tbuckley/cabot-search huggingface dataset:
Rurality, Health Care Resource Use, and Care Trajectories in Patients With Head and Neck Cancer
Authors: Abigail Thomas, Joseph Clyde Dort, Steven C. Nakoneshny, Thomas Wayne Matthews, Shamir Chandarana, Robert Hart, Khara M. Sauro
Journal: JAMA Network Open (2025)

Importance Head and neck cancer (HNC) epidemiology varies geographically, and rural populations (typically less affluent) may face barriers accessing cancer care, which could lead to worse outcomes. Objective To compare health care resource use between patients with HNC living in urban and rural areas. Design, Setting, and Participants Retrospective cohort study in Alberta, Canada. Participants were adult patients (aged ≥18 years) diagnosed with HNC with at least 1 year of posttreatment follow-up between January 2012 and September 2020. Data were analyzed from August to September 2024. Exposure Rural location of residence at HNC diagnosis, defined using the forward sortation area of the patients’ postal code. Main Outcomes and Measures The primary outcomes were health care resource use and patient care trajectories, including hospital length of stay, 30-day hospital readmissions, emergency department visits, time from diagnosis to first treatment, first type of practitioner seen after hospital discharge, and most common practitioner-to-practitioner transitions. Results The cohort included 2189 patients with a median (IQR) age of 63 (55-71) years, who were mostly men (1557 patients [71.1%]) with stage IV cancer (1149 patients [52.5%]) of the tongue (640 patients [29.2%]), of which 375 (17.1%) lived in a rural area. There was no difference in cumulative hospital length of stay between urban and rural patients; however, male patients living in rural areas had a longer surgical hospital length of stay than male patients living in urban areas (incidence rate ratio, 1.24; 95% CI, 1.03-1.50). Patients living in rural areas had more 30-day hospital readmissions (63 patients [16.8%] vs 183 patients [10.1%]) and emergency department visits (median [IQR], 8 [3-17] vs 4 [2-9]) than their urban counterparts. Time to first treatment was longer in patients living in rural areas compared with patients living in urban areas (median [IQR], 64 [46-95] days vs 57 [40-84] days). Patients living in rural areas without comorbid conditions had greater odds of being discharged directly to the care of a general practitioner after a hospital stay than urban patients (odds ratio, 1.97; 95% CI, 1.23-3.15). Conclusions and Relevance In this cohort study of patients with HNC, living in rural areas was associated with higher health care resource use than patients living in urban areas. Recommendations specific to patients with HNC living in rural areas may be warranted given these differences.
National opioid prescription decline across outpatient specialty surgeries: a claims database study
Authors: Surya A Veerabagu, Shannon T Nugent, Zhi Geng, Arianna F Yanes, John P Fischer, Robert Kovell, Andrew F Kuntz, Karthik Rajasekaran, Brian L VanderBeek, Christopher J Miller, Jeremy R Etzkorn, Joseph F Sobanko, H William Higgins, Joanna Walker, Junqian Zhang, Cerrene N Giordano
Journal: Journal of the American Academy of Dermatology (2025)
Racial and Ethnic Differences in Potentially Inappropriate Medication Use Among Medicare Beneficiaries
Authors: Eli Raver, Jeah Jung, Caroline Carlin, Roger Feldman, Sheldon Retchin, Wendy Xu
Journal: JAMA Network Open (2025)

