tbuckley/cabot-search huggingface dataset:
Tripartite Motif Containing 65 Deficiency Confers Protection Against Acute Kidney Injury via Alleviating Voltage‐Dependent Anion Channel 1–Mediated Mitochondrial Dysfunction
Authors: Tao Chen, Yang Zhang, Liting Ding, Chenlu Xiong, Chao Mei, Sisi Wei, Ming Jiang, Yingjie Huang, Jianrong Chen, Tao Xie, Qing Zhu, Qi Zhang, Xuan Huang, Shibiao Chen, Yong Li
Journal: MedComm (2025)

ABSTRACT Acute kidney injury (AKI) is a prevalent and serious clinical disease with a high incidence rate and significant health burden. The limited understanding of the complex pathological mechanisms has hindered the development of efficacious therapeutics. Tripartite motif containing 65 (TRIM65) has recently been identified as a key regulator of acute inflammation. However, its role in AKI remains unclear. The present study observed that TRIM65 expression was upregulated in AKI. Moreover, the knockout of the Trim65 gene in mice exhibited a substantial protective impact against rhabdomyolysis, ischemia‐reperfusion (I/R), and cisplatin‐induced AKI. Mechanistically, TRIM65 directly binds and mediates K48/K63‐linked polyubiquitination modifications of voltage‐dependent anion channel 1 (VDAC1) at its K161 and K200 amino acid sites. TRIM65 plays a role in maintaining the stability of VDAC1 and preventing its degradation by the autophagy pathway. TRIM65 deficiency attenuates mitochondrial dysfunction in renal tubular epithelial cells during AKI. Conversely, the overexpression of VDAC1 in renal tissues has been demonstrated to negate the protective effect of TRIM65 deficiency on AKI. These findings suggest that TRIM65 may play a role regulating of AKI through the targeting of VDAC1‐dependent mitochondrial function, offering potential avenues for the development of new drug targets and strategies for the treatment of AKI.
Integrating Multiplex Immunohistochemistry and Machine Learning for Glioma Subtyping and Prognosis Prediction
Authors: Houshi Xu, Zhen Fan, Shan Jiang, Maoyuan Sun, Huihui Chai, Ruize Zhu, Xiaoyu Liu, Yue Wang, Jiawen Chen, Junji Wei, Ying Mao, Zhifeng Shi
Journal: MedComm (2025)

ABSTRACT Glioma subtyping is crucial for treatment decisions, but traditional approaches often fail to capture tumor heterogeneity. This study proposes a novel framework integrating multiplex immunohistochemistry (mIHC) and machine learning for glioma subtyping and prognosis prediction. 185 patient samples from the Huashan hospital cohort were stained using a multi‐label mIHC panel and analyzed with an AI‐based auto‐scanning system to calculate cell ratios and determine the proportion of positive tumor cells for various markers. Patients were divided into two cohorts (training: N = 111, testing: N = 74), and a machine learning model was then developed and validated for subtype classification and prognosis prediction. The framework identified two distinct glioma subtypes with significant differences in prognosis, clinical characteristics, and molecular profiles. The high‐risk subtype, associated with older age, poorer outcomes, astrocytoma/glioblastoma, higher tumor grades, elevated mesenchymal scores, and an inhibitory immune microenvironment, exhibited IDH wild‐type, 1p19q non‐codeletion, and MGMT promoter unmethylation, suggesting chemotherapy resistance. Conversely, the low‐risk subtype, characterized by younger age, better prognosis, astrocytoma/oligodendroglioma, lower tumor grades, and favorable molecular profiles (IDH mutation, 1p19q codeletion, MGMT promoter methylation), indicated chemotherapy sensitivity. The mIHC‐based framework enables rapid glioma classification, facilitating tailored treatment strategies and accurate prognosis prediction, potentially improving patient management and outcomes.
SRSF7 promotes pulmonary fibrosis through regulating PKM alternative splicing in lung fibroblasts
Authors: Tongzhu Jin, Huiying Gao, Yuquan Wang, Zhiwei Ning, Danyang Bing, Yan Wang, Yi Chen, Xiaomu Tian, Qiudi Liu, Zhihui Niu, Jiayu Guo, Jian Sun, Ruoxuan Yang, Qianqian Wang, Shifen Li, Tianyu Li, Yuhong Zhou, Wenxin He, Yanjie Lu, Yunyan Gu, Haihai Liang
Journal: Acta Pharmaceutica Sinica B (2025)
Matching-adjusted Indirect Comparison of Arterial FOLFOX and Atezolizumab-Bevacizumab in Unresectable Hepatocellular Carcinoma
Authors: Yi-Min Zhang, Xin-Tong Wu, Jun-Zhe Yi, Jie Xu, Yu-Nan Zhang, Ning Lyu, Ming Zhao
Journal: Liver Cancer (2025)

