tbuckley/cabot-search huggingface dataset:
Abstract 15524: The Methyltransferase Setd7 Drives Myocardial Ischemic Injury by Modulating the Hippo Pathway: A Study in Mice and Humans
Authors: Samuele Ambrosini, Fabrizio Montecucco, Daniela Pedicino, Alexander Akhmedov, Shafeeq Ahmed Mohammed, Giovanna Liuzzo, Antonio Paolo P Beltrami, Filippo Crea, Thomas F Luescher, Sarah Costantino, Francesco Paneni
Journal: Circulation (2020)

Introduction: Ischemic heart disease is a leading cause of death worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop heart failure. Protein methylation is emerging as a key biological signal implicated in the pathophysiology of cardiovascular (CV) disease. In this regard, the methyltransferase SETD7 was recently shown to methylate proteins relevant to CV homeostasis. Hypothesis: To investigate SETD7 role in myocardial ischemia-reperfusion (I/R) injury. Methods: Experiments were performed in neonatal rat ventricular myocytes (NRVM), SETD7 knockout mice (SETD7 -/- ) undergoing myocardial I/R injury, myocardial samples from patients with and without ischemic heart failure as well as peripheral blood mononuclear cells from patients with ST elevation MI (STEMI, n=25) and age-matched healthy controls (n=20). Results: Glucose deprivation (GD) in NRVM led to upregulation of SETD7 and direct mono-methylation of the Hippo signaling effector YAP. SETD7-dependent methylation of YAP led to its cytosolic retention thus impeding YAP binding to the promoter of pro-survival genes. Selective pharmacological inhibition of SETD7 by (R)-PFI-2 blunted YAP mono-methylation thereby restoring its nuclear retention. We show that YAP binds the promoter of antioxidant genes catalase and superoxide dismutase, thus preventing GD-induced mitochondrial oxidative stress, organelle swelling and apoptosis. Consistently, infarct size, myocardial oxidative stress and left ventricular dysfunction were reduced in SETD7 -/- mice undergoing I/R as compared to wild-type littermates. Of clinical relevance, we found that SETD7/YAP signaling was deregulated in myocardial samples from patients with ischemic heart failure as well as in peripheral blood mononuclear cells from STEMI patients. Conclusions: We demonstrate that SETD7-dependent methylation of YAP is an important mechanism underpinning myocardial oxidative stress, mitochondrial damage and apoptosis during ischemia. Pharmacological modulation of SETD7 by (R)-PFI-2 may represent a potential therapeutic approach to prevent myocardial ischemic damage through modulation of the Hippo pathway.
59P Outcomes of women HER2 positive T1a/bN0M0 breast cancer treated with adjuvant trastuzumab: A retrospective population-based cohort study
Authors: J. Hendry, S. Ali, O. Ahmed, H. Chalchal, A. El-Gayed, K. Haider, N. Iqbal, K. Johnson, D. Le, B. Maas, M. Manna, M. Pauls, M. Salim, A. Sami, P. Wright, M. Younis, S. Ahmed
Journal: Annals of Oncology (2021)
SARS-CoV-2 cell entry and targeted antiviral development
Authors: Zinuo Chen, Ruikun Du, Jazmin M. Galvan Achi, Lijun Rong, Qinghua Cui
Journal: Acta Pharmaceutica Sinica B (2021)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic coronavirus disease 2019 (COVID-19), which threatens human health and public safety. In the urgent campaign to develop anti-SARS-CoV-2 therapies, the initial entry step is one of the most appealing targets. In this review, we summarize the current understanding of SARS-CoV-2 cell entry, and the development of targeted antiviral strategies. Moreover, we speculate upon future directions toward next-generation of SARS-CoV-2 entry inhibitors during the upcoming post-pandemic era.
PEG-polyaminoacid based micelles for controlled release of doxorubicin: Rational design, safety and efficacy study
Authors: Silvia Brunato, Francesca Mastrotto, Federica Bellato, Chiara Bastiancich, Alessandra Travanut, Mariangela Garofalo, Giuseppe Mantovani, Cameron Alexander, Veronique Preat, Stefano Salmaso, Paolo Caliceti
Journal: Journal of Controlled Release (2021)
Abstract P052: Less Appendicular Lean Mass Adjusted For Body Mass Index Is Associated With Higher Incident Diabetes In Middle-aged Adults In The CARDIA Study
Authors: Melanie S Haines, Aaron Leong, Bianca Porneala, Victor W Zhong, Cora E Lewis, Pamela J Schreiner, Karen K Miller, James B Meigs, Mercedes R Carnethon
Journal: Circulation (2021)

