tbuckley/cabot-search huggingface dataset:
Outcomes of front‐line ibrutinib treated CLL patients excluded from landmark clinical trial
Authors: Anthony R. Mato, Lindsey E. Roeker, John N. Allan, John M. Pagel, Danielle M. Brander, Brian T. Hill, Bruce D. Cheson, Richard R. Furman, Nicole Lamanna, Constantine S. Tam, Sasanka Handunnetti, Ryan Jacobs, Frederick Lansigan, Erica Bhavsar, Paul M. Barr, Mazyar Shadman, Alan P. Skarbnik, Andre Goy, Douglas F. Beach, Jakub Svoboda, Jeffrey J. Pu, Alison R. Sehgal, Clive S. Zent, Hande H. Tuncer, Stephen J. Schuster, Peter V. Pickens, Nirav N. Shah, Joanna Rhodes, Chaitra S. Ujjani, Chadi Nabhan
Journal: American Journal of Hematology (2018)

Abstract Ibrutinib demonstrated superior response rates and survival for treatment‐naïve chronic lymphocytic leukemia (CLL) patients in a pivotal study that excluded patients younger than 65 (&lt;65) and/or with chromosome 17p13 deletion (del[17p13]). We examined outcomes and toxicities of CLL patients who would have been excluded from the pivotal study, specifically &lt;65 and/or those with del[17p13]. This multicenter, retrospective cohort study examined CLL patients treated with front‐line ibrutinib at 20 community and academic centers, categorizing them based on key inclusion criteria for the RESONATE‐2 trial: &lt;65 vs ≥65 and present vs absent del[17p13]. Of 391 included patients, 57% would have been excluded from the pivotal study. Forty‐one percent of our cohort was &lt;65, and 30% had del(17p13). Patients &lt;65 were more likely to start 420 mg of ibrutinib daily; those who started at reduced doses had inferior PFS. The most common adverse events were arthralgias, fatigue, rash, bruising, and diarrhea. Twenty‐four percent discontinued ibrutinib at 13.8 months median follow‐up; toxicity was the most common reason for discontinuation, though progression and/or transformation accounted for a larger proportion of discontinuations in &lt;65 and those with del(17p13). Response rates were similar for &lt;65 and those with del(17p13). However, patients with del(17p13) had inferior PFS and OS. Ibrutinib in the front‐line setting has extended beyond the population in which it was initially studied and approved. This study highlights and compares important differences in ibrutinib dosing, treatment interruptions, toxicities, reasons for discontinuation, and survival outcomes in two important patient populations not studied in RESONATE‐2.
Abstract 14981: Transcriptome Analysis Identifies Cardiomyopathy-Specific Mechanisms in Explanted Human Hearts
Authors: Mary E Sweet, Andrea Cocciolo, Dobromir Slavov, Sharon L Graw, Kenneth Jones, Luisa Mestroni, Matthew R Taylor
Journal: Circulation (2016)

The genetic and phenotypic architecture of cardiomyopathy is diverse but has been proposed to progress via a “final common pathway” towards heart failure. The goal of this study was to determine if there are differentially regulated pathways of heart failure in cardiomyopathy patients. We used RNA-sequencing (RNA-seq) and pathway analysis in 42 samples of explanted left ventricular tissue. We investigated differential expression between ischemic cardiomyopathy (ICM, n=14) and dilated cardiomyopathy (DCM, n=28) as well as between DCM sub-phenotypes, arrhythmogenic DCM (aDCM, n=13) and non-arrhythmogenic DCM (naDCM, n=15). Pathway analysis was performed using Ingenuity Pathway Analysis (IPA). Between ICM and DCM, 878 genes were differentially expressed (p < 0.05, q < 0.05). Pathway analysis showed enrichment for mTOR signaling (p = 4x10-13), epithelial adherens junction remodeling (p = 3x10-10), and Rho signaling (p = 1x10-7) with functional enrichment in immune response (p = 7x10-7). These results support ...
Abstract 12959: Clinical Utility of Normal Findings on Non-Invasive Cardiac Assessment in a Population-Based Study of Older Adults
Authors: Sanjay Venkatesh, Wesley T O’Neal, Stephen T Broughton, Amit J Shah, Elsayed Z Soliman
Journal: Circulation (2016)

