tbuckley/cabot-search huggingface dataset:
Abstract 16043: Pulmonary Artery Proportional Pulse Pressure Predicts Adverse Clinical Outcomes in Advanced Heart Failure
Authors: Sula Mazimba, Jaime L Kennedy, James Bergin, Jose A Tallaj, Mohammad Abuannadi, Kenneth C Bilchick
Journal: Circulation (2015)

Introduction: There is increasing interest in ventriculo-arterial hemodynamics in heart failure (HF). Hypothesis: Based on the normal physiological distribution of Pulmonary artery (PA) systolic pressure (PASP) being more than twice the PA diastolic pressure (PADP), we hypothesized that PA proportional pressure (PAPP), defined as (PASP-PADP)/PASP, would be associated with clinical outcomes using data from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. Methods: Multivariable Cox proportional hazards and logistic regression was performed using independent covariates of creatinine at discharge, PAPP, and pulmonary capillary wedge pressure (PCWP) (based on final hemodynamic measurement) for the 6-month outcome of death, transplant, left ventricular assist device (LVAD), or rehospitalization (DTxLVADHF), as well as secondary outcomes of death alone and death, transplant, or LVAD (DTxLVAD). Results: Among n=175 patients, there were 110 (62.9 %) and 65 (37.1%), respectively, with optimal PAPP (&gt; 0.50) and non-optimal PAPP (&lt;=0.50). During 6 months of follow-up, 15.5% and 33.9%, respectively, died in these 2 groups (p=0.008). In Cox models adjusted for final PCWP and creatinine at discharge, an increase of 0.10 in the final PAPP (continuous variable, range 0-1) was associated with a 26.4% reduction in DTxLVADHF (HR 0.736, 95% CI = 0.592-0.913). Furthermore, non-optimal PAPP status was associated with increased risk for the outcomes of DTxLVADHF, DTxLVAD, and death alone with hazard ratios of 1.82 (95% CI 1.22-2.73), 2.09 (95% CI 1.09-4.02), and 2.72 (95% CI 1.29-5.72), respectively. The AUC obtained with multivariable logistic regression for the outcome of death with the model containing final PAPP, final PCWP, and creatinine at discharge was 0.804 (p&lt;0.0001), with p&lt; 0.05 for the odds ratios of each covariate in the model. Conclusions: PAPP at final hemodynamic measurement in patients undergoing hemodynamically guided therapy for ADHF is strongly associated with adverse clinical outcomes even after adjustment for final PCWP and creatinine at discharge. These results have important clinical implications for hemodynamic targets in patients treated for ADHF.
Association of Assisted Reproductive Technologies With Arterial Hypertension During Adolescence
Authors: Théo A. Meister, Stefano F. Rimoldi, Rodrigo Soria, Robert von Arx, Franz H. Messerli, Claudio Sartori, Urs Scherrer, Emrush Rexhaj
Journal: Journal of the American College of Cardiology (2018)
Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell–Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis
Authors: Johanna Steen, Björn Forsström, Peter Sahlström, Victoria Odowd, Lena Israelsson, Akilan Krishnamurthy, Sara Badreh, Linda Mathsson Alm, Joanne Compson, Daniel Ramsköld, Welcome Ndlovu, Stephen Rapecki, Monika Hansson, Philip J. Titcombe, Holger Bang, Daniel L. Mueller, Anca I. Catrina, Caroline Grönwall, Karl Skriner, Peter Nilsson, Daniel Lightwood, Lars Klareskog, Vivianne Malmström
Journal: Arthritis & Rheumatology (2018)

Objective Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis ( RA ), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies ( mA b) derived from RA synovial plasma cells and address the question of antigen cross‐reactivity. Methods IgG‐secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full‐length mA b (n = 93) and also as germline‐reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mA b to promote osteoclastogenesis were investigated. Results Four unrelated anti–citrullinated protein autoantibodies ( ACPA s), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA . The ACPA s recognized &gt;3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell–derived mA b were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay. Conclusion These findings suggest that the high level of cross‐reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.
Abstract MP61: Dairy Products Such as Milk are Associated with a Lower Risk of Hypertension in Singapore Chinese
Authors: Mohammad Talaei Pashiri, An Pan, Jian-Min Yuan, Woon-Puay Koh
Journal: Circulation (2016)

