Citations

Abstract Purpose: The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors. Experimental Design: To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes. Results: We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA. Conclusions: Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.

A novel hydroxyethylamine compound was synthesised that displayed biological potency against SARS-CoV-2.

AbstractThe Society for Cardiovascular Angiography and Interventions (SCAI) Think Tank is a collaborative venture that brings together interventional cardiologists, administrative partners, and select members of the cardiovascular industry community annually for high‐level field‐wide discussions. The 2021 Think Tank was organized into four parallel sessions reflective of the field of interventional cardiology: (a) coronary intervention, (b) endovascular medicine, (c) structural heart disease, and (d) congenital heart disease. Each session was moderated by a senior content expert and co‐moderated by a member of SCAI's Emerging Leader Mentorship program. This document presents the proceedings to the wider cardiovascular community in order to enhance participation in this discussion, create additional dialog from a broader base, and thereby aid SCAI, the industry community and external stakeholders in developing specific action items to move these areas forward.

INTRODUCTION: Obesity has been associated with adverse disease-related outcomes and inferior treatment response to biologic agents in patients with inflammatory bowel diseases (IBDs), but its impact on the risk of treatment-related complications is unknown. We performed a cohort study examining the association between obesity and risk of serious infections in biologic-treated patients with IBD. METHODS: Using an administrative claims database, in a cohort of biologic-treated patients with IBD between 2014 and 2018 with follow-up 1 year before and after treatment initiation, we compared the risk of serious infections (infections requiring hospitalization) between obese vs nonobese patients (based on validated administrative claims) using Cox proportional hazard analysis. RESULTS: We included 5,987 biologic-treated patients with IBD (4,881 on tumor necrosis factor-α antagonists and 1,106 on vedolizumab), of whom 524 (8.8%) were classified as obese. Of the 7,115 person-year follow-up, 520 patients developed serious infection. Risk of serious infection was comparable in obese vs nonobese patients (8.8% vs 8.5%; unadjusted hazard ratio, 1.15; 95% confidence interval, 0.86–1.54). After adjusting for age, comorbidities, disease characteristics, health care utilization, use of corticosteroids, immunomodulators, and opiates, obesity was not associated with an increased risk of serious infection (adjusted hazard ratio, 0.74 [95% confidence interval, 0.55–1.01]). Similar results were seen on stratified analysis by disease phenotype (Crohn's disease and ulcerative colitis) and index biologic therapy (tumor necrosis factor-α antagonists and vedolizumab). DISCUSSION: After adjusting for comorbid conditions and disease characteristics, obesity is not independently associated with an increased risk of serious infections in biologic-treated patients with IBD.

Introduction: The relative performance of carotid artery stenting (CAS) and carotid endarterectomy (CEA) among Medicare beneficiaries in routine clinical practice has not been established. Objective: To compare the performance of CAS relative to CEA among Medicare beneficiaries. Methods: We linked Medicare data (2000-2009) to the Society for Vascular Surgery’s Vascular Registry (SVS-VR; 2005-2008) and to the NCDR® Carotid Artery Revascularization and Endarterectomy Registry (CARE; 2006-2008/9). Medicare patients aged ≥66 years undergoing CAS or CEA were followed from the procedure date for the outcomes of death, stroke/transient ischemic attack (TIA), peri-procedural myocardial infarction (MI) or a composite endpoint for these outcomes. We derived high-dimensional propensity scores using registry and Medicare data to control for patient-level factors and adjusted for provider-level factors including past-year CAS/CEA physician and hospital volume, hospital ownership, teaching affiliation, and hospital size in a Cox regression model comparing CAS to CEA. Results: Among 5,254 SVS-VR (1,999 CAS and 3,255 CEA) and 4,055 CARE (2,824 CAS and 1,231 CEA) patients, CAS patients were more often at higher surgical risk (SVS-VR: 96.7% vs. 44.5%; CARE: 71.3% vs. 44.7%) and had a higher comorbidity burden. Crude outcome risks for death and stroke/TIA were lower for CEA. Adjusting for patient-level factors drove estimates downwards for CAS relative to CEA but only after further adjustment for provider-level factors did the performance of CAS and CEA become comparable on all outcomes (figure 1). Conclusion: Performance of CAS and CEA among Medicare beneficiaries was comparable after accounting for patient- and provider-level factors, which is consistent with landmark trials. Further studies are needed to understand the role of heterogeneity in provider-level characteristics.

Abstract Platinum-based DNA cross-linking agents are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). Remarkably, despite >30 years of literature on platinum responses in human cancer, none of these findings is used clinically as a predictive biomarker to stratify patients for platinum resistance, nor exploited therapeutically to treat platinum-resistant disease. Thus, understanding mechanisms of platinum resistance is an urgent goal, both to identify predictive biomarkers of platinum response (to spare patients with platinum-resistant tumors futile platinum therapy) and to develop efficacious therapies for platinum-resistant disease. To better understand mechanisms underlying platinum resistance in HGSOC, we performed comprehensive, dynamic (+/-carboplatin), multiomic profiling of DNA, RNA, protein and post-translational modifications (phosphorylation, ubiquitination, acetylation) to identify the cellular networks that respond to platinum treatment and associate with platinum resistance in three HGSOC intra-patient cell line pairs (PEA1S/PEA2R, PEO1S/PEO4R, PEO14S/PEO23R). The cell line pairs were derived from ascites or pleural effusions (Langdon et al., 1988) from three patients both before (PEA1S, PEO1S, PEO14S) and after (PEA2R, PEO4R, PEO23R, respectively) their tumors became clinically platinum resistant (i.e., in vivo development of resistance). The molecular profiles revealed extensive responses to carboplatin and differential responses between platinum-sensitive and platinum-resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that pharmacologic inhibition or CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO, and CPT1A in particular, represent a candidate therapeutic target to overcome platinum resistance in HGSOC. Citation Format: Hong Wang, Dongqing Hugang, Shrabanti Chowdhury, Sara Savage, Richard Ivey, Jacob Kennedy, Jeffrey Whiteaker, Chenwei Lin, Xiaonan Hou, Catherine Huntoon, Uliana Voytovich, Zahra Shire, Qing Yu, Steven Gygi, Andrew Hoofnagle, Zachary Herbert, Anna Calinawan, Larry Karnitz, S. John Weroha, Scott Kaufmann, Bing Zhang, Pei Wang, Michael Birrer, Amanda Paulovich. Multiomic analysis identifies CPT1A and fatty acid oxidation as a potential therapeutic target in platinum-refractory high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1426.

Background: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs). Design: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions. Results: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland ( p = 0.0034 and p < 0.001, respectively), with median difference of 3–4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients ( p < 0.001). Conclusions: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.