tbuckley/cabot-search huggingface dataset:
Abstract MP24: Sedentary Behavior (SB) In Mid-life And Structural Brain Magnetic Resonance Imaging (MRI) Markers Of Cerebrovascular Disease And Neurodegeneration In Late-life: The Atherosclerosis Risk In Communities Neurocognitive Study (ARIC-NCS)
Authors: Kelley Pettee Gabriel, Keith Diaz, Aarti Kumar, A Richey Sharrett, Kelly R Evenson, Rebecca F Gottesman, Thomas Mosley, Gerardo M Heiss, Priya Palta
Journal: Circulation (2021)

Introduction: Few prospective studies have examined the associations of SB on brain MRI markers. We tested the hypotheses that higher levels of, and persistence of mid-life television viewing, a cognitively passive SB, are associated with structural brain MRI markers in late-life, and that these associations are independent from physical activity (PA). Methods: ARIC participants (n=1,601, mean age: 76.2 years, 60.5% female, 27.2% Black) with reported television viewing at visits 1 (1987-89) and 3 (1993-95), and brain MRI in 2011-13 were included. Participants were categorized as low [never/seldom], medium [sometimes], or high [often/very often] television viewing. Persistent pattern of television viewing was quantified as the same frequency of reported television viewing at visits 1 and 3 (n=971). Imaging using 3T brain MRI quantified the presence of cerebrovascular lesions, white matter microstructural integrity and disease, and grey matter volumes using a standardized protocol. Models were adjusted for age, race-center, sex, education, APOE-ε4, smoking status, and total intracranial volume in volumetric analysis. Sampling weights were included to generalize MRI sample to the visit 5 cohort. Interactions by meeting (or not) 2018 PA guidelines were tested. Results: Compared to low television viewing, medium and high television viewing in midlife was significantly associated with smaller deep grey matter volumes in late-life after multivariable adjustment; associations were stronger for persistent television viewing ( Table ). All other associations of midlife, or persistent midlife, television viewing with structural brain MRI markers were statistically null. Interactions with meeting PA guidelines were also non-significant. Conclusions: Findings suggest an inverse association of mid-life television viewing with later-life deep grey matter volumes. Studies examining the associations of daily accumulated SB, and differences by SB type (active versus passive), with brain MRI markers are needed.
A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks
Authors: Chongze Yuan, Haojie Chen, Shiqi Tu, Hsin-Yi Huang, Yunjian Pan, Xiuqi Gui, Muyu Kuang, Xuxia Shen, Qiang Zheng, Yang Zhang, Chao Cheng, Hui Hong, Xiaoting Tao, Yizhou Peng, Xingxin Yao, Feilong Meng, Hongbin Ji, Zhen Shao, Yihua Sun
Journal: Genome biology (2021)

Abstract Background Lung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains largely unknown. To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we investigate the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explore the role of epigenetic alterations in LUAD progression. Results A high intertumoral epigenetic heterogeneity is observed across the LUAD H3K27ac profiles. We quantitatively model the intertumoral variability of H3K27ac levels at proximal gene promoters and distal enhancers and propose a new epigenetic classification of LUAD patients. Our classification defines two LUAD subgroups which are highly related to histological subtypes. Group II patients have significantly worse prognosis than group I, which is further confirmed in the public TCGA-LUAD cohort. Differential RNA-seq analysis between group I and group II groups reveals that those genes upregulated in group II group tend to promote cell proliferation and induce cell de-differentiation. We construct the gene co-expression networks and identify group-specific core regulators. Most of these core regulators are linked with group-specific regulatory elements, such as super-enhancers. We further show that CLU is regulated by 3 group I-specific core regulators and works as a novel tumor suppressor in LUAD. Conclusions Our study systematically characterizes the epigenetic alterations during LUAD progression and provides a new classification model that is helpful for predicting patient prognosis.
CONSORT 2010 statement: extension to randomised pilot and feasibility trials
Authors: Sandra M Eldridge, Claire L Chan, Michael J Campbell, Christine M Bond, Sally Hopewell, Lehana Thabane, Gillian A Lancaster
Journal: BMJ (2016)