Introductions: Dairy products are rich sources of calcium. Epidemiologic evidence from Western populations suggests that intake of dairy products and calcium may reduce risk of hypertension. However, there are few reports from Asian populations which generally have lower consumption of dairy products and calcium than their Western counterparts. Hypothesis: The association between intake of calcium and dairy products and risk of developing hypertension was evaluated in a prospective cohort study. Methods: This study was based on the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women aged 45-74 years at enrolment in 1993-1998 living in Singapore. The analysis included 37,124 participants who had no history of cancer, physician-diagnosed hypertension, and cardiovascular disease at recruitment. Diet at baseline was assessed using a validated 165-item semi-quantitative food-frequency questionnaire. The incident hypertension was defined as physician-diagnosed hypertension that the study subject reported during two follow-up interviews during 1999-2004 and 2006-2010, respectively. Cox proportional hazard regression method was used to calculate hazard ratios (HRs) and 95% confidence interval (CI) for incident hypertension associated with intake of calcium and dairy products with adjustment for potential confounders. Results: During 354,226 person-years of follow-up, we identified 13,148 new cases of hypertension. Milk accounted for about 80% of all dairy products consumed in this population. Among all study subjects, 67% (n=24,832) hardly drank milk, 9% (n=3,236) drank at least monthly, 9% (n=3,394) drank at least weekly, and 15% (n=5,662) drank daily. Non-dairy calcium intake contributed up to 76% of total calcium intake. Compared to non-drinkers, those who drank milk daily had a statistically significant 7% lower risk of hypertension (HR 0.93; 95% CI 0.89-0.98, P -trend=0.005) after controlling for other potential lifestyle and diet risk factors and supplement usage. The intake of all dairy food was inversely associated with risk of hypertension in a dose-dependent manner: the HR (95% CI) for the second, third, and fourth quartile was 0.96 (0.92-1.02), 0.98 (0.93-1.03) and 0.93 (0.88-0.98), respectively, compared with the lowest quartile ( P -trend=0.005). While total calcium intake was inversely associated with hypertension risk (HR comparing extreme quartiles 0.93; 95% CI 0.88-0.98; P -trend=0.002) there was a null association between non-dairy calcium intake and hypertension risk (HR comparing extreme quartiles 1.00; 95% CI 0.92-1.08; P -trend=0.89). Conclusions: Consumption of milk and other dairy products may offer beneficial effect on reducing risk of hypertension in Chinese population. This beneficial effect might be independent of calcium in the dairy food.
Is GPNMB the Achilles' Heel of Mo-MDSC While Marking Their Suppressive Activity?
Authors: Mario P. Colombo
Journal: Clinical Cancer Research (2018)

Glycoprotein nonmetastatic B/DC-Hil/Osteoactivin on myeloid-derived suppressor cells impairs T lymphocytes through the binding of Syndecan-4, delineating a new checkpoint pair to be targeted perhaps in combination with PD-1/PD-L1 blockage.See related article by Kobayashi et al., p. 828.
Cardiac scan nearly halves future risk of heart attack in patients with chest pain, finds study
Authors: Susan Mayor
Journal: BMJ (2018)

Investigating patients with stable chest pain using coronary computed tomographic angiography (CTA) nearly halves their risk of death due to coronary heart disease or of non-fatal myocardial infarction over the next five years, a study has shown.1 This was first randomised trial to investigate adding this type of scan to standard care.

“This relatively simple heart scan ensures that patients get the right treatment,” said lead author David Newby, from the British Heart Foundation Centre for Cardiovascular Science at the University of Edinburgh.