Introduction: Previous phase 3 FOHAIC-1 study demonstrated that hepatic arterial infusion chemotherapy (HAIC) of FOLFOX regimen displayed favorable outcomes in advanced hepatocellular carcinoma (HCC) patients, including those with high-risk features (main portal tumor invasion and &gt; 50% liver infiltration). This study aimed to compare the treatment efficacy of HAIC-FOLFOX versus atezolizumab-bevacizumab in HCC patients. Methods: Individual patient data from the Chinese FOHAIC-1 study and aggregate data from the global IMbrave150 study were used to conduct an anchored matching-adjusted indirect comparison (MAIC). Hazard ratios (HR) and restricted mean survival times (RMST) were calculated to assess survival differences. Landmark analysis was performed to evaluate time-sensitive treatment effects, and simulated treatment comparison (STC) was conducted as sensitivity analysis. Rates of treatment-related adverse events (TRAEs) and TRAE-related discontinuations were also compared. Results: After matching baseline characteristics, HAIC showed a numerical OS benefit (HR 0.57, 95% CI, 0.30–1.08) and similar PFS benefit (HR 0.79, 95% CI, 0.43–1.47) compared to atezolizumab-bevacizumab in the overall population. In high-risk patients, HAIC demonstrated significantly improved OS (HR 0.30, 95% CI, 0.12–0.72) and 2.89-month longer RMST compared to atezolizumab-bevacizumab (95% CI, 0.15–5.64 months). Additionally, HAIC showed superior PFS (HR 0.25, 95% CI, 0.10–0.64) and 2.88-month longer RMST over atezolizumab-bevacizumab (95% CI, 0.90–4.86). Landmark analysis in high-risk group revealed that HAIC was associated with significant improvements in both OS (HR 0.32, 95% CI, 0.13–0.79) and PFS (HR 0.24, 95% CI, 0.09–0.63) during the 0–12 months following treatment initiation. Sensitivity analysis using the anchored STC analysis yielded consistent results. HAIC was associated with lower rates of grade 3-4 TRAEs and TRAE-related discontinuation in both the overall population and high-risk group. Conclusion: HAIC treatment provided superior survival benefits and a favorable safety profile compared to atezolizumab-bevacizumab in high-risk HCC patients.
Colistin exerts potent activity against mcr+ Enterobacteriaceae via synergistic interactions with the host defense
Authors: Monika Kumaraswamy, Angelica Riestra, Anabel Flores, Samira Dahesh, Fatemeh Askarian, Satoshi Uchiyama, Jonathan Monk, Sean Jung, Gunnar Bondsäter, Victoria Nilsson, Melanie Chang, Jürgen B Bulitta, Yinzhi Lang, Armin Kousha, Elisabet Bjånes, Natalie Chavarria, Ty'Tianna Clark, Hideya Seo, George Sakoulas, Victor Nizet
Journal: Journal of Clinical Investigation (2025)

