tbuckley/cabot-search huggingface dataset:
The Two-Hit Hypothesis Meets Epigenetics
Authors: Jean-Pierre Issa
Journal: Cancer Research (2022)

Abstract The landmark paper by Kane and colleagues was the first report of DNA methylation in the promoter of the human MLH1 gene in sporadic colon cancers with mismatch repair (MMR) deficiency. In both cell lines and primary tumors, promoter methylation was associated with loss of MLH1 protein expression and with a lack of mutations in the MLH1 coding region. Together with subsequent papers that showed that this methylation was directly responsible for loss of MLH1 expression and MMR deficiency, the observation expanded the two-hit hypothesis of tumor suppressor gene loss in cancer to include both genetic and epigenetic mechanisms of gene inactivation. More broadly, the paper contributed to normalization of the hypothesis of an epigenetic basis for cancer development. See related article by Kane and colleagues, Cancer Res 1997;57:808–11
93P Noncancer-specific mortality in patients with stage IA1 NSCLC after surgical resection: The role of comorbidities in prognosis
Authors: W. Huang, H-Y. Deng, Y-Q. Wang, Y-F. Wang, K. Xu, M-Y. Lin, J-H. Weng, S-K. He, Q. Zhou
Journal: Annals of Oncology (2022)
The Challenge of Respiratory Syncytial Virus Human Challenge Studies
Authors: Larry J. Anderson, Edward E. Walsh
Journal: New England Journal of Medicine (2022)

The development of drugs for the treatment of respiratory syncytial virus (RSV), a major cause of respiratory disease in young children and high-risk adults, is a high priority.1-3 In this issue of the Journal, Ahmad et al. report the results of a human challenge trial of EDP-938, a small molecule targeting the RSV nucleoprotein (N protein).4 Challenge studies with predictable virus shedding and mild-to-moderate symptoms affecting the upper respiratory tract in study participants have been used to evaluate the efficacy of antiviral drugs and to collect data that would support the conduct of subsequent clinical trials. Multiple drugs targeting the . . .
Abstract 002: Self-reported Experiences Of Discrimination In Relation To Incident Dementia: The Multi-ethnic Study Of Atherosclerosis (mesa)
Authors: Michael P Bancks, Goldie S Byrd, Allison Caban-Holt, Annette L Fitzpatrick, Sarah N Forrester, Kathleen M Hayden, Susan R Heckbert, Kiarri N Kershaw, Stephen R Rapp, Bonnie C Sachs, Timothy M Hughes
Journal: Circulation (2022)

Introduction: Black and Hispanic Americans have higher rates for dementia than other racial/ethnic groups. Perceived discrimination has many adverse health effects and may contribute to racial disparities in dementia risk. Our objective was to assess the association between lifetime experiences of discrimination and incident dementia. Methods: We included data for 6509 participants, 45-84 years of age at baseline (2000-2002) enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). We assessed lifetime experiences of discrimination at baseline in six domains related to: hiring; promotion; police; education; housing; and from neighbors. Incidence of dementia was determined from International Classification of Diseases codes and medication inventory. We used Cox proportional hazards to estimate hazard ratios (HR) for incident dementia over 17 years after accounting for cohort attrition and sociodemographic, clinical, and behavioral factors. We assessed effect modification of the association by race/ethnicity. Results: Of the sample, 42% reported experiencing discrimination in their lifetime. We observed 466 incident cases of dementia and lifetime discrimination was associated with incident dementia (Wald χ 2 p=0.03). Individuals reporting lifetime discrimination in ≥2 domains (compared to none) had greater risk for dementia (HR: 1.40; 95%: 1.08, 1.82) after adjustment for sociodemographic, clinical, and behavioral risk factors ( Table ). Associations did not differ by race/ethnicity (p-interaction &gt;0.1). Conclusion: Our findings demonstrate an association between discrimination and incident dementia and provide justification to advance research on the association of discrimination with race-disparities in dementia risk.
Abstract 10717: Role of Integrin Signaling in Pulmonary Arterial Hypertension
Authors: Sarah-eve Lemay, Mónica S Montesinos, Yann Grobs, Tsukasa Shimauchi, Sandra Breuils Bonnet, Sandra Martineau, Xinqiang Huang, James E Dowling, Min Lu, Adrian S Ray, Roxane Paulin, François Potus, Steeve Provencher, Olivier BOUCHERAT, Sebastien Bonnet
Journal: Circulation (2021)