“This is the first time that CT guided management has been …
Hypertensive Disorders of Pregnancy and 10-Year Cardiovascular Risk Prediction
Authors: Jennifer J. Stuart, Lauren J. Tanz, Nancy R. Cook, Donna Spiegelman, Stacey A. Missmer, Eric B. Rimm, Kathryn M. Rexrode, Kenneth J. Mukamal, Janet W. Rich-Edwards
Journal: Journal of the American College of Cardiology (2018)
Abstract 19593: Sirtuin-3 is Essential for Glucagon-like Peptide-1-mediated Restoration of Diabetic Cardiomyopathy
Authors: Akio Monji, Yasuko K Bando, Haruya Kawase, Hiroyuki Nishimura, Morihiko Aoyama, Toko Mitsui, Toyoaki Murohara
Journal: Circulation (2015)

Introduction: Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase and its expression is increased by fasting and exercise in skeletal muscle; however, the impact of anti-diabetic intervention on diabetic myocardium remained uncertain. Hypothesis: We hypothesized that the anti-diabetic remedy glucagon-like peptide-1 agonist (exendin-4; Ex4) may ameliorate mitochondrial remodeling observed in diabetic cardiomyopathy. Methods: Type 2 diabetic mice [T2DM; KKAy and dietary diabetes induced by high fat and high sucrose diet (HF/HS), male 14-16 w/o] and age- and gender-matched SIRT3 knockout mice with dietary diabetes (sirHF/HS) diet were allocated into Ex4 (24 nmole/kg/day for 40 days) and vehicle (CON) groups. Results: T2DM-CON and sirHF/HS-CON exhibited myocardial hypertrophy, increased fibrosis, decreased cardiac capillary density, and defragmented mitochondria, which were reversed by Ex4. Consistently with the changes in mitochondrial morphology, the mitochondrial regulatory proteins mitofusin-1 (Mfn1) and mitofusin-2 (Mfn2) ratio was reduced in T2DM-CON and sirHF/HS-CON, which were ameliorated by Ex4 treatment exclusively to T2DM-CON. T2DM-CON exhibited decrease in cardiac SIRT3 level compared to nondiabetic counterpart, which was ameliorated by Ex4. Interestingly, cardiac remodeling of sirHF/HS-CON remained unchanged by Ex4 treatment, exclusively to cardiac capillary density. T2DM-CON and sirHF/HS-CON exhibited decrease in cardiac cyclic AMP level, which were attenuated by Ex4. The GLP-1 inactive analog (Ex9-39) failed to increase cardiac cyclic AMP concentration in mouse heart. In vitro analysis using cultured cardiomyocytes revealed that increase in intracellular cAMP levels by isoprotelenol (10microM) or 8-bromo-cyclic AMP (10 microM) enhanced SIRT3 mRNA, which was reversed by protein kinase A (PKA) inhibition. Conclusions: Our results indicate that Ex4 reversed abnormal suppression of SIRT3 in mitochondria of diabetic heart via restoration of cardiac cAMP.
Abstract 15691: Myocardial Annular Velocity Change During Mental Stress Predicts Outcome in Patients With Stable Coronary Artery Disease
Authors: Fawaz A Alenezi, Beverly Brummett, Stephen Boyle, Zainab Samad, Michael Babyak, Jennifer Wilson, Julia Sun, Brenda Sedberry, Mads Ersboll, Christopher O’Connor, Svati Shah, Eric Velazquez, Wei Jiang
Journal: Circulation (2016)

Introduction: Mental stress-induced myocardial ischemia (MSIMI) is common and a prognostic factor of adverse cardiovascular outcomes in patients with coronary artery disease (CAD). While baseline m...
HDAC inhibition improves autophagic and lysosomal function to prevent loss of subcutaneous fat in a mouse model of Cockayne syndrome
Authors: Marc Majora, Kevin Sondenheimer, Maren Knechten, Ingo Uthe, Charlotte Esser, Alfonso Schiavi, Natascia Ventura, Jean Krutmann
Journal: Science Translational Medicine (2018)

The HDAC inhibitor SAHA rescues the skin phenotype in CSB-deficient mice by enhancing protein acetylation and inducing autophagy.
Capsid-CPSF6 Interaction Licenses Nuclear HIV-1 Trafficking to Sites of Viral DNA Integration
Authors: Vasudevan Achuthan, Jill M. Perreira, Gregory A. Sowd, Maritza Puray-Chavez, William M. McDougall, Adriana Paulucci-Holthauzen, Xiaolin Wu, Hind J. Fadel, Eric M. Poeschla, Asha S. Multani, Stephen H. Hughes, Stefan G. Sarafianos, Abraham L. Brass, Alan N. Engelman
Journal: Cell Host & Microbe (2018)
Abstract 17874: Aerobic Exercise Training Improves Exercise Capacity, Reduces Arrhythmia Susceptibility but Does Not Normalize Ryanodine Receptor Mediated Aberrant Calcium Release in Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Zoe Swain, Hsiang-Ting Ho, Minori Minagawa, Bjorn C Knollmann, Sandor Gyorke, Muthu Periasamy, Anuradha Kalyanasundaram
Journal: Circulation (2015)

