tbuckley/cabot-search huggingface dataset:
Cardiovascular Safety of Varenicline, Bupropion, and Nicotine Patch in Smokers
Authors: Neal L. Benowitz, Andrew Pipe, Robert West, J. Taylor Hays, Serena Tonstad, Thomas McRae, David Lawrence, Lisa St Aubin, Robert M. Anthenelli
Journal: JAMA Internal Medicine (2018)

<h3>Importance</h3> Quitting smoking is enhanced by the use of pharmacotherapies, but concerns have been raised regarding the cardiovascular safety of such medications. <h3>Objective</h3> To compare the relative cardiovascular safety risk of smoking cessation treatments. <h3>Design, Setting, and Participants</h3> A double-blind, randomized, triple-dummy, placebo- and active-controlled trial (Evaluating Adverse Events in a Global Smoking Cessation Study [EAGLES]) and its nontreatment extension trial was conducted at 140 multinational centers. Smokers, with or without established psychiatric diagnoses, who received at least 1 dose of study medication (n = 8058), as well as a subset of those who completed 12 weeks of treatment plus 12 weeks of follow up and agreed to be followed up for an additional 28 weeks (n = 4595), were included. <h3>Interventions</h3> Varenicline, 1 mg twice daily; bupropion hydrochloride, 150 mg twice daily; and nicotine replacement therapy, 21-mg/d patch with tapering. <h3>Main Outcomes and Measures</h3> The primary end point was the time to development of a major adverse cardiovascular event (MACE: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) during treatment; secondary end points were the occurrence of MACE and other pertinent cardiovascular events (MACE+: MACE or new-onset or worsening peripheral vascular disease requiring intervention, coronary revascularization, or hospitalization for unstable angina). <h3>Results</h3> Of the 8058 participants, 3553 (44.1%) were male (mean [SD] age, 46.5 [12.3] years). The incidence of cardiovascular events during treatment and follow-up was low (&lt;0.5% for MACE; &lt;0.8% for MACE+) and did not differ significantly by treatment. No significant treatment differences were observed in time to cardiovascular events, blood pressure, or heart rate. There was no significant difference in time to onset of MACE for either varenicline or bupropion treatment vs placebo (varenicline: hazard ratio, 0.29; 95% CI, 0.05-1.68 and bupropion: hazard ratio, 0.50; 95% CI, 0.10-2.50). <h3>Conclusions and Relevance</h3> No evidence that the use of smoking cessation pharmacotherapies increased the risk of serious cardiovascular adverse events during or after treatment was observed. The findings of EAGLES and its extension trial provide further evidence that smoking cessation medications do not increase the risk of serious cardiovascular events in the general population of smokers. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01574703
Suspended graphene oxide nanosheets maintain the self-renewal of mouse embryonic stem cells via down-regulating the expression of Vinculin
Authors: Guoxin Jing, Zhaojie Wang, Xizhen Zhuang, Xiaolie He, Huijun Wu, Qingxiu Wang, Liming Cheng, Zhongmin Liu, Shilong Wang, Rongrong Zhu
Journal: Biomaterials (2018)
Abstract 15932: A Systematic Review for Sudden Cardiac Death in Hypertrophic Cardiomyopathy Patients With Myocardial Fibrosis: A CMR LGE Study
Authors: Nackle J Silva, F Antonio Tito Paladino, Mark Doyle, Sahadev T Reddy, Diane Vido, Geetha Rayarao, June Yamrozik, Ronald Williams, Robert W Biederman
Journal: Circulation (2011)

BACKGROUND Hypertrophic cardiomyopathy (HCM) is a genetic disease that affects the cardiac sarcomere, resulting in myocardial hypertrophy and disarray. Affected patients have a predisposition for m...
Nanoemulsion adjuvant–driven redirection of TH2 immunity inhibits allergic reactions in murine models of peanut allergy
Authors: Jessica J. O'Konek, Jeffrey J. Landers, Katarzyna W. Janczak, Rishi R. Goel, Anna M. Mondrusov, Pamela T. Wong, James R. Baker
Journal: Journal of Allergy and Clinical Immunology (2018)
Cytokine profile of sipuleucel-T (sip-T) in differentiating reactivation of latent immunity from de novo immune responses.
Authors: Charles G. Drake, Daniel Peter Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem Anwar Sheikh, David I. Quinn
Journal: Journal of Clinical Oncology (2017)

