tbuckley/cabot-search huggingface dataset:
Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs
Authors: Dong Han, Maryam Labaf, Yawei Zhao, Jude Owiredu, Songqi Zhang, Krishna Patel, Kavita Venkataramani, Jocelyn S Steinfeld, Wanting Han, Muqing Li, Mingyu Liu, Zifeng Wang, Anna Besschetnova, Susan Patalano, Michaela J Mulhearn, Jill A Macoska, Xin Yuan, Steven P Balk, Peter S Nelson, Stephen R Plymate, Shuai Gao, Kellee R Siegfried, Ruihua Liu, Mary M Stangis, Gabrielle Foxa, Piotr J Czernik, Bart O Williams, Kourosh Zarringhalam, Xiaohong Li, Changmeng Cai
Journal: Journal of Clinical Investigation (2024)

One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared with the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remain unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.
Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury
Authors: Ye Feng, Zeguo Sun, Jia Fu, Fang Zhong, Weijia Zhang, Chengguo Wei, Anqun Chen, Bi-Cheng Liu, John C. He, Kyung Lee
Journal: Kidney International (2024)

Retinoic acid receptor responder protein-1 (RARRES1) is a podocyte-enriched transmembrane protein whose increased expression correlates with human glomerular disease progression. RARRES1 promotes podocytopenia and glomerulosclerosis via p53-mediated podocyte apoptosis. Importantly, the cytopathic actions of RARRES1 are entirely dependent on its proteolytic cleavage into a soluble protein (sRARRES1) and subsequent podocyte uptake by endocytosis, as a cleavage mutant RARRES1 exerted no effects in vitro or in vivo. As RARRES1 expression is upregulated in human glomerular diseases, here we investigated the functional consequence of podocyte-specific overexpression of RARRES1 in mice in the experimental focal segmental glomerulosclerosis and diabetic kidney disease. We also examined the effects of long-term RARRES1 overexpression on slowly developing aging-induced kidney injury. As anticipated, the induction of podocyte overexpression of RARRES1 (Pod-RARRES1WT) significantly worsened glomerular injuries and worsened kidney function in all three models, while overexpression of RARRES1 cleavage mutant (Pod-RARRES1MT) did not. Remarkably, direct uptake of sRARRES1 was also seen in proximal tubules of injured Pod-RARRES1WT mice and associated with exacerbated tubular injuries, vacuolation, and lipid accumulation. Single cell RNA sequence analysis of mouse kidneys demonstrated RARRES1 led to a marked deregulation of lipid metabolism in proximal tubule subsets. We further identified matrix metalloproteinase 23 (MMP23) as a highly podocyte-specific metalloproteinase and responsible for RARRES1 cleavage in disease settings, as adeno-associated virus 9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo. Thus, our study delineates a previously unrecognized mechanism by which a podocyte-derived protein directly facilitates podocyte and tubular injury in glomerular diseases and suggests that podocyte-specific functions of RARRES1 and MMP23 may be targeted to ameliorate glomerular disease progression in vivo.
Toripalimab Plus Bevacizumab as First-line Treatment for Advanced Hepatocellular Carcinoma: A Prospective, Multicenter, Single-Arm, Phase II Trial
Authors: Yajin Chen, Cheng-You Du, Shunli Shen, Wu Zhang, Yunfeng Shan, Ang Lyu, Jianhui Wu, Changzhen Shang, Xuan Luo, Jinxing Wei, Heng Xiao, Jianguo Qiu, Yunpeng Hua, Shutong Wang, Ting Wang, Shengjie Dai, Shuhao Zhang, Bingying Xie, Yinghao Wu, Chunyi Hao
Journal: Clinical Cancer Research (2024)

