tbuckley/cabot-search huggingface dataset:
Efficacy of unsupervised exercise in adults with obstructive lung disease: a systematic review and meta-analysis
Authors: Daniel Taylor, Alex R Jenkins, Kate Parrott, Alex Benham, Samantha Targett, Arwel W Jones
Journal: Thorax (2021)

The benefits of unsupervised exercise programmes in obstructive lung disease are unclear. The aim of this systematic review was to synthesise evidence regarding the efficacy of unsupervised exercise versus non-exercise-based usual care in patients with obstructive lung disease.Electronic databases (MEDLINE, CINAHL, Embase, Allied and Complementary Medicine Database, Web of Science, Cochrane Central Register of Controlled Trials and Physiotherapy Evidence Database) and trial registers (ClinicalTrials.gov, Current Controlled Trials, UK Clinical Trials Gateway and WHO International Clinical Trials Registry Platform) were searched from inception to April 2020 for randomised trials comparing unsupervised exercise programmes with non-exercise-based usual care in adults with chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis or asthma. Primary outcomes were exercise capacity, quality of life, mortality, exacerbations and respiratory cause hospitalisations.Sixteen trials (13 COPD, 2 asthma, 1 chronic bronchitis: 1184 patients) met the inclusion criteria. Only data on COPD populations were available for meta-analysis. Unsupervised exercise resulted in a statistically but not clinically significant improvement in the 6-Minute Walk Test (n=5, MD=22.0 m, 95% CI 4.4 to 39.6 m, p=0.01). However, unsupervised exercise did lead to statistically significant and clinically meaningful improvements in St. George's Respiratory Questionnaire (n=4, MD=-11.8 points, 95% CI -21.2 to -2.3 points, p=0.01) and Chronic Respiratory Disease Questionnaire domains (dyspnoea: n=4, MD=0.5 points, 95% CI 0.1 to 0.8 points, p<0.01; fatigue: n=4, MD=0.7 points, 95% CI 0.4 to 1.0 points, p<0.01; emotion: n=4, MD=0.5 points, 95% CI 0.2 to 0.7 points, p<0.01; mastery: unable to perform meta-analysis) compared with non-exercise-based usual care.This review demonstrates clinical benefits of unsupervised exercise interventions on health-related quality of life in patients with COPD. High-quality randomised trials are needed to examine the effectiveness of prescription methods.
Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial
Authors: Melanie Meersch, Christoph Schmidt, Andreas Hoffmeier, Hugo Van Aken, Carola Wempe, Joachim Gerss, Alexander Zarbock
Journal: Intensive Care Medicine (2017)

Care bundles are recommended in patients at high risk for acute kidney injury (AKI), although they have not been proven to improve outcomes. We sought to establish the efficacy of an implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines to prevent cardiac surgery-associated AKI in high risk patients defined by renal biomarkers.In this single-center trial, we examined the effect of a "KDIGO bundle" consisting of optimization of volume status and hemodynamics, avoidance of nephrotoxic drugs, and preventing hyperglycemia in high risk patients defined as urinary [TIMP-2]·[IGFBP7] > 0.3 undergoing cardiac surgery. The primary endpoint was the rate of AKI defined by KDIGO criteria within the first 72 h after surgery. Secondary endpoints included AKI severity, need for dialysis, length of stay, and major adverse kidney events (MAKE) at days 30, 60, and 90.AKI was significantly reduced with the intervention compared to controls [55.1 vs. 71.7%; ARR 16.6% (95 CI 5.5-27.9%); p = 0.004]. The implementation of the bundle resulted in significantly improved hemodynamic parameters at different time points (p < 0.05), less hyperglycemia (p < 0.001) and use of ACEi/ARBs (p < 0.001) compared to controls. Rates of moderate to severe AKI were also significantly reduced by the intervention compared to controls. There were no significant effects on other secondary outcomes.An implementation of the KDIGO guidelines compared with standard care reduced the frequency and severity of AKI after cardiac surgery in high risk patients. Adequately powered multicenter trials are warranted to examine mortality and long-term renal outcomes.
Abstract 13679: Survival in Combined Heart-Liver Transplantation is Superior to Heart Transplantation Alone in Patients With Significant Liver Dysfunction
Authors: Daniel Rinewalt, John W MacArthur, Yuanjia Zhu, Maria Currie, Anson M Lee, Jack H Boyd, William Hiesinger, Bharathi Lingala, Yasuhiro Shudo, Y Joseph Y Woo
Journal: Circulation (2019)