Pulmonary arterial hypertension (PAH) is characterized by progressive obstruction and decreased compliance of pulmonary arteries (PA), leading to right ventricular (RV) failure and premature death. It is now recognized that, like cancer cells, PA smooth muscle cells (PASMCs) exhibit exaggerated proliferation and resistance to apoptosis in response to increased PA stiffness caused by extracellular matrix (ECM) remodeling. Integrins (members of the cell adhesion receptors superfamily) are known to promote cell proliferation, survival, hypertrophic growth and fibrosis, which are key elements in the progression of PAH. Therefore, we explored integrins expression and its effects on PA remodeling and RV failure. By RNA sequencing, we demonstrated a significant upregulation of integrin signaling pathways. Among all integrins, the fibronectin binding integrin (FiBI) family was the most abundant in PASMCs and RV fibroblasts (RVFbs) isolated from PAH patients (n=5). By western blot (WB) we showed that integrin expression is significantly changed in distal PAs, PASMCs and RV from PAH patients (n=6-8) compared to controls (n=5-8). Similarly, increased expression was found in monocrotaline (MCT) and pulmonary artery banding (PAB) rats (n=20, p&lt;0.05.) In vitro , pharmacological inhibition of FiBI decreases PAH-PASMCs proliferation (WB: PCNA and Ki67 labeling; p&lt;0.05) and resistance to apoptosis (WB: Survivin and Annexin V labeling; p&lt;0.05). These effects were associated with a decreased activation of the AKT/mTOR pathway. In cardiomyocytes and human RVFbs, FiBI inhibition decreased phenylephrine-induced hypertrophy (Phalloidin labeling; p&lt;0.001) and TGFβ1-induced RVFbs activation (WB: αSMA, CTGF, FN and Col1; p&lt;0.05) and proliferation (Ki67; p&lt;0.05). In vivo , pharmacological FiBI inhibition improved PAs remodeling (EVG staining) and RV function (SV, CO, TAPSE, S-Wave, as assessed by echocardiography and right heart catheterization) in MCT rats with established PAH (n=20; p&lt;0.05). We demonstrated that upregulation of fibronectin binding integrins and broad spectrum integrin inhibition resulted in improvements in distal PAs remodeling and RV failure. These results suggest that integrins play an important role in the pathophysiology of PAH.
Molecular epidemiology of the SARS-CoV-2 variant Omicron BA.2 sub-lineage in Denmark, 29 November 2021 to 2 January 2022
Authors: Jannik Fonager, Marc Bennedbæk, Peter Bager, Jan Wohlfahrt, Kirsten Maren Ellegaard, Anna Cäcilia Ingham, Sofie Marie Edslev, Marc Stegger, Raphael Niklaus Sieber, Ria Lassauniere, Anders Fomsgaard, Troels Lillebaek, Christina Wiid Svarrer, Frederik Trier Møller, Camilla Holten Møller, Rebecca Legarth, Thomas Vognbjerg Sydenham, Kat Steinke, Sarah Juel Paulsen, José Alfredo Samaniego Castruita, Uffe Vest Schneider, Christian Højte Schouw, Xiaohui Chen Nielsen, Maria Overvad, Rikke Thoft Nielsen, Rasmus L Marvig, Martin Schou Pedersen, Lene Nielsen, Line Lynge Nilsson, Jonas Bybjerg-Grauholm, Irene Harder Tarpgaard, Tine Snejbjerg Ebsen, Janni Uyen Hoa Lam, Vithiagaran Gunalan, Morten Rasmussen
Journal: Eurosurveillance (2022)