Although less muscle mass is associated with greater diabetes prevalence in cross-sectional studies, prospective data in middle-aged Black and White adults are lacking. Middle age is a critical window as accelerated muscle loss is yet to occur, and preventing diabetes reduces lifelong morbidity and mortality. We hypothesized that lower appendicular lean mass adjusted for body mass index (ALM/BMI) is associated with higher incident diabetes in middle-aged Black and White adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study. ALM/BMI was measured by dual x-ray energy absorptiometry (DXA) in 2005-06 among middle-aged US men (n=855) and women (n=1045) in CARDIA. Incident diabetes occurred if any of the following were met in 2010-11 or 2015-16 among persons without diabetes in 2005-06: fasting glucose ≥7 mmol/L (126 mg/dL), 2-hour glucose ≥11.1 mmol/L (200 mg/dL) on a 75-gram glucose tolerance test, HbA 1C ≥48 mmol/mol (6.5%), or use of glucose-lowering medications. We used logistic regression models with sex stratification given sex differences in ALM. In men, mean age was 45.0 ± 3.5 y, BMI 28.0 ± 4.3 kg/m 2 , and ALM/BMI 1.07 ± 0.14 m 2 . In women, mean age was 45.2 ± 3.6 years, BMI 28.4 ± 6.4 kg/m 2 , and ALM/BMI 0.73 ± 0.12 m 2 . Diabetes developed in 70 men (8.2%) and 72 women (6.9%). For each standard deviation increase in ALM/BMI (m 2 ), the risk of diabetes decreased by 22% in men and 29% in women (Table 1). After adjusting for age, race, smoking, education, physical activity, and waist circumference, the association of ALM/BMI with diabetes incidence was no longer significant. Associations were similar between race-ethnic groups. In conclusion, less relative skeletal muscle mass is associated with a greater risk of developing diabetes in middle-aged men and women over 10 years, which is largely explained by the relationship of ALM/BMI to other metabolic risk factors. Low skeletal muscle mass in middle age is a marker for greater diabetes risk and may be a target for preventative interventions.
BET inhibitors repress expression of interferon-stimulated genes and synergize with HDAC inhibitors in glioblastoma
Authors: Olga Gusyatiner, Pierre Bady, Minh D T Pham, Yvonne Lei, Jungyeon Park, Roy T Daniel, Mauro Delorenzi, Monika E Hegi
Journal: Neuro-Oncology (2021)

Abstract Background The development of rational combination therapies is key to overcome inherent treatment resistance of glioblastoma (GBM). We aim at identifying new druggable targets by disturbing GBM cells with inhibitors of bromodomain and extra-terminal motif (BET) proteins to reveal cancer-relevant vulnerabilities that may sensitize to a second drug. BET proteins are epigenetic modulators and have been associated with proto-oncogene overexpression in cancer. Methods A GBM-derived sphere-line was treated with the BET inhibitor (BETi) JQ1 over a time-course of 48 hours, followed by RNA-sequencing. Four chromatin marks were investigated by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Signatures of interest were functionally validated in vitro and in orthotopic xenografts. Combination therapies were evaluated for synergistic effects. Results Cancer-relevant pathways significantly modulated by JQ1 comprised interferon alpha (IFN-α) response genes and response signatures to histone deacetylase inhibitors (HDACi). The IFN-signature was reminiscent of a GBM-derived IFN-signature comprising CD274 (PD-L1). Functional pathway analysis suggested that JQ1 was acting directly on the transcriptional level of IFN-response genes and not via the canonical JAK/STAT pathway. This was in line with JQ1 modulated expression and BRD4 and Pol II occupancy at IFN-signature genes, supporting a direct mechanistic interaction. Finally, we showed that combining HDACi with JQ1 acts synergistically in reducing cell viability of GS-lines. Conclusions Our approach identified BETi-induced vulnerabilities in cancer-relevant pathways, potentially amenable to synergistic combinatorial therapy, such as combination with HDACi. The direct inhibitory effect of BETi on IFN-responsive genes in GBM cells, including CD274, indicates modulation of the tumor immune landscape and warrants further studies.
72TiP ROSALINE: A phase II, single-arm, neoadjuvant study of targeting ROS1 in combination with endocrine therapy (ET) in invAsive Lobular carcINoma of the brEast
Authors: E. Agostinetto, M. Paesmans, L. Ameye, I. Veys, L. Buisseret, P. Neven, D. Taylor, C. Fontaine, F.P. Duhoux, J-L. Canon, H. Denys, F. Coussy, C. Chakiba, B. Pistilli, M. Piccart, M. Ignatiadis, P.G. Aftimos
Journal: Annals of Oncology (2021)
Perinatal Outcomes During the COVID-19 Pandemic in Ontario, Canada
Authors: Andrea N. Simpson, John W. Snelgrove, Rinku Sutradhar, Karl Everett, Ning Liu, Nancy N. Baxter
Journal: JAMA Network Open (2021)

