tbuckley/cabot-search huggingface dataset:
Thyroid and Cardiovascular Disease
Authors: Anne R. Cappola, Akshay S. Desai, Marco Medici, Lawton S. Cooper, Debra Egan, George Sopko, Glenn I. Fishman, Steven Goldman, David S. Cooper, Samia Mora, Peter J. Kudenchuk, Anthony N. Hollenberg, Cheryl L. McDonald, Paul W. Ladenson, Francesco S. Celi, Wolfgang Dillman, Christina Ellervik, A. Martin Gerdes, Carolyn Ho, Giorgio Iervasi, Amir Lerman, Ayako Makino, Kaie Ojamaa, Robin Peeters, Alessandro Pingitore, Salman Razvi, Ari J. Wassner
Journal: Circulation (2019)

Thyroid hormones have long been known to have a range of effects on the cardiovascular system. However, significant knowledge gaps exist concerning the precise molecular and biochemical mechanisms governing these effects and the optimal strategies for management of abnormalities in thyroid function in patients with and without preexisting cardiovascular disease. In September 2017, the National Heart, Lung, and Blood Institute convened a Working Group with the goal of developing priorities for future scientific research relating thyroid dysfunction to the progression of cardiovascular disease. The Working Group reviewed and discussed the roles of normal thyroid physiology, the consequences of thyroid dysfunction, and the effects of therapy in 3 cardiovascular areas: cardiac electrophysiology and arrhythmias, the vasculature and atherosclerosis, and the myocardium and heart failure. This report describes the current state of the field, outlines barriers and challenges to progress, and proposes research opportunities to advance the field, including strategies for leveraging novel approaches using omics and big data. The Working Group recommended research in 3 broad areas: (1) investigation into the fundamental biology relating thyroid dysfunction to the development of cardiovascular disease and into the identification of novel biomarkers of thyroid hormone action in cardiovascular tissues; (2) studies that define subgroups of patients with thyroid dysfunction amenable to specific preventive strategies and interventional therapies related to cardiovascular disease; and (3) clinical trials focused on improvement in cardiovascular performance and cardiovascular outcomes through treatment with thyroid hormone or thyromimetic drugs.
First-in-Class, First-in-Human Study Evaluating LV305, a Dendritic-Cell Tropic Lentiviral Vector, in Sarcoma and Other Solid Tumors Expressing NY-ESO-1
Authors: Neeta Somaiah, Matthew S. Block, Joseph W. Kim, Geoffrey I. Shapiro, Khanh T. Do, Patrick Hwu, Joseph P. Eder, Robin L. Jones, Hailing Lu, Jan H. ter Meulen, Chet Bohac, Michael Chen, Frank J. Hsu, Sacha Gnjatic, Seth M. Pollack
Journal: Clinical Cancer Research (2019)

Abstract Purpose: LV305 is a modified, third-generation, nonreplicating, integration-deficient lentivirus-based vector designed to selectively transduce dendritic cells in vivo. LV305 induces expression of the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer testis antigen in dendritic cells, promoting immune responses against NY-ESO-1–expressing tumors. This phase I study evaluated the safety, immunogenicity, and preliminary efficacy of LV305 in patients with sarcoma or other solid tumors. Patients and Methods: Adults with previously treated, advanced, NY-ESO-1–positive solid tumors and limited tumor burden were eligible. LV305 was administered every 3 weeks by intradermal injection in four dose cohorts (Cohort 1: 108 vector genomes (vg) x 3 doses; Cohorts 1A, 2, and 3: 108 vg, 109 vg, 1010 vg x 4 doses). Results: Thirty-nine patients were enrolled: 3 patients each in Cohorts 1, 1A, and 2, and 30 patients in Cohort 3. No dose-limiting toxicities were observed. Tumor types included sarcoma (n = 24), ovarian (n = 8), melanoma (n = 6), and lung cancer (n = 1). All treatment-related adverse events were grade 1 or 2. Common treatment-related adverse events were fatigue (49%), injection site reactions (46%), and myalgia (21%). The disease control rate was 56.4% in all patients and 62.5% in sarcoma patients. One patient with synovial sarcoma achieved a partial response lasting &amp;gt;36 months. Anti–NY-ESO-1-specific CD4+ and/or CD8+ T cells were induced in 57% of evaluable sarcoma patients. Induction of an anti–NY-ESO-1 immune response was associated with improved 1-year survival in an exploratory analysis. Conclusions: This first-in-class, first-in-human study of LV305 demonstrated a favorable safety profile, induction of antigen-specific responses, and potential clinical activity in patients with advanced cancer.
Cross-border outbreak of Yersinia enterocolitica O3 associated with imported fresh spinach, Sweden and Denmark, March 2019
Authors: Laura Espenhain, Maximilian Riess, Luise Müller, Soledad Colombe, Steen Ethelberg, Eva Litrup, Cecilia Jernberg, Sharon Kühlmann-Berenzon, Mats Lindblad, Nikolas Kühn Hove, Mia Torpdahl, Marie Jansson Mörk
Journal: Eurosurveillance (2019)