Importance Older Medicare beneficiaries are susceptible to receiving potentially inappropriate medications (PIMs), where the risks outweigh the benefits. Racial and ethnic differences in PIM use may perpetuate health disparities and disproportionately lead to costly adverse drug events for some groups. Objective To examine associations of race and ethnicity with PIM use among older Medicare beneficiaries. Design, Setting, and Participants This cross-sectional study used nationwide Medicare Part D Event files, fee-for-service claims, and Medicare Advantage (MA) encounter data among Medicare beneficiaries 65 years or older with Part D prescription drug coverage. The study population included random samples of 20% of traditional Medicare (TM) beneficiaries and 50% of MA enrollees from January 1, 2016, to December 31, 2019. Analysis was conducted from May 28 to September 16, 2024. Exposure Race and ethnicity. Main Outcomes and Measures Linear probability models were estimated for outcomes of (1) high-risk medication use among older adults, (2) potentially harmful drug-disease interactions in patients with dementia, and (3) potentially harmful drug-disease interactions in patients with a history of falls. Results The study sample included 21 193 170 patients with 32 199 587 beneficiary-year observations (mean [SD] age, 75.5 [7.3] years; 18 936 697 [58.8%] female; 983 513 [3.1%] Asian or Pacific Islander, 3 190 515 [9.9%] Black, 2 710 930 [8.4%] Hispanic, and 25 314 629 [78.6%] White). Compared with White beneficiaries, the rates of high-risk medication use were 1.7 [95% CI, −1.8 to −1.6] percentage points lower for Asian or Pacific Islander beneficiaries, 3.4 [95% CI, −3.4 to −3.3] percentage points lower for Black beneficiaries, and 0.6 [95% CI, −0.6 to −0.5] percentage points lower for Hispanic beneficiaries. Similarly, White beneficiaries had the highest rates of potentially harmful drug-disease interactions among those with dementia as well as those with a history of falls. The pattern of racial and ethnic differences was similar in analyses stratified by enrollment in TM or MA plans. However, the differences between White individuals and other groups were smaller in MA than in TM plans for all comparisons. Conclusions and Relevance In this cross-sectional study of 32 199 587 Medicare beneficiary-years from 2016 to 2019, White Medicare beneficiaries had consistently higher rates of PIM use compared with other racial and ethnic groups. The observed differences may be partially explained by racial and ethnic differences in overall prescription drug use and suggest the need to reduce PIM use in all racial and ethnic groups.
Projected Lifetime Cancer Risks From Current Computed Tomography Imaging
Authors: Rebecca Smith-Bindman, Philip W. Chu, Hana Azman Firdaus, Carly Stewart, Matthew Malekhedayat, Susan Alber, Wesley E. Bolch, Malini Mahendra, Amy Berrington de González, Diana L. Miglioretti
Journal: JAMA Internal Medicine (2025)

Importance Approximately 93 million computed tomography (CT) examinations are performed on 62 million patients annually in the United States, and ionizing radiation from CT is a known carcinogen. Objective To project the number of future lifetime cancers in the US population associated with CT imaging in 2023. Design, Setting, and Participants This risk model used a multicenter sample of CT examinations prospectively assembled between January 2018 and December 2020 from the University of California San Francisco International CT Dose Registry. Data analysis was conducted from October 2023 to October 2024. Main Outcomes and Measures Distributions of CT examinations and associated organ-specific radiation doses were estimated by patient age, sex, and CT category and scaled to the US population based on the number of examinations in 2023, quantified by the IMV national survey. Lifetime radiation-induced cancer incidence and 90% uncertainty limits (UL) were estimated by age, sex, and CT category using National Cancer Institute software based on the National Research Council’s Biological Effects of Ionizing Radiation VII models and projected to the US population using scaled examination counts. Results An estimated 61 510 000 patients underwent 93 000 000 CT examinations in 2023, including 2 570 000 (4.2%) children, 58 940 000 (95.8%) adults, 32 600 000 (53.0%) female patients, and 28 910 000 (47.0%) male patients. Approximately 103 000 (90% UL, 96 400-109 500) radiation-induced cancers were projected to result from these examinations. Estimated radiation-induced cancer risks were higher in children and adolescents, yet higher CT utilization in adults accounted for most (93 000; 90% UL, 86 900-99 600 [91%]) radiation-induced cancers. The most common cancers were lung cancer (22 400 cases; 90% UL, 20 200-25 000 cases), colon cancer (8700 cases; 90% UL, 7800-9700 cases), leukemia (7900 cases; 90% UL, 6700-9500 cases), and bladder cancer (7100 cases, 90% UL, 6000-8500 cases) overall, while in female patients, breast was second most common (5700 cases; 90% UL, 5000-6500 cases). The largest number of cancers was projected to result from abdomen and pelvis CT in adults, reflecting 37 500 of 103 000 cancers (37%) and 30 million of 93 million CT examinations (32%), followed by chest CT (21 500 cancers [21%]; 20 million examinations [21%]). Estimates remained large over a variety of sensitivity analyses, which resulted in a range of 80 000 to 127 000 projected cancers across analyses. Conclusions and Relevance This study found that at current utilization and radiation dose levels, CT examinations in 2023 were projected to result in approximately 103 000 future cancers over the course of the lifetime of exposed patients. If current practices persist, CT-associated cancer could eventually account for 5% of all new cancer diagnoses annually.
Drug Decriminalization in British Columbia and Changes in Drug Crime and Opioid and Stimulant Harms
Authors: Adrienne Gaudreault, Robert Talarico, Matthew Herder, Daniel T. Myran
Journal: JAMA (2025)

