tbuckley/cabot-search huggingface dataset:
PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2
Authors: Chun-Liang Yang, Fa-Xi Wang, Jia-Hui Luo, Shan-Jie Rong, Wan-Ying Lu, Qi-Jie Chen, Jun Xiao, Ting Wang, Dan-Ni Song, Jing Liu, Qian Mo, Shuo Li, Yu Chen, Ya-Nan Wang, Yan-Jun Liu, Tong Yan, Wei-Kuan Gu, Shu Zhang, Fei Xiong, Qi-Lin Yu, Zi-Yun Zhang, Ping Yang, Shi-Wei Liu, Decio Eizirik, Ling-Li Dong, Fei Sun, Cong-Yi Wang
Journal: Molecular Therapy (2024)

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.Graphical abstract
Towards long-tailed, multi-label disease classification from chest X-ray: Overview of the CXR-LT challenge
Authors: Gregory Holste, Yiliang Zhou, Song Wang, Ajay Jaiswal, Mingquan Lin, Sherry Zhuge, Yuzhe Yang, Dongkyun Kim, Trong-Hieu Nguyen-Mau, Minh-Triet Tran, Jaehyup Jeong, Wongi Park, Jongbin Ryu, Feng Hong, Arsh Verma, Yosuke Yamagishi, Changhyun Kim, Hyeryeong Seo, Myungjoo Kang, Leo Anthony Celi, Zhiyong Lu, Ronald M Summers, George Shih, Zhangyang Wang, Yifan Peng
Journal: Medical Image Analysis (2024)
Preoperative GLP-1 Receptor Agonists and Risk of Postoperative Respiratory Complications
Authors: Marc Levi
Journal: JAMA (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders
Authors: Daniel Greene, Chantal Thys, Ian R. Berry, Joanna Jarvis, Els Ortibus, Andrew D. Mumford, Kathleen Freson, Ernest Turro
Journal: Nature Medicine (2024)

Most people with intellectual disability (ID) do not receive a molecular diagnosis following genetic testing. To identify new etiologies of ID, we performed a genetic association analysis comparing the burden of rare variants in 41,132 noncoding genes between 5,529 unrelated cases and 46,401 unrelated controls. RNU4-2, which encodes U4 small nuclear RNA, a critical component of the spliceosome, was the most strongly associated gene. We implicated de novo variants among 47 cases in two regions of RNU4-2 in the etiology of a syndrome characterized by ID, microcephaly, short stature, hypotonia, seizures and motor delay. We replicated this finding in three collections, bringing the number of unrelated cases to 73. Analysis of national genomic diagnostic data showed RNU4-2 to be a more common etiological gene for neurodevelopmental abnormality than any previously reported autosomal gene. Our findings add to the growing evidence of spliceosome dysfunction in the etiologies of neurological disorders.
Blood Proteomics for Biomarkers of Kidney Pathology
Authors: Andrew Beenken, Krzysztof Kiryluk
Journal: Journal of the American Society of Nephrology (2024)

Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York Correspondence: Dr. Krzysztof Kiryluk, email: [email protected] See related article, "Plasma Proteins Associated with Chronic Histopathologic Lesions on Kidney Biopsy," on pages XXX–XXX.
Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks
Authors: Marc A Riedl, Henriette Farkas, Emel Aygören-Pürsün, Fotis Psarros, Daniel F Soteres, Maria Staevska, Mauro Cancian, David Hagin, Daisuke Honda, Isaac Melamed, Sinisa Savic, Marcin Stobiecki, Paula J Busse, Eunice Dias de Castro, Nancy Agmon-Levin, Richard Gower, Aharon Kessel, Marcin Kurowski, Ramon Lleonart, Vesna Grivcheva Panovska, H James Wedner, Paul K Audhya, James Hao, Matthew Iverson, Michael D Smith, Christopher M Yea, William R Lumry, Andrea Zanichelli, Jonathan A Bernstein, Marcus Maurer, Danny M Cohn
Journal: New England Journal of Medicine (2024)

Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy.
Unveiling ferroptosis as a promising therapeutic avenue for colorectal cancer and colitis treatment
Authors: Aaron T. Kao, Christian V. Cabanlong, Kendra Padilla, Xiang Xue
Journal: Acta Pharmaceutica Sinica B (2024)

Ferroptosis is a novel type of regulated cell death (RCD) involving iron accumulation and lipid peroxidation. Since its discovery in 2012, various studies have shown that ferroptosis is associated with the pathogenesis of various diseases. Ferroptotic cell death has also been linked to intestinal dysfunction but can act as either a positive or negative regulator of intestinal disease, depending on the cell type and disease context. The continued investigation of mechanisms underlying ferroptosis provides a wealth of potential for developing novel treatments. Considering the growing prevalence of intestinal diseases, particularly colorectal cancer (CRC) and inflammatory bowel disease (IBD), this review article focuses on potential therapeutics targeting the ferroptotic pathway in relation to CRC and IBD.
Corticosteroid Injections and Risk of Fracture
Authors: Terin T. Sytsma, Shannon Thomas, Karen M. Fischer, Laura S. Greenlund
Journal: JAMA Network Open (2024)