Introduction: The lack of abnormalities found on noninvasive cardiac testing may improve cardiovascular disease (CVD) risk stratification efforts and convey reduced risk despite the presence of traditional risk factors. Methods: We examined the clinical utility of normal findings on routine noninvasive cardiac assessment in 3,805 (95% white; 61% women) participants from the Cardiovascular Health Study (CHS) without baseline CVD. The combination of normal electrocardiogram (ECG) + normal echocardiogram was assessed for the development of CVD events. Normal ECG was defined as absence of major or minor Minnesota code abnormalities. Normal echocardiogram was defined as absence of contractile dysfunction, wall motion abnormalities, or abnormal left ventricular mass. Cox regression was used to compute the 10-year risk of developing coronary heart disease (CHD), stroke, and heart failure events. Results: There were 1,555 (41%) participants with normal ECG + normal echocardiogram at baseline. During 10 years of follow up, 783 CHD events, 414 strokes, and 576 cases of heart failure were detected. After accounting for traditional cardiovascular risk factors, a protective benefit was observed for all outcomes among participants who had normal ECG + normal echocardiogram (CHD: multivariable HR=0.56, 95%CI=0.46, 0.69; Stroke; multivariable HR=0.57, 95%CI=0.43, 0.76; Heart Failure: multivariable HR=0.36, 95%CI=0.29, 0.41). The addition of normal ECG + normal echocardiogram resulted in significant net reclassification improvement (NRI) of the Framingham risk score for heart failure (risk categories: &lt;10%, 10-20%, &gt;20%; NRI=0.043, 95%CI=0.010, 0.80). Conclusions: Normal findings on the routine ECG and transthoracic echocardiogram identify a group of individuals aged &gt;65 years in which CVD risk is low. Our data support the existence of a low-risk noninvasive cardiac profile and further studies are needed to explore the utility of this profile regarding the decision to implement certain risk factor modification strategies, including invasive measures, to reduce CVD burden in older adults.
Evaluation of a Combined Reflectance Confocal Microscopy–Optical Coherence Tomography Device for Detection and Depth Assessment of Basal Cell Carcinoma
Authors: Aditi Sahu, Oriol Yélamos, Nicusor Iftimia, Miguel Cordova, Christi Alessi-Fox, Melissa Gill, Gopi Maguluri, Stephen W. Dusza, Cristián Navarrete-Dechent, Salvador González, Anthony M. Rossi, Ashfaq A. Marghoob, Milind Rajadhyaksha, Chih-Shan J. Chen
Journal: JAMA Dermatology (2018)

The limited tissue sampling of a biopsy can lead to an incomplete assessment of basal cell carcinoma (BCC) subtypes and depth. Reflectance confocal microscopy (RCM) combined with optical coherence tomography (OCT) imaging may enable real-time, noninvasive, comprehensive three-dimensional sampling in vivo, which may improve the diagnostic accuracy and margin assessment of BCCs.To determine the accuracy of a combined RCM-OCT device for BCC detection and deep margin assessment.This pilot study was carried out on 85 lesions from 55 patients referred for physician consultation or Mohs surgery at Memorial Sloan Kettering Skin Cancer Center in Hauppauge, New York. These patients were prospectively and consecutively enrolled in the study between January 1, 2017, and December 31, 2017. Patients underwent imaging, with the combined RCM-OCT probe, for previously biopsied, histopathologically confirmed BCCs and lesions clinically or dermoscopically suggestive of BCC. Only patients with available histopathologic examination after imaging were included.Improvements in sensitivity, specificity, and diagnostic accuracy for BCC using the combined RCM-OCT probe as well as the correlation between OCT-estimated depth and histopathologically measured depth were investigated.In total, 85 lesions from 55 patients (27 [49%] were female and 28 [51%] were male with a median [range] age of 59 [21-90] years) were imaged. Imaging was performed on 25 previously biopsied and histopathologically confirmed BCCs and 60 previously nonbiopsied but clinically or dermoscopically suspicious lesions. Normal skin and BCC features were correlated and validated with histopathologic examination. In previously biopsied lesions, residual tumors were detected in 12 of 25 (48%) lesions with 100% sensitivity (95% CI, 73.5%-100%) and 23.1% specificity (95% CI, 5.0%-53.8%) for combined RCM-OCT probe. In previously nonbiopsied and suspicious lesions, BCCs were diagnosed in 48 of 60 (80%) lesions with 100% sensitivity (95% CI, 92.6%-100%) and 75% specificity (95% CI, 42.8%-94.5%). Correlation was observed between depth estimated with OCT and depth measured with histopathologic examination: the coefficient of determination (R2) was 0.75 (R = 0.86; P < .001) for all lesions, 0.73 (R = 0.85; P < .001) for lesions less than 500 μm deep, and 0.65 (R = 0.43; P < .001) for lesions greater than 500 μm deep.Combined RCM-OCT imaging may be prospectively used to comprehensively diagnose lesions suggestive of BCC and triage for treatment. Further validation of this device must be performed on a larger cohort.
Abstract 19523: Liver Injury in Alcohol Drinkers and Incidence of Heart Failure - The Atherosclerosis Risk in Communities Study
Authors: Odilson M Silvestre, Alexandra Gonçalves, Gabriela Q Roca, Brian Claggett, Chiadi E Ndumele, Mariana Lazo, Scott D Solomon
Journal: Circulation (2015)

