tbuckley/cabot-search huggingface dataset:
CXCL12+ fibroblastic reticular cells in lymph nodes facilitate immune tolerance by regulating T cell–mediated alloimmunity
Authors: Yuta Yamamura, Gianmarco Sabiu, Jing Zhao, Sungwook Jung, Andy J Seelam, Xiaofei Li, Yang Song, Marina W Shirkey, Lushen Li, Wenji Piao, Long Wu, Tianshu Zhang, Soyeon Ahn, Pilhan Kim, Vivek Kasinath, Jamil R Azzi, Jonathan S Bromberg, Reza Abdi
Journal: Journal of Clinical Investigation (2025)

Fibroblastic reticular cells (FRCs) are the master regulators of the lymph node (LN) microenvironment. However, the role of specific FRC subsets in controlling alloimmune responses remains to be studied. Single-cell RNA sequencing (scRNA-Seq) of naive and draining LNs (DLNs) of heart-transplanted mice and human LNs revealed a specific subset of CXCL12hi FRCs that expressed high levels of lymphotoxin-β receptor (LTβR) and are enriched in the expression of immunoregulatory genes. CXCL12hi FRCs had high expression of CCL19, CCL21, indoleamine 2,3-dioxygenase (IDO), IL-10, and TGF-β1. Adoptive transfer of ex vivo-expanded FRCs resulted in their homing to LNs and induced immunosuppressive environments in DLNs to promote heart allograft acceptance. Genetic deletion of LTβR and Cxcl12 in FRCs increased alloreactivity, abrogating the effect of costimulatory blockade in prolonging heart allograft survival. As compared with WT recipients, CXCL12+ FRC-deficient recipients exhibited increased differentiation of CD4+ T cells into Th1 cells. Nano delivery of CXCL12 to DLNs improved allograft survival in heart-transplanted mice. Our study highlights the importance of DLN CXCL12hi FRCs in promoting transplant tolerance.
Post-marketing Safety Evaluation of Lutathera (177Lu-DOTATATE)
Authors: Heng Chen, Junlong Ma
Journal: Clinical Nuclear Medicine (2025)

Lutathera, a key therapy for gastroenteropancreatic neuroendocrine tumors, has demonstrated efficacy, but its real-world safety profile remains unclear. This study aims to conduct a comprehensive analysis of the adverse events (AEs) associated with Lutathera using FDA Adverse Event Reporting System (FAERS) data. A retrospective pharmacovigilance analysis was conducted using FAERS data from Q4 2019 to Q3 2024. AE reports involving Lutathera were identified, and a case/non-case approach was employed to evaluate AE signals using disproportionality analysis methods, including the reporting odds ratio and information component (IC). Patient demographics, time to AE onset, and system organ class (SOC) involvement were analyzed. After data processing, a total of 4284 AE reports associated with Lutathera were analyzed. The median time to AE onset was 113.5 days. Lutathera-related AEs exhibited a notably high mortality rate, reaching as much as 31.2%. Statistically significant signals were detected across 13 SOCs and multiple preferred terms (PTs). Among the SOCs, the most pronounced signals were observed in the category of endocrine disorders. The leading PTs included nonspecific disorders (IC025: 5.92), carcinoid syndrome (IC025: 5.69), and carcinoid crisis (IC025: 5.62). Moreover, several PTs not documented in the drug's labeling were reported, such as encephalitis, intestinal ischemia, and disseminated intravascular coagulation. Our study utilized real-world data to identify multiple risk signals associated with Lutathera, providing additional evidence to support its rational use. However, due to the inherent limitations of the FAERS database, further research is warranted to validate these findings.
Development and Validation of a Cell-Free DNA Fragmentomics–Based Model for Early Detection of Pancreatic Cancer
Authors: Lingdi Yin, Cheng Cao, Jianzhen Lin, Zheng Wang, Yunpeng Peng, Kai Zhang, Cheng Xu, Ruowei Yang, Dongqin Zhu, Fufeng Wang, Shuang Chang, Hua Bao, Shanshan Yang, Ningyou Li, Xue Wu, Yang Shao, Zheng Wu, Shuai Wu, Ning Pu, Zhihang Xu, Feng Guo, Xu Feng, Jianmin Chen, Bin Xiao, Min Tu, Qiang Li, Jishu Wei, Junli Wu, Wentao Gao, Yi Miao, Liang Liu, Zipeng Lu, Kuirong Jiang
Journal: Journal of Clinical Oncology (2025)