The Consolidated Standards of Reporting Trials (CONSORT) statement is a guideline designed to improve the transparency and quality of the reporting of randomised controlled trials (RCTs). In this article we present an extension to that statement for randomised pilot and feasibility trials conducted in advance of a future definitive RCT. The checklist applies to any randomised study in which a future definitive RCT, or part of it, is conducted on a smaller scale, regardless of its design (eg, cluster, factorial, crossover) or the terms used by authors to describe the study (eg, pilot, feasibility, trial, study). The extension does not directly apply to internal pilot studies built into the design of a main trial, non-randomised pilot and feasibility studies, or phase II studies, but these studies all have some similarities to randomised pilot and feasibility studies and so many of the principles might also apply. The development of the extension was motivated by the growing number of studies described as feasibility or pilot studies and by research that has identified weaknesses in their reporting and conduct. We followed recommended good practice to develop the extension, including carrying out a Delphi survey, holding a consensus meeting and research team meetings, and piloting the checklist. The aims and objectives of pilot and feasibility randomised studies differ from those of other randomised trials. Consequently, although much of the information to be reported in these trials is similar to those in randomised controlled trials (RCTs) assessing effectiveness and efficacy, there are some key differences in the type of information and in the appropriate interpretation of standard CONSORT reporting items. We have retained some of the original CONSORT statement items, but most have been adapted, some removed, and new items added. The new items cover how participants were identified and consent obtained; if applicable, the prespecified criteria used to judge whether or how to proceed with a future definitive RCT; if relevant, other important unintended consequences; implications for progression from pilot to future definitive RCT, including any proposed amendments; and ethical approval or approval by a research review committee confirmed with a reference number. This article includes the 26 item checklist, a separate checklist for the abstract, a template for a CONSORT flowchart for these studies, and an explanation of the changes made and supporting examples. We believe that routine use of this proposed extension to the CONSORT statement will result in improvements in the reporting of pilot trials. Editor's note: In order to encourage its wide dissemination this article is freely accessible on the <i>BMJ</i> and <i>Pilot and Feasibility Studies</i> journal websites.
CD137 (4-1BB) stimulation leads to metabolic and functional reprogramming of human monocytes/macrophages enhancing their tumoricidal activity
Authors: A. Stoll, H. Bruns, M. Fuchs, S. Völkl, F. Nimmerjahn, M. Kunz, M. Peipp, A. Mackensen, D. Mougiakakos
Journal: Leukemia (2021)

Abstract Immunotherapies have heralded a new era in the cancer treatment. In addition to checkpoint inhibitors, agonistic antibodies against co-stimulatory immune receptors hold the potential to invoke efficient antitumor immunity. Targeting CD137 has gained momentum based on its ability to drive NK- and T-cell-based responses. CD137-engaging mAbs have already entered clinical trials for different types of tumors showing promising results. Despite the efforts to translate CD137-mediated immunotherapy into clinical practice, little remains known regarding the role of CD137 in human monocytes/macrophages. We found CD137 being expressed on monocytes of healthy controls and at even higher levels in patients with multiple myeloma or CLL. CD137 HI(GH) monocytes displayed a distinct phenotypic, transcriptomic, and metabolic profile. They possessed an increased phagocytic capacity enabling superior antibody-dependent phagocytosis (ADPC) of multiple myeloma and lymphoma cells that were treated with anti-CD38 or anti-CD20 mAbs. Triggering CD137 promoted both metabolic and tumoricidal activity in an extracellular signal-regulated kinase (ERK)-dependent fashion. In addition, we observed a phenotypic, transcriptomic, and functional skewing towards a M1-like phenotype. Overall, we introduce CD137 as a positive immune checkpoint on human monocytes/macrophages, which can have therapeutic implications especially in view of synergistic effects when combining CD137 agonists with tumor-targeting antibodies.
Abstract 16882: Exercise Prescription Patterns After Spontaneous Coronary Artery Dissection: Insights From a Large Multinational Registry
Authors: Audry Chacin Suarez, Amanda R Bonikowske, Jose R Medina-inojosa, Rajiv Gulati, Patricia J Best, Sharonne N Hayes, Marysia S Tweet
Journal: Circulation (2020)