Introduction: Alcohol liver toxicity occurs earlier than heart toxicity, but it is unknown if markers of liver damage predict incident heart failure (HF). Methods: We studied 10,263 participants from the Atherosclerosis Risk in Communities (ARIC) study, mean age 62.2±5.5 years, free of HF, who had liver enzymes measured in 2010 from stored Visit 4 (1996-99) samples. Liver enzymes were considered elevated when alanine aminotransferase (ALT) &gt;24 UI/L(men) and &gt;21 UI/L(women); aspartate aminotransferase (AST) &gt; 32 UI/L(men) and &gt;28 UI/L(women); gama-glutamyl transpeptidase (GGT)&gt;56 UI/L(men) and &gt;50 UI/L(women); AST:ALT ratio ≥2. Participants were classified into 3 categories based on self-reported drinking: never (21%), former (29%), and current drinkers (50%). Multivariable Cox proportional hazards models were used to evaluate the relationship between liver enzymes and incident HF (hospitalization or death) occurring after Visit 4 through 12/31/2012. Results: During 13.2 years of follow-up, HF occurred in 1399 (13%) participants. Higher AST, GGT, and AST:ALT ratio were associated with higher alcohol intake and incident HF among current drinkers (Figure). Compared to current drinkers with normal liver enzymes, current drinkers with increased level of AST or GGT had a higher risk of HF (1.38 HR 95%CI 1.09-1.73, p=0.005 and 1.34 HR 95% CI 1.04-1.74, p=0.02, respectively). AST:ALT ratio≥2 was associated with a 35% increased risk of HF (1.35 HR 95% CI 1.01-1.82, p=0.04) in the current drinkers group, adjusting for age, sex, race, center, hypertension, BMI, LDL, smoking, diabetes, statin use, coronary disease, quantity of alcohol, and kidney function. Elevated liver enzymes were not associated with higher incidence of HF among never and former drinkers participants. Conclusion: Liver damage, as marked by elevation of AST, GGT or an AST: ALT ratio≥2, was related to a higher risk of incident HF among alcohol drinkers, independently of the quantity of alcohol intake.
Abstract 14575: Celastramycin Inhibits Pulmonary Arterial Smooth Muscle Cell Proliferation and Ameliorates Hypoxia-induced Pulmonary Hypertension in Mice
Authors: Ryo Kurosawa, Kimio Satoh, Nobuhiro Kikuchi, Junichi Omura, Taijyu Satoh, Masamichi Nogi, Shinichiro Sunamura, Kazuhiko Numano, Kota Suzuki, Mohammad Abdul Hai Siddique, Elias Al-Mamun, Hiroaki Shimokawa
Journal: Circulation (2016)

Background: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by enhanced proliferation of pulmonary arterial smooth muscle cells (PASMCs). However, all the drugs in clinical u...
Screening for Cervical Cancer With High-Risk Human Papillomavirus Testing
Authors: Joy Melnikow, Jillian T. Henderson, Brittany U. Burda, Caitlyn A. Senger, Shauna Durbin, Meghan S. Weyrich
Journal: JAMA (2018)