This population-based study examines changes in police-reported drug incidents as well as deaths and hospitalizations from opioids and stimulants following decriminalization in British Columbia and the rest of Canada.
Application of a Digital Injury-Surveillance Platform
Authors: Liuyan Zheng, Xiaoyong Li, Zhike Liu, Kun Wang, Qiang Sun, Lei Zhao, Huairong Wang, Jingxian Wu, Huan Yu, Siyan Zhan, Peng Shen, Yiqun Wu
Journal: JAMA Network Open (2025)

This cross-sectional study evaluates the validity of a digital injury-surveillance platform in Yinzhou, China.
Visit-to-Visit Variability in Lipid Levels and Risk of Incident Heart Failure in Adults With Type 2 Diabetes
Authors: Arnaud D. Kaze, Chiadi E. Ndumele, Seth S. Martin, Prasanna Santhanam, Beeletsega T. Yeneneh, Mookadam Farouk, Roderick Tung, Gregg C. Fonarow, Justin B. Echouffo-Tcheugui
Journal: Diabetes Care (2025)

OBJECTIVE Limited data exist on the relation between long-term variability in blood lipid fractions and incident heart failure (HF) in the setting of type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Among 9,443 T2DM participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, with lipid measurements available at six time points (baseline, 4, 8, 12, 24, and 36 months), we assessed variability in total cholesterol (TC), LDL cholesterol, HDL cholesterol, and triglycerides (TG) across visits, using coefficient of variation (CV), SD, and variability independent of the mean. Cox proportional hazards models were employed to estimate adjusted hazard ratios (HRs) for incident HF. RESULTS During a median follow-up of 5.0 years, 345 participants developed HF. Participants in the highest quartile of CV of TC had a 68% higher relative risk of HF compared with those in the lowest quartile (adjusted HR [aHR] 1.68, 95% CI 1.22–2.30). Similarly, those in the highest quartile of LDL cholesterol CV had a 76% higher relative risk (aHR 1.76, 95% CI 1.27–2.42) of HF, while those in the highest quartile of HDL cholesterol CV had a 53% higher risk (aHR 1.53, 95% CI 1.13–2.06). For TG CV, participants in the highest quartile had a 49% higher risk of HF compared with the lowest quartile (aHR 1.49, 95% CI 1.09–2.04). Similar patterns were observed for other variability metrics. CONCLUSIONS Increased variability in TC, LDL- cholesterol, HDL- cholesterol, or TG is independently associated with a higher HF risk among individuals with T2DM.
Novel molecular mechanisms of immune evasion in hepatocellular carcinoma: NSUN2‐mediated increase of <i>SOAT2</i> RNA methylation
Authors: Jinhua Jiang, Feng Liu, Dan Cui, Caixia Xu, Jiachang Chi, Tinghua Yan, Fang Guo
Journal: Cancer Communications (2025)

