarction (AMI). Methods: We enrolled 582 patients presenting with suspected AMI to the emergency department (ED) in a prospective observational study. Twelve lead ECG’s of five minutes were recorded at presentation to the ED. The V-index was calculated in a blinded fashion. Final diagnosis was adjudicated by two independent cardiologists. Patients were followed for the endpoint of all-cause mortality. Results: AMI was the final diagnosis in 16% of patients. Values for the V-index at presentation were higher in patients with AMI compared to other causes of chest pain (23ms (IQR 18-28) vs. 18ms (IQR 15-24), p&lt;0.001). The diagnostic accuracy of the V-index at presentation for the diagnosis of AMI as quantified by the area under the receiver operating characteristic curve (AUC) was 0.64 (95% CI 0.57-0.71). The use of the V-index in addition to conventional ECG criteria improved the sensitivity of the ECG for MAI from 41% to 85% (p&lt;0.001). Median V-index levels in deceased patients were significantly higher as compared to survivors (28ms (IQR 22-37) vs. 19ms (IQR 15-24), p&lt;0.001). Cumulative 24-month mortality rates were 99.5%, 97.2% and 90.4% according to tertiles of the V-index (p&lt;0.001). In multivariable Cox proportional hazard analysis, the V-index significantly predicted mortality independently of age and high-sensitive cardiac Troponin T (hs cTnT). Conclusion: The V-index, an ECG marker quantifying the spatial heterogeneity of ventricular repolarization, significantly improves the sensitivity of the ECG for the diagnosis of AMI and predicts mortality in patients with suspected AMI independently of age and hs-cTnT.
Risks and Benefits of Dolutegravir- and Efavirenz-Based Strategies for South African Women With HIV of Child-Bearing Potential
Authors: Caitlin M. Dugdale, Andrea L. Ciaranello, Linda-Gail Bekker, Madeline E. Stern, Landon Myer, Robin Wood, Paul E. Sax, Elaine J. Abrams, Kenneth A. Freedberg, Rochelle P. Walensky
Journal: Annals of Internal Medicine (2019)

Dolutegravir is superior to efavirenz for HIV antiretroviral therapy (ART) but may be associated with an increased risk for neural tube defects (NTDs) in newborns if used by women at conception.
Effects of exosomes on pre-metastatic niche formation in tumors
Authors: Yaxin Guo, Xiang Ji, Jinbo Liu, Dandan Fan, Quanbo Zhou, Chen Chen, Weiwei Wang, Guixian Wang, Haijiang Wang, Weitang Yuan, Zhenyu Ji, Zhenqiang Sun
Journal: Molecular Cancer (2019)

A pre-metastatic niche is a microenvironment prepared for the colonization of circulating tumor cells in specific organs. Exosomes are extracellular vesicles with a variety of biological functions. Exosomes play an irreplaceable role in the development of pre-metastatic niches, and mainly function as communication medium. In this review, we analyzed the effects of exosomes on pre-metastatic niches from various perspectives, including inflammation, immune response, angiogenesis, organotropism, matrix remodeling and biomarker expression. In particular, exosomes express programmed death ligand 1 (PD-L1) and cause the immune escape of tumor cells. The immunomodulatory effects of exosomes and their potential in liquid diagnosis have drawn our attention. The potential value of exosomes and pre-metastatic niches will be realized in the field of immunity therapy.
Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis
Authors: W. Vallen Graham, Weiqi He, Amanda M. Marchiando, Juanmin Zha, Gurminder Singh, Hua-Shan Li, Amlan Biswas, Ma. Lora Drizella M. Ong, Zhi-Hui Jiang, Wangsun Choi, Harmon Zuccola, Yitang Wang, James Griffith, Jingshing Wu, Harry J. Rosenberg, Yingmin Wang, Scott B. Snapper, David Ostrov, Stephen C. Meredith, Lawrence W. Miller, Jerrold R. Turner
Journal: Nature Medicine (2019)
Cytochrome P450 promotes breast cancer cell proliferation.
Authors: Ranjana Mitra, Anjaiah Srirangam, Jorge Capdevila, David A. Potter
Journal: Cancer Research (2006)

