tbuckley/cabot-search huggingface dataset:
Abstract MP16: Reallocating Sedentary Behavior With Sleep or Physical Activity is Associated With Favorable Cardiovascular Health in the Multi-Ethnic Study of Atherosclerosis: MESA
Authors: Charles German, Nour Makarem, Jason Fanning, Susan Redline, Tali Elfassy, Amanda McClain, Marwah Abdalla, Brooke A Aggarwal, Norrina B Allen, Mercedes R Carnethon
Journal: Circulation (2020)

Introduction: Sleep, sedentary behavior, and physical activity are each independently associated with cardiovascular health (CVH). However, many studies have investigated these relationships in isolation even though a change in any one given behavior will affect the time spent in the others. It is unknown how reallocating time in sedentary behavior with sleep or physical activity effects overall CVH in a diverse cohort of men and women at risk of cardiovascular disease (CVD). Hypothesis: Reallocating 30 minutes of sedentary time with sleep, light (LIPA), or moderate to vigorous physical activity (MVPA) is associated with more favorable overall CVH due to improvements in risk factors for CVD. Methods: Data for this analysis were taken from the Multi-Ethnic Study on Atherosclerosis (MESA) Sleep Ancillary Study. Eligible participants (n= 1718) wore Actiwatch accelerometers for 24 hours a day, and had at least 3 days of valid accelerometry. Time spent in sleep, sedentary behavior, LIPA, and MVPA was determined based on an established algorithm. The American Heart Association’s life simple 7 was used to represent the CVH score after excluding the physical activity component, with higher scores indicating more favorable CVH. All components were ascertained from MESA exam 5. Isotemporal substitution modeling was conducted to examine the effect of substituting 30 minutes of sedentary time for an equivalent amount of sleep, LIPA, or MVPA. Results: The mean age of participants was 68.3, 54.0% were female and 38.6% were white. The mean CVH score was 5.9 (95%CI: 5.8-6.0). On average, participants spent 499.3 minutes/day in sedentary time, 415.3 minutes/day in LIPA, 26.0 minutes/day in MVPA, and 388.2 minutes/day sleeping. Reallocating 30 minutes of sedentary time to sleep, LIPA, and MVPA was associated with a significantly higher CVH score [β(SE): 0.077(0.023), 0.039(0.017), and 0.485(0.065) respectively]. Reallocating 30 minutes of sedentary time to sleep was associated with lower BMI. Reallocating 30 minutes of sedentary time to LIPA was associated with higher diastolic blood pressure and total cholesterol, and lower BMI. Reallocating 30 minutes of sedentary time to MVPA was associated with lower systolic and diastolic blood pressure, and lower BMI. Conclusions: Our study demonstrates that sleep, LIPA, and MVPA are all positively associated with more favorable overall CVH and several key CVD risk factors. These findings underscore the importance of lifestyle modifications in improving CVH.
Abstract P228: The Relationship Between Obesity and Cardiometabolic Risk Factors Differs by Race/Ethnicity
Authors: Madiha F Abdel-maksoud, Tim E Byers, John E Hokanson, Robert H Eckel
Journal: Circulation (2013)

Obesity is a major public health problem in the US, and is associated with several adverse health outcomes such as cardiovascular disease (CVD), diabetes and cancer. Research suggests that the association between obesity and certain diseases may not be similar in all racial/ethnic groups. To our knowledge, no published study has assessed the association of obesity with cardiometabolic risk factors simultaneously for Hispanics, non-Hispanic Whites (NHW) and African-Americans. Methods We used data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES) to examine, cross-sectionally, whether race/ethnicity modifies the relationship between body mass index (BMI) and: high sensitivity C-reactive protein (hsCRP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apoB, 2-hr glucose (OGTT) and insulin levels. Study subjects (age 20-75 ys) included 1508 Hispanics, 2192 NHWs and 1078 African-Americans (~50% women). Results Hispanics h...
Brevinin-2R, a peptide inducing semi-selectively cancer cell death by a mechanism involving the mitochondrial death pathway
Authors: Anne Zuse, Saeid Ghavami, Ahmad Asoodeh, Kamran Kadkhoda, Tadeusz Kroczak, Hossein Naderi-Manesh, Marek Los
Journal: Cancer Research (2007)