In April 2019, a cross-border outbreak of Yersinia entercolitica O3 was identified in Sweden and Denmark and confirmed using whole genome sequencing. Close cross-border collaboration with representatives from human and food authorities helped direct resources and investigations. Combined epidemiological and trace-back investigations pointed to imported fresh spinach as the outbreak vehicle and highlight that other vehicles of Y. enterocolitica outbreaks than pork should be considered.
Current and Future Considerations in the Use of Mechanical Circulatory Support Devices: An Update, 2008–2018
Authors: Marc A. Simon, Timothy N. Bachman, John Watson, J. Timothy Baldwin, William R. Wagner, Harvey S. Borovetz
Journal: Annual Review of Biomedical Engineering (2019)

Our review in the 2008 volume of this journal detailed the use of mechanical circulatory support (MCS) for treatment of heart failure (HF). MCS initially utilized bladder-based blood pumps generating pulsatile flow; these pulsatile flow pumps have been supplanted by rotary blood pumps, in which cardiac support is generated via the high-speed rotation of computationally designed blading. Different rotary pump designs have been evaluated for their safety, performance, and efficacy in clinical trials both in the United States and internationally. The reduced size of the rotary pump designs has prompted research and development toward the design of MCS suitable for infants and children. The past decade has witnessed efforts focused on tissue engineering–based therapies for the treatment of HF. This review explores the current state and future opportunities of cardiac support therapies within our larger understanding of the treatment options for HF.
Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma
Authors: Robert F. Cornell, Bonnie Ky, Brendan M. Weiss, Cherie N. Dahm, Deepak K. Gupta, Liping Du, Joseph R. Carver, Adam D. Cohen, Brian G. Engelhardt, Alfred L. Garfall, Stacey A. Goodman, Shelton Lacy Harrell, Adetola A. Kassim, Trafina Jadhav, Madan Jagasia, Javid Moslehi, Rupal O’Quinn, Michael R. Savona, David Slosky, Amanda Smith, Edward A. Stadtmauer, Dan T. Vogl, Adam Waxman, Daniel Lenihan
Journal: Journal of Clinical Oncology (2019)

Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs.Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs.Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib (P = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; P < .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; P < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank P = .01) and overall survival (log-rank P < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications.CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.
NICE reply to Jeba and Murray’s letter on palliative care in lung cancer guidelines
Authors: Ross Maconachie, Neal Navani
Journal: BMJ (2019)

Jeba and Murray point out that we did not mention palliative care in our article on the updates to the National Institute for Health and Care Excellence’s (NICE’s) guideline on the diagnosis and management of lung cancer.1

The guideline was first published in 2005 …
Abstract P354: Assessment of Phased Implementation of a Mobile Stroke Unit for Acute Ischemic Stroke Treatment
Authors: Soraya Sanchez Molero, Cynthia Diaz, James Boozan, Michael F Stiefel
Journal: Circulation (2018)