Introduction: Spontaneous coronary artery dissection (SCAD) is an important cause of myocardial infarction in otherwise healthy and most times presumably fit young women. In the absence of evidence for benefit or harm, exercise prescription (EXP) after SCAD remains arbitrary. We assessed EXP patterns among participants in a large multinational SCAD registry. Methods: Participants with SCAD as confirmed by coronary angiography completed surveys detailing exercise (EX) habits prior to SCAD (initial survey), and EXP from their provider on initial and subsequent visits after SCAD (follow-up survey). Demographic and clinical characteristics were collected by electronic health record review by trained nurse abstractors. EXP was categorized according to EX components that include: type, intensity, frequency, time/session, and external conditions. Results: Among 950 participants, mean ± age was 46.8 ± 9.5 years, 96% were women and 77% reported attending ≥1 Cardiopulmonary Rehabilitation session. Prior to SCAD, 49% were aerobically exercising ≥ 3times per week, and only 32% performed strength-building EX regularly. Initial and subsequent post-SCAD visit details in 299/950 participants showed that most (93%) patients received some form of EX (Figure 1-A) counseling, namely: EXP, unspecific advice or were discouraged from any EX (Figure 1-B) . Limits regarding EX type and intensity were the most common advice received among EXP group (Figure 1-C) . Conclusions: Insights from our study show that only 40% of patients were achieving current exercise recommendations for adults prior to SCAD (vs 53% adult U.S population; CDC, 2018) which suggests that SCAD patients may not be as active as previously described. Most patients receive some form of EX counseling after SCAD; however, a structured EXP is needed to avoid overly cautious approaches that could lead to uncertainty, deconditioning, impaired quality of life, or increase risks associated with a sedentary lifestyle.
Inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection: a prospective cohort study and immunological network analysis
Authors: Elsa Du Bruyn, Kiyoshi F Fukutani, Neesha Rockwood, Charlotte Schutz, Graeme Meintjes, María B Arriaga, Juan M Cubillos-Angulo, Rafael Tibúrcio, Alan Sher, Catherine Riou, Katalin A Wilkinson, Bruno B Andrade, Robert J Wilkinson
Journal: The Lancet Microbe (2021)
Modeling the Evolutionary Architectures of Transcribed Human Enhancer Sequences Reveals Distinct Origins, Functions, and Associations with Human Trait Variation
Authors: Sarah L Fong, John A Capra
Journal: Molecular Biology and Evolution (2021)

Despite the importance of gene regulatory enhancers in human biology and evolution, we lack a comprehensive model of enhancer evolution and function. This substantially limits our understanding of the genetic basis of species divergence and our ability to interpret the effects of noncoding variants on human traits. To explore enhancer sequence evolution and its relationship to regulatory function, we traced the evolutionary origins of transcribed human enhancer sequences with activity across diverse tissues and cellular contexts from the FANTOM5 consortium. The transcribed enhancers are enriched for sequences of a single evolutionary age ("simple" evolutionary architectures) compared with enhancers that are composites of sequences of multiple evolutionary ages ("complex" evolutionary architectures), likely indicating constraint against genomic rearrangements. Complex enhancers are older, more pleiotropic, and more active across species than simple enhancers. Genetic variants within complex enhancers are also less likely to associate with human traits and biochemical activity. Transposable-element-derived sequences (TEDS) have made diverse contributions to enhancers of both architectures; the majority of TEDS are found in enhancers with simple architectures, while a minority have remodeled older sequences to create complex architectures. Finally, we compare the evolutionary architectures of transcribed enhancers with histone-mark-defined enhancers. Our results reveal that most human transcribed enhancers are ancient sequences of a single age, and thus the evolution of most human enhancers was not driven by increases in evolutionary complexity over time. Our analyses further suggest that considering enhancer evolutionary histories provides context that can aid interpretation of the effects of variants on enhancer function. Based on these results, we propose a framework for analyzing enhancer evolutionary architecture.
Abstract 14583: Repeated Phenotyping and Arrhythmia Mapping of Human Induced Pluripotent Stem Cell Derived Cardiac Cellular-Sheets Expressing Genetically-Encoded Voltage Indicator
Authors: Naim Shaheen, Assad Shiti, Irit Huber, Idit Goldfracht, Rami Shinnawi, Gil Arbel, Amira Gepstein, Lior Gepstein
Journal: Circulation (2017)