Colistin (COL) is a cationic cyclic peptide that disrupts negatively-charged Gram-negative bacterial cell membranes and frequently serves as an antibiotic of last resort to combat multidrug-resistant Gram-negative bacterial infections. Emergence of the horizontally transferable plasmid-borne mobilized colistin resistance (mcr) determinant and its spread to Gram-negative strains harboring extended-spectrum β-lactamase and carbapenemase resistance genes threatens futility of our chemotherapeutic arsenal. COL is widely regarded to have zero activity against mcr+ strains based on standard antimicrobial susceptibility testing (AST) performed in enriched bacteriological growth media; consequently, the drug is withheld from patients with mcr+ infections. However, these standard testing media poorly mimic in vivo physiology and omit host immune factors. Here we observed that COL exhibits bactericidal activities against mcr+ isolates of Escherichia coli, Klebsiella pneumoniae, and Salmonella enterica in tissue culture media containing the physiological buffer bicarbonate. Moreover, COL promoted serum complement deposition on the mcr-1+ Gram-negative bacterial surface and synergized potently with active human serum in pathogen killing. At COL concentrations readily achievable with standard dosing, the peptide antibiotic killed mcr-1+ E. coli, K. pneumoniae, and S. enterica in freshly isolated human blood and proved effective as monotherapy in a murine model of E. coli bacteremia. Our results suggest that COL, currently ignored as a treatment option based on traditional AST, may in fact benefit patients with mcr-1+ Gram negative infections based on evaluations performed in a more physiologic context. These concepts warrant careful consideration in the clinical microbiology laboratory and for future clinical investigation of their merits in high-risk patients with limited therapeutic options.
Comparison of Gadoxetic Acid-enhanced Liver MRI and Contrast-enhanced CT for the Noninvasive Diagnosis of Hepatocellular Carcinoma
Authors: Jeong Hee Yoon, Won Chang, Young Kon Kim, Chang Hee Lee, Jeong Woo Kim, Beom Jin Park, Jin-Young Choi, Seung-seob Kim, Hee Sun Park, Eun Sun Lee, Jeong-Sik Yu, Seong Jin Park, Myung-Won You, Myoung-jin Jang, Joon-Il Choi, Jeong Min Lee
Journal: Liver Cancer (2025)

Introduction: Magnetic resonance imaging (MRI) has been shown to outperform computed tomography (CT) in diagnosing hepatocellular carcinoma (HCC), although inconsistencies exist across studies. We compared the performance of CT and gadoxetic acid-enhanced MRI in diagnosing HCC according to various guidelines, and to assess the incremental value of a second-line examination. Methods: This retrospective multicenter study included patients at risk of developing HCC with focal liver lesions (FLLs) ≥10 mm. These patients underwent both contrast-enhanced CT and gadoxetic acid-enhanced MRI between January 2015 and June 2018. Four radiologists independently assessed the images using criteria from the Liver Imaging Reporting and Data System (LI-RADS), the Asian Pacific Association for the Study of the Liver (APASL), and the Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) guidelines. The diagnostic performance of CT and MRI was compared across guidelines. Results: In total, 1590 FLLs (median size, 22.6 mm) were analyzed in 1445 patients (median age, 59 years; male, 1101). Sensitivity was higher with MRI than with CT for APASL (89.3% [95% CI: 87.7%, 90.8%] vs. 78.9% [95% CI: 77.0%, 80.8%], respectively) and KLCA-NCC (78.7% [95% CI: 76.7%, 85.0%] vs. 73.7% [95% CI: 71.6%, 75.7%], respectively) (P = 0.002 for both). However, LI-RADS showed lower sensitivity with MRI than with CT (70.6% [95% CI: 68.4%, 72.6%] vs. 74.7% [95% CI: 72.6%, 76.7%], P = 0.002), due to fewer nonperipheral washout. MRI re-categorized 22.4%, 32.2%, and 53.5% of non-HCC observations on CT as HCC with LI-RADS, KLCA-NCC, and APASL, respectively. CT re-classified 30.2%, 29.0%, and 25.8% of non-HCC observations on MRI as HCC with LI-RADS, KLCA-NCC, and APASL, respectively. Conclusion: The added value of gadoxetic acid-enhanced MRI after CT depends on the diagnostic criteria used. Restricting washout timing to the portal venous phase in LI-RADS reduces the sensitivity of gadoxetic acid-enhanced MRI relative to CT.
Lymphatic dysfunction in lupus contributes to cutaneous photosensitivity and lymph node B cell responses
Authors: Mir J Howlader, William G Ambler, Madhavi Latha S Chalasani, Aahna Rathod, Ethan S Seltzer, Ji Hyun Sim, Jinyeon Shin, Noa Schwartz, William D Shipman Iii, Dragos C Dasoveanu, Camila B Carballo, Ecem Sevim, Salma Siddique, Yurii Chinenov, Scott A Rodeo, Doruk Erkan, Raghu P Kataru, Babak J Mehrara, Theresa T Lu
Journal: Journal of Clinical Investigation (2025)