Public health measures to control the COVID-19 pandemic may be associated with reduced risk of preterm birth (PTB).1,2 Conversely, avoidance of health care may be associated with increased risk of stillbirth.3 We evaluated rates of PTB and stillbirth during the first 6 months of the pandemic because previous studies conducted early in the pandemic have had inconsistent results.
Abstract 15207: The Risk of Alcohol Consumption Habit in Japanese Atrial Fibrillation Patients: The Fushimi Af Registry
Authors: KOSUKE DOI, Kenjiro Ishigami, Syuhei Ikeda, Yasuhiro Hamatani, Yoshimori An, MITSURU ISHII, Moritake Iguchi, Hisashi Ogawa, Nobutoyo Masunaga, Masahiro Esato, Hiromichi Wada, Koji Hasegawa, Mitsuru Abe, Masaharu Akao
Journal: Circulation (2020)

Background: Excessive alcohol intake is the risk of death, cerebrovascular event and bleeding. On the other hand, moderate drinking reduces the risk of cardiovascular event. However, the effect of alcohol consumption habit on mortality and cardiovascular event in AF patients remains unclear. Method: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, which is a typical urban district of Japan. We started to enroll patients from March 2011, and follow-up data were available for 4,466 patients by the end of November 2019. In the entire cohort, data of alcohol drinking were available for 2,944 patients. 834 patients drank daily, 554 socially and 1556 hardly (daily, socially and hardly group, respectively). Result: Compared with hardly groups, patients in daily and socially groups were younger, more often male, more in body weight and more likely to have persistent/permanent type AF. Daily and socially groups were less likely to have heart failure, chronic kidney disease and had lower CHA 2 DS 2 -VASc score. Hypertension and prior stroke/SE were the highest in daily group. Pulse rate, diabetes mellitus and prior bleeding were comparable between three groups. During the median follow-up of 1,482 days, the incidence rate of stroke/SE was significantly higher in hardly group than daily or socially groups (daily vs. socially vs. hardly: 1.19 vs. 1.11 vs. 1.49 per 100 person-years, respectively, log rank p=0.006). The incidence rates of all-cause death (2.45 vs. 3.15 vs. 4.44, p&lt;0.0001) and cardiac death (0.26 vs. 0.46 vs. 0.67, p=0.0004) were also significantly higher in hardly group than the other two groups. The incidence rate of major bleeding was not significantly different between three groups (1.35 vs. 1.20 vs. 1.30, p=0.39). On multivariate Cox regression analysis, daily drinking was significantly associated with lower risk of all-cause death and cardiac death. There was no other association between the groups. Conclusion: As compared with patients drinking alcohol, the risk of stroke/SE, all-cause death, cardiac death in hardly drinking patients were significantly higher. Daily drinking was significantly associated with lower risk of all-cause death and cardiac death.
124P Talazoparib in locally advanced or metastatic breast cancer patients: Experience from an early access program in Turkey
Authors: M.A.N. Sendur, B. Cakar, M. Hızal, E. Eraslan, S. Aksoy, S. Paydas, N. Demir, F. Sen, G. Bulut, K. Oruc, B. Oyan Uluc, N. Ozdemir, A. Sakin, D. Erdem, M. Ozkan, U. Disel, F. Ekinci, I.N. Okten, L. Ozer, E. Gokmen
Journal: Annals of Oncology (2021)
Genomic profiling of advanced cervical cancer to predict response to programmed death-1 inhibitor combination therapy: a secondary analysis of the CLAP trial
Authors: Xin Huang, Minjun He, Hongyu Peng, Chongjie Tong, Zhimin Liu, Xiaolong Zhang, Yang Shao, Dongqin Zhu, Junli Zhang, Jiani C Yin, Fan Yang, Chunyan Lan
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background The Camrelizumab Plus Apatinib in Patients with Advanced Cervical Cancer trial was a single-arm, phase II study that showed promising activity of the programmed death-1 (PD-1) inhibitor camrelizumab plus the vascular endothelial growth factor receptor-2 inhibitor apatinib in patients with advanced cervical cancer. However, the predictive biomarkers for treatment outcomes are unknown. In this study, we aimed to identify potential predictors of treatment response in PD-1 inhibitor combination therapy. Methods Genomic profiling was performed on patients with available biopsy or surgical samples by targeted next-generation sequencing of 425 cancer-related genes in this preplanned, secondary analysis. Somatic alterations, including all non-synonymous mutations, and tumor mutational burden (TMB) were assessed for their predictive values in objective response rate, progression-free survival (PFS), and overall survival (OS). Results A subset of 32 patients was included in this analysis. Top altered genes included PIK3CA (43.8%), STK11 (25%), FBXW7 (15.6%), and PTEN (15.6%). The PI3K/AKT pathway was among the most frequently dysregulated pathways, and its genetic alterations were identified in 68.8% of patients. PIK3CA (PFS HR 0.33, p=0.05; OS HR 0.23, p=0.04) and PTEN (PFS HR 3.71 e-09 , p=0.05; OS HR 3.64 e-09 , p=0.08) alterations were associated with improved outcomes. PI3K/AKT pathway genetic alterations showed improved predictive power compared with either PIK3CA or PTEN alterations alone (PFS HR 0.33, p=0.03; OS HR 0.25, p=0.02), while ERBB3 mutations (PFS HR 34.9, p&lt;0.001; OS HR 19.8, p&lt;0.001) correlated with poor survival. TMB-high (≥5 mut/Mb) was associated with prolonged PFS (HR 0.26, p&lt;0.01) and OS (HR 0.31, p=0.05). Multivariate analysis showed ERBB3 mutations (PFS p=0.01, OS p&lt;0.001), PD-L1 positive (PFS p=0.01, OS p=0.05), and high TMB (PFS p=0.01, OS p=0.05) remained significantly associated with survival. Conclusions We uncovered that genetic alterations in PIK3CA , PTEN , ERBB3 , and PI3K/AKT pathway, as well as TMB, could be novel predictive biomarkers in patients with cervical cancer treated with PD-1 inhibitor combination therapy. Trial registration number NCT03816553 .
Abstract 10959: Inhibition of CTRP9, a Novel and Cardiac-Abundantly Expressed Cell Survival Molecule, by TNFα-Initiated Oxidative Signaling Contributes to Exacerbated Cardiac Injury in Diabetic Mice
Authors: Hui Su, Yuexing Yuan, Xiaoming Wang, Wayne Bond Lau, Yajing Wang, Xiaoliang Wang, Erhe Gao, Walter Koch, Xin L Ma
Journal: Circulation (2012)