Abstract Background Hepatocellular carcinoma (HCC) is a deadly malignancy known for its ability to evade immune surveillance. NOP2/Sun RNA methyltransferase family member 2 (NSUN2), an RNA methyltransferase involved in carcinogenesis, has been associated with immune evasion and energy metabolism reprogramming. This study aimed to examine the molecular mechanisms underlying the involvement of NSUN2 in immune evasion and metabolic reprogramming of HCC. Methods Single‐cell transcriptomic sequencing was applied to examine cellular composition changes, particularly immune cell dynamics, in HCC and adjacent normal tissues. Bulk RNA‐seq and proteomics identified key genes and proteins. Methylation sequencing and methylated RNA immunoprecipitation (MeRIP) were carried out to characterize the role of NSUN2 in 5‐methylcytosine (m5C) modification of sterol O‐acyltransferase 2 ( SOAT2 ). Clinical samples from 30 HCC patients were analyzed using reverse transcription‐quantitative polymerase chain reaction and Western blotting. Gene expression was manipulated using CRISPR/Cas9 and lentiviral vectors. In vitro co‐culture models and metabolomics were used to study HCC cell‐T cell interactions, energy metabolism, and immune evasion. Tumor growth in an orthotopic mouse model was monitored by bioluminescence imaging, with subsequent measurements of tumor weight, volume, and immunohistochemical staining. Results Single‐cell transcriptomic analysis identified a marked increase in malignant cells in HCC tissues. Cell communication analysis indicated that tumor cells might promote cancer progression by evading immune clearance. Multi‐omics analyses identified NSUN2 as a key regulator in HCC development. MeRIP confirmed that NSUN2 facilitated the m5C modification of SOAT2 . Analysis of human HCC tissue samples demonstrated pronounced upregulation of NSUN2 and SOAT2 , along with elevated m5C levels in HCC tissues. In vitro experiments uncovered that NSUN2 augmented the reprogramming of energy metabolism and repressed the activity and cytotoxicity of CD8 + T cells, contributing to immune evasion. In vivo studies further substantiated the role of NSUN2 in fostering immune evasion and tumor formation of HCC by modulating the m5C modification of SOAT2 . Conclusions The findings highlight the critical role of NSUN2 in driving HCC progression through the regulation of m5C modification on SOAT2 . These findings present potential molecular markers for HCC diagnosis and therapeutic targets for its treatment.
Transient pain and long-term gain: adjuvant dose directs immune memory
Authors: Pabitra B Pal, Smita S Iyer
Journal: Journal of Clinical Investigation (2025)

Vaccine hesitancy is often fueled by fears of side effects; however, most reactions result from innate immune activation and cytokine production, which are required for lasting immunity. For effective vaccines against HIV, innate activation is essential for differentiation of CD4+ T cells into T follicular helper cells (TFH), which guide rare B cells to mature into long-lived plasma cells that produce durable neutralizing antibodies (nAbs). In this issue of the JCI, Parham Ramezani-Rad et al. show that higher doses of saponin QS-21-MPLA nanoparticle (SMNP) adjuvant, combined with BG505 MD39 envelope (Env) protein, enhanced cytokine responses, drove stronger Env-specific TFH responses in blood, and increased Env-specific bone marrow plasma cells compared with lower doses. While tier 2 nAbs were sustained at memory in only a subset of animals, predominantly at the highest adjuvant dose, these findings highlight transient reactogenicity as an essential mechanism - not a flaw - for building durable immune memory.
Addiction of primary cutaneous γδ T cell lymphomas to JAK/STAT signaling
Authors: Yue Zhang, Julia A Yescas, Kristy Tefft, Spencer Ng, Kevin Qiu, Erica B Wang, Shifa Akhtar, Addie Walker, Macartney Welborn, Martin Zaiac, Joan Guitart, Aamir M Qureshi, Youn H Kim, Michael S Khodadoust, Naiem T Issa, Jaehyuk Choi
Journal: Journal of Clinical Investigation (2025)
Immunotherapeutic strategies in head and neck cancer: challenges and opportunities
Authors: Xia Liu, R Alex Harbison, Mark A Varvares, Sidharth V Puram, Guangyong Peng
Journal: Journal of Clinical Investigation (2025)