Patients with systemic lupus erythematosus (SLE) are photosensitive, developing skin inflammation with even ambient ultraviolet radiation (UVR), and this cutaneous photosensitivity can be associated with UVR-induced flares of systemic disease, which can involve increased autoantibodies and further end organ injury. Mechanistic insight into the link between the skin responses and autoimmunity is limited. Signals from skin are transmitted directly to the immune system via lymphatic vessels, and here we show evidence for potentiation of UVR-induced lymphatic flow dysfunction in SLE patients and murine models. Improving lymphatic flow by manual lymphatic drainage (MLD) or with a transgenic model with increased lymphatic vessels reduces both cutaneous inflammation and lymph node B and T cell responses, and long term MLD reduces splenomegaly and titers of a number of autoantibodies. Mechanistically, improved flow restrains B cell responses in part by stimulating a lymph node fibroblastic reticular cell-monocyte axis. Our results point to lymphatic modulation of lymph node stromal function as a link between photosensitive skin responses and autoimmunity and as a therapeutic target in lupus, provide insight into mechanisms by which the skin state regulates draining lymph node function, and suggest the possibility of MLD as an accessible and cost-effective adjunct to add to ongoing medical therapies for lupus and related diseases.
Antimicrobial Peptide Developed with Machine Learning Sequence Optimization Targets Drug Resistant Staphylococcus aureus in Mice
Authors: Biswajit Mishra, Anindya Basu, Fadi Shehadeh, LewisOscar Felix, Sai Sundeep Kollala, Yashpal Singh Chhonker, Mandar T Naik, Charilaos Dellis, Liyang Zhang, Narchonai Ganesan, Daryl J Murry, Jianhua Gu, Michael B Sherman, Frederick M Ausubel, Paul P Sotiriadis, Eleftherios Mylonakis
Journal: Journal of Clinical Investigation (2025)

As antimicrobial resistance rises, new antibacterial candidates are urgently needed. Using sequence space information from over 14,743 functional antimicrobial peptides (AMPs), we improved the antimicrobial properties of citropin 1.1, an AMP with weak anti-methicillin resistant Staphylococcus aureus (MRSA) activity, producing a short and potent anti-staphylococcal peptide, CIT-8 (13 residues). At 40 μg/ml, CIT-8 eradicated 1 × 108 drug-resistant MRSA and VRSA (vancomycin resistant S. aureus) persister cells within 30 mins of exposure and reduced the number of viable biofilm cells of MRSA and VRSA by 3 log10 and 4 log10 in established biofilms, respectively. CIT-8 (at 32 μg/ml) depolarized and permeated the S. aureus MW2 membrane. In a mouse model of MRSA skin infection, CIT-8 (2% w/w in petroleum jelly) significantly reduced the bacterial burden by 2.3 log10 (p < 0.0001). Our methodology accelerates AMP design by combining traditional peptide design strategies, such as truncation, substitution, and structure-guided alteration, with machine learning (ML)-backed sequence optimization.
Manganese-Based Nanoadjuvants for the Synergistic Enhancement of Immune Responses in Breast Cancer Therapy via Disulfidptosis-Induced ICD and cGAS-STING Activation
Authors: Ke Zhang, Chengyao Huang, Yu Ren, Mingyue Zhang, Xiaotong Lu, Bangliu Yang, Peiran Chen, Shiyao Guo, Xueqian Wang, Yuhong Zhuo, Chao Qi, Kaiyong Cai
Journal: Biomaterials (2025)
The pharmacokinetic profile of mitomycin C released from an injectable supramolecular hydrogel in a rodent model
Authors: Anne G W E Wintjens, Peter-Paul K H Fransen, Kaatje Lenaerts, Hong Liu, Geert C van Almen, Marion J Gijbels, Ben J A Janssen, Ignace H J T de Hingh, Patricia Y W Dankers, Kurt Van Der Speeten, Nicole D Bouvy, Wouter Marchal
Journal: Journal of Controlled Release (2025)
Plasma endotrophin levels correlate with insulin resistance in people with obesity
Authors: Gordon I Smith, Samuel Klein
Journal: Journal of Clinical Investigation (2025)