163 Background: Sip-T is an FDA-approved immunotherapy for treating patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). It is manufactured from autologous peripheral blood mononuclear cells (PBMCs) cultured with PA2024, a fusion of prostatic acid phosphatase (PAP) and granulocyte macrophage colony-stimulating factor. Survival of sip-T–treated mCRPC pts correlates with immune responses to PA2024 and/or PAP. PA2024- or PAP-specific CD4+ and CD8+ T cell proliferation and cytokine production and release were assessed to better understand sip-T–induced T cell responses. Methods: Pts with biochemical recurrence or mCRPC were from sip-T trials (NCT01431391, NCT01981122). PBMCs collected at baseline through 6 mo post–sip-T were cultured in vitro and stimulated with PA2024 or PAP. CD4+ and CD8+ T cells were assessed (n=19) for proliferation and intracellular IL-2 and IFN-γ. The cytokine profile was confirmed in supernatant with a meso scale discovery assay. P&lt;0.10 was statistically significant. Results: Compared with baseline, PA2024-specific proliferating CD4+ and CD8+ T cells had increased intracellular IL-2 and IFN-γ levels at wk 6 and mo 6, with a similar trend for PAP-specific proliferating T cells (Table 1). Compared with unstimulated controls, a significant &gt;2-fold increase in PA2024-stimulated IL-2 and IFN-γ in supernatant was observed at wk 6 and mo 6 over baseline (p&lt;0.001). PAP-stimulated IL-2 and IFN-γ supernatant levels increased over baseline and were significantly elevated for IFN-γ at wk 6 (p&lt;0.10). Conclusions: Sip-T therapy generated a de novo PA2024-specific T cell response, as indicated by the cytokine release profile. The PAP-stimulated cytokine profile suggests that pre-existing immunity with terminally differentiated T cells are expanded. Thus, sip-T reactivated an anti-PAP response in memory T cells, thereby overcoming immunosuppressive mechanisms in PC. Clinical trial information: NCT01431391; NCT01981122. [Table: see text]
Current Marijuana Use by Industry and Occupation — Colorado, 2014–2015
Authors: Roberta Smith, Katelyn E. Hall, Paul Etkind, Mike Van Dyke
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

The effects of marijuana use on workplace safety are of concern for public health and workplace safety professionals. Twenty-nine states and the District of Columbia have enacted laws legalizing marijuana at the state level for recreational and/or medical purposes. Employers and safety professionals in states where marijuana use is legal have expressed concerns about potential increases in occupational injuries, such as on-the-job motor vehicle crashes, related to employee impairment. Data published in 2017 by the Colorado Department of Public Health and Environment (CDPHE) showed that more than one in eight adult state residents aged ≥18 years currently used marijuana in 2014 (13.6%) and 2015 (13.4%) (1). To examine current marijuana use by working adults and the industries and occupations in which they are employed, CDPHE analyzed data from the state's Behavioral Risk Factor Surveillance System (BRFSS) regarding current marijuana use (at least 1 day during the preceding 30 days) among 10,169 persons who responded to the current marijuana use question. During 2014 and 2015, 14.6% of these 10,169 Colorado workers reported current marijuana use, with the highest reported prevalence among workers in the Accommodation and Food Services industry (30.1%) and Food Preparation and Serving (32.2%) occupations. Understanding the industries and occupations of adults with reported marijuana use can help direct and maximize impact of public health messaging and potential safety interventions for adults.
Abstract 15005: PI3-Kinase δ-Deficiency in Regulatory T Cells Aggravates Atherosclerosis in LDLR-/- Mice
Authors: Mario Zierden, Christopher Millarg, Marius Vantler, Eva Berghausen, Stephan Baldus, Stephan Rosenkranz
Journal: Circulation (2016)