Pancreatic ductal adenocarcinoma (PDAC), known for its high fatality rate, is often diagnosed in its advanced stages where surgical options are not viable. This highlights the critical need for innovative and effective early detection techniques. This study focuses on the potential of cell-free DNA (cfDNA) fragmentomics integrating advanced machine learning to identify early-stage PDAC with high accuracy. Our study included a broad cohort of 1,167 participants, from which plasma was collected and subjected to shallow whole-genome sequencing. After rigorous quality assessments, 166 individuals diagnosed with PDAC and 167 healthy participants were in the training cohort, whereas the validation cohort consisted of 112 patients with PDAC and 111 healthy individuals. A separate group of 67 individuals with nonmalignant pancreatic cysts was also included to validate the model's accuracy. Finally, two additional external validation cohorts and one additional independent early-stage data set were included to evaluate the robustness of model. Our analysis used fragmentomic profiling, integrating copy-number variations, fragment size, mutational signatures, and methylation patterns analyzed using machine learning. The model demonstrated remarkable accuracy in distinguishing patients with PDAC from controls, with an AUC of 0.992 in the training data set and 0.987 in the validation data set. At a cutoff of 0.52, the training set reached a sensitivity of 93.4% and a specificity of 95.2%. In the validation data set, the sensitivity was 97.3% with a specificity of 92.8%, while the external data set demonstrated a sensitivity of 90.91% and a specificity of 94.5%. This study underscores the effectiveness of using cfDNA fragmentomics and machine learning for early detection of PDAC. Our approach promises significant potential in reducing PDAC mortalities through early intervention and could serve as a breakthrough in oncologic diagnostics.
Weight loss in MASLD restores the balance of liver fatty acid sources
Authors: Jennifer E Lambert, Maria A Ramos-Roman, Maressa J Valdez, Jeffrey D Browning, Thomas Rogers, Elizabeth J Parks
Journal: Journal of Clinical Investigation (2025)

BACKGROUNDLipogenesis contributes substantially to the pathological accumulation of intrahepatic triacylglycerol (IHTG) in metabolic dysfunction-associated steatotic liver disease (MASLD). Since hepatic lipogenesis is highly sensitive to energy intake, we hypothesized that mechanisms of MASLD regression induced by weight loss would be driven by a marked reduction in the lipogenic pathway.METHODSOverweight adults with high liver fat (HighLF; n = 9; IHTG ≥ 5.6% measured by 1H-magnetic resonance spectroscopy) or low (normal) liver fat (LowLF; n = 6; IHTG < 5.6%) received dietary counseling for 6 months and underwent comprehensive metabolic phenotyping during inpatient studies that captured fasting and fed states. Multiple stable isotopes were used to assess the contribution of lipogenesis, free fatty acids (FFAs), and dietary fat to IHTG.RESULTSBody weight loss (-10% ± 2%) reduced IHTG in individuals with MASLD (19.4% ± 3.6% to 4.5% ± 2.1%, P < 0.001). Insulin sensitivity improved significantly (46%, P < 0.01), while fasting FFA flux from adipose tissue was not different. VLDL-triacylglycerol (VLDL-TG) concentrations fell by 38% (P = 0.02) because of a 67% reduction in contribution from lipogenesis (P = 0.02), whereas the absolute contributions from FFAs and dietary fat to VLDL-TG were not different. Reduced lipogenesis was significantly associated with loss of IHTG.CONCLUSIONThese data underscore the primary role of lipogenesis in MASLD pathology and highlight the importance of controlling this pathway through treatment strategies.TRIAL REGISTRATIONClinicalTrials.gov (NCT01371396).FUNDINGNational Institutes of Health (NIH) grant RL1DK081187; Task Force for Obesity Research at Southwestern (TORS) NIH UL1DE019584; and Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences UL1-RR024982.
Complement’s involvement in allergic Th2 immunity: a cross-barrier perspective
Authors: Sarah A Thomas, Stephane Lajoie
Journal: Journal of Clinical Investigation (2025)