Importance Corticosteroid injections (CSIs) are an important tool for pain relief in many musculoskeletal conditions, but the longitudinal effects of these treatments on bone health and fracture risk are unknown. Objective To determine whether cumulative doses of corticosteroid injections are associated with higher risk of subsequent osteoporotic and nonosteoporotic fractures. Design, Setting, and Participants This cohort study included adult patients receiving any CSI from May 1, 2018, through July 1, 2022. Eligible patients resided in Olmsted County, Minnesota, and were empaneled to receive primary care within the Mayo Clinic. Cox proportional hazards regression models were used to evaluate risk of fracture based on cumulative injected corticosteroid dose. Exposure Receipt of any CSI during the study period. Main Outcomes and Measures The primary outcome was risk of fracture by total triamcinolone equivalents received. Secondary outcomes consisted of risks of fracture based on triamcinolone equivalents received in subgroups of patients not at high risk for fracture and patients with osteoporosis. Results A total of 7197 patients were included in the study (mean [SD] age, 64.4 [14.6] years; 4435 [61.6%] women; 183 [2.5%] Black and 6667 [92.6%] White), and 346 (4.8%) had a new fracture during the study period. Of these fractures, 149 (43.1%) were considered osteoporotic. In the adjusted Cox proportional hazards regression model, there was no association of higher fracture risk based on cumulative CSI dose (adjusted hazard ratio [HR], 1.04 [95% CI, 0.96-1.11]). There was also no associated higher risk of fracture in the non–high-risk (adjusted HR, 1.11 [95% CI, 0.98-1.26]) or osteoporosis (adjusted HR, 1.01 [95% CI, 0.90-1.11]) subgroups. Age, Charleson Comorbidity Index, and previous fracture were the only factors that were associated with higher fracture risk. Conclusions and Relevance In this cohort study of cumulative injected corticosteroid dose and risk of subsequent fracture, no association was observed, including in patients with a preexisting diagnosis of osteoporosis. Treatment of painful conditions with CSI should not be withheld or delayed owing to concern about fracture risk.
Providing Groceries and Transportation to Poverty-Exposed Pediatric Oncology Families
Authors: Haley Newman, Emily Jones, Yimei Li, Puja J. Umaretiya, Julie A. Wolfson, Joanne Wolfe, Kira Bona
Journal: JAMA Network Open (2024)

This randomized clinical trial evaluates the Pediatric Cancer Resource Equity (PediCARE) intervention, which provided groceries and transportation, vs usual care, for poverty-exposed pediatric oncology families.
Patient Lung Cancer Screening Decisions and Environmental and Psychosocial Factors
Authors: Jennifer Richmond, Jessica R. Fernandez, Kemberlee Bonnet, Ashley Sellers, David G. Schlundt, Allana T. Forde, Consuelo H. Wilkins, Melinda C. Aldrich
Journal: JAMA Network Open (2024)

Importance Screening for lung cancer using low-dose computed tomography is associated with reduced lung cancer–specific mortality, but uptake is low in the US; understanding how patients make decisions to engage with lung cancer screening is critical for increasing uptake. Prior research has focused on individual-level psychosocial factors, but environmental factors (eg, historical contexts that include experiencing racism) and modifying factors—those that can be changed to make it easier or harder to undergo screening—also likely affect screening decisions. Objective To investigate environmental, psychosocial, and modifying factors influencing lung cancer screening decision-making and develop a conceptual framework depicting relationships between these factors. Design, Setting, and Participants This multimethod qualitative study was conducted from December 2021 to June 2022 using virtual semistructured interviews and 4 focus groups (3-4 participants per group). All participants met US Preventive Services Task Force eligibility criteria for lung cancer screening (ie, age 50-80 years, at least a 20 pack-year smoking history, and either currently smoke or quit within the past 15 years). Screening-eligible US participants were recruited using an online panel. Main Outcomes and Measures Key factors influencing screening decisions (eg, knowledge, beliefs, barriers, and facilitators) were the main outcome. A theory-informed, iterative inductive-deductive approach was applied to analyze data and develop a conceptual framework summarizing results. Results Among 34 total participants (interviews, 20 [59%]; focus groups, 14 [41%]), mean (SD) age was 59.1 (4.8) years and 20 (59%) identified as female. Half had a household income below $20 000 (17 [50%]). Participants emphasized historical and present-day racism as critical factors contributing to mistrust of health care practitioners and avoidance of medical procedures like screening. Participants reported that other factors, such as public transportation availability, also influenced decisions. Additionally, participants described psychosocial processes involved in decisions, such as perceived screening benefits, lung cancer risk appraisal, and fear of a cancer diagnosis or harmful encounters with practitioners. In addition, participants identified modifying factors (eg, insurance coverage) that could make receiving screening easier or harder. Conclusions and Relevance In this qualitative study of patient lung cancer screening decisions, environmental, psychosocial, and modifying factors influenced screening decisions. The findings suggest that systems-level interventions, such as those that help practitioners understand and discuss patients’ prior negative health care experiences, are needed to promote effective screening decision-making.
Cytisinicline More Than Doubled Chances of Quitting E-Cigarettes
Authors: Emily Harris
Journal: JAMA (2024)