<h3>Importance</h3> Cervical cancer can be prevented with detection and treatment of precancerous cell changes caused primarily by high-risk types of human papillomavirus (hrHPV), the causative agents in more than 90% of cervical cancers. <h3>Objective</h3> To systematically review benefits and harms of cervical cancer screening for hrHPV to inform the US Preventive Services Task Force. <h3>Data Sources</h3> MEDLINE, PubMed, PsycINFO, and the Cochrane Collaboration Registry of Controlled Trials from January 2011 through February 15, 2017; surveillance through May 25, 2018. <h3>Study Selection</h3> Randomized clinical trials (RCTs) and cohort studies comparing primary hrHPV screening alone or hrHPV cotesting (both hrHPV testing and cytology) with cytology (Papanicolaou [Pap] test) screening alone. <h3>Data Extraction and Synthesis</h3> Two investigators independently reviewed abstracts and full-text articles and quality rated included studies; data were qualitatively synthesized. <h3>Main Outcomes and Measures</h3> Invasive cervical cancer; cervical intraepithelial neoplasia (CIN); false-positive, colposcopy, and biopsy rates; psychological harms. <h3>Results</h3> Eight RCTs (n = 410 556), 5 cohort studies (n = 402 615), and 1 individual participant data (IPD) meta-analysis (n = 176 464) were included. Trials were heterogeneous for screening interval, number of rounds, and protocol. For primary hrHPV screening, evidence was consistent across 4 trials demonstrating increased detection of CIN 3 or worse (CIN 3+) in round 1 (relative risk [RR] range, 1.61 [95% CI, 1.09-2.37] to 7.46 [95% CI, 1.02-54.66]). Among 4 hrHPV cotesting trials, first-round CIN 3+ detection was not significantly different between screening groups; RRs for cumulative CIN 3+ detection over 2 screening rounds ranged from 0.91 to 1.13. In first-round screening, false-positive rates for primary hrHPV screening ranged from 6.6% to 7.4%, compared with 2.6% to 6.5% for cytology. For cotesting, false-positives ranged from 5.8% to 19.9% in the first round of screening, compared with 2.6% to 10.9% for cytology. First-round colposcopy rates were also higher, ranging 1.2% to 7.9% for primary hrHPV testing, compared with 1.1% to 3.1% for cytology alone; colposcopy rates for cotesting ranged from 6.8% to 10.9%, compared with 3.3% to 5.2% for cytology alone. The IPD meta-analysis of data from 4 cotesting trials and 1 primary hrHPV screening trial found lower risk of invasive cervical cancer with any hrHPV screening compared with cytology alone (pooled RR, 0.60 [95% CI, 0.40-0.89]). <h3>Conclusions and Relevance</h3> Primary hrHPV screening detected higher rates of CIN 3+ at first-round screening compared with cytology. Cotesting trials did not show initial increased CIN 3+ detection. Both hrHPV screening strategies had higher false-positive and colposcopy rates than cytology, which could lead to more treatments with potential harms.
Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development
Authors: Richard S. Smith, Connor J. Kenny, Vijay Ganesh, Ahram Jang, Rebeca Borges-Monroy, Jennifer N. Partlow, R. Sean Hill, Taehwan Shin, Allen Y. Chen, Ryan N. Doan, Anna-Kaisa Anttonen, Jaakko Ignatius, Livija Medne, Carsten G. Bönnemann, Jonathan L. Hecht, Oili Salonen, A. James Barkovich, Annapurna Poduri, Martina Wilke, Marie Claire Y. de Wit, Grazia M.S. Mancini, Laszlo Sztriha, Kiho Im, Dina Amrom, Eva Andermann, Ritva Paetau, Anna-Elina Lehesjoki, Christopher A. Walsh, Maria K. Lehtinen
Journal: Neuron (2018)
Abstract 17104: Smooth Muscle Protein 22 alpha Promoter-driven Insulin-like Growth Factor I (IGF-1) Receptor Deficiency Increases Atherosclerosis and Promotes Atherosclerotic Plaque Destabilization
Authors: Sergiy Sukhanov, Yusuke Higashi, Shaw-Yung Shai, Patricia Snarski, Xuwei Hou, Svitlana Danchuk, Bysani Chandrasekar, Patrice Delafontaine
Journal: Circulation (2016)

We have previously shown that IGF-1 reduces atherosclerosis in Apoe-null mice. We have now generated Apoe-null mice with SM22a promoter-driven IGF-1 receptor (IGF-1R) deficiency (22KI mice). IGF-1R...
Abstract P300: Associations of Sarcopenia and Low Muscular Strength With All-cause Mortality Among US Older Adults: The National Health and Nutrition Examination Surveys 1999-2002
Authors: Ran Li, Jin Xia, Xi Zhang, Jianjun Guo, Yiqing Song
Journal: Circulation (2017)