Following emergence of the SARS-CoV-2 variant Omicron in November 2021, the dominant BA.1 sub-lineage was replaced by the BA.2 sub-lineage in Denmark. We analysed the first 2,623 BA.2 cases from 29 November 2021 to 2 January 2022. No epidemiological or clinical differences were found between individuals infected with BA.1 versus BA.2. Phylogenetic analyses showed a geographic east-to-west transmission of BA.2 from the Capital Region with clusters expanding after the Christmas holidays. Mutational analysis shows distinct differences between BA.1 and BA.2.
Abstract EP49: 6-minute Walk Test Distance And Atherosclerosis, Expressed As Carotid Intima-media Thickness, In Older Korean Adults
Authors: Tae Kyung Yoo, Jong-Young Lee
Journal: Circulation (2022)

Background: Carotid intima-media thickness (cIMT) is a well-known marker of atherosclerosis and future cardiovascular events such as myocardial infarction. The 6-minute walk test (6MWT) is a widely used method for evaluating aerobic fitness and functional exercise capacity. However, no studies have assessed the relationship between 6MWT distance and cIMT in older adults. Therefore, this study aimed to examine the association between aerobic fitness expressed as the 6MWT distance and cIMT in older Korean adults. Methods: We retrospectively reviewed raw data of the 2014-2015 Korean Institute of Sports Science Fitness Standards, a national fitness measurement project in Korea. Participants older than 65 years and who underwent 6MWT and cIMT measurements were included in the study. The 6MWT was performed, and the total distance that the participants covered in 6 min was measured. The cIMT was defined as the distance between the lumen-intima and the media-adventitia interfaces. The cIMT was measured at the proximal 1 cm of the right common carotid bulb. A high-resolution ultrasound device with a frequency of ≥11.4 MHz was used for cIMT measurement. We adjusted the data for multiple confounding factors. Statistical analyses were performed using generalized linear regression analysis. Results: Overall, 608 participants were included (male, n=302 [49.67%]; female, n=306 [50.32%]). The mean participant age was 70.99±4.22 years (male 71.48±4.40 years, female 70.50±3.98 years). The mean cIMT was 0.74±0.18 mm (male 0.78±0.19 mm, female 0.70±0.16 mm). The mean 6MWT distance was 479.15±92.82 m (male 499.96±85.88 m, female 458.60±94.94 m). After multivariable adjustment, the highest 6MWT distance tertile was inversely associated with cIMT (β [95% confidence interval (CI)]: -0.042 [-0.080, -0.005]; p=0.027) versus the lower tertiles. In the subgroup analysis, the male group did not show a significant association with cIMT, while the highest 6MWT distance tertile in the female group showed a significant inverse association with cIMT ((β [95% CI]: -0.049 [-0.098, -0.001]; p=0.049). Conclusion: Our results suggest that there is an inverse relationship between 6MWT distance and atherosclerosis, expressed as cIMT, in older Korean adults.
144P Real-world data of consolidative radiotherapy for extensive stage (ES)-SCLC treated by chemo-immunotherapy (chemo-IO)
Authors: S.N. Daher, A. Allen, Y. Rottenberg, H. Nasrallah, L. Yosef, P. Blumenfeld, M. Wollner, S. Appel, H. Nechushtan, M. Moskovitz, J. Bar, A. Zer
Journal: Annals of Oncology (2022)
Abstract MP63: Longitudinal Analysis Of Handgrip Strength And Cognitive Function During Aging- Share
Authors: Cristina P Baena, Ariele Barreto Haagsma, Dyego Souza, GRAZIELLA MARTINS DE DE MELLO, Marcia Olandoski, Javier J Roig
Journal: Circulation (2022)