Abstract Purpose: This phase II, multicenter, prospective, single-arm study aimed to evaluate the efficacy and safety of toripalimab plus bevacizumab for treating advanced hepatocellular carcinoma (HCC). Patients and Methods: Treatment-naïve patients with advanced HCC received toripalimab 240 mg plus bevacizumab 15 mg/kg every 3 weeks. The primary endpoints included safety and tolerability and objective response rate (ORR) assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Fifty-four patients were enrolled between April 17, 2020, and December 11, 2020. As assessed by the investigator according to RECIST v1.1, the ORR was 31.5% [95% confidence interval (CI), 19.5–45.6] and the lower bound of the 95% CI was above the prespecified boundary of 10%. The independent review committee (IRC) assessed ORR according to the modified RECIST (mRECIST), which was 46.3% (95% CI, 32.6–60.4). The median progression-free survival was 8.5 (95% CI, 5.5–11.0) and 9.8 months (95% CI, 5.6 to not evaluable) as assessed by the investigator according to RECIST v1.1 and IRC according to mRECIST criteria, respectively. The median overall survival (OS) was not reached, and the 12- and 24-month OS rates were 77.3% and 63.5%, respectively. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 27 patients (50.0%). The most common TEAEs were proteinuria (59.3%), hypertension (38.9%), increased aspartate aminotransferase (33.3%), increased amylase (29.6%), decreased platelet count (27.8%), and increased bilirubin levels (27.8%). Conclusions: Toripalimab plus bevacizumab showed a favorable efficacy and safety profile, supporting further studies on this combination regimen as a first-line treatment for advanced HCC.
Weight-Bearing Physical Activity, Lower-Limb Muscle Mass, and Risk of Knee Osteoarthritis
Authors: Yahong Wu, Cindy G. Boer, Amy Hofman, Dieuwke Schiphof, Marienke van Middelkoop, Ingrid A. Szilagyi, Bahar Sedaghati-Khayat, Sita M. A. Bierma-Zeinstra, Trudy Voortman, Joyce B. J. van Meurs
Journal: JAMA Network Open (2024)

It has been demonstrated that total physical activity is not associated with risk of osteoarthritis. However, the association of different types of physical activity with incident knee osteoarthritis remains unclear.
Accuracy of Event Rate and Effect Size Estimation in Major Cardiovascular Trials
Authors: Christoph B. Olivier, Lasse Struß, Nathalie Sünnen, Klaus Kaier, Lukas A. Heger, Dirk Westermann, Joerg J. Meerpohl, Kenneth W. Mahaffey
Journal: JAMA Network Open (2024)

For the design of a randomized clinical trial (RCT), estimation of the expected event rate and effect size of an intervention is needed to calculate the sample size. Overestimation may lead to an underpowered trial.
Primary Care Physicians’ Experiences With and Adaptations to Time Constraints
Authors: Michelle-Linh T. Nguyen, Vlad Honcharov, Dawna Ballard, Shannon Satterwhite, Aoife M. McDermott, Urmimala Sarkar
Journal: JAMA Network Open (2024)

The primary care workforce shortage is significant and persistent, with organizational and policy leaders urgently seeking interventions to enhance retention and recruitment. Time constraints are a valuable focus for action; however, designing effective interventions requires deeper understanding of how time constraints shape employees' experiences and outcomes of work.
Dietary dicarboxylic acids provide a nonstorable alternative fat source that protects mice against obesity
Authors: Eric S. Goetzman, Bob B. Zhang, Yuxun Zhang, Sivakama S. Bharathi, Joanna Bons, Jacob Rose, Samah Shah, Keaton J. Solo, Alexandra V. Schmidt, Adam C. Richert, Steven J. Mullett, Stacy L. Gelhaus, Krithika S. Rao, Sruti S. Shiva, Katherine E. Pfister, Anne Silva Barbosa, Sunder Sims-Lucas, Steven F. Dobrowolski, Birgit Schilling
Journal: Journal of Clinical Investigation (2024)

Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for nine weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized by many tissues. In tissues expressing the "a" isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.
Prescription and Dispensation of QT-Prolonging Medications in Individuals Receiving Hemodialysis
Authors: Virginia Wang, Chin-Hua (Lily) Wang, Magdalene M. Assimon, Patrick H. Pun, Wolfgang C. Winkelmayer, Jennifer E. Flythe
Journal: JAMA Network Open (2024)

Individuals with dialysis-dependent kidney failure have numerous risk factors for medication-related adverse events, including receipt of care by multiple clinicians and initiation of some QT-prolonging medications with known risk of torsades de pointes (TdP), which is associated with higher risk of sudden cardiac death. Little is known about the prescription and dispensation patterns of QT-prolonging medications among people receiving dialysis, hindering efforts to reduce drug-related harm from these and other medications in this high-risk population.
Toward More Equitable Breast Cancer Outcomes
Authors: Joann G. Elmore, Christoph I. Lee
Journal: JAMA (2024)