Atherosclerosis is a chronic inflammatory disease of arteries and represents the main underlying cause of death worldwide. Although macrophages outnumber other leukocytes in atherosclerotic lesions, T-helper 1 (Th1) cells and regulatory T cells (Tregs) can shape the course of disease by possessing inflammatory and regulatory functions. T cells express the catalytic phosphoinositide 3-kinase isoform p110δ (PI3Kδ), exerting a key role in the regulation of immune responses including activation, differentiation and effector function. Since Th1 cells and Tregs play a crucial role in atherosclerosis, we aimed to understand the role of PI3Kδ in T cells during atherogenesis. Therefore, we transplanted PI3Kδ -/-  or PI3Kδ +/+  bone marrow into atherogenic diet-fed LDLR -/-  mice. Hypercholesterolemic PI3Kδ -/-  recipient LDLR -/-  mice displayed strongly impaired CD4 +  T-cell activation and proatherogenic Th1 responses as well as profoundly reduced numbers of atheroprotective Tregs in paraaortic lymph nodes and spleen compared with PI3Kδ +/+  transplanted controls. Surprisingly, the net effect of PI3Kδ-deficiency was a substantial aggravation of atherosclerosis in LDLR -/-  mice. Atherosclerotic lesion area at the aortic root and whole aorta of PI3Kδ -/-  recipient LDLR -/-  mice was significantly increased by 72% and 118% compared with PI3Kδ +/+  recipients, respectively (n = 12-22;  P   -/-  transplanted LDLR -/-  mice were characterized by a lower fraction of CD4 +  T cells and a higher proportion of macrophages compared with controls. Whereas PI3Kδ-deficiency had only a modest impact on circulating monocytes and macrophage function including foam cell formation, efferocytosis and polarization, PI3Kδ-deficient Tregs exhibited strongly impaired immunosuppressive capabilities. Consequently, adoptive transfer of PI3Kδ +/+  Tregs into PI3Kδ -/-  transplanted LDLR -/-  mice rescued the atherosclerotic phenotype of PI3Kδ -/-  transplanted LDLR -/-  animals. In summary, we demonstrate that PI3Kδ plays a crucial role in both Th1 cells and Tregs during atherogenesis. Lack of PI3Kδ signaling in atheroprotective Treg responses outplays its impact on proatherogenic Th1 responses, thus leading to aggravated atherosclerosis.
78O Immune microenvironment of small cell lung cancer (SCLC): Distribution of PD-L1 expression and prognostic role of FOXP3-positive tumor infiltrating lymphocytes
Authors: A. Pavan, M. Fassan, M.V. Dieci, I. Attili, G. Pasello, F. Calabrese, F. Rea, M. Rugge, P.F. Conte, L. Bonanno
Journal: Journal of Thoracic Oncology (2018)
First-line carboplatin, pemetrexed, and panitumumab in patients with advanced nonsquamous <i>KRAS</i> wild type (WT) non-small cell lung cancer (NSCLC).
Authors: Tarek Mekhail, David Michael Waterhouse, Terence J. Hadley, Charles D. Webb, Howard A. Burris, John D. Hainsworth, F Anthony Greco, David R. Spigel
Journal: Journal of Clinical Oncology (2013)

8062 Background: KRAS WT colorectal cancer (CRC) is responsive to the EGFR inhibitors panitumumab (P) and cetuximab. Phase III data suggest a small, but statistically significant overall survival (OS) advantage with cetuximab + chemotherapy in KRAS unselected NSCLC (Pirker, Lancet 2009); and phase I data suggest P alone has activity in non-CRC tumors including NSCLC (Weiner, Clin Ca Res. 2008). This single-arm phase II trial examined the safety and efficacy of P in combination with carboplatin (C) and pemetrexed (Pem) in patients (pts) with advanced non-squamous KRAS WT NSCLC. The addition of P was hypothesized to improve the median time-to-progression (TTP) from 3.6 months (mos) (historical) to 5.4 mos (1-sided α .10, 80% power). Methods: Pts with previously untreated, unresectable stage IIIB/IV non squamous KRAS WT NSCLC received P 9 mg/kg, Pem 500 mg/m 2 , and C AUC=6 IV day 1 every 21 days for 6 cycles, followed by P and Pem maintenance every 21 days until progressive disease or unacceptable toxicity. Responses were evaluated every 2 cycles per RECIST 1.1. KRAS mutation testing was performed centrally (DxS kit). Tissue was also collected for EGFR FISH testing. Results: 60 pts were enrolled; median age, 65 years; 58% female, ECOG PS 0-1 (98%), and prior adjuvant chemotherapy (10%). Median number of cycles was 5 (range 1-22). At a median follow-up of 8.7 mos, the median TTP was 6.2 mos (95% CI: 3.7, 9.5), PFS 6.2 mos (95% CI 3.0, 9.0), 1 year OS 65.5% (95% CI 44.8%, 80%). 23 pts (38%) had partial responses (PR); the disease control rate (PR + proportion with stable disease) was 68%. Treatment-related toxicity (TRT) included (all grades) nausea (38%), fatigue (30%), rash (30%), and mucositis (23%). Severe (grade 3/4) TRT in &gt; 2 pts included: thrombocytopenia (11%), neutropenia (7%), and dehydration (5%). There were no treatment-related deaths. EGFR mutation and FISH analyses will be presented. Conclusions: The addition of panitumumab to carboplatin and pemetrexed in the first-line treatment of advanced KRAS WT NSCLC was safe and well-tolerated; the median TTP of 6.2 mos met the primary endpoint. Definitive assessment of the value of panitumumab in this setting requires a randomized trial. Clinical trial information: NCT01042288.
Early evolutionary divergence between papillary and anaplastic thyroid cancers
Authors: J. Capdevila, R. Mayor, F.M. Mancuso, C. Iglesias, G. Caratù, I. Matos, C. Zafón, J. Hernando, A. Petit, P. Nuciforo, J.M. Cameselle-Teijeiro, C. Álvarez, J.A. Recio, J. Tabernero, X. Matias-Guiu, A. Vivancos, J. Seoane
Journal: Annals of Oncology (2018)