Background: Aging is associated with various chronic conditions, such as cognitive and muscle strength decline. Previous studies have analysed the association between physical factors and cognitive decline however, the magnitude and the direction of the association between handgrip strength (HGS) and cognitive decline are not fully understood. Objectives: To analyse the association between HGS and cognitive decline in numeracy, recall and verbal fluency according to sex in a large multicentric population. Methods: A longitudinal study including people aged 50 and over from the Survey of Health, Aging and Retirement in Europe (SHARE) was conducted, involving participants from 28 European countries. Repeated HGS measures from a dynamometer and cognitive scores in numeracy, recall, and verbal fluency were biannually analysed for 4 years. Individuals with Parkinson along the study or dementia diagnosis at baseline were excluded. For the analysis of HGS as a predictor of future cognitive decline, HGS was categorized in quintiles by sex. In men HGS quintiles were Q1 (8-35kg), Q2 (36-41kg), Q3 (42-45kg), Q4 (46-50kg) and Q5 (51-80kg). In women HGS quintiles were Q1 (4-21kg), Q2 (22-25 kg), Q3 (26-28 kg), Q4 (29-32 kg) and Q5 (33-55 kg). First quintile in each sex was used as reference. In the analysis of cognitive performance as a predictor of HGS decline, different cognitive scores were treated in their logarithmical form as a function of HGS continuously. Possible confounding factors were controlled through general estimated equations and adjusted for baseline handgrip strength quintile and time-varying covariates as age, time, education, smoking status, alcohol consumption, physical activity, BMI index, chronical illnesses, Alzheimer disease, depression, functionality scores, and sarcopenia. Results: A total of 8,236 individuals were included, 55.73% were females with a mean age of 67.55 (± 8.4) years, while in males it was of 68.42 (±7.7) years. A significant longitudinal association between HGS and cognitive function in all three domains was found in both sexes, except numeracy in males. The fully adjusted β coefficients CI (95%) for the fifth HGS quintile in numeracy, verbal fluency and recall were 0.041 (0.004-0.082), 0.078 (0.038-0.117) and 0.095 (0.039-0.151) respectively for men and 0.076 (0.039-0.113), 0.094 (0.060-0.0128) and 0.092 (0.047-0.137) respectively for women. On the other hand the greatest cognitive predictor of HGS was verbal fluency in both sexes, β(95%), 0.796 (0.464 to 1.128)kg in men and 0.801 (0.567 to 1.109)kg in women. Conclusion: There is a significant and bidirectional association between HGS and the cognitive performance in men and women over 50 years studied in SHARE.
A Genetic Bottleneck of Mitochondrial DNA During Human Lymphocyte Development
Authors: Zhongjie Tang, Zhaolian Lu, Baizhen Chen, Weixing Zhang, Howard Y. Chang, Zheng Hu, Jin Xu
Journal: Molecular Biology and Evolution (2022)

Mitochondria are essential organelles in eukaryotic cells that provide critical support for energetic and metabolic homeostasis. Although the elimination of pathogenic mitochondrial DNA (mtDNA) mutations in somatic cells has been observed, the mechanisms to maintain proper functions despite their mtDNA mutation load are poorly understood. In this study, we analyzed somatic mtDNA mutations in more than 30,000 single human peripheral and bone marrow mononuclear cells. We observed a significant overrepresentation of homoplasmic mtDNA mutations in B, T, and natural killer (NK) lymphocytes. Intriguingly, their overall mutational burden was lower than that in hematopoietic progenitors and myeloid cells. This characteristic mtDNA mutational landscape indicates a genetic bottleneck during lymphoid development, as confirmed with single-cell datasets from multiple platforms and individuals. We further demonstrated that mtDNA replication lags behind cell proliferation in both pro-B and pre-B progenitor cells, thus likely causing the genetic bottleneck by diluting mtDNA copies per cell. Through computational simulations and approximate Bayesian computation (ABC), we recapitulated this lymphocyte-specific mutational landscape and estimated the minimal mtDNA copies as <30 in T, B, and NK lineages. Our integrative analysis revealed a novel process of a lymphoid-specific mtDNA genetic bottleneck, thus illuminating a potential mechanism used by highly metabolically active immune cells to limit their mtDNA mutation load.
Abstract P228: Social Networks And Cardiovascular Disease Events Among Men And Women From The Jackson Heart Study
Authors: LaShaunta M Glover, Janiyah Sutton, Loretta Cain, Emily C OBrien, Mario Sims
Journal: Circulation (2022)