US Preventive Services Task Force; Wanda K. Nicholson, MD, MPH, MBA; Michael Silverstein, MD, MPH; John B. Wong, MD; Michael J. Barry, MD; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; Marie Krousel-Wood, MD, MSPH; Sei Lee, MD, MAS; Li Li, MD, PhD, MPH; Carol M. Mangione, MD, MSPH; Goutham Rao, MD; John M. Ruiz, PhD; James J. Stevermer, MD, MSPH; Joel Tsevat, MD, MPH; Sandra Millon Underwood, PhD, RN; Sarah Wiehe, MD, MPH
Screening for Breast Cancer
Authors: Wanda K. Nicholson, Michael Silverstein, John B. Wong, Michael J. Barry, David Chelmow, Tumaini Rucker Coker, Esa M. Davis, Carlos Roberto Jaén, Marie Krousel-Wood, Sei Lee, Li Li, Carol M. Mangione, Goutham Rao, John M. Ruiz, James J. Stevermer, Joel Tsevat, Sandra Millon Underwood, Sarah Wiehe
Journal: JAMA (2024)

Importance Among all US women, breast cancer is the second most common cancer and the second most common cause of cancer death. In 2023, an estimated 43 170 women died of breast cancer. Non-Hispanic White women have the highest incidence of breast cancer and non-Hispanic Black women have the highest mortality rate. Objective The USPSTF commissioned a systematic review to evaluate the comparative effectiveness of different mammography-based breast cancer screening strategies by age to start and stop screening, screening interval, modality, use of supplemental imaging, or personalization of screening for breast cancer on the incidence of and progression to advanced breast cancer, breast cancer morbidity, and breast cancer–specific or all-cause mortality, and collaborative modeling studies to complement the evidence from the review. Population Cisgender women and all other persons assigned female at birth aged 40 years or older at average risk of breast cancer. Evidence Assessment The USPSTF concludes with moderate certainty that biennial screening mammography in women aged 40 to 74 years has a moderate net benefit. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of screening mammography in women 75 years or older and the balance of benefits and harms of supplemental screening for breast cancer with breast ultrasound or magnetic resonance imaging (MRI), regardless of breast density. Recommendation The USPSTF recommends biennial screening mammography for women aged 40 to 74 years. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening mammography in women 75 years or older. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of supplemental screening for breast cancer using breast ultrasonography or MRI in women identified to have dense breasts on an otherwise negative screening mammogram. (I statement)
New Recommendations for Breast Cancer Screening—In Pursuit of Health Equity
Authors: Lydia E. Pace, Nancy L. Keating
Journal: JAMA Network Open (2024)

US Preventive Services Task Force; Wanda K. Nicholson, MD, MPH, MBA; Michael Silverstein, MD, MPH; John B. Wong, MD; Michael J. Barry, MD; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; Marie Krousel-Wood, MD, MSPH; Sei Lee, MD, MAS; Li Li, MD, PhD, MPH; Carol M. Mangione, MD, MSPH; Goutham Rao, MD; John M. Ruiz, PhD; James J. Stevermer, MD, MSPH; Joel Tsevat, MD, MPH; Sandra Millon Underwood, PhD, RN; Sarah Wiehe, MD, MPH
Patient Perceptions of Chatbot Supervision in Health Care Settings
Authors: Jessica Ellis, Mika K. Hamer, Marlee Akerson, Matt Andazola, Annie Moore, Eric G. Campbell, Matthew DeCamp
Journal: JAMA Network Open (2024)

This survey study assesses whether patients communicating with a chatbot in a large health care system were able to accurately identify it as an unsupervised computer application.
Collaborative Modeling to Compare Different Breast Cancer Screening Strategies
Authors: Amy Trentham-Dietz, Christina Hunter Chapman, Jinani Jayasekera, Kathryn P. Lowry, Brandy M. Heckman-Stoddard, John M. Hampton, Jennifer L. Caswell-Jin, Ronald E. Gangnon, Ying Lu, Hui Huang, Sarah Stein, Liyang Sun, Eugenio J. Gil Quessep, Yuanliang Yang, Yifan Lu, Juhee Song, Diego F. Muñoz, Yisheng Li, Allison W. Kurian, Karla Kerlikowske, Ellen S. O’Meara, Brian L. Sprague, Anna N. A. Tosteson, Eric J. Feuer, Donald Berry, Sylvia K. Plevritis, Xuelin Huang, Harry J. de Koning, Nicolien T. van Ravesteyn, Sandra J. Lee, Oguzhan Alagoz, Clyde B. Schechter, Natasha K. Stout, Diana L. Miglioretti, Jeanne S. Mandelblatt
Journal: JAMA (2024)