Introduction: Liver dysfunction is common in chronic heart failure patients secondary to global hypoperfusion and congestive hepatopathy. The potential for reversibility of these derangements and b...
Treatment outcome of clonal cytopenias of undetermined significance: a single-institution retrospective study
Authors: Zhuoer Xie, Ahmad Nanaa, Antoine N. Saliba, Rong He, David Viswanatha, Phuong Nguyen, Dragan Jevremovic, Patricia Greipp, Mohamad E. Salama, Naseema Gangat, Hassan B. Alkhateeb, Ayalew Tefferi, Mark Litzow, Mrinal Patnaik, Mithun Shah, Aref Al-Kali
Journal: Blood Cancer Journal (2021)
Abstract PO-041: Shape features predicting intrahepatic progression-free and overall survival for SBRT treated HCC patients using radiomics and deep learning based survival models
Authors: Lise Wei, Jue Jiang, Harini Veeraraghavan, Issam El Naqa
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Intrahepatic failure is a major concern in the treatment of hepatocellular carcinoma (HCC) but lacks clinically reliable predictive markers. This work aims to identify a radiomic signature for risk prediction of intrahepatic progression in HCC patients treated with stereotactic body radiation therapy (SBRT) by extracting magnetic resonance imaging (MRI) and contrast-enhanced CT phenotypes from tumor(s) and liver parenchyma. Materials/Methods: 94 HCC patients treated with SBRT were retrospectively analyzed. The range of follow-up time is 57-1768 days. Samples were right censored if there was no intrahepatic progression within the follow-up time. The event rates is 43/94=45.7%. 112 radiomics features were extracted from tumors and liver parenchyma from CECT and MRI using pyradiomics platform. CT images were first added a 1000 HU shift and MRI images were standardized by the mean and standard deviation. Univariate Cox analysis was applied for radiomics features analysis. Multivariate Cox models and survival neural networks were also used to predict the outcome. Multiple folds cross-validation was used for model evaluation. Models’ performances were assessed using Harrell’s c-index and Kaplan-Meier plot. Results: Sphericity, small dependence emphasis, small dependence high gray level emphasis, run high gray level emphasis and coarseness are significant predictors from MR tumors for the outcome. The Cox models showed c-index of 0.600 (CI 95%: 0.558-0.642). Sphericity and maximal correlation coefficient are significant predictors from CT tumors for the outcome, with a c-index of 0.613 (CI 95%: 0.576-0.649). Volume, elongation and sphericity are significant predictors for overall survival, with a c-index of 0.584 (CI 95%: 0.532-0.636). None of the liver parenchyma features were important predictors. Interestingly, convolutional neural networks (CNN) were applied on the contour of the tumors and the c-index was 0.668 (CI 95%: 0.612-0.723). The 2 channel (MR-tumor region and contour mask) CNN network showed better performance of 0.698 (CI 95%: 0.658-0.749). Conclusions: Shape features showed predictive power for both intrahepatic progression-free and overall survival endpoints, which was proven using both radiomics feature based Cox modeling and CNN based contour methods. Adding MR imaging improved the performance. Citation Format: Lise Wei, Jue Jiang, Harini Veeraraghavan, Issam El Naqa. Shape features predicting intrahepatic progression-free and overall survival for SBRT treated HCC patients using radiomics and deep learning based survival models [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-041.
DNA Methylation Signatures Reveal the Diversity of Processes Remodeling Hepatocellular Carcinoma Methylomes
Authors: Léa Meunier, Théo Z. Hirsch, Stefano Caruso, Sandrine Imbeaud, Quentin Bayard, Amélie Roehrig, Gabrielle Couchy, Jean‐Charles Nault, Josep M. Llovet, Jean‐Frédéric Blanc, Julien Calderaro, Jessica Zucman‐Rossi, Eric Letouzé
Journal: Hepatology (2021)