5204  Purpose: Three enzymatic pathways of arachidonic acid metabolism, involving cyclooxygenases, lipooxygenases, and cytochrome P450 (CYP) epoxygenases have been identified in mammalian cells, but the latter pathway has been not been as well characterized in cancer. The aim of this study is to determine whether CYP enzymes induce cancer cell proliferation. Experimental Design: RT PCR was used to measure CYP3A4 and 3A5 levels in ER+ and ER- breast cancer lines. siRNA was used to knock down the level of CYP3A4 and 3A5, to determine effects on cell proliferation and apoptosis. Effects of pharmacological inhibition of CYP3A4 and 3A5 by the HIV protease inhibitor ritonavir and the epoxygenase inhibitor 17-ODYA were also determined. Results: CYP3A4 mRNA is expressed in the breast cancer lines T47D, MCF7 and MDA-MB-231 and, whereas CYP3A5 mRNA is expressed in the T47D and MCF7 lines, but not in MDA-MB-231. Although the corresponding proteins cannot be detected by western blot, inhibition of CYP3A4 by siRNA, verified by reduction of mRNA levels, inhibits the proliferation of each of the lines by 30% (P
Research Priorities for In-Hospital Cardiac Arrest: An Agenda for the Next Decade
Authors: Paul Chan
Journal: Circulation (2013)

There are an estimated 200,000 to 300,000 cardiac arrests which occur annually in U.S. hospitals, with relatively low survival rates. In-hospital cardiac arrest (IHCA) remains a ‘silent epidemic’, and as many patients die of IHCA each year in the U.S. as lung cancer. Until recently, however, little was known about the epidemiology, processes of care, and outcomes of IHCA. In the past decade, a number of key studies have provided important insights. We now know that certain process of care factors, such as defibrillation time and duration of resuscitations, are tightly linked to patient survival and neurological outcomes. Several studies have also demonstrated substantial hospital variation in processes of care and survival, suggesting that some hospitals are able to excel in the treatment of IHCA. In fact, survival after IHCA has improved markedly over the past decade (14% in 2000 to 22% in 2009), but these gains have been uneven across sites. Nonetheless, the factors which distinguish top-performer hospitals in IHCA survival from other hospitals have yet to be defined. In this lecture, Dr. Chan will review the seminal epidemiological and outcomes studies on IHCA over the past decade. He will then propose a research agenda for IHCA for the next decade, as well as promote a paradigm shift in the conceptual model of IHCA, investigator collaborations, and research methodologies.
Abstract 11764: Body Mass Index is Associated With Risk of Critical Limb Ischemia in the General Population
Authors: Caitlin W Hicks, Chao Yang, Chiadi E Ndumele, Aaron Folsom, Gerardo Heiss, James H Black, Elizabeth Selvin, Kunihiro Matsushita
Journal: Circulation (2017)

Introduction: Body mass index (BMI) is higher in individuals with risk factors for peripheral arterial disease (PAD), but there is currently no quantitative assessment of the prospective associatio...
Abstract 16184: Single Cell RNA Sequencing Reveals Dynamic and Heterogeneous Changes of Transcriptome During Cardiac Differentiation in vitro
Authors: shunsuke funakoshi, Masaki Nomura, Chikako Okubo, Kenji Miki, Takeshi Kimura, Shinya Yamanaka, Akira Watanabe, Yoshinori Yoshida
Journal: Circulation (2014)

Human induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs) are expected to be clinically applicable, especially in the field of disease modeling and drug screening. However, one of the ...
Membrane assembly of aquaporin-4 autoantibodies regulates classical complement activation in neuromyelitis optica
Authors: John Soltys, Yiting Liu, Alanna Ritchie, Scott Wemlinger, Kristin Schaller, Hannah Schumann, Gregory P. Owens, Jeffrey L. Bennett
Journal: Journal of Clinical Investigation (2019)