Introduction: Loss of Calsequestrin (CASQ2) promotes abnormal calcium (Ca2+) release events via the cardiac Ryanodine receptor (RyR2) during adrenergic stimulation, which trigger Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Rationale: Since aerobic exercise training (AET) has been shown to normalize Sarcoplasmic reticulum (SR) Ca2+ cycling parameters in diseased hearts, we explored if AET impacts RyR2 dysfunction and CPVT susceptibility in CASQ2-/- mice. Methods and Results: Age matched wildtype (WT) and CASQ2-/- male mice (n=8) were subjected to treadmill running for 6 weeks (16mts/min for 1hr, 5 days/week at 10% incline). Subsequently, a graded exercise test showed that sedentary (Sed) CASQ2-/- mice have a significantly lower exercise capacity relative to SedWT. Compared to trained (Ex) WT mice, AET moderately increased maximal running speed, time, and RER values in ExCASQ2-/- mice, indicating improved aerobic capacity. Electrocardiographic analyses showed that ExCASQ2-/- mice were resistant to triggered arrhythmias compared to their Sed controls. Spectral analyses of heart rate variability indicated that the high frequency band power increased significantly in ExCASQ2-/- mice, especially during Isoproterenol (Iso) challenge compared to ExWT. Despite fewer arrhythmias, confocal Ca2+ imaging revealed that ExCASQ2-/- ventricular cardiomyocytes are prone to spontaneous Ca2+ sparks and waves even at baseline (compared to ExWT) along with a concomitant decrease in Ca2+ transient amplitude and SR Ca2+ load, both at baseline and during Iso challenge. Conclusions: Our results thus far indicate that AET partially improves exercise capacity and aerobic fitness in the CASQ2-/- mouse model of CPVT. Paradoxically, although arrhythmia incidence is reduced, RyR2 mediated dysfunctions in SR Ca2+ cycling are not normalized after 6 weeks of AET. Importantly, the parasympathetic tone is significantly enhanced in the ExCASQ2-/- mice particularly during Iso challenge. Ongoing studies will address mechanisms (SR protein expression, post translational modifications and pharmacological interventions to investigate the observed autonomic imbalance) that could underlie the intriguing effects of exercise in this model of CPVT.
The c-Myc-regulated lncRNA NEAT1 and paraspeckles modulate imatinib-induced apoptosis in CML cells
Authors: Chengwu Zeng, Sichu Liu, Shuai Lu, Xibao Yu, Jing Lai, Yifan Wu, Shaohua Chen, Liang Wang, Zhi Yu, Gengxin Luo, Yangqiu Li
Journal: Molecular Cancer (2018)

Chronic myeloid leukemia (CML) is a clonal disease characterized by the presence of the constitutively active tyrosine kinase BCR-ABL oncoprotein. Although BCR-ABL is crucially important for pathogenesis and treatment response, it is thought that some additional factors might be involved in the regulation of these processes. Aberrant expression of long noncoding RNAs (lncRNAs) has recently been identified to be involved in various diseases including cancer, suggesting that lncRNAs may play a role in BCR-ABL-mediated CML. In this study, we found that nuclear-enriched abundant transcript 1 (NEAT1), a lncRNA essential for the formation of nuclear body paraspeckles, is significantly repressed in primary CML cells. NEAT1 expression could be restored by inhibiting BCR-ABL expression or its kinase activity in K562 cells. We also demonstrated that NEAT1 is regulated by c-Myc. Knockdown of NEAT1 could promote imatinib (IM)-induced apoptosis, and we demonstrated that the NEAT1-binding paraspeckle protein splicing factor proline/glutamine-rich (SFPQ) is required for NEAT1-mediated apoptosis in K562 cells. RNA-seq analysis revealed that SFPQ regulates cell growth and death pathway-related genes, confirming its function in IM-induced apoptosis. Collectively, these results assign a biological function to the NEAT1 lncRNA in CML apoptosis and may lead to fuller understanding of the molecular events leading to CML.
Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With <i>EGFR</i>-Mutated, MET Factor–Dysregulated Non–Small-Cell Lung Cancer
Authors: Yi-Long Wu, Li Zhang, Dong-Wan Kim, Xiaoqing Liu, Dae Ho Lee, James Chih-Hsin Yang, Myung-Ju Ahn, Johan F. Vansteenkiste, Wu-Chou Su, Enriqueta Felip, Vincent Chia, Sabine Glaser, Philippe Pultar, Sylvia Zhao, Bin Peng, Mikhail Akimov, Daniel S.W. Tan
Journal: Journal of Clinical Oncology (2018)