Background: Cardiovascular disease (CVD) burden disproportionately affects African-American adults in the United States. Greater social networks, or social integration, may lower CVD risk among African-American adults. Objective: To determine the association of social networks and incident coronary heart disease (CHD), stroke, and heart failure (HF) and test whether there are differences by sex. Methods: Among participants of the Jackson Heart Study without CVD at baseline (mean age: 54.4 years, n=3,053 women, n=1684 men), we used the Social Networks Index at baseline (2000-2004) to develop a continuous social networks score in standard deviation units (range 0-5) and binary categories (high vs. low relative to the median). Surveillance of CHD, stroke, and HF events occurred after exam 1 (2005 for HF) until 2016. We utilized Cox proportional hazards regression to estimate hazard ratios (HR 95% confidence interval-CI) of each CVD event by levels of social networks, adjusting for demographics, education, behaviors, risk factors and depressive symptoms. Interaction terms by sex were used to evaluate sex differences. Results: There were 262 CHD events, 213 stroke events, and 331 HF events that occurred by 2016. P-values for interaction terms by sex were statistically significant for stroke and HF ( p &lt;0.05). After full adjustment, a 1-SD unit increase in social networks was associated with a lower hazard of CHD and HF among women (HR 0.80, 95% CI 0.72, 0.90 and HR 0.81 95% CI 0.69, 0.98, respectively). Men had a lower hazard of CHD with every 1-SD unit increase in social networks (HR 0.88, 95% CI 0.79, 0.99) after full adjustment. High vs. low social networks was associated with a lower hazard of stroke (HR 0.58, 95% CI 0.35, 0.98) and HF (HR 0.61, 95% CI 0.39, 0.94) among women after full adjustment. Conclusion: Men and women who reported greater social networks were less likely to have a CHD event, but women with greater social networks were less likely to have stroke and HF.
78TiP Clinical evaluation of NVL-520, a highly selective ROS1 inhibitor in patients with advanced ROS1-positive solid tumors: The phase I/II ARROS-1 study
Authors: B. Besse, M. Johnson, S-H.I. Ou, S. Gadgeel, A. Spira, J. Lin, E. Felip, A.J. van der Wekken, A. Calles, M.J. de Miguel, D.R. Camidge, Y. Elamin, G.D.L. Lopes, S. Liu, J. Bauman, D. Haggstrom, G. Riley, H.E. Pelish, V.W. Zhu, A. Drilon
Journal: Annals of Oncology (2022)
Randomized Trial of Cytoreductive Surgery for Relapsed Ovarian Cancer
Authors: Philipp Harter, Jalid Sehouli, Ignace Vergote, Gwenael Ferron, Alexander Reuss, Werner Meier, Stefano Greggi, Berit J. Mosgaard, Frederic Selle, Frédéric Guyon, Christophe Pomel, Fabrice Lécuru, Rongyu Zang, Elisabeth Avall-Lundqvist, Jae-Weon Kim, Jordi Ponce, Francesco Raspagliesi, Gunnar Kristensen, Jean-Marc Classe, Peter Hillemanns, Pernille Jensen, Annette Hasenburg, Sadaf Ghaem-Maghami, Mansoor R. Mirza, Bente Lund, Alexander Reinthaller, Ana Santaballa, Adeola Olaitan, Felix Hilpert, Andreas du Bois
Journal: New England Journal of Medicine (2021)

Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear.We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival.A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery.In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).
Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis
Authors: Satoshi Kawamura, Yuki Matsushita, Shigeyuki Kurosaki, Mizuki Tange, Naoto Fujiwara, Yuki Hayata, Yoku Hayakawa, Nobumi Suzuki, Masahiro Hata, Mayo Tsuboi, Takahiro Kishikawa, Hiroto Kinoshita, Takuma Nakatsuka, Masaya Sato, Yotaro Kudo, Yujin Hoshida, Atsushi Umemura, Akiko Eguchi, Tsuneo Ikenoue, Yoshihiro Hirata, Motonari Uesugi, Ryosuke Tateishi, Keisuke Tateishi, Mitsuhiro Fujishiro, Kazuhiko Koike, Hayato Nakagawa
Journal: Journal of Clinical Investigation (2022)

Enhanced de novo lipogenesis mediated by sterol regulatory element-binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage-activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.