Type 2 (Th2) allergic diseases are chronic conditions characterized by a Th2-polarized immune response to allergens. These diseases can be categorized by affected barrier sites: skin (atopic dermatitis, allergic contact dermatitis), gut (food allergy), and respiratory tract (e.g., asthma, chronic rhinosinusitis). The global prevalence of Th2 allergic diseases has increased the need for a deeper understanding of their pathophysiology. Several associations have been identified between genetic variants in the genes encoding components of the complement system and allergic disease. Moreover, levels of several complement proteins are elevated in patients with allergy. Experimental evidence demonstrates that the complement system plays a critical role in the development of these diseases across barrier sites. While site-specific differences exist in the complement components involved, key pathways, particularly C3 and C5, are prominent across the skin, gut, and lung.
The complement system and kidney cancer: pathogenesis to clinical applications
Authors: Ravikumar Aalinkeel, Richard J. Quigg, Jessy Alexander
Journal: Journal of Clinical Investigation (2025)

Kidney cancer poses unique clinical challenges because of its resistance to conventional treatments and its tendency to metastasize. The kidney is particularly susceptible to dysfunction of the complement system, an immune network that tumors often exploit. Recent discoveries have highlighted that the complement system not only plays a crucial role in immune surveillance and defense in the circulatory system, but also functions intracellularly and autonomously. This concept has shifted the focus of investigation toward understanding how complement proteins influence cancer progression by regulating the tumor microenvironment (TME), cell signaling, proliferation, metabolism, and the immune response. With the complement system and its inhibitors emerging as a promising new class of immunotherapeutics and potential complement-targeted treatments advancing through development pipelines and clinical trials, this Review provides a timely examination of how harnessing the complement system could lead to effective tumor treatments and how to strategically combine complement inhibitors with other cancer treatments, offering renewed hope in the fight against kidney cancer.
GLP-1 receptor agonists for the treatment of alcohol use disorder
Authors: Gavin N Petrie, Leah M Mayo
Journal: Journal of Clinical Investigation (2025)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, are widely used in the treatment of metabolic disorders, including type 2 diabetes (T2D) and obesity. These medications primarily function by enhancing insulin secretion; however, emerging evidence suggests that the effects extend beyond metabolic regulation. In this issue of the JCI, Farokhnia et al. evaluated the effects of GLP-1RAs alongside another T2D treatment, dipeptidyl peptidase-4 inhibitors (DPP-4Is), on alcohol consumption in humans and preclinical models. In humans, GLP1-RAs, but not DPP-4Is, were associated with reductions in alcohol consumption. Similarly, DPP-4 inhibition had no effect on alcohol intake in rodents. These findings invite further exploration of the mechanisms by which GLP-1RAs reduce alcohol consumption and redefine our pharmacotherapy approach to alcohol use disorder (AUD) by opening the possibility for application as an early harm-reduction tool.
The differential effects of sex hormone therapy on kidney function: insights into biological sex differences
Authors: David Collister, Adeera Levin
Journal: Journal of Clinical Investigation (2025)