Introduction: The timing of administering tissue-type plasminogen activator (tPA) in patients with an ischemic stroke is directly related to clinical outcomes. The use of a mobile stroke unit (MSU) is a strategy to provide acute ischemic stroke assessment and treatment in a more rapid fashion compared to standard stroke transport and management. Our program initiated the use of a MSU in 2017 as a part of a phased implementation program. We sought to determine the impact of the MSU on the timing of stroke care in the region as it related to proximity to the hospital. Methods: We collected data during the first 9 months of 2017 on patients who were transported to the hospital as pre-hospital stroke alerts (PHSA) via conventional ambulance or via the MSU. Using a retrospective case-controlled design we compared process metrics associated with the phased implementation of the MSU with conventional pre-hospital stroke alerts as standard of care (SOC). Results: There was a total of 178 stroke alert patients; 72 in the MSU group and 106 in the PHSA group. 35 patients received tPA, 16 in the MSU, 19 in SOC. There was no significant difference in age, body weight, race, gender, and length of stay in the hospital in the two groups. The time from 911 call to arrival on scene was 12.06 min versus 20.4 min in the PHSA and MSU groups, respectively. Despite a longer time for arrival TPA administration for patients within a 5 miles radius of the hospital was 89 ± 25 mins in the SOC group and 78±12 mins in the MSU group (p=0.11). For 911 calls originating 10-20 miles from the hospital, the time for 911 call to tPA was 106 ± 23 mins in the PHSA group (n = 4) and 86 ± 2 mins in the MSU group (n = 4). Conclusion: Our initial results are comparable with previously reported data . Our data suggests the MSU may have a greater impact on reducing time to tPA for those further from the hospital or where transport time is delayed. The role of the MSU for non tPA patients such as mechanical thrombectomy, intracerebral hemorrhage and subarachnoid hemorrhage warrants further investigation.
PB2028 PLATELET COUNTS WITHIN THE NORMAL RANGE UPON HOSPITALIZATION ARE PREDICTOR OF MORTALITY IN PATIENTS WITH COMMUNITY-ACQUIRED PNEUMONIA
Authors: G. Moulis, C. Christiansen, B. Darvalics, I. Andersen, H. Sorensen, M. Norgaard
Journal: HemaSphere (2019)

Background: Apart their role in haemostasis, platelets are immune cells and play a role in controlling infections. They have direct interaction with pathogens, like pneumococcus that activates platelets. Thrombocytopenia (<150 x 109/L) and thrombocytosis (>400 x 109/L) upon admission to hospital are predictors of mortality in community-acquired pneumonia patients. Because of a tight regulation of platelet count, we hypothesized that a slight increased platelet count in comparison with the mean (250 x 109/L), still within the normal range, also predicts mortality in these patients. Conversely, we hypothesized that a slight decreased platelet count, still within the normal range, reflects an appropriate involvement and consumption of activated platelets as immune system cells, and predicts a lower mortality. Aims: The objective of this study was to assess these hypotheses. Methods: The study included all adults in North and Central Denmark Regions with a first acute admission for community-acquired pneumonia during 2006-2012. Patients were identified within the Danish National Patient Registry using validated discharge diagnostic codes (J12-J18 of the International Classification of Diseases, version 10). We considered the first platelet count within +/- 24 hours of admission. We assessed the association between platelet count (within normal range: 150-400 x 109/L) and 30-day mortality using spline regression Cox models. Analyses were adjusted for age, sex, Charlson Comorbidity Index score, hemoglobin level, leukocyte count, and creatinine level upon admission. Sensitivity analysis was restricted to non-severe patients (not admitted to intensive care units within the first 48 hours following admission). Results: Among the 14 158 study patients, the 30-day mortality was 12.5%. Mean platelet count upon admission was 250 x 109/L. Compared with the mean, platelet counts between 175-250 x 109/L predicted up to 10% lower 30-day mortality, while platelet counts between 350-400 x 109/L predicted up to 20% higher 30-day mortality (Figure). A similar pattern was observed in non-severe patients.Summary/Conclusion: Platelet counts, even within the normal range, predict mortality in adults hospitalized for community-acquired pneumonia. A platelet count between 175-250 x 109/L may reflect an appropriate response of platelets against the pathogen.
Exercise as a Candidate Antitumor Strategy: A Window into the Future
Authors: Graeme J. Koelwyn, Lee W. Jones
Journal: Clinical Cancer Research (2019)