BackgroundPapillary thyroid cancer (PTC) is the most common thyroid carcinoma and exhibits an almost uniformly good prognosis, while anaplastic thyroid cancer (ATC) is less frequent and is one of the most aggressive cancers usually resistant to conventional treatment. Current hypothesis posits that ATC derives from PTC through the progressive acquisition of a discrete number of genomic alterations and implies that the mutational landscape of ATC resembles that of PTC. However, the clinical behaviour of ATC and PTC is radically different. We decided to address the disconnection between the clinical behaviour of ATC and PTC and the proposed model of the progressive development of ATC from PTC.Patients and methodsWe carried out exome sequencing of DNA from 14 ATC specimens including three cases of concomitant ATC and PTC as well as their corresponding normal DNA from 14 patients. The sequencing results were validated using droplet digital PCR. We carried out immunohistochemistry and immunofluorescence studies of the concomitant ATC and PTC cases. In addition, we integrated our sequencing results with the existing TCGA data.ResultsMost of the somatic mutations identified in the ATC component differed from the ones in PTC in the cases of concomitant ATC and PTC. The trunks of the phylogenetic trees representing the somatic mutations were short with long branches. In one case of concomitant PTC and ATC specimens, we observed an infiltration of PTC cells within the ATC component. Moreover, we integrated our results with data obtained from TCGA and observed that the most frequent mutations found in ATC presented high cancer cell fraction values and were significantly different from the PTC ones.ConclusionATC diverge from PTC early in tumour development and both tumour types evolve independently. Our work allows the understanding of the relationship between ATC and PTC facilitating the clinical management of these malignancies.
DNA vaccine with pembrolizumab to elicit antitumor responses in patients with metastatic, castration-resistant prostate cancer (mCRPC).
Authors: Douglas G. McNeel, Jens C. Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu
Journal: Journal of Clinical Oncology (2017)

168 Background: We have previously investigated a DNA vaccine encoding prostatic acid phosphatase (PAP, pTVG-HP) in patients with PSA-recurrent prostate cancer, and have demonstrated that this can be safely administered over many months and can elicit PAP-specific T cells. A phase 2 trial is currently underway. In preclinical models, we have found that blockade of regulatory receptors, including PD-1, at the time of T cell activation with vaccination produced anti-tumor responses in vivo. Similarly, we have recently found that patients with prostate cancer previously immunized with a DNA vaccine develop PD-1-regulated T cells. These findings suggested that combined PD-1 blockade with vaccination should elicit superior anti-tumor responses in patients with prostate cancer. Methods: A clinical trial was designed to evaluate the immunological and clinical efficacy of pTVG-HP when delivered in combination or in sequence with pembrolizumab, in patients with mCRPC. Serial biopsies, blood draws, and exploratory FLT PET/CT imaging are being conducted for correlative analyses. Results: While trial accrual continues, 1 of 14 subjects has experienced a grade 3 adverse event. There have been no grade 4 events. Several patients treated with the combination have experienced serum PSA declines, and several have experienced decreases in tumor volume by radiographic imaging at 12 weeks, including one partial response. Expansion of PAP-specific Th1-biased T cells has been detected in peripheral blood samples. Exploratory FLT PET/CT imaging has demonstrated proliferative responses in metastatic lesions and in vaccine-draining lymph nodes. Evaluation of biopsy specimens for recruitment of antigen-specific T cells is currently underway. Conclusions: PD-1 pathway inhibitors have demonstrated little clinical activity to date when used as single agents for treating prostate cancer. Our findings suggest that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells, detectable within the peripheral blood and by imaging, and result in objective anti-tumor changes. Clinical trial information: NCT02499835.
Higher Collagen VI Formation Is Associated With All-Cause Mortality in Patients With Type 2 Diabetes and Microalbuminuria
Authors: Daniel G.K. Rasmussen, Tine W. Hansen, Bernt J. von Scholten, Signe H. Nielsen, Henrik Reinhard, Hans-Henrik Parving, Martin Tepel, Morten A. Karsdal, Peter K. Jacobsen, Federica Genovese, Peter Rossing
Journal: Diabetes Care (2018)