There are known sex (i.e., biological) and gender (i.e., social) differences in the epidemiology and outcomes of chronic kidney disease. In this issue of the JCI, van Eeghen et al. provide a prospective multicenter observational study of transgender individuals initiating masculinizing and feminizing hormone therapy. Testosterone and estrogen with testosterone blockade had differential effects on kidney physiology including renal plasma blood flow, measured glomerular filtration rate, tubular biomarkers, and various proteins involved in inflammatory and repair pathways. The findings suggest that estrogen is renoprotective and that testosterone may be harmful to kidney function, but requires validation in larger, more diverse cohorts. The insights gained also need to be examined in the context of both endogenous and exogenous sex hormones in individuals over the life cycle.
Extraskeletal Ewing Sarcoma of the Abdominopelvic Cavity Revealed by 18F-FDG PET/CT
Authors: Yanmei Li, Zhehao Lyu, Xingrong Lan, Ziyue Zhang, Huiqi Gao
Journal: Clinical Nuclear Medicine (2025)

Extraskeletal Ewing sarcoma in the abdominopelvic cavity is a relatively rare tumor. We reporte 18F-FDG PET/CT findings of primary peritoneal Ewing sarcoma in a 36-year-old man. The patient complained of abdominal distension for over a month. 18F-FDG PET/CT has shown increasing glucose metabolism uptake in the peritoneum, greater omentum, lesser omentum, and mesentery, which was confirmed as extraskeletal Ewing sarcoma.
Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia
Authors: Carlos Bravo-Perez, Carmelo Gurnari, Jani Huuhtanen, Naomi Kawashima, Luca Guarnera, Aashray Mandala, Nakisha D Williams, Christopher Haddad, Michaela Witt, Serhan Unlu, Zachary Brady, Olisaemeka Ogbue, Mark Orland, Arooj Ahmed, Yasuo Kubota, Simona Pagliuca, Arda Durmaz, Satu Mustjoki, Valeria Visconte, Jaroslaw P Maciejewski
Journal: Journal of Clinical Investigation (2025)

BACKGROUNDT cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disorder of cytotoxic T lymphocytes (CTLs), often with gain-of-function STAT3 mutations. T-LGLL represents a unique model for the study of persistent CTL expansions. Albeit autoimmunity is implied, various paradoxical observations led us to investigate whether immunodeficiency traits underpin T-LGLL.METHODSThis is a comprehensive immunogenomic study of 92 consecutive patients from a large T-LGLL cohort with full laboratory-clinical characterization (n = 271). Whole-exome profiling of variants associated with inborn errors of immunity (IEI) and somatic mutations in T cell lymphoid drivers was analyzed. Single-cell RNA-Seq and TCR-Seq in T-LGLL samples and RNA-Seq in T cell cancer cell lines were utilized to establish biological correlations.RESULTSLymphocytopenia and/or hypogammaglobulinemia were identified in 186 of 241 (77%) T-LGLL patients. Genetic screening for IEI revealed 43 rare heterozygous variants in 38 different immune genes in 34 of 92 (36%) patients (vs. 167/63,026 [0.26%] in controls). High-confidence deleterious variants associated with dominant, adult-onset IEIs were detected in 15 of 92 (16%) patients. Carriers showed atypical features otherwise tied to the cryptic IEI, such as earlier onset, lower lymphocyte counts, lower STAT3 mutational rate, and higher proportions of hypogammaglobulinemia and immune cytopenia/bone marrow failure than noncarriers. Somatic mutational landscape, RNA-Seq, and TCR-Seq analyses supported immune imbalance caused by the IEI variants and interactions with somatic mutations in T cell lymphoid drivers.CONCLUSIONSOur findings in T-LGLL reveal that maladaptive CTL expansions may stem from cryptic immunodeficiency traits and open the horizon of IEIs to clonal hematopoiesis and bone marrow failure.FUNDINGNIH; Aplastic Anemia and MDS International Foundation; VeloSano; Edward P. Evans Foundation; Instituto de Salud Carlos III; European Research Council; European Research Area Network on Personalised Medicine; Academy Finland; Cancer Foundation Finland.
Chronic kidney disease enhances alternative pathway activity: a new paradigm
Authors: Diana I Jalal, Joshua M Thurman, Richard Jh Smith
Journal: Journal of Clinical Investigation (2025)