Neuromyelitis optica (NMO) is an autoimmune CNS disorder mediated by pathogenic aquaporin-4 (AQP4) water channel autoantibodies (AQP4-IgG). Although AQP4-IgG-driven complement-dependent cytotoxicity (CDC) is critical for the formation of NMO lesions, the molecular mechanisms governing optimal classical pathway activation are unknown. We investigated the molecular determinants driving CDC in NMO using recombinant AQP4-specific autoantibodies (AQP4 rAbs) derived from affected patients. We identified a group of AQP4 rAbs targeting a distinct extracellular loop C epitope that demonstrated enhanced CDC on target cells. Targeted mutations of AQP4 rAb Fc domains that enhance or diminish C1q binding or antibody Fc-Fc interactions showed that optimal CDC was driven by the assembly of multimeric rAb platforms that increase multivalent C1q binding and facilitate C1q activation. A peptide that blocks antibody Fc-Fc interaction inhibited CDC induced by AQP4 rAbs and polyclonal NMO patient sera. Super-resolution microscopy revealed that AQP4 rAbs with enhanced CDC preferentially formed organized clusters on supramolecular AQP4 orthogonal arrays, linking epitope-dependent multimeric assembly with enhanced C1q binding and activation. The resulting model of AQP4-IgG CDC provides a framework for understanding classical complement activation in human autoantibody-mediated disorders and identifies a potential new therapeutic avenue for treating NMO.
Abstract 17319: Changes in Profile and Early Outcomes of STEMI Patients According to Use of Reperfusion Therapy: Data Over 20 Years From the FAST-MI Program 1995-2015
Authors: Etienne Puymirat, Guillaume Cayla, Yves Cottin, Meyer Elbaz, Patrick Henry, Edouard Gerbaud, Gilles Lemesle, Batric Popovic, Je Noel Labeque, Francois Roubille, Stephane Andrieu, Bruno Farah, Jean Ferrieres, Francois Schiele, Tabassome Simon, Nicolas Danchin
Journal: Circulation (2017)

Introduction: the use of reperfusion therapy in STEMI patients has increased over time, and is generally considered the main determinant of improved outcomes. We assessed 20-year trends in clinical...
Molecular Characterization of Neuroendocrine-like Bladder Cancer
Authors: José Batista da Costa, Ewan A. Gibb, Trinity J. Bivalacqua, Yang Liu, Htoo Zarni Oo, David T. Miyamoto, Mohammed Alshalalfa, Elai Davicioni, Jonathan Wright, Marc A. Dall’Era, James Douglas, Joost L. Boormans, Michiel S. Van der Heijden, Chin-Lee Wu, Bas W.G. van Rhijn, Shilpa Gupta, Petros Grivas, Kent W. Mouw, Paari Murugan, Ladan Fazli, Seong Ra, Badrinath R. Konety, Roland Seiler, Siamak Daneshmand, Omar Y. Mian, Jason A. Efstathiou, Yair Lotan, Peter C. Black
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth. Experimental Design: Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes. Results: In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65% NE-like vs. 82% overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors. Conclusions: A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.
Modified shave surgery combined with nail window technique for the treatment of longitudinal melanonychia: Evaluation of the method on a series of 67 cases
Authors: Yuan Zhou, Wei Chen, Zhen-ru Liu, Juan Liu, Fei-ran Huang, Da-guang Wang
Journal: Journal of the American Academy of Dermatology (2019)

BackgroundNail matrix histopathologic examination is still the criterion standard to diagnose longitudinal melanonychia (LM).ObjectiveTo introduce modified shave surgery combined with the nail window technique for managing LM and evaluate the postoperative outcome of the procedure.MethodsWe retrospectively reviewed the medical records of 67 patients with LM who underwent shave surgery combined with the longitudinal-strip nail window technique at our institution from March 2015 to June 2018.ResultsPathologic diagnosis was accessible in all cases, and 60 cases were assessable for the postoperative outcomes. A total of 45 cases (75.0%) had no postoperative nail dystrophy, and recurrence of nail pigmentation was found in only 8 cases (13.3%).LimitationsThis was a retrospective study.ConclusionModified shave surgery combined with the nail window technique is the preferable management for LM cases, with limited postoperative nail dystrophy and recurrence of pigmentation. Nail matrix histopathologic examination is still the criterion standard to diagnose longitudinal melanonychia (LM). To introduce modified shave surgery combined with the nail window technique for managing LM and evaluate the postoperative outcome of the procedure. We retrospectively reviewed the medical records of 67 patients with LM who underwent shave surgery combined with the longitudinal-strip nail window technique at our institution from March 2015 to June 2018. Pathologic diagnosis was accessible in all cases, and 60 cases were assessable for the postoperative outcomes. A total of 45 cases (75.0%) had no postoperative nail dystrophy, and recurrence of nail pigmentation was found in only 8 cases (13.3%). This was a retrospective study. Modified shave surgery combined with the nail window technique is the preferable management for LM cases, with limited postoperative nail dystrophy and recurrence of pigmentation.