Of primarily adipocyte origin, the adipokine adiponectin (APN) is also expressed in cardiomyocytes. However, as cardiac expression of APN is extremely low (<1/120,000 of adipocytes), its physiologi...
Total Ischemic Event Reduction With Rivaroxaban After Peripheral Arterial Revascularization in the VOYAGER PAD Trial
Authors: Rupert M. Bauersachs, Michael Szarek, Marianne Brodmann, Ivan Gudz, Eike Sebastian Debus, Mark R. Nehler, Sonia S. Anand, Manesh R. Patel, Connie N. Hess, Warren H. Capell, Kevin Rogers, Eva Muehlhofer, Lloyd P. Haskell, Scott D. Berkowitz, William R. Hiatt, Marc P. Bonaca
Journal: Journal of the American College of Cardiology (2021)

Patients with peripheral artery disease (PAD) undergoing lower extremity revascularization (LER) are at high risk of major adverse limb and cardiovascular events. The VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) trial demonstrated that rivaroxaban 2.5 mg twice daily reduced first events by 15%. The benefit of rivaroxaban on total (first and subsequent) events in this population is unknown. This study sought to evaluate the total burden of vascular events in patients with PAD after LER and the efficacy of low-dose rivaroxaban on total events. VOYAGER PAD randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily plus aspirin or aspirin alone. The primary endpoint was time to first event of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The current analysis considered all events (first and subsequent) for components of the primary endpoint as well as additional vascular events including peripheral revascularizations and venous thromboembolism. HRs were estimated by marginal proportional hazards models. Among 6,564 randomized events, there were 4,714 total first and subsequent vascular events including 1,614 primary endpoint events and 3,100 other vascular events. Rivaroxaban reduced total primary endpoint events (HR: 0.86; 95% CI: 0.75-0.98; P = 0.02) and total vascular events (HR: 0.86; 95% CI: 0.79-0.95; P = 0.003). An estimated 4.4 primary and 12.5 vascular events per 100 participants were avoided with rivaroxaban over 3 years. Patients with symptomatic PAD who are undergoing LER have a high total event burden that is significantly reduced with rivaroxaban. Total event reduction may be a useful metric to quantify the efficacy of rivaroxaban in this setting. (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities [VOYAGER PAD]; NCT02504216)
Abstract 16170: Impact of Anemia on Outcomes in Patients With Heart Failure With Preserved Ejection Fraction: A Meta-analysis
Authors: Monil Majmundar, Ashish Kumar, Rajkumar P Doshi, Palak shah, Mariam Shariff, devina adalja, Tikal Kansara, Vivekkumar Rakholiya, Harshvardhan Zala, Savi Mushiyev, Ferdinand Visco
Journal: Circulation (2020)