Background and Aims DNA methylation patterns are highly rearranged in HCCs. However, diverse sources of variation are intermingled in cancer methylomes, precluding the precise characterization of underlying molecular mechanisms. We developed a computational framework (methylation signature analysis with independent component analysis [MethICA]) leveraging independent component analysis to disentangle the diverse processes contributing to DNA methylation changes in tumors. Approach and Results Applied to a collection of 738 HCCs, MethICA unraveled 13 stable methylation components preferentially active in specific chromatin states, sequence contexts, and replication timings. These included signatures of general processes associated with sex and age but also signatures related to specific driver events and molecular subgroups. Catenin beta 1 mutations were major modulators of methylation patterns in HCC, characterized by a targeted hypomethylation of transcription factor 7–bound enhancers in the vicinity of Wnt target genes as well as a widespread hypomethylation of late‐replicated partially methylated domains. By contrast, demethylation of early replicated highly methylated domains was a signature of replication stress, leading to an extensive hypomethylator phenotype in cyclin‐activated HCC. Inactivating mutations of the chromatin remodeler AT‐rich interactive domain‐containing protein 1A were associated with epigenetic silencing of differentiation‐promoting transcriptional networks, also detectable in cirrhotic liver. Finally, a hypermethylation signature targeting polycomb‐repressed chromatin domains was identified in the G1 molecular subgroup with progenitor features. Conclusions This study elucidates the diversity of processes remodeling HCC methylomes and reveals the epigenetic and transcriptional impact of driver alterations.
Abstract PO-046: MethylationToActivity: A deep-learning framework that reveals promoter activity landscapes from DNA methylomes in individual tumors
Authors: Justin Williams, Beisi Xu, Daniel Putnam, Andrew Thrasher, Chunliang Li, Jun Yang, Xiang Chen
Journal: Clinical Cancer Research (2021)

Abstract Although genome-wide DNA methylomes have demonstrated their clinical value as reliable biomarkers for tumor detection, subtyping, and classification, their direct biological impacts at the individual gene level remain elusive. Here we present MethylationToActivity (M2A), a machine learning framework that uses convolutional neural networks to infer promoter activities based on H3K4me3 and H3K27ac enrichment, from DNA methylation patterns for individual genes. Using publicly available datasets in real-world test scenarios, we demonstrate that M2A is highly accurate and robust in revealing promoter activity landscapes in various pediatric and adult cancers, including both solid and hematologic malignant neoplasms. Citation Format: Justin Williams, Beisi Xu, Daniel Putnam, Andrew Thrasher, Chunliang Li, Jun Yang, Xiang Chen. MethylationToActivity: A deep-learning framework that reveals promoter activity landscapes from DNA methylomes in individual tumors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-046.
Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19
Authors: Kathryn E. Stephenson, Mathieu Le Gars, Jerald Sadoff, Anne Marit de Groot, Dirk Heerwegh, Carla Truyers, Caroline Atyeo, Carolin Loos, Abishek Chandrashekar, Katherine McMahan, Lisa H. Tostanoski, Jingyou Yu, Makda S. Gebre, Catherine Jacob-Dolan, Zhenfeng Li, Shivani Patel, Lauren Peter, Jinyan Liu, Erica N. Borducchi, Joseph P. Nkolola, Morgana Souza, Chen Sabrina Tan, Rebecca Zash, Boris Julg, Ruvandhi R. Nathavitharana, Roger L. Shapiro, Ahmed Abdul Azim, Carolyn D. Alonso, Kate Jaegle, Jessica L. Ansel, Diane G. Kanjilal, Caitlin J. Guiney, Connor Bradshaw, Anna Tyler, Tatenda Makoni, Katherine E. Yanosick, Michael S. Seaman, Douglas A. Lauffenburger, Galit Alter, Frank Struyf, Macaya Douoguih, Johan Van Hoof, Hanneke Schuitemaker, Dan H. Barouch
Journal: JAMA (2021)

Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines.To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses.Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S.Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group).Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses.Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced.In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine.ClinicalTrials.gov Identifier: NCT04436276.
Socio-environmental conditions associated with geospatial clusters of urothelial carcinoma: A multi-institutional analysis.
Authors: Daniel C. Edwards, Gabrielle R Yankelevich, Paulette C Dreher, Gabriela Narowska, Daniel Kim, Zachariah Taylor, Sharon H Larson, Meghan Buckley, Laurence H Belkoff, Guy T Bernstein
Journal: Journal of Clinical Oncology (2021)

