tbuckley/cabot-search huggingface dataset:
Tumor Mutational Burden as a Predictor of Immunotherapy Response: Is More Always Better?
Authors: John H. Strickler, Brent A. Hanks, Mustafa Khasraw
Journal: Clinical Cancer Research (2020)

Abstract Immune checkpoint inhibitors, including antibodies that block programmed cell death protein-1 (PD-1) and PD-L1, have transformed the management of many cancers. However, the majority of patients have primary or acquired resistance to these immunotherapies. There is a significant unmet need for predictive biomarkers that can reliably identify patients who derive a clinically meaningful response from PD-1/PD-L1 blockade. High tumor mutational burden (TMB-H) has shown promise as a biomarker in lung cancer, but the broad applicability of TMB-H as a biomarker of response across all solid tumors is unclear. The FDA has approved the PD-1 inhibitor, pembrolizumab, as a therapy for all solid tumors with TMB equal to or greater than 10 mutations/megabase as measured by the FoundationOne CDx assay. This approval was based on an exploratory analysis of the KEYNOTE-158 study, which was a single-arm, phase II multi-cohort study of pembrolizumab for select, previously treated advanced solid tumors. Here, we elucidate the caveats of using TMB as a biomarker with a universal threshold across all solid tumors. While we recognize the importance of this and other FDA pan-cancer approvals, several questions about TMB as a predictive biomarker remain unanswered. In this perspective, we discuss clinical trial evidence in this area. We review the relationship between TMB and the tumor immune microenvironment. We highlight the risks of extrapolating evidence from a limited number of tumor histologies to all solid tumors, and we propose avenues for future research.
Abstract 14960: Empagliflozin Reduces the Total Burden of Cardiovascular Events Including Recurrent Events in the EMPA-REG OUTCOME Trial
Authors: David H Fitchett, Silvio E Inzucchi, Bernard Zinman, Christoph Wanner, Stefan D Anker, Stuart Pocock, Stefan Kaspers, Jyothis T George, Odd Erik Johansen, Waheed Jamal, Stefan Hantel, Søren S Lund
Journal: Circulation (2020)

Introduction: In EMPA-REG OUTCOME, empagliflozin (EMPA) reduced the risk of major adverse cardiovascular (CV) events (MACE), CV mortality and hospitalization for heart failure (HHF) in analyses of first events in patients with type 2 diabetes (T2D) and atherosclerotic CV disease (ASCVD). We assessed the effect of EMPA on the total burden of CV events. Methods: Patients were randomized to EMPA 10 mg, EMPA 25 mg, or placebo. We assessed the effects of EMPA pooled vs placebo on any (first plus recurrent) adjudicated CV event (composite of myocardial infarction (MI), stroke, coronary revascularization (CR), hospitalization for unstable angina, transient ischemic attack, HHF, and CV death) using a negative binomial model. Results: Among 7,020 treated patients (mean [SD] age 63 [9] years), there were 2,142 total adjudicated CV events, most frequently CR (585), MI (421), and HHF (321). EMPA reduced the risk of total adjudicated CV events by 24% vs placebo (event rate ratio (95% CI): 0.76 (0.67, 0.87), p&lt;0.0001) (Figure). Risk reductions were driven predominantly by reductions in HHF (0.58 (0.42, 0.81), p=0.0012), MI (0.79 (0.620, 0.998), p=0.0486), and CV death (0.62 (0.49, 0.77), p&lt;0.0001). The estimated number of total CV events prevented with EMPA was 414.4, and the number of patients needed to treat over 3 years to prevent one event was 10.2 (6.6, 22.7). Conclusions: EMPA produced a sizeable risk reduction in the total burden of any adjudicated CV outcome, including HHF, MI and CV death, in patients with T2D and ASCVD.
Ivabradine: A Ray of Hope for Inappropriate Sinus Tachycardia⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Melvin M. Scheinman, Vasanth Vedantham
Journal: Journal of the American College of Cardiology (2012)
Treatment of depression.
Authors: S Lieberman
Journal: BMJ (1977)