Nancy A. Rigotti, MD; Neal L. Benowitz, MD; Judith J. Prochaska, PhD, MPH; Daniel F. Cain, BSc; Julie Ball, MS; Anthony Clarke, PhD; Brent A. Blumenstein, PhD; Cindy Jacobs, PhD, MD
In-Hospital vs 30-Day Sepsis Mortality at US Safety-Net and Non–Safety-Net Hospitals
Authors: Anica C. Law, Nicholas A. Bosch, Yang Song, Archana Tale, Karen E. Lasser, Allan J. Walkey
Journal: JAMA Network Open (2024)

In-hospital mortality of patients with sepsis is frequently measured for benchmarking, both by researchers and policymakers. Prior studies have reported higher in-hospital mortality among patients with sepsis at safety-net hospitals compared with non-safety-net hospitals; however, in critically ill patients, in-hospital mortality rates are known to be associated with hospital discharge practices, which may differ between safety-net hospitals and non-safety-net hospitals.
Tweety homolog 3 promotes colorectal cancer progression through mutual regulation of histone deacetylase 7
Authors: Pengyan Lu, Shumin Deng, Jiaxin Liu, Qing Xiao, Zhengwei Zhou, Shuojie Li, Jiaxuan Xin, Guang Shu, Bo Yi, Gang Yin
Journal: MedComm (2024)

Abstract Colorectal cancer (CRC) is one of the leading cancers worldwide, with metastasis being a major cause of high mortality rates among patients. In this study, dysregulated gene Tweety homolog 3 (TTYH3) was identified by Gene Expression Omnibus database. Public databases were used to predict potential competing endogenous RNAs (ceRNAs) for TTYH3. Quantitative real‐time polymerase chain reaction, western blot, and immunohistochemistry were utilized to analyze TTYH3 and histone deacetylase 7 (HDAC7) levels. Luciferase assays confirmed miR‐1271‐5p directly targeting the 3′ untranslated regions of TTYH3 and HDAC7. In vitro experiments such as transwell and human umbilical vein endothelial cell tube formation, as well as in vivo mouse models, were conducted to assess the biological functions of TTYH3 and HDAC7. We discovered that upregulation of TTYH3 in CRC promotes cell migration by affecting the Epithelial–mesenchymal transition pathway, which was independent of its ion channel activity. Mechanistically, TTYH3 and HDAC7 functioned as ceRNAs, reciprocally regulating each other's expression. TTYH3 competes for binding miR‐1271‐5p, increasing HDAC7 expression, facilitating CRC metastasis and angiogenesis. This study reveals the critical role of TTYH3 in promoting CRC metastasis through ceRNA crosstalk, offering new insights into potential therapeutic targets for clinical intervention.
Oncogenes and tumor suppressor genes: functions and roles in cancers
Authors: Tikam Chand Dakal, Bhanupriya Dhabhai, Anuja Pant, Kareena Moar, Kanika Chaudhary, Vikas Yadav, Vipin Ranga, Narendra Kumar Sharma, Abhishek Kumar, Pawan Kumar Maurya, Jarek Maciaczyk, Ingo G. H. Schmidt‐Wolf, Amit Sharma
Journal: MedComm (2024)

Abstract Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X‐linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X‐linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X‐linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X‐linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X‐linked TSGs in sex chromosome–autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X‐linked TSG in immunomodulation and in gender‐based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X‐linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies.
Shifting the Lens on Lung Cancer Screening Inequities
Authors: Lisa Carter-Bawa
Journal: JAMA Network Open (2024)