392 Background: Industrial byproducts and environmental pollutants (IBP/EP) are associated with the development of urothelial carcinoma (UC). While tobacco exposure (TE) is the major risk factor for UC, the interaction between sources of IBP/EP and incidence of UC in surrounding communities has been infrequently explored. We seek to identify high-density microregions of UC prevalence and spatially-related industrial and environmental risk factors. Methods: We queried a multi-institutional database for patients diagnosed with UC between 2008-2018. Geocoded addresses and ArcGIS software were used to calculate the Getis-Ord-Gi* statistic and perform hotspot analysis on the census-block level to identify UC hotspots. Demographics, clinicopathologic disease characteristics, and proximity to sources of IBP/EP were compared using Pearson’s chi-square and Student’s T-test. Univariate analyses and multivariable multilevel logistic random-intercept regression models were fitted to test the association between patient and census block-level factors and living in a UC hot spot. Results: Of 5,080 patients meeting inclusion/exclusion criteria, 148 patients (2.9%) were associated with one of three UC hotspots. In univariate analyses, hotspot patients were less likely to be tobacco users (OR 0.24, p=0.004) or of white race (OR 0.10, p&lt;0.001) and less likely to have higher income (OR 0.73, p=0.005). They were more likely to be associated with IBP/EP exposure (OR 8.24, p=0.001) (Table). Multivariable analysis confirmed increased likelihood of residing in a UC hotspot and proximity to high-traffic density (OR &gt;999, p=&lt;0.001) and sites of IBP/EP contamination (OR 106.90, p=0.009), with decreased likelihood of tobacco use (OR 0.11, p=0.045) and white race (OR 0.02, p=0.004). Conclusions: Patients residing in geospatial hotspots of UC prevalence are less likely to be white, higher income or tobacco users and more likely to reside in proximity to sources of IBP/EP. Further research is necessary to investigate the interplay between socioeconomic status, race and environmental risk factors in order to better identify at-risk populations and improve screening, referral, diagnosis and timely intervention. [Table: see text]
The Emerging Roles of RNA m6A Methylation and Demethylation as Critical Regulators of Tumorigenesis, Drug Sensitivity, and Resistance
Authors: Qing Lan, Pei Y. Liu, Jessica L. Bell, Jenny Y. Wang, Stefan Hüttelmaier, Xu Dong Zhang, Lirong Zhang, Tao Liu
Journal: Cancer Research (2021)

Abstract RNA N6-methyladenosine (m6A) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA m6A is regulated by the RNA m6A methyltransferases methyltransferase-like 3 (METTL3), METTL14, and METTL16 (writers), demethylases FTO and ALKBH5 (erasers), and binding proteins YTHDC1–2, YTHDF1–3, IGF2BP1–3, and SND1 (readers). These RNA m6A modification proteins are frequently upregulated or downregulated in human cancer tissues and are often associated with poor patient prognosis. By modulating pre-mRNA splicing, mRNA nuclear export, decay, stability, and translation of oncogenic and tumor suppressive transcripts, RNA m6A modification proteins regulate cancer cell proliferation, survival, migration, invasion, tumor initiation, progression, metastasis, and sensitivity to anticancer therapies. Importantly, small-molecule activators of METTL3, as well as inhibitors of METTL3, FTO, ALKBH5, and IGF2BP1 have recently been identified and have shown considerable anticancer effects when administered alone or in combination with other anticancer agents, both in vitro and in mouse models of human cancers. Future compound screening and design of more potent and selective RNA m6A modification protein inhibitors and activators are expected to provide novel anticancer agents, appropriate for clinical trials in patients with cancer tissues harboring aberrant RNA m6A modification protein expression or RNA m6A modification protein–induced resistance to cancer therapy.
MicroRNA-221 and -222 modulate intestinal inflammatory Th17 cell response as negative feedback regulators downstream of interleukin-23
Authors: Yohei Mikami, Rachael L. Philips, Giuseppe Sciumè, Franziska Petermann, Françoise Meylan, Hiroyuki Nagashima, Chen Yao, Fred P. Davis, Stephen R. Brooks, Hong-Wei Sun, Hayato Takahashi, Amanda C. Poholek, Han-Yu Shih, Behdad Afzali, Stefan A. Muljo, Markus Hafner, Yuka Kanno, John J. O’Shea
Journal: Immunity (2021)
Poly(l-glutamic acid)-cisplatin nanoformulations with detachable PEGylation for prolonged circulation half-life and enhanced cell internalization
Authors: Zhongyu Jiang, Xiangru Feng, Haoyang Zou, Weiguo Xu, Xiuli Zhuang
Journal: Bioactive Materials (2021)

PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect, which consequently improves the intratumoral accumulation. However, cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG, which limits their therapeutic effect. To this end, we designed and prepared two kinds of poly(l-glutamic acid)-cisplatin (PLG-CDDP) nanoformulations with detachable PEG, which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization. The extracellular pH (pHe)-responsive cleavage 2-propionic-3-methylmaleic anhydride (CDM)-derived amide bond and matrix metalloproteinases-2/9 (MMP-2/9)-sensitive degradable peptide PLGLAG were utilized to link PLG and PEG, yielding pHe-responsive PEG-pHe-PLG and MMP-sensitive PEG-MMP-PLG. The corresponding smart nanoformulations PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were then prepared by the complexation of polypeptides and cisplatin (CDDP). The circulation half-lives of PEG-pHe-PLG-Pt and PEG-MMP-PLG-Pt were about 4.6 and 4.2 times higher than that of the control PLG-Pt, respectively. Upon reaching tumor tissue, PEG on the surface of nanomedicines was detached as triggered by pHe or MMP, which increased intratumoral CDDP retention, enhanced cell uptake, and improved antitumor efficacy toward a fatal high-grade serous ovarian cancer (HGSOC) mouse model, indicating the promising prospects for clinical application of detachable PEGylated nanoformulations.
Impact of comorbidity burden on renal cell carcinoma prognosis: A Danish nationwide cohort study.
Authors: Trine Allerslev Horsbøll, Susanne Oksbjerg Dalton, Jane Christensen, Astrid Petersen, Nessn H. Azawi, Frede Donskov, Ole Andersen, Mette Nørgaard, Lars Lund
Journal: Journal of Clinical Oncology (2021)

360 Background: The incidence of renal cell carcinoma is increasing worldwide and have a 5-year relative survival rates of around 75%. Comorbidity has been found to be associated with complications and mortality after renal cancer surgery. No studies have focused on comorbidity as a prognostic factor in a nationwide cohort of patients with renal cell carcinoma with long-term follow-up. Purpose: The primary aim was to evaluate the prognostic impact of comorbidity on survival in older (≥70 years) and younger (&lt;70 years) patients diagnosed with renal cell carcinoma. Methods: We established a nationwide register-based cohort of 7,894 patients aged 18 or more diagnosed with renal cell carcinoma in Denmark between 2006 and 2017, and followed their vital status for up to 13 years. We computed 1- and 5-year overall survival and hazard ratios (HRs) of death according to comorbidity status using Charlson Comorbidity Index (CCI) among patients aged &lt; 70 years and ≥ 70 years. Results: In all, 36% of the patients had registered comorbidity at the time of diagnosis. Survival decreased with increasing CCI score. It did though increase for all groups of CCI scores (0, 1-2 and 3+) over time. For patients without comorbidity diagnosed in 2006-2008 and 2015-2017, 5-year survival rate increased from 57% to 69%. For patients with a CCI score of 1-2 vs 3, the 5-year survival rate increased from 46% to 62% vs 39% to 44%. In age- and gender-stratified analyses, patients with a CCI score of 1-2 and 3+ had increased mortality compared to patients without registered comorbidity (HR 1.15, 95 % CI 1.06-1.24) and (HR 1.56, 95 % CI 1.40-1.73). Patterns were similar for older (≥70 years) and younger (&lt;70 years) patients. Particularly, diagnoses of congestive heart failure, peripheral vascular and cerebrovascular disease, dementia, chronic pulmonary disease, preexisting renal and liver disease, diabetes and lymphoma led to increased mortality. Conclusions: Comorbidity leads to inferior survival outcomes in patients with renal cell carcinoma, irrespective of age, despite an overall increasing survival. These data may guide patient counseling and prompt initiatives for controlling comorbidity.