The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known.
Definition of Implanted Neurological Device Abandonment
Authors: Michael S. Okun, Timothy Marjenin, Jinendra Ekanayake, Frederic Gilbert, Sean P. Doherty, Jack Pilkington, Jennifer French, Cynthia Kubu, Gabriel Lázaro-Muñoz, Timothy Denison, James Giordano
Journal: JAMA Network Open (2024)

Establishing a formal definition for neurological device abandonment has the potential to reduce or to prevent the occurrence of this abandonment.
Screening for Breast Cancer
Authors: Jillian T. Henderson, Elizabeth M. Webber, Meghan S. Weyrich, Marykate Miller, Joy Melnikow
Journal: JAMA (2024)

Importance Breast cancer is a leading cause of cancer mortality for US women. Trials have established that screening mammography can reduce mortality risk, but optimal screening ages, intervals, and modalities for population screening guidelines remain unclear. Objective To review studies comparing different breast cancer screening strategies for the US Preventive Services Task Force. Data Sources MEDLINE, Cochrane Library through August 22, 2022; literature surveillance through March 2024. Study Selection English-language publications; randomized clinical trials and nonrandomized studies comparing screening strategies; expanded criteria for screening harms. Data Extraction and Synthesis Two reviewers independently assessed study eligibility and quality; data extracted from fair- and good-quality studies. Main Outcomes and Measures Mortality, morbidity, progression to advanced cancer, interval cancers, screening harms. Results Seven randomized clinical trials and 13 nonrandomized studies were included; 2 nonrandomized studies reported mortality outcomes. A nonrandomized trial emulation study estimated no mortality difference for screening beyond age 74 years (adjusted hazard ratio, 1.00 [95% CI, 0.83 to 1.19]). Advanced cancer detection did not differ following annual or biennial screening intervals in a nonrandomized study. Three trials compared digital breast tomosynthesis (DBT) mammography screening with digital mammography alone. With DBT, more invasive cancers were detected at the first screening round than with digital mammography, but there were no statistically significant differences in interval cancers (pooled relative risk, 0.87 [95% CI, 0.64-1.17]; 3 studies [n = 130 196]; I 2 = 0%). Risk of advanced cancer (stage II or higher) at the subsequent screening round was not statistically significant for DBT vs digital mammography in the individual trials. Limited evidence from trials and nonrandomized studies suggested lower recall rates with DBT. An RCT randomizing individuals with dense breasts to invitations for supplemental screening with magnetic resonance imaging reported reduced interval cancer risk (relative risk, 0.47 [95% CI, 0.29-0.77]) and additional false-positive recalls and biopsy results with the intervention; no longer-term advanced breast cancer incidence or morbidity and mortality outcomes were available. One RCT and 1 nonrandomized study of supplemental ultrasound screening reported additional false-positives and no differences in interval cancers. Conclusions and Relevance Evidence comparing the effectiveness of different breast cancer screening strategies is inconclusive because key studies have not yet been completed and few studies have reported the stage shift or mortality outcomes necessary to assess relative benefits.
From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations for Developing Precision Medicine in the ICU
Authors: Anthony C. Gordon, Narges Alipanah-Lechner, Lieuwe D. Bos, Jose Dianti, Janet Victoria Diaz, Simon Finfer, Tomoko Fujii, Evangelos J. Giamarellos-Bourboulis, Ewan C. Goligher, Michelle Ng Gong, Eleni Karakike, Vincent Liu, Nuttha Lumlertgul, John C. Marshall, David K. Menon, Nuala J Meyer, Elizabeth S. Munroe, Sheila N. Myatra, Marlies Ostermann, Hallie C Prescott, Adrienne G. Randolph, Edward J. Schenck, Christopher W Seymour, Manu Shankar-Hari, Mervyn Singer, Marry R. Smit, Aiko Tanaka, Fabio Silvio Taccone, B. Taylor Thompson, Lisa K Torres, Tom Van der Poll, Jean-Louis Vincent, Carolyn S Calfee
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. To impact clinical care, identification of subpopulations must do more than differentiate prognosis. It must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway, but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry, and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields.
Errors in Results and Tables
Journal: JAMA Network Open (2024)

Investigation titled "Intravesical Interferon Therapy vs Hyaluronic Acid for Pain Among Female Individuals With Interstitial Cystitis: a Randomized Clinical Trial," 1 published April 8, 2024, there were numerical errors in the results section and Tables.The mean (SD) voiding frequency in 24 hours for the hyaluronic acid group should have read 19.7 (4.5) times.Additionally, in the first paragraph of the Results section, the mean (SD) values for nocturia episodes and functional bladder capacity were swapped.This article has been corrected.