Jennifer Richmond, PhD, MSPH; Jessica R. Fernandez, PhD; Kemberlee Bonnet, MA; Ashley Sellers, MS, CCC-SLP; David G. Schlundt, PhD; Allana T. Forde, PhD, MPH; Consuelo H. Wilkins, MD, MSCI; Melinda C. Aldrich, PhD, MPH
Clinician-Driven Reanalysis of Exome Sequencing Data From Patients With Inherited Retinal Diseases
Authors: Dongheon Surl, Dongju Won, Seung-Tae Lee, Christopher Seungkyu Lee, Junwon Lee, Hyun Taek Lim, Seung Ah Chung, Won Kyung Song, Min Kim, Sung Soo Kim, Saeam Shin, Jong Rak Choi, Riccardo Sangermano, Suk Ho Byeon, Kinga M. Bujakowska, Jinu Han
Journal: JAMA Network Open (2024)

Importance Despite advances in next-generation sequencing (NGS), a significant proportion of patients with inherited retinal disease (IRD) remain undiagnosed after initial genetic testing. Exome sequencing (ES) reanalysis in the clinical setting has been suggested as one method for improving diagnosis of IRD. Objective To investigate the association of clinician-led reanalysis of ES data, which incorporates updated clinical information and comprehensive bioinformatic analysis, with the diagnostic yield in a cohort of patients with IRDs in Korea. Design, Setting, and Participants This was a multicenter prospective cohort study involving 264 unrelated patients with IRDs, conducted in Korea between March 2018 and February 2020. Comprehensive ophthalmologic examinations and ES analyses were performed, and ES data were reanalyzed by an IRD specialist for single nucleotide variants, copy number variants, mobile element insertions, and mitochondrial variants. Data were analyzed from March to July 2023. Main Outcomes and Measures Diagnostic rate of conventional bioinformatic analysis and clinician-driven ES reanalysis. Results A total of 264 participants (151 [57.2%] male; mean [SD] age at genetic testing, 33.6 [18.9] years) were enrolled, including 129 patients (48.9%) with retinitis pigmentosa and 26 patients (9.8%) with Stargardt disease or macular dystrophy. Initial bioinformatic analysis diagnosed 166 patients (62.9%). Clinician-driven reanalysis identified the molecular cause of diseases in an additional 22 patients, corresponding to an 8.3–percentage point increase in diagnostic rate. Key factors associated with new molecular diagnoses included clinical phenotype updates (4 patients) and detection of previously overlooked variation, such as structural variants (9 patients), mitochondrial variants (3 patients), filtered or not captured variants (4 patients), and noncanonical splicing variants (2 patients). Among the 22 patients, variants in 7 patients (31.8%) were observed in the initial analysis but not reported to patients, while those in the remaining 15 patients (68.2%) were newly detected by the ES reanalysis. Conclusions and Relevance In this cohort study, clinician-centered reanalysis of ES data was associated with improved molecular diagnostic yields in patients with IRD. This approach is important for uncovering missed genetic causes of retinal disease.
Study: 2 <i>APOE4</i> Copies May Indicate Genetic Form of Alzheimer Disease
Authors: Emily Harris
Journal: JAMA (2024)

Almost all people who inherited 2 identical copies of the APOE4 gene variant had abnormally high levels of amyloid in their cerebrospinal fluid and brain by age 65 years, according to a new study that combined data from more than 3200 brain donors and about 10 000 participants with clinical data.
X-chromosome inactivation in human iPSCs provides insight into X-regulated gene expression in autosomes
Authors: Hande Topa, Clara Benoit-Pilven, Taru Tukiainen, Olli Pietiläinen
Journal: Genome biology (2024)

Abstract Background Variation in X chromosome inactivation (XCI) in human-induced pluripotent stem cells (hiPSCs) can impact their ability to model biological sex biases. The gene-wise landscape of X chromosome gene dosage remains unresolved in female hiPSCs. To characterize patterns of de-repression and escape from inactivation, we performed a systematic survey of allele specific expression in 165 female hiPSC lines. Results XCI erosion is non-random and primarily affects genes that escape XCI in human tissues. Individual genes and cell lines vary in the frequency and degree of de-repression. Bi-allelic expression increases gradually after modest decrease of XIST in cultures, whose loss is commonly used to mark lines with eroded XCI. We identify three clusters of female lines at different stages of XCI. Increased XCI erosion amplifies female-biased expression at hypomethylated sites and regions normally occupied by repressive histone marks, lowering male-biased differences in the X chromosome. In autosomes, erosion modifies sex differences in a dose-dependent way. Male-biased genes are enriched for hypermethylated regions, and de-repression of XIST-bound autosomal genes in female lines attenuates normal male-biased gene expression in eroded lines. XCI erosion can compensate for a dominant loss of function effect in several disease genes. Conclusions We present a comprehensive view of X chromosome gene dosage in hiPSCs and implicate a direct mechanism for XCI erosion in regulating autosomal gene expression in trans . The uncommon and variable reactivation of X chromosome genes in female hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans.