tbuckley/cabot-search huggingface dataset:
Perceived Economic Burden, Mortality, and Health Status in Patients With Heart Failure
Authors: Yuan Yu, Jiamin Liu, Lihua Zhang, Runqing Ji, Xiaoming Su, Zhiping Gao, Shuang Xia, Jing Li, Liwen Li
Journal: JAMA Network Open (2024)

Importance In the face of an emerging heart failure (HF) epidemic, describing the association between perceived economic burden (PEB) and health care outcomes is an important step toward more equitable and achievable care. Objectives To examine the association between PEB and risk of 1-year clinical outcomes and HF–specific health status in patients with acute decompensated HF. Design, Setting, and Participants This prospective, multicenter, hospital-based cohort study prospectively enrolled adult patients hospitalized for acute decompensated HF at 52 hospitals in China from August 2016 to May 2018, with 1-year follow-up. Data were analyzed on June 17, 2022. Exposure Perceived economic burden, categorized as severe (cannot undertake expenses), moderate (can almost undertake expenses), or little (can easily undertake expenses). Main Outcomes and Measures The clinical outcomes of the study were 1-year all-cause death and rehospitalization for HF. Heart failure–specific health status was assessed by the 12-Item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Results Among 3386 patients, median age was 67 years (IQR, 58-75 years) and 2116 (62.5%) were men. Of these patients, 404 (11.9%) had severe PEB; 2021 (59.7%), moderate PEB; and 961 (28.4%), little PEB. Compared with patients with little PEB, those with severe PEB had increased risk of 1-year mortality (hazard ratio [HR], 1.61; 95% CI, 1.21-2.13; P &amp;amp;lt; .001) but not 1-year HF rehospitalization (HR, 1.21; 95% CI, 0.98-1.49; P = .07). The mean (SD) adjusted KCCQ-12 score was lowest in patients with severe PEB and highest in patients with little PEB at baseline (40.0 [1.7] and 50.2 [1.0] points, respectively; P &amp;amp;lt; .001) and at each visit (eg, 12 months: 61.5 [1.6] and 75.5 [0.9] points respectively; P &amp;amp;lt; .001). Patients reporting severe PEB had a clinically significant lower 1-year KCCQ-12 score compared with those reporting little PEB (mean difference, −11.3 points; 95% CI, −14.9 to −7.6 points; P &amp;amp;lt; .001). Conclusions and Relevance In this cohort study of patients with acute decompensated HF, greater PEB was associated with higher risk of mortality and poorer health status but not with risk of HF rehospitalization. The findings suggest that PEB may serve as a convenient tool for risk estimation and as a potential target for quality-improvement interventions for patients with HF.
Long-Term Body Mass Index Variability and Adverse Cardiovascular Outcomes
Authors: Zakaria Almuwaqqat, Qin Hui, Chang Liu, Jin J. Zhou, Benjamin F. Voight, Yuk-Lam Ho, Daniel C. Posner, Jason L. Vassy, J. Michael Gaziano, Kelly Cho, Peter W. F. Wilson, Yan V. Sun
Journal: JAMA Network Open (2024)

Importance Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is a commonly used estimate of obesity, which is a complex trait affected by genetic and lifestyle factors. Marked weight gain and loss could be associated with adverse biological processes. Objective To evaluate the association between BMI variability and incident cardiovascular disease (CVD) events in 2 distinct cohorts. Design, Setting, and Participants This cohort study used data from the Million Veteran Program (MVP) between 2011 and 2018 and participants in the UK Biobank (UKB) enrolled between 2006 and 2010. Participants were followed up for a median of 3.8 (5th-95th percentile, 3.5) years. Participants with baseline CVD or cancer were excluded. Data were analyzed from September 2022 and September 2023. Exposure BMI variability was calculated by the retrospective SD and coefficient of variation (CV) using multiple clinical BMI measurements up to the baseline. Main Outcomes and Measures The main outcome was incident composite CVD events (incident nonfatal myocardial infarction, acute ischemic stroke, and cardiovascular death), assessed using Cox proportional hazards modeling after adjustment for CVD risk factors, including age, sex, mean BMI, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking status, diabetes status, and statin use. Secondary analysis assessed whether associations were dependent on the polygenic score of BMI. Results Among 92 363 US veterans in the MVP cohort (81 675 [88%] male; mean [SD] age, 56.7 [14.1] years), there were 9695 Hispanic participants, 22 488 non-Hispanic Black participants, and 60 180 non-Hispanic White participants. A total of 4811 composite CVD events were observed from 2011 to 2018. The CV of BMI was associated with 16% higher risk for composite CVD across all groups (hazard ratio [HR], 1.16; 95% CI, 1.13-1.19). These associations were unchanged among subgroups and after adjustment for the polygenic score of BMI. The UKB cohort included 65 047 individuals (mean [SD] age, 57.30 (7.77) years; 38 065 [59%] female) and had 6934 composite CVD events. Each 1-SD increase in BMI variability in the UKB cohort was associated with 8% increased risk of cardiovascular death (HR, 1.08; 95% CI, 1.04-1.11). Conclusions and Relevance This cohort study found that among US veterans, higher BMI variability was a significant risk marker associated with adverse cardiovascular events independent of mean BMI across major racial and ethnic groups. Results were consistent in the UKB for the cardiovascular death end point. Further studies should investigate the phenotype of high BMI variability.
An Underappreciated Risk Factor for Heart Failure—Financial Toxicity
Authors: Paul Heidenreich
Journal: JAMA Network Open (2024)