Background: Sarcopenia is defined as aging-related loss of muscle mass and knee extension strength serves as a marker of lower extremity muscular strength in populations. Sarcopenia and low muscular strength (LMS) may be important but understudied risk factors for aging-related morbidity and mortality in the older and elderly populations. However, data from prospective studies are limited. Objective: We aimed to prospectively examine individual or joint associations of sarcopenia and LMS with all-cause mortality in a nationally representative sample of US older adults in the National Health and Nutrition Examination Survey (NHANES). Methods: Data sources included the NHANES 1999-2002 with public-use 2011 linked mortality files, which comprised 4,449 participants aged 50 years and older with complete data on body composition by dual-energy x-ray absorptiometry and isokinetic knee extensor strength measurement. Sarcopenia was defined by two definitions proposed by the National Institutes of Health Sarcopenia Project according to appendicular lean mass (ALM) and ALM divided by BMI (ALM/BMI). LMS was defined as the lowest 25% of measurements of knee extensor strength. Weighted multivariable logistic regression models were used to account for multistage stratified and clustered sampling. Models were adjusted for age, sex, race, BMI, smoking, alcohol use, education, leisure time physical activity, sedentary time, and history of cardiovascular diseases, diabetes, cancer, chronic obstructive pulmonary disease, or chronic kidney disease. Results: Overall, the weighted prevalence of sarcopenia was 23.1% defined by ALM and 17.0% defined by ALM/BMI; the weighted prevalence of low muscular strength was 19.4%. In the multivariate-adjusted models, sarcopenia was significantly associated with increased risk of all-cause mortality for ALM/BMI definition (OR: 1.44; 95% confidence interval [CI], 1.06-1.97) but not for ALM definition (OR: 1.37; 95% CI, 0.90-2.09) while LMS was strongly associated with all-cause mortality (OR: 2.32; 95% CI, 1.70-3.18). In the joint analyses, a significantly increased all-cause mortality was observed only among participants with LMS and non-sarcopenia (OR range: 2.03-2.50) and those with LMS and sarcopenia (OR range: 2.15-2.56) while those without sarcopenia and LMS were the reference group. Conclusions: Low knee extensor strength indicative of low muscular strength was independently and significantly associated with an increased risk of all-cause mortality among US older adults regardless of the presence or absence of sarcopenia.
Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis
Authors: Joseph K. Rathkey, Junjie Zhao, Zhonghua Liu, Yinghua Chen, Jie Yang, Hannah C. Kondolf, Bryan L. Benson, Steven M. Chirieleison, Alex Y. Huang, George R. Dubyak, Tsan S. Xiao, Xiaoxia Li, Derek W. Abbott
Journal: Science Immunology (2018)

Necrosulfonamide inhibits pyroptosis through direct inhibition of gasdermin D.
Abstract 16332: Remnant Cholesterol and Myocardial Infarction in Normal Weight, Overweight, and Obese Individuals From the General Population
Authors: Anette Varbo, Jacob J Freiberg, Børge G Nordestgaard
Journal: Circulation (2017)

Introduction: Remnant cholesterol is causally associated with cardiovascular disease risk, and remnant cholesterol is a mediator from obesity to ischemic heart disease. Hypothesis: We tested whethe...
Abstract 17793: Apolipoprotein(a) Phenotype Determines the Correlation of Lipoprotein(a) and Protein Convertase Subtilisin-Kexin Type 9 Levels in Patients With Hypercholesterolemia
Authors: Olga Afanasieva, Marat Ezhov, Oxana Razova, Anna Popova, Marina Afanasieva, Sergei Pokrovsky
Journal: Circulation (2017)

Introduction: Mechanism of reducing of plasma Lp(a) concentration by protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors is not clear and is actively studied. The aim of this study was to...
24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer
Authors: Hossein Borghaei, Corey J. Langer, Shirish Gadgeel, Vassiliki A. Papadimitrakopoulou, Amita Patnaik, Steven F. Powell, Ryan D. Gentzler, Renato G. Martins, James P. Stevenson, Shadia I. Jalal, Amit Panwalkar, James Chih-Hsin Yang, Matthew Gubens, Lecia V. Sequist, Mark M. Awad, Joseph Fiore, Sanatan Saraf, Steven M. Keller, Leena Gandhi
Journal: Journal of Thoracic Oncology (2018)
Sodium Excretion in Population Subgroups—Reply
Authors: Mary E. Cogswell, Catherine M. Loria, Lawrence J. Appel
Journal: JAMA (2018)

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