Introduction: Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) offer unique opportunities for cardiac disease modeling and drug testing. Yet, fulfilling their potential for st...
Abstract 12947: Development of Molecular Targeted Therapy Against Right Ventricular Failure: Involvement in A Network of Immunocompetent Cells
Authors: Shogo Ito, Shinsuke Yuasa, Jin Komuro, Mai Kimura, Dai Kusumoto, Hisayuki Hashimoto, Keiichi Fukuda, Yoshihiro Fukumoto
Journal: Circulation (2020)

Backgrounds: Right ventricular (RV) failure plays a critical role in right heart failure and left heart failure. However, there is no specific therapy developed for RV failure. To elucidate a novel therapeutic target against RV failure, we focus on differentially expressed genes in RV to develop novel therapeutics for RV failure. Methods: Microarray analysis using several parts of adult murine heart was conducted and differentially expressed genes (DEGs) were applied to pathway analysis by Ingenuity Pathway Analysis R . Molecular mechanism was examined by using neonatal rat ventricular cardiomyocyte (NRVM) in vitro . To understand the function of target molecule in vivo , we induced RV failure by pulmonary artery constriction (PAC) in mice and inhibition experiments were performed using these RV failure model mice. Results: In microarray analysis for RV, left ventricle and ventricular septum, 995 genes were extracted as DEGs in RV. Pathway analysis revealed that alternative complement pathway-related genes were significantly up-regulated in RV. Moreover, complement factor D (Cfd) and C3a was a potential upstream factor attributable to unique feature of RV. Administration of C3a recombinant protein to NRVM phosphorylated several MAP kinases. Moreover, in C3KO PAC mice, RV dysfunction was significantly suppressed, and histological study suggested that RV fibrosis was significantly suppressed by comparing to wild type PAC mice. Furthermore, administration of C3a receptor antagonist to wild type PAC mice dramatically improved RV dysfunction and reduced RV fibrosis. Additionally, in vivo electrophysiological study revealed that the inducibility of ventricular arrhythmia was increased in wild type PAC mice, but ventricular arrhythmia was significantly attenuated in C3KO PAC mice. Conclusion: We revealed that complement C3a was highly produced in RV, and genetic or chemical blockade of C3a ameliorates RV dysfunction and RV fibrosis in RV failure model mice. C3a was to be a potent bioactive protein for immunocompetent cells that played an important role in modulating RV function. Accordingly, we demonstrated that the blockade of C3a had a potential role for novel therapeutic target of RV failure.
Voiding dysfunction after colpectomy and urethral lengthening in transgender men
Authors: Rüdiger Hochstätter, Marie-Christine Bertholin y Galvez, Riccarda Hartleb, Christian Laback, Thomas Aigmüller, Karl Tamussino, Daniela Gold
Journal: International Journal of Transgender Health (2021)