some studies.As an example of a possible relationship between malignant lymphoma and PMR on this ground they refer to a case described by usI in which malignant lymphoma occurred four years after the diagnosis of PMR was made.Among our 54 patients with PMR we have recently reported another case', in which chronic lymphatic leukaemia developed five years after the onset of typical PMR.In this patient lymphocytic infiltration was detected in renal, liver, and muscle biopsy specimens at the time of diagnosis of PMR, when the number of lymphocytes in the peripheral blood and bone marrow was normal.The significance of the combination of the two diseases in this patient is unclear.It may simply be the coincidental coexistence of two diseases, both relatively common in elderly people.However, the clinical course does point to a more direct relationship.Histocompatibility antigens have been studied in patients with chronic lymphatic leukaemia, but, so far as I know, no increase in any specific HLA haplotype has been shown.
Abstract 13873: Arterial Stiffness in Response to Eight Weeks of Exercise Training in African Americans versus Caucasians
Authors: Chueh-lung Hwang, Melissa M Rader, Laurel A Thur, Jerome Javier, Gaurav V Dambal, Richard S Severin, Yuliya Drab, Bo Fernhall, Shane A Phillips
Journal: Circulation (2020)

Introduction: Arterial stiffness predicts risks of cardiovascular disease in apparently healthy individuals. Exercise training decreases risks of cardiovascular disease, potentially via reductions in arterial stiffness. Compared with Caucasians, African Americans have higher risks of cardiovascular disease. However, lack of evidence supports the beneficial effects of arterial stiffness in African Americans. We hypothesize that arterial stiffness decreases in African Americans following eight weeks of exercise training and the effect is similar compared with Caucasians. Methods: A total of 13 African American and 10 Caucasian men and women, free of cardiovascular disease participated this study (age: 38±2 yrs; body mass index: 31.0±1.1 kg/m 2 ; systolic blood pressures: 125±2 mmHg, diastolic blood pressure: 78±2 mmHg; mean±SE). Participants performed either aerobic exercise (65-85% of heart rate reserve) or resistance exercise (8-12 repetitions at 65-85% of 10-RM) for 30-45 minutes/time, three times/week for eight weeks. Arterial stiffness, assessed by carotid-to-femoral pulse wave velocity (cfPWV), and aortic blood pressure (BP) were measured by using the cuff-based SphygmoCor Xcel before and after the exercise training. Results: After the eight weeks of exercise training, cfPWV did not change in all participants, regardless of African Americans (6.7±0.3 vs. 6.5±0.3 m/sec; pre- vs. post-intervention) or Caucasians (6.3±0.4 vs. 6.0±0.3 m/sec; P=0.9 for raceхtime interaction, P=0.08 for time, and P=0.3 for race effect). Aortic systolic BP (African Americans: 123±5 vs. 120±3 mmHg and Caucasians: 111±2 vs. 110±3 mmHg; P=0.6 for raceхtime interaction, P=0.2 for time, and P=0.02 for race effect) and aortic diastolic BP (African Americans: 85±3 vs. 83±2 mmHg and Caucasians: 75±3 vs. 74±3 mmHg; P=0.6 for raceхtime interaction, P=0.5 for time, and P=0.01 for race effect) remained unchanged with the exercise training. Conclusions: An eight-week exercise training may not improve arterial stiffness in African Americans, and the effect appears to be similar in Caucasians.
Evinacumab in Patients with Refractory Hypercholesterolemia
Authors: Robert S. Rosenson, Lesley J. Burgess, Christoph F. Ebenbichler, Seth J. Baum, Erik S.G. Stroes, Shazia Ali, Nagwa Khilla, Robert Hamlin, Robert Pordy, Yuping Dong, Vladimir Son, Daniel Gaudet
Journal: New England Journal of Medicine (2020)

Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known.In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo.In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups.In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).
Abstract 14895: Shear Stress-induced Endothelial Inflammatory Response and EndMT Promote Adverse Remodeling in a Microengineered Coronary-artery-on-a-chip
Authors: Peng Zhao, Qingzhou Yao, Lihua Ao, Michael Jarrett, Peijian Zhang, Erlinda The, Yufeng Zhai, David Fullerton, Xianzhong Meng
Journal: Circulation (2020)

Background: Atherosclerotic lesions preferentially occur at bifurcations and branching points where blood flow exerts low and bidirectional oscillatory shear stress (OSS) to the vascular walls. This study aims to determine the role of OSS in the induction of inflammatory activation and phenotypic transition in coronary artery endothelial cells and investigate the interaction between endothelial cells and smooth muscle cells in a coronary-artery-on-a-chip. Methods and Results: A three-dimensional microengineered human coronary-artery-on-a-chip was developed and incorporated with OSS to mimic the flow patterns within the microenvironment of coronary artery in atheroprone regions. Human coronary artery endothelial cells (HCAECs) were cultured on the upper surface of a collagen I-coated membrane, and human coronary artery smooth muscle cells (HCASMCs) were seeded on the opposite side of the membrane. Single-cell RNA sequencing analysis revealed that HCAECs were segregated into four subgroups after being exposed to OSS for 24 h, and inflammatory response and EndMT-related genes were enriched simultaneously in most HCAECs. OSS-induced inflammatory response and EndMT in HCAECs were confirmed by immunoblotting and immunofluorescence, and these changes were mediated by the Notch1/p38 MAPK-NF-κB signaling pathways. Moreover, HCAECs exposed to OSS induced extracellular matrix (ECM) protein remodeling and proliferation in HCASMCs through a paracrine mechanism. Multiplex ELISA analysis identified that RANTES exhibited the greatest increase after OSS in HCAEC culture and played a major role in modulation of ECM protein remodeling in HCASMCs. Further, IL-37 was able to prevent OSS-induced inflammatory response and EndMT in HCAECs and thereby abrogated ECM protein remodeling and proliferation in HCASMCs. Conclusion: OSS provokes inflammatory response and EndMT in HCAECs through activating the Notch1/p38 MAPK-NF-κB signaling pathways. The novel findings demonstrate that OSS-induced endothelial inflammatory response and associated EndMT promote vascular adverse remodeling and that anti-inflammatory cytokine IL-37 may have therapeutic potential for suppressing endothelial changes and resultant vascular adverse remodeling.
Abstract 15048: Ischaemic Pre-conditioning: A Non-invasive Intervention That Improves Maternal Endothelial Function in Women With Preeclampsia And at Risk of Preeclampsia
Authors: Tamara Kubba, Sean M Davidson, David Williams
Journal: Circulation (2020)

Introduction: Preeclampsia is a pregnancy syndrome defined by the gestational onset of hypertension and proteinuria and characterised by maternal endothelial dysfunction with placental ischaemia. Preeclampsia affects approximately 4% of first-time pregnant mothers, but approximately 20% of women with pre-existing hypertension. Ischaemic pre-conditioning (IPC) is a phenomenon whereby transient episodes of ischaemia protect against future ischaemic injury. IPC has never previously been studied in pregnant women. We investigated whether IPC could improve maternal endothelial function in women at risk of preeclampsia and with preeclampsia. Hypothesis: We hypothesised that IPC would improve maternal endothelial function in women with preeclampsia and at risk of preeclampsia. Methods: We measured brachial artery flow mediated dilatation (FMD), before and after IPC in 3 groups of pregnant women between 24+0 and 36+6 weeks gestation: normotensive pregnancy (n=42), at risk of preeclampsia (n=20) and established preeclampsia (n=11). Following a baseline measure of brachial artery FMD, 3 cycles of 5-minutes of upper arm ischaemia were alternated with 5-minutes of reperfusion. Twenty-four hours later, maternal FMD was re-measured. Results: Women with preeclampsia had the lowest baseline FMD 4.09% +/- 0.73%: mean +/- SEM, which increased to 6.25% +/- 0.83% (p=0.0024) following IPC. Women at risk of pre-eclampsia had baseline FMD 7.57% +/- 0.82%, which increased to 8.93% +/- 0.73% (p=0.025) following IPC. Normotensive pregnant women had the highest baseline FMD (10.32% +/- 0.69%), which did not increase further following IPC (10.52% +/- 0.69%). However, normotensive pregnant women reached peak flow-mediated dilatation more quickly following IPC; 414 s +/- 2.94 s v 425 s +/- 4.22 s (p=0.0302). Conclusions: IPC is a non-invasive technique that we have shown improves local endothelial function in women with preeclampsia and at risk of preeclampsia. IPC merits further study as an intervention to improve systemic endothelial function and pregnancy outcomes for women with hypertensive pregnancies.
Abstract 13706: Differences in the Distribution of Systolic Blood Pressure by Rural and Urban Residence
Authors: Brittain Heindl, George Howard, Elizabeth A Jackson
Journal: Circulation (2020)

Introduction: The incidence of stroke is higher in rural areas. Hypertension is the leading risk factor for stroke, but the difference in systolic blood pressure (SBP) for those living in rural and urban areas is unknown. Hypothesis: We hypothesized that rural residence is associated with higher SBP levels, and this difference is modified by race, sex, and United States (US) division. Methods: We analyzed 26,113 participants enrolled in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, recruited between 2003 and 2007. Participants were grouped based on the Rural-Urban Commuting Area (RUCA) scheme into urban, large-rural, and small-isolated rural groups. Resting SBP was measured during the initial home visit. Differences in percentiles of SBP distribution were compared using multivariate models with adjustment for age, race, sex, and US Census Bureau division. Results: Of the participants, 20,976 (80.3%) were classified as urban, 3,020 (11.6%) as large-rural, and 2,137 (8.2%) as small-isolated rural, reflecting the distribution of the population. The large-rural group had a 0.09 mmHg higher mean SBP compared to the urban group (95% CI, 0.33 to 1.52 mmHg, p = 0.0023), but the difference in SBP at the 95th percentile between these groups was 3.23 mmHg (95% CI, 1.43 to 4.73 mmHg, p = 0.0006). A similar difference was present between the small-isolated rural and urban groups at the highest percentiles. No urban-rural interaction was observed by race, sex, or US division. However, large SBP differences were present between US divisions, especially at the highest percentiles. To illustrate, SBP at the 95th percentile was 9.51 mmHg higher in the East North Central division than in the Pacific (95% CI, 6.41 to 12.61 mmHg, p &lt; 0.0001). Conclusions: Residence in a rural area is associated with higher SBP, with larger differences at the highest percentiles of distribution. SBP differences are present between US divisions, independent of urban-rural status.
Abstract 14909: The Sweet Spot - Achieving Less Mitral Regurgitation at the Cost of Increasing Mitral Gradients Improves Short-term Outcomes in Percutaneous Mitral Valve Repair
Authors: Giorgio A Medranda, Kunal Brahmbhatt, William Kokotos, Daniel Donohue, Richard K Schwartz, Stephen Green
Journal: Circulation (2020)

Background: In the last year, percutaneous mitral valve repair (PMVR) using the MitraClip system (Evalve Inc., Menlo Park, California) has established itself as a proven treatment option for patients with inoperable mitral regurgitation (MR). However, reduction of MR usually comes at the expense of forward flow and mean mitral gradients (MMG). Finding the ideal balance of reduction of MR grade and acceptable MMG carries significant clinical implications. The purpose of this study was to compare short-term outcomes in patients with less than moderate MR but elevated MMG to patients with at least moderate MR. Methods: This was a retrospective, observational study from 2014-2019 of 128 patients who underwent PMVR at our institution. Patients were separated into cohorts depending on their post-PMVR MR grade and MMG. Cohort 1 included patients with the best possible result post-PMVR, less than moderate MR and a MMG &lt;5mmHg. Cohort 2 included patients less than moderate MR but a MMG &gt;5mmHg post-PMVR. Cohort 3 included patients with at least moderate MR post-PMVR. Our primary outcome of interest was a composite of inpatient death and 30-day readmission. Results: Cohort 1 included 30 patients who had less than moderate MR and a MMG &lt;5mmHg post-PMVR. This cohort had the primary composite endpoint in 10.0% of patients. Cohort 2 included 33 patients who had less than moderate MR but a MMG &gt;5mmHg. Cohort 3 included 65 patients who had more than moderate MR post-PMVR. We found that our primary composite endpoint occurred more frequently in patients who had at least moderate residual MR (cohort 3) (9.1% vs. 27.7%, p=0.0438). Patients with less than moderate MR post-PMVR despite a MMG &gt;5mmHg were 3.8 times less likely to have inpatient death or a 30-day readmission when compared to patients with at least moderate MR post-PMVR (CI 0.071, 0.963). Conclusions: Our study suggests that achieving a goal of less than moderate MR despite modest increases in MMG can result in better short-term outcomes (inpatient death + 30-day readmission) when compared to patients who are left with at least moderate MR post-PMVR.
Cobomarsen, an Oligonucleotide Inhibitor of miR-155, Slows DLBCL Tumor Cell Growth <i>In Vitro</i> and <i>In Vivo</i>
Authors: Eleni Anastasiadou, Anita G. Seto, Xuan Beatty, Melanie Hermreck, Maud-Emmanuelle Gilles, Dina Stroopinsky, Lauren C. Pinter-Brown, Linda Pestano, Cinzia Marchese, David Avigan, Pankaj Trivedi, Diana M. Escolar, Aimee L. Jackson, Frank J. Slack
Journal: Clinical Cancer Research (2020)

Abstract Purpose: miRNA-155 is an oncogenic miRNA highly expressed in B-cell malignancies, particularly in the non–germinal center B-cell or activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL), where it is considered a potential diagnostic and prognostic biomarker. Thus, miR-155 inhibition represents an important therapeutic strategy for B-cell lymphomas. In this study, we tested the efficacy and pharmacodynamic activity of an oligonucleotide inhibitor of miR-155, cobomarsen, in ABC-DLBCL cell lines and in corresponding xenograft mouse models. In addition, we assessed the therapeutic efficacy and safety of cobomarsen in a patient diagnosed with aggressive ABC-DLBCL. Experimental Design: Preclinical studies included the delivery of cobomarsen to highly miR-155–expressing ABC-DLBCL cell lines to assess any phenotypic changes, as well as intravenous injections of cobomarsen in NSG mice carrying ABC-DLBCL xenografts, to study tumor growth and pharmacodynamics of the compound over time. To begin to test its safety and therapeutic efficacy, a patient was recruited who underwent five cycles of cobomarsen treatment. Results: Cobomarsen decreased cell proliferation and induced apoptosis in ABC-DLBCL cell lines. Intravenous administration of cobomarsen in a xenograft NSG mouse model of ABC-DLBCL reduced tumor volume, triggered apoptosis, and derepressed direct miR-155 target genes. Finally, the compound reduced and stabilized tumor growth without any toxic effects for the patient. Conclusions: Our findings support the potential therapeutic application of cobomarsen in ABC-DLBCL and other types of lymphoma with elevated miR-155 expression.
SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 Are Expressed in the Microvasculature and Ducts of Human Pancreas but Are Not Enriched in β Cells
Authors: Katie C. Coate, Jeeyeon Cha, Shristi Shrestha, Wenliang Wang, Luciana Mateus Gonçalves, Joana Almaça, Meghan E. Kapp, Maria Fasolino, Ashleigh Morgan, Chunhua Dai, Diane C. Saunders, Rita Bottino, Radhika Aramandla, Regina Jenkins, Roland Stein, Klaus H. Kaestner, Golnaz Vahedi, Marcela Brissova, Alvin C. Powers
Journal: Cell Metabolism (2020)