MET dysregulation occurs in up to 26% of non-small-cell lung cancers (NSCLCs) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Capmatinib (INC280) is a potent and selective MET inhibitor with preclinical activity in combination with gefitinib in EGFR-mutant, MET-amplified/overexpressing models of acquired EGFR-TKI resistance. This phase Ib/II study investigated the safety and efficacy of capmatinib plus gefitinib in patients with EGFR-mutated, MET-dysregulated (amplified/overexpressing) NSCLC who experienced disease progression while receiving EGFR-TKI treatment.Patients in phase Ib received capmatinib 100- to 800-mg capsules once per day or 200- to 600-mg capsules or tablets twice per day, plus gefitinib 250 mg once per day. Patients in phase II received the recommended phase II dose. The primary end point was the overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.Sixty-one patients were treated in phase Ib, and 100 were treated in phase II. The recommended phase II dose was capmatinib 400 mg twice per day plus gefitinib 250 mg once per day. Preliminary clinical activity was observed, with an ORR across phase Ib/II of 27%. Increased activity was seen in patients with high MET-amplified tumors, with a phase II ORR of 47% in patients with a MET gene copy number ≥ 6. Across phases Ib and II, the most common drug-related adverse events were nausea (28%), peripheral edema (22%), decreased appetite (21%), and rash (20%); the most common drug-related grade 3/4 adverse events were increased amylase and lipase levels (both 6%). No significant drug-drug interactions between capmatinib and gefitinib were evident.This study, focused on a predominant EGFR-TKI resistance mechanism in patients with EGFR-mutated NSCLC, shows that the combination of capmatinib with gefitinib is a promising treatment for patients with EGFR-mutated, MET-dysregulated NSCLC, particularly MET-amplified disease.
Is This How It's Supposed to Be?
Authors: Maria Maldonado
Journal: Annals of Internal Medicine (2018)

On Being a Doctor4 September 2018Is This How It's Supposed to Be?Maria Maldonado, MDMaria Maldonado, MDMount Sinai Health System, New York, New York (M.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M18-0782 Audio Reading - “Is This How It's Supposed to Be?” Audio. Virginia L. Hood, MD, reads "Is This How It's Supposed to Be?," by M. Maldonado. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail It was what we call a bread-and-butter encounter. After I took my new patient's medical history, I asked him to put on a gown. He looked surprised. I wondered whether this was how his former physician learned to save time, by examining him in his street clothes. I told him I'd be back in a moment.Mr. J was 79 years old. He was tall and slightly balding, with strong, roughened hands that spoke of years of hard work. He was born in Guyana and had lived in the United States for most of his life. He had worked as ... Author, Article, and Disclosure InformationAffiliations: Mount Sinai Health System, New York, New York (M.M.)Corresponding Author: Maria Maldonado, MD, Icahn School of Medicine at Mount Sinai, 1010 North Broadway, Yonkers, NY 10701; e-mail, [email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “Is This How It's Supposed to Be?” Audio. Virginia L. Hood, MD, reads "Is This How It's Supposed to Be?," by M. Maldonado. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetailsSee AlsoAnnals On Call - Is This How It Is Supposed to Be? Robert M. Centor and Maria Maldonado Metrics 4 September 2018Volume 169, Issue 5Page: 347-348KeywordsAcademic medicineHealth careHeartMotivationOsteoarthritisPatientsPrimary care physiciansProstate cancerProstatectomyResidency ePublished: 4 September 2018 Issue Published: 4 September 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...