Colpectomy is a frequent part of gender-affirming surgery in transgender men. Urologic complications with these procedures can complicate and delay further management. Aim: We reviewed the rate of postoperative voiding dysfunction after colpectomy with urethral lengthening in transgender men.We reviewed postoperative voiding in 47 transgender men (age, 19-50 years) who underwent colpectomy with urethral lengthening. Thirty-eight patients (81%) had undergone hysterectomy (36 total, 2 subtotal/supracervical) previously and 11 (23%) underwent concomitant hysterectomy or removal of the residual cervix (4 abdominal, 6 laparoscopic, 1 transvaginal). Colpectomy was done transvaginally by opening and developing laterally the vesicovaginal and rectovaginal spaces and then transecting the lateral vaginal attachments with bipolar vessel sealing. Urethral lengthening with an anterior vaginal flap was performed in the same procedure as colpectomy. A transurethral catheter was left in situ for 14 days postoperatively. Voiding dysfunction was defined as failure of spontaneous micturition after removal of the catheter at 14 days.40/47 (85%) patients were able to void after catheter removal, 7 (15%) were not. Voiding dysfunction occurred in 3/11 (27%) patients undergoing concomitant hysterectomy or removal of a residual cervix and in 4/36 patients (11%) status post total hysterectomy. Voiding dysfunction persisted for a median of 3 months (2 days - 46 months).In this series voiding dysfunction developed in 15% of transgender men undergoing colpectomy with urethral lengthening and appeared to be more common in patients undergoing concomitant hysterectomy or removal of a residual cervix than in those status post hysterectomy. Patients should be counseled accordingly.
Comparison of Endluminal Angioplasty and Subintimal Angioplasty for the Treatment of Femoropopliteal Occlusive Disease: 1-Year Outcomes
Authors: Kawasaki Daizo, Fujii Kenichi, Fukunaga Masashi, Akahori Hirokuni, Oka Katsumi, Lee-Kawabata Masaaki, Masutani Motomaru, Tsujino Takeshi, Ohyanagi Mitsumasa, Masuyama Tohru
Journal: Circulation (2010)
Abstract 14750: Characteristics Associated With Postpartum Physical Activity Levels Among Women With Hypertensive Disorders of Pregnancy
Authors: Jennifer Lewey, Samantha Murphy, Michal Elovitz, Lisa Levine
Journal: Circulation (2020)

Background: Hypertensive disorders of pregnancy (HDP), such as preeclampsia, are associated with increased risk of CV disease. Postpartum interventions may mitigate this risk but have not been well studied in women with HDP. STEP UP Mom is a randomized clinical trial to increase physical activity (PA) in postpartum women with HDP using remote monitoring and social incentives (NCT04119232). We analyzed patient characteristics associated with daily step count prior to study randomization to understand factors associated with postpartum PA. Methods: Between October 2019 and May 2020, 168 women were enrolled. Participant characteristics were collected from surveys and chart abstraction. We used univariate and multivariable linear regression to identify characteristics associated with step count, as measured by wearable devices. We also compared women with low step count (defined as ≤ 4800 steps/day, the lowest step count quartile) vs. &gt; 4800 steps per day using chi-square test. This analysis includes 137 participants with complete baseline data available at end of enrollment. Results: Mean daily baseline step count was 7444 (SD 3453). The associations between participant characteristics and baseline daily step count are presented in the Table. In multivariable regression, characteristics associated with higher baseline step count were self-reported health as good or better (2789 steps, p&lt;0.001), tobacco use (2622 steps, p=0.03) high school education or less (1676 steps, p=0.019) and weeks since delivery (293 steps per week, p=0.011). Participants with low baseline step count (≤ 4800 steps/day) were more likely to enroll after the COVID-19 pandemic (34% vs. 18%, p=0.04) and be married (71% vs. 49%, p=0.029) compared to those with normal/high step count. Conclusion: Multiple patient characteristics impact postpartum PA levels, which may be helpful in planning lifestyle interventions in high-risk postpartum women.
Gut-brain communication and obesity: understanding functions of the vagus nerve
Authors: Hans-Rudolf Berthoud, Vance L. Albaugh, Winfried L. Neuhuber
Journal: Journal of Clinical Investigation (2021)

Given the crucial role of the gastrointestinal tract and associated organs in handling nutrient assimilation and metabolism, it has long been known that its communication with the brain is important for the control of ingestive behavior and body weight regulation. It is also clear that gut-brain communication is bidirectional and utilizes both rapid neural and slower humoral mechanisms and pathways. However, progress in understanding these mechanisms and leveraging them for the treatment of obesity and metabolic disease has been hindered by the enormous dimension of the gut mucosa, the complexity of the signaling systems, and lack of specific tools. With the ascent of modern neurobiological technology, our understanding of the role of vagal afferents in gut-brain communication has begun to change. The first function-specific populations of vagal afferents providing nutritional feedback as well as feed-forward signals have been identified with genetics-guided methodology, and it is hoped that extension of the methodology to other neural communication pathways will follow soon. Currently, efficient clinical leveraging of gut-brain communication to treat obesity and metabolic disease is limited to a few gut hormones, but a more complete understanding of function-specific and projection-specific neuronal populations should make it possible to develop selective and more effective neuromodulation approaches.