3604  Recently a novel defensin, Brevinin-2R, a 25-amino acid polypeptide was isolated from the skin of the frog Rana ridibunda. The novel molecule kills semi-selectively cancer cells, but does not exhibit the typical hemolytic activity for the majority of the Brevinin-family defensins. The anti-cancer activity was demonstrated on various malignant cells such as Jurkat (T-cell leukemia), BJAB (B-cell lymphoma), SW742 (colon carcinoma), and MCF-7 (breast adenocarcinoma). Also data have shown that L929 and MCF-7 cells stably transfected with a dominant-negative mutant of the pro-apoptotic Bcl-2-family member BNIP3 (DTM-BNIP3) were significantly more resistant towards Brevinin-2R triggered cell death. Furthermore, we observed decrease in mitochondrial membrane potential (ΔΨm) and that induction of cell death is independent of caspase activation. Over-expressing of Bcl-2 in cancer cell lines significantly counteracted ΔΨm triggered by Brevinin-2R. Malignant hematopoietic cell lines were more sensitive towards Brevinin-2R than primary peripheral blood mononuclear cells (PBMC). Our results demonstrate that the polypeptide leads to activation of the mitochondrial death pathway, but does not induce cell death in cancer cells by classical apoptosis. The semi-selective anti-cancer effect of Brevinin-2R makes it a promising lead molecule for the development of anti-cancer drugs.
Dnmt3a and Dnmt3b-Decommissioned Fetal Enhancers are Linked to Kidney Disease
Authors: Yuting Guan, Hongbo Liu, Ziyuan Ma, Szu-Yuan Li, Jihwan Park, Xin Sheng, Katalin Susztak
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Cytosine methylation plays a key role in determining cell fate and response to stimuli. Using mice with kidney-specific deletion of genes encoding de novo DNA methyltransferases Dnmt3a and Dnmt3b, the authors showed that these genes are responsible for methylation of gene regulatory regions that act as enhancers during kidney development but are then decommissioned in adult mice. Although the knock-out mice displayed no obvious kidney abnormalities at baseline, they showed resistance to induced AKI. The authors also discovered that human kidney disease risk loci were enriched on fetal regulatory regions (enhancers) that were decommissioned by Dnmt3a / 3b and no longer active in the adult kidney. These findings suggest that adult kidney diseases could have a developmental origin and that genetic and epigenetic (such as Dnmt3a / 3b ) factors could converge on the same genetic regions resulting in kidney disease development. Background Cytosine methylation is an epigenetic mark that dictates cell fate and response to stimuli. The timing and establishment of methylation logic during kidney development remains unknown. DNA methyltransferase 3a and 3b are the enzymes capable of establishing de novo methylation. Methods We generated mice with genetic deletion of Dnmt3a and Dnmt3b in nephron progenitor cells ( Six2 Cre Dnmt3a/3b ) and kidney tubule cells ( Ksp Cre Dnmt3a/3b ). We characterized Ksp Cre Dnmt3a/3b mice at baseline and after injury. Unbiased omics profiling, such as whole genome bisulfite sequencing, reduced representation bisulfite sequencing and RNA sequencing were performed on whole-kidney samples and isolated renal tubule cells. Results Ksp Cre Dnmt3a/3b mice showed no obvious morphologic and functional alterations at baseline. Knockout animals exhibited increased resistance to cisplatin-induced kidney injury, but not to folic acid–induced fibrosis. Whole-genome bisulfite sequencing indicated that Dnmt3a and Dnmt3b play an important role in methylation of gene regulatory regions that act as fetal-specific enhancers in the developing kidney but are decommissioned in the mature kidney. Loss of Dnmt3a and Dnmt3b resulted in failure to silence developmental genes. We also found that fetal-enhancer regions methylated by Dnmt3a and Dnmt3b were enriched for kidney disease genetic risk loci. Methylation patterns of kidneys from patients with CKD showed defects similar to those in mice with Dnmt3a and Dnmt3b deletion. Conclusions Our results indicate a potential locus-specific convergence of genetic, epigenetic, and developmental elements in kidney disease development.
Abstract P511: Adherence to the Dietary Portfolio is Associated With Lower Cardiovascular Disease Risk in the Women's Health Initiative Study
Authors: Andrea J Glenn, Kenneth Lo, Beatrice A Boucher, Mara Z Vitolins, Joann E Manson, Linda G Snetselaar, Cyril W Kendall, David J Jenkins, Simin Liu, John L Sievenpiper
Journal: Circulation (2020)