Introduction: The effect of anemia on outcomes in Heart failure with preserved ejection fraction (HFpEF) patients is not well-established. Some previous studies have shown increased mortality and hospitalizations in HFpEF patients with anemia. Hypothesis: We hypothesize that anemia affects all-cause mortality and hospitalization in HFpEF patients. Methods: A review of literature for studies comparing outcomes in HFpEF with and without anemia was done in PubMed, MEDLINE, and EMBASE databases through June 1st, 2020. The standard definitions of HFpEF and anemia were used for inclusion criteria. Two investigators extracted the study data independently. The primary outcome of interest was all-cause mortality. The secondary outcome was all-cause hospitalizations. We used the PM estimator of Tau with Knapp-Hartung adjustment to pool adjusted hazard ratio (HR) and 95% confidence interval (CI). P curve analysis was used to assess publication bias. R version 3.6.2 was used for all statistical analyses. Results: Seven studies (23,424 patients) were included in the final analysis. Anemia in patients with HFpEF was associated with higher rates of all-cause mortality [HR: 1.35, 95% CI: 1.17-1.55]. Additionally, anemia in HFpEF patients was associated with higher rates of all-cause hospitalization [HR: 1.22, 95% CI: 1.03-1.44]. P curve analysis for all-cause mortality didn’t report publication bias or P hacking (Figure) . Conclusions: Anemia in HFpEF patients was associated with higher rates of all-cause mortality and all-cause hospitalizations compared to HFpEF patients without anemia.
Percutaneous Mitral Valve Annuloplasty in Patients With Secondary Mitral Regurgitation and Severe Left Ventricular Enlargement
Authors: Stefan D. Anker, Randall C. Starling, Muhammad Shahzeb Khan, Tim Friede, Gerasimos Filippatos, JoAnn Lindenfeld, Ralph Stephan von Bardeleben, Andrew J.S. Coats, Javed Butler
Journal: JACC Heart Failure (2021)

This study sought to determine the effect of percutaneous mitral valve annuloplasty with the Carillon device versus guideline-directed medical therapy (GDMT) alone in patients with secondary mitral regurgitation (MR) and severe left ventricular (LV) enlargement. The clinical impact of the Carillon device in patients with severe LV dilation is not well established. This is a pooled analysis involving 3 prospective trials (TITAN [Transcatheter Implantation of Carillon Mitral Annuloplasty Device], TITAN II, and REDUCE FMR [CARILLON Mitral Contour System for Reducing Functional Mitral Regurgitation] trials) in which patients with functional MR and severe LV enlargement (LV end-diastolic diameter >65 mm) were treated with GDMT and the Carillon device versus GDMT alone. Key outcomes of this analysis were changes over 1 year of follow-up in mitral valve and LV echocardiographic parameters, functional outcome, quality of life, mortality, and heart failure hospitalization (HFH). A total of 95 patients (67 in the Carillon group, 28 in the GDMT group) with severe LV enlargement were included. In the Carillon group, all mitral valve and LV morphology parameters were significantly improved at 1 year. Regurgitant volume decreased by 12 ml (p < 0.001), MR grade decreased by 0.6 U (p < 0.001), LV end-diastolic volume decreased by 25 cm3 (p = 0.005), and LV end-systolic volume decreased by 21 cm3 (p = 0.01). Significant functional improvement differences were also noted between the Carillon group and the GDMT group including an improvement of Kansas City Cardiomyopathy Questionnaire score (15 ± 4 vs. 6 ± 6; p = 0.03). The incidence of HFH was 29.9% versus 50.0% and the cumulative rate of HFH was 0.43 versus 0.75 (p < 0.001). In patients with functional MR and severe LV enlargement, the Carillon device improved mitral valve function, LV morphology, and functional outcome compared with patients receiving GDMT only. Preoperative LV dimension should not be a limiting factor when evaluating patient eligibility or anticipated response to therapy with the Carillon device.