Reduced kidney function is associated with increased risk of cardiovascular disease in addition to kidney disease progression. Kidney disease is considered an inflammatory state, based on elevated levels of C-reactive protein and inflammatory cytokines. A key mediator of cardiovascular and kidney disease progression in the setting of reduced kidney function is systemic and vascular inflammation. However, the exact pathways that link chronic kidney disease (CKD) with inflammation remain incompletely understood. For decades it has been known that factor D, the main activator of the alternative complement pathway, is increased in the plasma of patients with reduced kidney function. Recent biomarker evidence suggests alternative pathway activation in this setting. CKD, therefore, seems to alter the balance of alternative pathway proteins, promoting inflammation and potentially exacerbating complement-mediated diseases and CKD-associated complications. In this manuscript, we review the impact of reduced kidney function on biomarkers of the alternative complement pathway and the implications of alternative pathway activation on cardiovascular disease and kidney disease progression. Importantly, we highlight the need for ongoing research efforts that may lead to opportunities to target the alternative pathway of complement withx the goal of improving kidney and cardiovascular outcomes in persons with reduced kidney function.
ALK-positive Histiocytosis Mimicking Colon Cancer on 18F-FDG PET/CT
Authors: Haijiang Wang, Wei Zhang, Wenjie Zhang, Guohua Shen
Journal: Clinical Nuclear Medicine (2025)

As a subtype of histiocytic neoplasm, ALK-positive histiocytosis is rare, especially with colorectal involvement. We herein describe 18F-FDG PET/CT findings of ALK-positive histiocytosis with colon involvement in a 33-year-old man. The PET/CT scan demonstrated intense FDG uptake in the colonic lesion, along with multiple hypermetabolic lymph nodes. The colon cancer with lymph node metastases was initially suspected; however, the final pathological findings confirmed the diagnosis of ALK-positive histiocytosis.
Stop smoking intervention in emergency departments helps people quit
Authors: Helen Saul, Samantha Cassidy, Laura Swaithes, Ian Pope
Journal: BMJ (2025)

The studyPope I, Clark LV, Clark A, et al. Cessation of Smoking Trial in the Emergency Department (COSTED): a multicentre randomised controlled trial. Emergency Medicine Journal 2024;41:276-282.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/stop-smoking-intervention-in-emergency-departments-helps-people-quit/.
A competitive disinhibitory network for robust optic flow processing in Drosophila
Authors: Mert Erginkaya, Tomás Cruz, Margarida Brotas, André Marques, Kathrin Steck, Aljoscha Nern, Filipa Torrão, Nélia Varela, Davi D Bock, Michael Reiser, M Eugenia Chiappe
Journal: Nature Neuroscience (2025)
Modeling the impact of vaccine campaigns on the epidemic transmission dynamics of chikungunya virus outbreaks
Authors: Pastor E Pérez-Estigarribia, Gabriel Ribeiro Dos Santos, Simon Cauchemez, Cynthia Vazquez, Ana Karina Ibarrola-Vannucci, Guillermo Sequera, Shirley Villalba, María José Ortega, Jose Luis Di Fabio, Danny Scarponi, Christinah Mukandavire, Arminder Deol, Águeda Cabello, Elsi Vargas, Cyntia Fernández, Liz León, Henrik Salje
Journal: Nature Medicine (2025)
Antibody–Drug Conjugates (ADCs): current and future biopharmaceuticals
Authors: Ruili Wang, Baohui Hu, Ziyu Pan, Chongxia Mo, Xin Zhao, Guojia Liu, Ping Hou, Qi Cui, Zhao Xu, Wenjia Wang, Zhaojin Yu, Lin Zhao, Miao He, Yan Wang, Chen Fu, Minjie Wei, Lifeng Yu
Journal: Journal of Hematology & Oncology (2025)
Infant mental health services for birth and foster families of maltreated pre-school children in foster care (BeST?): a cluster-randomized phase 3 clinical effectiveness trial
Authors: Karen Crawford, Robin Young, Philip Wilson, Manuela Deidda, Matt Forde, Susanne Millar, Alex McConnachie, Kathleen Boyd, Emma McIntosh, Dennis Ougrin, Marion Henderson, Christopher Gillberg, Gary Kainth, Fiona Turner, Edmund J S Sonuga-Barke, Bridie Fitzpatrick, Helen Minnis
Journal: Nature Medicine (2025)
CD206 <sup>+</sup> IL-4Rα <sup>+</sup> Macrophages Are Drivers of Adverse Cardiac Remodeling in Ischemic Cardiomyopathy
Authors: Qiongxin Wang, Mohamed Ameen Ismahil, Yujie Zhu, Gregg Rokosh, Tariq Hamid, Guihua Zhou, Steven M. Pogwizd, Sumanth D. Prabhu
Journal: Circulation (2025)