Introduction: The Dietary Portfolio is a plant-based dietary pattern of a combination of recognized cholesterol-lowering foods and has been shown to lower a number of cardiovascular disease (CVD) risk factors, including low-density lipoprotein cholesterol, blood pressure and C-reactive protein. However, no studies have assessed if following the Portfolio results in fewer CVD events. Hypothesis: Higher adherence to the Portfolio will be associated with fewer CVD events. Methods: We included 125,389 postmenopausal women from the Women’s Health Initiative Observational Study and Clinical Trials (from 1993 to 2017) who were free of CVD at baseline. Adherence to the Portfolio was assessed using an a priori diet index based on 6 food categories (high in plant protein [soy &amp; pulses], nuts, viscous fiber, plant sterols and monounsaturated fat, and low in saturated fat) that were found to lower CVD risk factors in the Portfolio trials. Adjusted hazard ratios (HRs) and 95% confidence intervals [CIs] for CVD were calculated using Cox regressions. We adjusted for CVD risk &amp; lifestyle factors and potential confounders (see Table 1). Results: During 1,826,176 person-years of follow-up, we documented 11,370 total CVD cases, including 5,739 coronary heart disease (CHD) cases, 4,451 stroke cases, 1,946 heart failure (HF) cases and 935 atrial fibrillation (AF) cases. Comparing the highest to the lowest quartile in the fully adjusted model, higher adherence to the Portfolio was associated with a reduced risk of total CVD (HR=0.89 [95% CI 0.84-0.95]), CHD (0.87 [0.79-0.95]) and HF (0.83 [0.70-0.98]). No association was found with stroke (0.97 [0.87-1.08]) and AF (1.09 [0.87-1.38]). Conclusions: In postmenopausal women, higher adherence to the Portfolio was inversely associated with total CVD, CHD and HF but not stroke or AF. These findings suggest that the Portfolio may assist with CVD, CHD and HF prevention and warrants further investigation. Table 1: Association of the Dietary Portfolio and risk of CVD in Postmenopausal Women
Monthly Injectable Antiretroviral Therapy — Version 1.0 of a New Treatment Approach
Authors: Judith S. Currier
Journal: New England Journal of Medicine (2020)

Combination antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) infection is one of the most important advances in medicine in the past quarter century. The availability of several single-tablet multidrug treatment regimens that effectively control the replication of HIV type 1 (HIV-1) has dramatically improved the prognosis of people living with HIV who are able to adhere to daily oral therapy. Now two pivotal international, phase 3, randomized trials — Antiretroviral Therapy as Long Acting Suppression (ATLAS) and First Long-Acting Injectable Regimen (FLAIR), the results of which are reported in the Journal1,2 — show 48-week outcomes among . . .
Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling
Authors: Yaoyao Shi, Wenxin Zheng, Kaiting Yang, Katharine G. Harris, Kaiyuan Ni, Lai Xue, Wenbin Lin, Eugene B. Chang, Ralph R. Weichselbaum, Yang-Xin Fu
Journal: The Journal of Experimental Medicine (2020)

Most studies focus on how intestinal microbiota influence cancer immunotherapy through activating gut immunity. However, immunotherapies related to innate responses such as CD47 blockade rely on the rapid immune responses within the tumor microenvironment. Using one defined anaerobic gut microbiota to track whether microbiota interact with host immunity, we observed that Bifidobacterium facilitates local anti-CD47 immunotherapy on tumor tissues through the capacity to accumulate within the tumor microenvironment. Systemic administration of Bifidobacterium leads to its accumulation within the tumor and converts the nonresponder mice into responders to anti-CD47 immunotherapy in a stimulator of interferon genes (STING)– and interferon-dependent fashion. Local delivery of Bifidobacterium potently stimulates STING signaling and increases cross-priming of dendritic cells after anti-CD47 treatment. Our study identifies the mechanism by which gut microbiota preferentially colonize in tumor sites and facilitate immunotherapy via STING signaling.
Distilling Heterogeneity of Mild Cognitive Impairment in the National Alzheimer Coordinating Center Database Using Latent Profile Analysis
Authors: Anna E. Blanken, Jung Yun Jang, Jean K. Ho, Emily C. Edmonds, S. Duke Han, Katherine J. Bangen, Daniel A. Nation
Journal: JAMA Network Open (2020)