Yuan Yu, MD, PhD; Jiamin Liu, MD; Lihua Zhang, MD, PhD; Runqing Ji, MD, PhD; Xiaoming Su, MSc; Zhiping Gao, MD, PhD; Shuang Xia, MD, PhD; Jing Li, MD, PhD; Liwen Li, MD, PhD
Citations of microRNA Biomarker Articles That Were Retracted
Authors: Hongmei Zhu, Yongliang Jia, Siu-wai Leung
Journal: JAMA Network Open (2024)

Importance Retraction is a tool that journals can use to deter research misconduct and alert their audience to erroneous content published in the journals. However, retracted articles may continue to damage science if they are still cited as legitimate articles. Objective To characterize patterns of postretraction citations, particularly in microRNA biomarker research, a field with one of the highest rates of retraction. Evidence Review Retracted scientific articles on microRNAs were retrieved from PubMed, Web of Science, and Retraction Watch between database inception and July 17, 2021, according to preestablished search strategies. Control articles with characteristics in common with retracted articles (ie, published in the same journals in the same years and months and with the same number of authors) were matched and retrieved from PubMed. Citation metrics of retractions and control articles were collected from Web of Science. PubPeer was referenced to examine the public response or comments on included retractions. Data were analyzed from September 2021 through March 2023. Findings A total of 10 461 articles were analyzed, with 887 retractions and 9574 articles as controls. Among retracted articles, which were published from 1999 to 2021, there were 756 articles (85.23%) written by researchers affiliated with Chinese institutions. Retracted articles were cited 6327 times after retraction. Of 792 retracted articles that were cited, 621 articles (78.41%) were cited at least once after retraction and 238 articles (30.05%) were cited more often after retraction than before retraction. Overall citations (comprising citations before and after retraction) and postretraction citations accumulated over time (eg, the median [IQR] number of postretraction citations was 1 [1-2] and 23 [9-44] citations at the first 6 and 66 months, respectively, between retraction and citation retrieval). A random sample of 87 retracted articles (9.81%) recorded 478 citations after retraction, with 208 citations (43.51%) in articles published 12 months or longer after retraction. Of these citing articles, 19 articles (3.97%) mentioned the retractions. Compared with the control group of 1620 nonretracted articles, no significant differences were found in overall number of citations or citations after retraction. Among 478 articles citing retracted articles, 414 articles were found on PubMed and had matched control articles; these articles had higher odds of being subsequently retracted than 7954 matched control articles (odds ratio, 6.57; 95% CI, 3.39-12.72). Conclusions and Relevance In this study, retraction was not associated with a reduction in citations of retracted articles, but articles that cited retracted publications had higher odds of later retraction. These findings suggest that journals may need to implement mechanisms for detection of postretraction citations.
Analysis and Optimization of Equitable US Cancer Clinical Trial Center Access by Travel Time
Authors: Hassal Lee, Alexander Shakeel Bates, Shawneequa Callier, Michael Chan, Nyasha Chambwe, Andrea Marshall, Mary Beth Terry, Karen Winkfield, Tobias Janowitz
Journal: JAMA Oncology (2024)

Racially minoritized and socioeconomically disadvantaged populations are currently underrepresented in clinical trials. Data-driven, quantitative analyses and strategies are required to help address this inequity.
Clinical drug screening reveals clofazimine potentiates the efficacy while reducing the toxicity of anti-PD-1 and CTLA-4 immunotherapy
Authors: Gang Xue, Xin Li, Muhammad Kalim, Jing Fang, Zhiwu Jiang, Ningbo Zheng, Ziyu Wang, Xiaoyin Li, Maen Abdelrahim, Zhiheng He, Mikhail Nikiforov, Guangxu Jin, Yong Lu
Journal: Cancer Cell (2024)
CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer
Authors: Raymond J. Lim, Ramin Salehi-Rad, Linh M. Tran, Michael S. Oh, Camelia Dumitras, William P. Crosson, Rui Li, Tejas S. Patel, Samantha Man, Cara E. Yean, Jensen Abascal, ZiLing Huang, Stephanie L. Ong, Kostyantyn Krysan, Steven M. Dubinett, Bin Liu
Journal: Cell Reports Medicine (2024)

Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient T cell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced T cell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4+ and CD8+ T cells, as well as CXCR3-dependent T cell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.
Memory/Active T-Cell Activation Is Associated with Immunotherapeutic Response in Fumarate Hydratase–Deficient Renal Cell Carcinoma
Authors: Junru Chen, Xu Hu, Junjie Zhao, Xiaoxue Yin, Linmao Zheng, Jingjing Guo, Jianhui Chen, Yongquan Wang, Xinan Sheng, Haiying Dong, Xiaodong Liu, Xingming Zhang, Jiayu Liang, Haolin Liu, Jin Yao, Jiyan Liu, Yali Shen, Zhibin Chen, Zhengyu He, Yaodong Wang, Ni Chen, Ling Nie, Mengni Zhang, Xiuyi Pan, Yuntian Chen, Haoyang Liu, Yaowen Zhang, Yanfeng Tang, Sha Zhu, Jinge Zhao, Jindong Dai, Zilin Wang, Yuhao Zeng, Zhipeng Wang, Haojie Huang, Zhenhua Liu, Pengfei Shen, Hao Zeng, Guangxi Sun
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. Experimental Design: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. Results: In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. Conclusions: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell–derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.
A Signal-Finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration–Resistant Prostate Cancer: Results from CYCLONE 1
Authors: Neeraj Agarwal, Daniel Castellano, Teresa Alonso-Gordoa, Jose Angel Arranz Arija, Emeline Colomba, Gwenaelle Gravis, Loic Mourey, Stephane Oudard, Aude Fléchon, Macarena González, Pablo M. Rey, Michael T. Schweizer, Enrique Gallardo, Erica Johnston, Arjun Balar, Nadine Haddad, Adams K. Appiah, Karim Nacerddine, José M. Piulats
Journal: Clinical Cancer Research (2024)

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC).
TGR5-mediated lateral hypothalamus-dCA3-dorsolateral septum circuit regulates depressive-like behavior in male mice
Authors: Xu-Yi Li, Shi-Ya Zhang, Yi-Zhou Hong, Zhi-Gang Chen, Yan Long, Dan-Hua Yuan, Jia-Jia Zhao, Su-Su Tang, Hao Wang, Hao Hong
Journal: Neuron (2024)
Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer
Authors: Pierluigi Di Chiaro, Lucia Nacci, Fabiana Arco, Stefania Brandini, Sara Polletti, Andrea Palamidessi, Benedetta Donati, Chiara Soriani, Francesco Gualdrini, Gianmaria Frigè, Luca Mazzarella, Alessia Ciarrocchi, Alessandro Zerbi, Paola Spaggiari, Giorgio Scita, Simona Rodighiero, Iros Barozzi, Giuseppe R. Diaferia, Gioacchino Natoli
Journal: Cancer Cell (2024)
Convergent evolution and targeting of diverse E2 epitopes by human broadly neutralizing antibodies are associated with HCV clearance
Authors: Clinton O. Ogega, Nicole E. Skinner, Marta V. Schoenle, Xander E. Wilcox, Nicole Frumento, Desiree A. Wright, Harry T. Paul, Ariadne Sinnis-Bourozikas, Kaitlyn E. Clark, Alexis Figueroa, Pamela J. Bjorkman, Stuart C. Ray, Andrew I. Flyak, Justin R. Bailey
Journal: Immunity (2024)

The early appearance of broadly neutralizing antibodies (bNAbs) in serum is associated with spontaneous hepatitis C virus (HCV) clearance, but to date, the majority of bNAbs have been isolated from chronically infected donors. Most of these bNAbs use the VH1-69 gene segment and target the envelope glycoprotein E2 front layer. Here, we performed longitudinal B cell receptor (BCR) repertoire analysis on an elite neutralizer who spontaneously cleared multiple HCV infections. We isolated 10,680 E2-reactive B cells, performed BCR sequencing, characterized monoclonal B cell cultures, and isolated bNAbs. In contrast to what has been seen in chronically infected donors, the bNAbs used a variety of VH genes and targeted at least three distinct E2 antigenic sites, including sites previously thought to be non-neutralizing. Diverse front-layer-reactive bNAb lineages evolved convergently, acquiring breadth-enhancing somatic mutations. These findings demonstrate that HCV clearance-associated bNAbs are genetically diverse and bind distinct antigenic sites that should be the target of vaccine-induced bNAbs.
Time is ticking faster for long genes in aging
Authors: Sourena Soheili-Nezhad, Olga Ibáñez-Solé, Ander Izeta, Jan H.J. Hoeijmakers, Thomas Stoeger
Journal: Trends in Genetics (2024)