HNSCC remains a substantial health issue, with treatment options including surgery, radiation, and platinum-based chemotherapy. Unfortunately, despite progress in research, only modest gains have been made in disease control, with existing treatments resulting in significant functional and quality-of-life issues. The introduction of immunotherapy in the treatment of HNSCC has resulted in some improvements in outlook for patients and is now standard of care for populations with both recurrent and metastatic disease. However, despite the early successes, responses to immune checkpoint inhibition (ICI) remain modest to low, approaching 14%-22% objective response rates. Challenges to the effectiveness of ICI and other immunotherapies are complex, including the diverse and dynamic molecular plasticity and heterogeneity of HNSCCs; lack of immunogenic antigens; accumulated suppressive immune populations such as myeloid cells and dysfunctional T cells; nutrient depletion; and metabolic dysregulation in the HNSCC tumor microenvironment. In this Review, we explore the mechanisms responsible for immunotherapy resistance, dissect these challenges, and discuss potential opportunities for overcoming hurdles to the development of successful immunotherapy for HNSCC.
Serotonin sets up neutrophil extracellular traps to promote neuroendocrine prostate cancer metastasis in the liver
Authors: Dean G Tang
Journal: Journal of Clinical Investigation (2025)

Castration-resistant prostate cancer frequently metastasizes to the liver, and prostate cancer liver metastases often present a neuroendocrine phenotype (i.e., neuroendocrine prostate cancer [NEPC]), but the underlying molecular underpinnings remain unclear. In this issue of the JCI, Liu et al. demonstrate that the neurotransmitter serotonin (also known as 5-hydroxytryptamine), produced by NEPC cells, gained access to and activated neutrophils by modifying histone 3 (H3) to form neutrophil extracellular traps, which in turn promoted NEPC macrometastases in the liver. The study suggests that blocking serotonin transport to neutrophils and inhibiting the enzymes that catalyze serotonin-mediated H3 modifications may represent alternative approaches to treating prostate cancer liver metastases.
CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders
Authors: Xiuying Bai, Dengshun Miao, Sophia Xiao, Dinghong Qiu, René St-Arnaud, Martin Petkovich, Ajay Gupta, David Goltzman, Andrew C. Karaplis
Journal: Journal of Clinical Investigation (2025)
STK4 regulates TLR pathways and protects against chronic inflammation–related hepatocellular carcinoma
Authors: Weiyun Li, Jun Xiao, Xin Zhou, Ming Xu, Chaobo Hu, Xiaoyan Xu, Yao Lu, Chang Liu, Shengjie Xue, Lei Nie, Haibin Zhang, Zhiqi Li, Yanbo Zhang, Fu Ji, Lijian Hui, Wufan Tao, Bin Wei, Hongyan Wang
Journal: Journal of Clinical Investigation (2025)
SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria
Authors: Joaquín Miguel Pellegrini, Anne Keriel, Laurent Gorvel, Sean Hanniffy, Vilma Arce-Gorvel, Mile Bosilkovski, Javier Solera, Stéphane Méresse, Sylvie Mémet, Jean-Pierre Gorvel
Journal: Journal of Clinical Investigation (2025)