The role of cardiac CD (cluster of differentiation) 206+ macrophages in chronic heart failure (HF) is unknown. We examined whether CD206+ macrophages expressing IL (interleukin)-4Rα are key drivers of adverse left ventricular (LV) remodeling in HF. Adult C57BL/6 mice underwent nonreperfused myocardial infarction to induce HF. Macrophages in murine and human hearts were profiled using flow cytometry and immunostaining. In vivo myeloid-specific IL-4Rα deletion and intramyocardial macrophage adoptive transfer defined the functional effects of M[IL-4] macrophages. Antisense oligonucleotides were used for in vivo IL-4Rα gene silencing in mice. CD206+ macrophages steadily expanded in hearts after myocardial infarction, such that at 8 weeks after myocardial infarction, they comprised ≈85% of all macrophages. These macrophages were proliferative, predominantly CCR2- (C-C motif chemokine receptor) and MHC (major histocompatibility complex) IIhi, and correlated with LV dysfunction and fibrosis. Nearly half of CD206+ macrophages expressed IL-4Rα, and the majority of CD206+IL-4Rα+ macrophages coexpressed profibrotic FIZZ (found in inflammatory zone) 1. IL-4-polarized bone marrow-derived CD206+ macrophages also exhibited marked upregulation of FIZZ1 and induced FIZZ1-dependent myofibroblast differentiation of both cardiac mesenchymal stem cells and cardiac fibroblasts, in part related to DLL-4/Jagged1-Notch1 signaling in cardiac mesenchymal stem cells. Intramyocardial adoptive transfer of M[IL-4], but not M[IL-10], CD206+ macrophages to naïve mice induced progressive LV remodeling over 4 weeks, increasing fibrosis, cardiomyocyte hypertrophy, and apoptosis. Myeloid-specific IL-4Rα gene deletion in HF (initiated 4 weeks after myocardial infarction) in IL-4Rαf/fLysM-CreERT2 mice significantly reduced CD206+ macrophage proliferation and effectively depleted CD206+IL-4Rα+ cardiac macrophages. This was associated with abrogation of LV remodeling progression, reduction of cardiac fibrosis, and improved neovascularization. In vivo IL-4Rα gene silencing in mice with established HF effectively depleted cardiac CD206+IL-4Rα+ macrophages and reversed LV remodeling, improving fibrosis, neovascularization, and dysfunction, and suppressed both local and systemic inflammation. Last, alternatively activated CD206+ and CD163+ macrophages were significantly expanded in human failing hearts and correlated with fibrosis. The majority of CD163+ macrophages expressed IL-4Rα and FIZZ3, the human homolog of FIZZ1. Cardiac CD206+IL-4Rα+ macrophages proliferate and expand in HF and are key mediators of pathological remodeling and fibrosis, in part through the secretion of FIZZ1. Inhibition of CD206+ macrophage IL-4Rα signaling alleviates LV remodeling in ischemic cardiomyopathy.
PILRα on tumor cells interacts with the T cell surface protein CD99 to suppress antitumor immunity
Authors: Lin Xia, Jun-Yi Liu, Chao Yu, Hong-Wei Lin, Ya-Hong Hu, Guo-Sheng Hu, Yao-Hui He, Yun-Yao Chen, Wen-Xin Luo, Ning-Shao Xia, Wen Liu
Journal: Nature Cancer (2025)