Observational findings suggest exercise is associated with improved outcomes in early-stage breast cancer. However, whether exercise has biological activity in patients with breast cancer has not been investigated. Preoperative window of opportunity studies provide a setting in which to test the short-term effects of novel treatment strategies on validated surrogates.See related article by Ligibel et al., p. 5398.
Identification of molecular markers of oxidative stress in human prostate cells
Authors: Christopher H. Kennedy, James B. Mitchell
Journal: Cancer Research (2004)

769  Exposure of cultured human prostate cancer cells to androgens has been shown to induce oxidative stress in androgen-responsive cells but not in androgen-independent cells. However, both types of cells have been shown to exhibit increased levels of reactive oxygen species in response to prostate-specific antigen (PSA). We measured the expression of oxidative DNA damage repair enzymes in cultured human prostate cells to identify molecular markers of oxidative stress. Protein levels of antioxidant enzymes were also measured to assess cellular oxidative stress. PSA levels were measured to determine the contribution of this protein to the induction of oxidative stress. Experiments were conducted with normal human prostate epithelial (NHPE) cells, virus-immortalized human prostate epithelial cells (RWPE-1, RWPE-2, PWR-1E), androgen-responsive prostate cancer cells (LNCaP) and androgen-independent prostate cancer cells (DU145, PC3). Protein levels of four enzymes involved in the repair of 8-oxo-2’-deoxyguanosine (8-oxo-dG) were quantified by Western analyses. Human MutT homologue 1 (hMTH1), an 8-oxo-dGTPase, was overexpressed in LNCaP cells and DU145 cells as compared to NHPE cells. Expression of human 8-oxo-guanine DNA glycosylase (hOGG1), which removes 8-oxo-dG residues from DNA, was similar in all cells except LNCaP cells (hOGG1 protein was barely detectable). Extremely high protein levels of the mitochondrial form of hOGG1 (mt hOGG1) were detected in PWR-1E, LNCaP and DU145 cells as compared to NHPE cells. Human MutY homologue (hMYH), which removes adenine from the 8-oxo-dG:A mispair, was expressed at similar levels in all cells except DU145 cells (extremely low hMYH level). Western analyses were also performed to measure protein levels of antioxidant enzymes [i.e., catalase (CAT), glutathione peroxidase (GPx), copper/zinc superoxide dismutase (Cu/Zn SOD), manganese superoxide dismutase (MnSOD) and thioredoxin (TRX)] and PSA. As compared to NHPE cells, both Cu/Zn SOD and TRX were overexpressed in all three prostate cancer cell lines while PSA was expressed at extremely high levels in LNCaP cells but undetectable in all other cells. The fact that both Cu/Zn SOD and TRX were overexpressed in prostate cancer cells suggests that these cells are undergoing persistent oxidative stress. Since PSA was only expressed in LNCaP cells, other cellular factors must be involved in the induction of oxidative stress in prostate cells. One result of persistent oxidative stress is elevated levels of both 8-oxo-dGTP and 8-oxo-dG. LNCaP and DU145 cells appear to upregulate both hMTH1 and mt hOGG1 protein expression to protect against oxidative DNA damage. Thus, these proteins may represent potential molecular markers to detect persistent oxidative stress in prostate cancer.
PRMT1-mediated FLT3 arginine methylation promotes maintenance of FLT3-ITD+ acute myeloid leukemia
Authors: Xin He, Yinghui Zhu, Yi-Chun Lin, Min Li, Juan Du, Haojie Dong, Jie Sun, Lei Zhu, Hanying Wang, Zonghui Ding, Lei Zhang, Lianjun Zhang, Dandan Zhao, Zhihao Wang, Herman Wu, Han Zhang, Wenjuan Jiang, Yang Xu, Jian Jin, Yudao Shen, Jeff Perry, Xinyang Zhao, Bin Zhang, Songbai Liu, Sheng-Li Xue, Binghui Shen, Chun-Wei Chen, Jianjun Chen, Samer Khaled, Ya-Huei Kuo, Guido Marcucci, Yun Luo, Ling Li
Journal: Blood (2019)
Abstract 18805: Vorapaxar, A Platelet Thrombin-Receptor Antagonist, in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Results from the TRACER Trial
Authors: Marco Valgimigli, Pierluigi Tricoci, Zhen Huang, Philip Aylward, Paul Armstrong, Harvey White, Petr Widimsky, Robert Harrington, Angel Cequier, Khaled Ziada, Ming-Fong Chen, Edmond Chen, Yuliya Lokhnygina, Lars Wallentin, John Strony, Kenneth Mahaffey, David Moliterno
Journal: Circulation (2012)

Objectives: Evaluate the effects of protease-activated-receptor 1 antagonist vorapaxar in NSTE ACS pts undergoing PCI during index hospitalization. Methods: This prespecified analysis of a post-randomization subgroup evaluated the effects of vorapaxar compared with placebo among TRACER pts undergoing PCI, focusing on implanted stent type (drug-eluting stent [DES] vs bare metal stent [BMS]). Results: Among 12,944 TRACER pts, 7479 (58%) underwent PCI during index hospitalization; 1576 (44.4%) of vorapaxar pts and 1484 (42.1%) of placebo pts received exclusively BMS implantation. During the treatment period with vorapaxar, the median duration of thienopyridine therapy was 133 (47-246) days with BMS and 221 (88-341) days with DES. At 1 yr, the primary endpoint (CV death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) occurred in 10.4% of pts with vorapaxar vs 10.6% of pts with placebo (HR 0.96; 95% CI 0.83-1.10). The key secondary endpoint (CV death, MI, stroke) occurred in 6.8% with vorapaxar and 7.3% with placebo (HR 0.89; 95% CI 0.75-1.05). A trend of interaction was noted on CV death, MI, and stroke between treatment and type of implanted stent, with pts receiving BMS showing a relatively greater effect from vorapaxar (Figure). GUSTO moderate/severe bleeding was overall increased with vorapaxar with no statistical interaction, although the relative increase appeared less with BMS (HR 1.27; 95% CI 0.85-1.90) than with DES (HR 1.70; 95% CI 1.14-2.53). Conclusions: In this post-randomization subgroup analysis, the efficacy of vorapaxar among PCI pts is consistent with the overall TRACER results. The duration of dual antiplatelet therapy was shorter with BMS than with DES, and a noteworthy signal of increased efficacy and less bleeding liability was noted in BMS pts. These results point to further research opportunities to evaluate the potential clinical role of vorapaxar.
AB1072C CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS THE CORRELATION BETWEEN CAROTID INTIMA-MEDIA THICKNESS AND MARKERS OF INFLAMATION TO DETERMINE PRE-CLINICAL ATHEROSCLEROSIS
Authors: Mustafa Armut, Ruhan DüŞünsel, Aysenur Pac Kisaarslan, Gonca KoÇ, Betül Sözeri, Ferhan Elmalı, Muammer Hakan Poyrazoglu, Zubeyde Gunduz
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. JIA is a heterogeneous group of disorders with different disease progression and prognosis. Cardiovascular morbidity and mortality are becoming major health concerns for children with inflammatory rheumatic diseases. Inflammation has been suggested to play an important role in the pathogenesis of both atherosclerosis and JIA. Objectives: objective of this study was to determine carotid intima-media thickness (cIMT) in children with JIA and their correlation with JIA subtype and markers of inflammation. <h3>Methods</h3> We included 112 patients (50 boys and 62 girls) with diagnosis of JIA for at least 6 mouths and 54 healthy control subjects (32 girls and 22 males).These all children were had normal body mass index, blood pressure, lipids and blood glucose levels to exclude conventional risk factors. Carotid ultrasound for evaluation of cIMT was performed by same radiologist who was blinded to the participants' clinical and laboratory data. Patients datas were collected. We compared all cMIT values of patients and controls and investigated the relationship between inflammatory markers, disease status,periods and therapies. <h3>Results</h3> Our study showed that children with JIA had more increased cIMT values than controls. There was no correlation between disease subgroups, activity status, ANA, HLA-B27, RF positivity, WBC, ESR and CRP with cIMT. The cIMT values were not differences between patients used steroid, DMARD and biologic agents and non used. An increased active disease and total disease periods, decreased in mean platelet volüme were determined as independent risk factors at increased of cIMT. <h3>Conclusion</h3> The study showed that the patients with JIA had more risks than healthy controls for cardiovascular diseases. <h3>Disclosure of Interests</h3> None declared