Plasmacytoid dendritic cells (pDCs), professional type I IFN-producing cells, have been implicated in host responses against bacterial infections. However, their role in host defense is debated, and the operating molecular mechanisms are unknown. Certain signaling lymphocyte activation molecule family (SLAMF) members act as microbial sensors and modulate immune functions in response to infection. Here, human blood transcriptomic analyses reveal the involvement of SLAMF7 and SLAMF8 in many infectious diseases, with elevated levels associated with type I IFN responses in salmonellosis and brucellosis patients. We further identify SLAMF7 and SLAMF8 as key regulators of human pDC function. They activate pDC maturation and cytokine production during infection with bacteria that induce acute (Salmonella) or chronic (Brucella) inflammation. SLAMF7 and SLAMF8 signal through NF-κB, IRF7, and STAT-1, and limit mitochondrial ROS accumulation upon Salmonella infection. Remarkably, this SLAMF7/8-dependent control of mitochondrial ROS levels favors bacterial persistence and NF-κB activation. Overall, our results unravel essential shared multifaceted roles of SLAMF7 and SLAMF8 in finely tuning human pDC responses to intracellular bacterial infections with potential for future diagnostic and therapeutic applications.
Developing cell-based therapies for pancreatic ductal adenocarcinoma
Authors: Rachel Elizabeth Ann Fincham, Joe Poh Sheng Yeong, Hemant Mahendrakumar Kocher
Journal: Journal of Clinical Investigation (2025)

Prostate stem cell antigen (PSCA) is highly and preferentially expressed on the surface of pancreatic ductal adenocarcinoma (PDAC) cells, raising the promise of tumor-selective cell-based immunotherapies. In this issue of the JCI, Dai et al. harness PSCA for the development of an off-the-shelf chimeric antigen receptor (CAR) invariant natural killer T (iNKT) cell-based treatment for PDAC. Through in vitro experiments and in vivo models, the authors demonstrate selectivity and therapeutic efficacy of PSCA CAR_sIL15 iNKT cells against both gemcitabine-sensitive and -resistant PDAC cells with comparable antitumor activity for freshly produced and frozen off-the-shelf PSCA CAR_sIL15 iNKT cells. This development opens another potential therapeutic option for pancreatic cancer.
Cell-intrinsic insulin signaling defects in human iPS cell–derived hepatocytes in type 2 diabetes
Authors: Arijeet K Gattu, Maria Tanzer, Tomer M Yaron-Barir, Jared L Johnson, Ashok Kumar Jayavelu, Hui Pan, Jonathan M Dreyfuss, Lewis C Cantley, Matthias Mann, C Ronald Kahn
Journal: Journal of Clinical Investigation (2025)

Hepatic insulin resistance is central to type 2 diabetes (T2D) and metabolic syndrome, but defining the molecular basis of this defect in humans is challenging because of limited tissue access. Utilizing inducible pluripotent stem cells differentiated into hepatocytes from control individuals and patients with T2D and liquid chromatography with tandem mass spectrometry-based (LC-MS/MS-based) phosphoproteomics analysis, we identified a large network of cell-intrinsic alterations in signaling in T2D. Over 300 phosphosites showed impaired or reduced insulin signaling, including losses in the classical insulin-stimulated PI3K/AKT cascade and their downstream targets. In addition, we identified over 500 phosphosites of emergent, i.e., new or enhanced, signaling. These occurred on proteins involved in the Rho-GTPase pathway, RNA metabolism, vesicle trafficking, and chromatin modification. Kinome analysis indicated that the impaired phosphorylation sites represented reduced actions of AKT2/3, PKCθ, CHK2, PHKG2, and/or STK32C kinases. By contrast, the emergent phosphorylation sites were predicted to be mediated by increased action of the Rho-associated kinases 1 and 2 (ROCK1/2), mammalian STE20-like protein kinase 4 (MST4), and/or branched-chain α-ketoacid dehydrogenase kinase (BCKDK). Inhibiting ROCK1/2 activity in T2D induced pluripotent stem cell-derived hepatocytes restored some of the alterations in insulin action. Thus, insulin resistance in the liver in T2D did not simply involve a loss of canonical insulin signaling but the also appearance of new phosphorylations representing a change in the balance of multiple kinases. Together, these led to altered insulin action in the liver and identified important targets for the therapy of hepatic insulin resistance.