This cohort study uses latent profile analysis to examine the variation in mild cognitive impairment among participants in the National Alzheimer Coordinating Center (NACC) database.
δ-secretase in neurodegenerative diseases: mechanisms, regulators and therapeutic opportunities
Authors: Zhentao Zhang, Ye Tian, Keqiang Ye
Journal: Translational Neurodegeneration (2020)

Abstract Mammalian asparagine endopeptidase (AEP) is a cysteine protease that cleaves its protein substrates on the C-terminal side of asparagine residues. Converging lines of evidence indicate that AEP may be involved in the pathogenesis of several neurological diseases, including Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. AEP is activated in the aging brain, cleaves amyloid precursor protein (APP) and promotes the production of amyloid-β (Aβ). We renamed AEP to δ-secretase to emphasize its role in APP fragmentation and Aβ production. AEP also cleaves other substrates, such as tau, α-synuclein, SET, and TAR DNA-binding protein 43, generating neurotoxic fragments and disturbing their physiological functions. The activity of δ-secretase is tightly regulated at both the transcriptional and posttranslational levels. Here, we review the recent advances in the role of δ-secretase in neurodegenerative diseases, with a focus on its biochemical properties and the transcriptional and posttranslational regulation of its activity, and discuss the clinical implications of δ-secretase as a diagnostic biomarker and therapeutic target for neurodegenerative diseases.
Abstract P559: National Burden &amp; Cardiovascular Risk Factor Profile of Stroke Among Young Adults in The United States
Authors: Javier Valero Elizondo, Rohan Khera, Farhaan S Vahidy, Prachi Dubey, Haider Warraich, Shiwani Mahajan, Michael J Blaha, Ron Blankstein, Salim S Virani, Miguel Cainzos Achirica, Bita Kash, Harlan M Krumholz, Khurram Nasir
Journal: Circulation (2020)

Introduction: Stroke is a leading cause of death and disability worldwide. While most prevalent in elderly, it’s not uncommon in the non-elderly (&lt;65), who also experience many more years of living with disability. In this study, we aimed to describe the scope and CVD determinants of stroke among young (18-44 years) adults in a US representative population. Methods: We analyzed the National Health Interview Survey (2012-2018), a nationally representative study sample. Stroke, as well as CVD risk factors (CRF) [diabetes, hypertension, ever-smoker, insufficient physical activity, obesity and high cholesterol] were self-reported. A CRF profile was then created, with the following categories: “Optimal”, “Average” and “Poor” (0-1, 2-3 &amp; ≥ 4 CRFs, respectively). All analyses took into consideration the survey’s complex design. Results: The 2012-2018 survey population consisted of 224,638 adults ≥ 18 yrs, ≈ 242 million US adults annually. Overall 2.8% (≈ 7 million) reported ever having history of stroke, with 45% noted in the non-elderly (&lt; 65). Among non-elderly, 21% of stroke-history was allocated among the young (18-44 years) adults, translating to nearly 642,810 individuals reporting ever having history of stroke per year. The most common risk factors noted in these patients were insufficient physical activity (56%), current/past smoking (48%), obesity (45%), and hypertension (44%). Overall among the young (&lt;45 years), stroke prevalence was 10-fold higher among those with poor (≈ 3.9 million young adults) vs optimal CRF profile (3.5% vs 0.3%, p &lt; 0.001). Adjusting for demographics, all CVD risk were significantly associated with history of stroke, with participants with poor CRF reporting a 7-fold higher history of stroke (Table). Conclusion: More than half a million adults 18-44 years of age reported a history stroke in US. Individuals with sub-optimal CRF profiles are highly susceptible, and population-level strategies emphasizing cardiovascular health may significantly reduce risk of stroke among young adults in US.
Impaired consciousness: new guidelines aim to ensure people aren’t “lost in system”
Authors: Adrian O’Dowd
Journal: BMJ (2020)

Doctors who look after patients in a vegetative or minimally conscious state must ensure they initiate regular conversations with relatives about what is in the best interests of the person so that they do not get “lost in the system,” says new guidance.

The Royal College of Physicians has published new and revised guidelines on prolonged disorders of consciousness (PDOC)1 to take into account changes in the law and developments in assessment and management.

Currently, there is no reliable information on how many people in the UK have PDOC—such as vegetative or minimally conscious states. Estimates range between 4000 and 16 000 patients in …
Mismatch Repair–Deficient Rectal Cancer and Resistance to Neoadjuvant Chemotherapy
Authors: Andrea Cercek, Gustavo Dos Santos Fernandes, Campbell S. Roxburgh, Karuna Ganesh, Shu Ng, Francisco Sanchez-Vega, Rona Yaeger, Neil H. Segal, Diane L. Reidy-Lagunes, Anna M. Varghese, Arnold Markowitz, Chao Wu, Bryan Szeglin, Charles-Etienne Gabriel Sauvé, Erin Salo-Mullen, Christina Tran, Zalak Patel, Asha Krishnan, Kaitlyn Tkachuk, Garrett M. Nash, Jose Guillem, Philip B. Paty, Jinru Shia, Nikolaus Schultz, Julio Garcia-Aguilar, Luis A. Diaz, Karyn Goodman, Leonard B. Saltz, Martin R. Weiser, J. Joshua Smith, Zsofia K. Stadler
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Evaluate response of mismatch repair–deficient (dMMR) rectal cancer to neoadjuvant chemotherapy. Experimental Design: dMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (pMMR) rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity. Results: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), six (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable with 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome with enrichment of germline MSH2 and MSH6 mutations when compared with 193 patients with Lynch syndrome–associated colon cancer (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P &amp;lt; 0.003). Conclusions: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for Lynch syndrome in patients with dMMR rectal cancer.
Considerations in Analysis of Medicare Graduate Medical Education Payment Policies
Authors: David Jacob Aizenberg, Lia Suzanne Logio
Journal: JAMA Internal Medicine (2020)

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Abstract P543: Association Of Tanning Bed Use With Depression In A Preventive Medicine Cohort: The Cooper Center Longitudinal Study
Authors: Katie Kinser, Beth B Wright, David Leonard, Laura F Defina
Journal: Circulation (2020)

Importance: The use of tanning beds continues despite evidence of increased skin cancer risk among users. In the US, the prevalence of indoor tanning ranges from 35% of adults to 59% of college students. Objective: To investigate the association between depressive symptoms and tanning bed use. Design: Cross-sectional study. Setting: A preventive medicine clinic in Dallas, Texas. Participants: Between September 2013 and June 2019, a total of 11,823 generally healthy men and women presented for preventive medical examinations. Exposure: Self-reported tanning bed use. Main Outcome and Measures: Depressive symptoms as indicated by a score of greater than or equal to 10 on the Center for Epidemiologic Studies Depression (CES-D) Scale. Results: Fifteen percent of participants had used a tanning bed prior to their examination. For men, tanning bed use was associated with an increased risk of depressive symptoms (OR: 1.86; 95% CI:1.41-2.44). For women, the association between the use of tanning beds and depressive symptoms was significant in an unadjusted model, but was no longer significant after adjustment for confounders (OR: 1.26; 95% CI:0.99-1.61). However, the odds ratio was still in the direction of increased risk. Women with a personal history of depression were more likely to tan frequently and have higher CES-D scores than women with no personal history of depression ( p = .003). Conclusions and Relevance: In a generally healthy population, depressive symptoms were associated with the use of a tanning bed. This association was more evident in those with a history of depression, although remained true for those without a history of depression. As recurrent tanning bed use is known to contribute to the diagnosis of melanoma, it is critical to help patients identify other options to treat depression as well as to educate them on the risks of routine tanning bed use.