Recent studies of aging organisms have identified a systematic phenomenon, characterized by a negative correlation between gene length and their expression in various cell types, species, and diseases. We term this phenomenon gene-length-dependent transcription decline (GLTD) and suggest that it may represent a bottleneck in the transcription machinery and thereby significantly contribute to aging as an etiological factor. We review potential links between GLTD and key aging processes such as DNA damage and explore their potential in identifying disease modification targets. Notably, in Alzheimer's disease, GLTD spotlights extremely long synaptic genes at chromosomal fragile sites (CFSs) and their vulnerability to postmitotic DNA damage. We suggest that GLTD is an integral element of biological aging.
CRISPR editing of anti-anemia drug target rescues independent preclinical models of retinitis pigmentosa
Authors: Nicholas D. Nolan, Xuan Cui, Brian M. Robbings, Aykut Demirkol, Kriti Pandey, Wen-Hsuan Wu, Hannah F. Hu, Laura A. Jenny, Chyuan-Sheng Lin, Daniel T. Hass, Jianhai Du, James B. Hurley, Stephen H. Tsang
Journal: Cell Reports Medicine (2024)

Retinitis pigmentosa (RP) is one of the most common forms of hereditary neurodegeneration. It is caused by one or more of at least 3,100 mutations in over 80 genes that are primarily expressed in rod photoreceptors. In RP, the primary rod-death phase is followed by cone death, regardless of the underlying gene mutation that drove the initial rod degeneration. Dampening the oxidation of glycolytic end products in rod mitochondria enhances cone survival in divergent etiological disease models independent of the underlying rod-specific gene mutations. Therapeutic editing of the prolyl hydroxylase domain-containing protein gene (PHD2, also known as Egln1) in rod photoreceptors led to the sustained survival of both diseased rods and cones in both preclinical autosomal-recessive and dominant RP models. Adeno-associated virus-mediated CRISPR-based therapeutic reprogramming of the aerobic glycolysis node may serve as a gene-agnostic treatment for patients with various forms of RP.
Diversity of CFTR variants across ancestries characterized using 454,727 UK biobank whole exome sequences
Authors: Justin E. Ideozu, Mengzhen Liu, Bridget M. Riley-Gillis, Sri R. Paladugu, Fedik Rahimov, Preethi Krishnan, Rakesh Tripathi, Patrick Dorr, Hara Levy, Ashvani Singh, Jeffrey F. Waring, Aparna Vasanthakumar
Journal: Genome Medicine (2024)

Abstract Background Limited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF. Methods We analyzed 454,727 UK Biobank (UKBB) whole-exome sequences to characterize the diversity of CFTR variants across ancestries. Using the PanUKBB classification, the participants were assigned into six major groups: African (AFR), American/American Admixed (AMR), Central South Asia (CSA), East Asian (EAS), European (EUR), and Middle East (MID). We segregated ancestry-specific CFTR variants, including those that are CF-causing or clinically relevant. The ages of certain CF-causing variants were determined and analyzed for selective pressure effects, and curated phenotype analysis was performed for participants with clinically relevant CFTR genotypes. Results We detected over 4000 CFTR variants, including novel ancestry-specific variants, across six ancestries. Europeans had the most unique CFTR variants [ n = 2212], while the American group had the least unique variants [ n = 23]. F508del was the most prevalent CF-causing variant found in all ancestries, except in EAS, where V520F was the most prevalent. Common EAS variants such as 3600G &gt; A, V456A, and V520, which appeared approximately 270, 215, and 338 generations ago, respectively, did not show evidence of selective pressure. Sixteen participants had two CF-causing variants, with two being diagnosed with CF. We found 154 participants harboring a CF-causing and varying clinical consequences (VCC) variant. Phenotype analysis performed for participants with multiple clinically relevant variants returned significant associations with CF and its pulmonary phenotypes [Bonferroni-adjusted p &lt; 0.05]. Conclusions We leveraged the UKBB database to comprehensively characterize the broad spectrum of CFTR variants across ancestries. The detection of over 4000 CFTR variants, including several ancestry-specific and uncharacterized CFTR variants, warrants the need for further characterization of their functional and clinical relevance. Overall, the presentation of classical CF phenotypes seen in non-CF diagnosed participants with more than one CF-causing variant indicates that they may benefit from current CFTR modulator therapies.
Myeloid cell replacement is neuroprotective in chronic experimental autoimmune encephalomyelitis
Authors: Marius Marc-Daniel Mader, Alan Napole, Danwei Wu, Micaiah Atkins, Alexa Scavetti, Yohei Shibuya, Aulden Foltz, Oliver Hahn, Yongjin Yoo, Ron Danziger, Christina Tan, Tony Wyss-Coray, Lawrence Steinman, Marius Wernig
Journal: Nature Neuroscience (2024)