Type 2 diabetes is a common risk factor for the development of chronic kidney disease (CKD). Enhanced de novo collagen type VI (COL VI) formation has been associated with renal fibrosis and CKD. We investigated the hypothesis that PRO-C6, a product specifically generated during COL VI formation, is prognostic for adverse outcomes in patients with type 2 diabetes and microalbuminuria.In a prospective, observational study, we measured PRO-C6 in the serum (S-PRO-C6) and urine (U-PRO-C6) of 198 patients with type 2 diabetes and microalbuminuria without symptoms of coronary artery disease. Patients were followed for a median of 6.5 years, and end points were a composite of cardiovascular events (n = 38), all-cause mortality (n = 26), and reduction of estimated glomerular filtration rate (eGFR) of >30% (disease progression [n = 42]). Cox models were unadjusted and adjusted for the conventional risk factors of sex, age, BMI, systolic blood pressure, LDL cholesterol, smoking, HbA1c, plasma creatinine, and urinary albumin excretion rate.Doubling of S-PRO-C6 increased hazards for cardiovascular events (hazard ratio 3.06 [95% CI 1.31-7.14]), all-cause mortality (6.91 [2.96-16.11]), and disease progression (4.81 [1.92-12.01]). Addition of S-PRO-C6 to a model containing conventional risk factors improved relative integrated discrimination by 22.5% for cardiovascular events (P = 0.02), 76.8% for all-cause mortality (P = 0.002), and 53.3% for disease progression (P = 0.004). U-PRO-C6 was not significantly associated with any of the outcomes.S-PRO-C6 generated during COL VI formation predicts cardiovascular events, all-cause mortality, and disease progression in patients with type 2 diabetes and microalbuminuria.
Case 11-2018: A 48-Year-Old Woman with Recurrent Venous Thromboembolism and Pulmonary Artery Aneurysm
Authors: Harrison W. Farber, Shaunagh McDermott, Alison S. Witkin, Noreen P. Kelly, Eli M. Miloslavsky, James R. Stone
Journal: New England Journal of Medicine (2018)

A 48-year-old woman with a history of venous thromboembolism presented with cough and decreased exercise tolerance. Magnetic resonance imaging of the chest revealed a 2.4-cm aneurysm of the segmental pulmonary artery in the left lower lobe. A diagnosis was made.
Sex Differences in 1-Year All-Cause Rehospitalization in Patients After Acute Myocardial Infarction
Authors: Rachel P. Dreyer, Kumar Dharmarajan, Kevin F. Kennedy, Philip G. Jones, Viola Vaccarino, Karthik Murugiah, Sudhakar V. Nuti, Kim G. Smolderen, Donna M. Buchanan, John A. Spertus, Harlan M. Krumholz
Journal: Circulation (2017)

Compared with men, women are at higher risk of rehospitalization in the first month after discharge for acute myocardial infarction (AMI). However, it is unknown whether this risk extends to the full year and varies by age. Explanatory factors potentially mediating the relationship between sex and rehospitalization remain unexplored and are needed to reduce readmissions. The aim of this study was to assess sex differences and factors associated with 1-year rehospitalization rates after AMI.We recruited 3536 patients (33% women) ≥18 years of age hospitalized with AMI from 24 US centers into the TRIUMPH study (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status). Data were obtained by medical record abstraction and patient interviews, and a physician panel adjudicated hospitalizations within the first year after AMI. We compared sex differences in rehospitalization using a Cox proportional hazards model, following sequential adjustment for covariates and testing for an age-sex interaction.One-year crude all-cause rehospitalization rates for women were significantly higher than men after AMI (hazard ratio, 1.29 for women; 95% confidence interval, 1.12-1.48). After adjustment for demographics and clinical factors, women had a persistent 26% higher risk of rehospitalization (hazard ratio, 1.26; 95% confidence interval, 1.08-1.47). However, after adjustment for health status and psychosocial factors (hazard ratio, 1.14; 95% confidence interval, 0.96-1.35), the association was attenuated. No significant age-sex interaction was found for 1-year rehospitalization, suggesting that the increased risk applied to both older and younger women.Regardless of age, women have a higher risk of rehospitalization compared with men over the first year after AMI. Although the increased risk persisted after adjustment for clinical factors, the poorer health and psychosocial state of women attenuated the difference.