Adipose tissue-derived endotrophin, a peptide cleaved from the α3 chain of collagen VI during fibrogenesis, causes systemic insulin resistance in rodent models. Here, we evaluated the potential importance of endotrophin in regulating whole-body insulin sensitivity in people. We evaluated: i) plasma endotrophin concentration, insulin sensitivity (assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose tracer infusion) and adipose tissue expression of genes involved in endotrophin production in three groups of participants that were rigorously stratified by adiposity and insulin sensitivity [lean insulin-sensitive (Lean-IS; n=10), obese insulin-sensitive (Obese-IS; n=10), and obesity insulin-resistant (Obese-IR; n=10)]; ii) plasma endotrophin concentration and insulin sensitivity in 15 people with obesity and type 2 diabetes before and after marked (~18%) weight loss; and iii) the effect of endotrophin on insulin signaling (AKTser473 phosporylation) and insulin action (insulin-stimulated glucose uptake) in primary human skeletal muscle myotubes. Plasma endotrophin progressively increased from the Lean-IS to the Obese-IS to the Obese-IR group, was negatively associated with insulin sensitivity and positively associated with factors involved in adipose tissue endotrophin production, namely adipose tissue gene expression of matrix metalloproteinases and markers of hypoxia, inflammation, and fibrosis. Marked weight loss increased insulin sensitivity in conjunction with a decrease in plasma endotrophin concentration. Endotrophin inhibited insulin insulin-stimulated AKTser473 phosphorylation and insulin-stimulated glucose uptake in myotubes, which was restored by incubation with a neutralizing endotrophin antibody. These results suggest plasma endotrophin is both a biomarker and cause of whole-body insulin resistance in people with obesity.
Vascular Endothelial Growth Factor and Endogenous Calcium-Capturing Hydrogels Promote Bone Tissue Regeneration
Authors: Zhengchao Yuan, Xinyi Wang, Peng Li, Muhammad Shafiq, Panpan Shang, Lu Han, Hao Feng, Yuan Xu, Mohamed El-Newehy, Meera Moydeen Abdulhameed, Lianyong Jiang, Xiumei Mo, Yijiu Ren
Journal: Biomaterials (2025)
Tumor-Specific Activated Polymeric Nanotuners Disrupt Positive Feedback Cycle of Hypoxia and Apoptosis Evasion for Potent Cancer Radiotherapy
Authors: Xiaoxue Hou, Chun Wang, Yu Zhao, Qian Wang, Dianyu Wang, Jingyu Zhao, Yang Liu, Fan Huang, Jianfeng Liu
Journal: Biomaterials (2025)
Polymersome-enabled brain Codelivery of STAT3 siRNA and CpG oligonucleotide boosts chemo-immunotherapy of malignant glioma
Authors: Songsong Zhao, Zhiwei Sun, Mingyu Xia, Beibei Guo, Yanyi Qu, Jingyi Wang, Zhiyuan Zhong, Fenghua Meng
Journal: Journal of Controlled Release (2025)
Childhood Exposure to Air Pollution, Body Mass Index Trajectories, and Insulin Resistance Among Young Adults
Authors: Fangqi Guo, Xinci Chen, Steve Howland, Zhongzheng Niu, Lu Zhang, W. James Gauderman, Rob McConnell, Nathan Pavlovic, Fred Lurmann, Theresa M. Bastain, Rima Habre, Carrie V. Breton, Shohreh F. Farzan
Journal: JAMA Network Open (2025)

Importance Emerging evidence suggests that exposure to air pollution affects children’s glucose metabolism. However, the underlying mechanisms are not fully understood. Objective To investigate whether body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) growth trajectories mediate the association between traffic-related air pollution (TRAP) and insulin resistance. Design, Setting, and Participants As part of the Southern California Children’s Health Study, the ongoing Meta-Air2 cohort substudy followed up participants from pregnancy to 24 years of age and examined the mediation role of BMI. Cardiometabolic follow-up was initiated as participants transitioned into adulthood. Data from the Meta-Air2 substudy were collected from November 27, 2018, to May 31, 2023. Exposures The California Line Source Dispersion Model was used to calculate mean childhood exposure to traffic-related total nitrogen oxides (NO x ) from pregnancy to 13 years of age by calculating mean monthly estimates. Traffic density within a 300-m buffer around participants’ residence was calculated as a secondary outcome. Main Outcomes and Measures Insulin resistance markers were assessed during the recent visit in young adulthood, including the homeostatic model assessment of insulin resistance (HOMA-IR; calculated from fasting glucose and insulin levels) and glycated hemoglobin (HbA 1c ) level. Participants’ BMI growth trajectories, including BMI at 13 years of age and accelerated BMI growth, were analyzed as potential mediators. Using fully adjusted PROCESS macro mediation models, their role in mediating the association between traffic-related total NO x exposure and insulin resistance was examined with adjustment for demographic characteristics, smoking status, and parental history of diabetes. Results Among the 282 participants (mean [SD] age, 24.0 [1.7] years), each 1-SD increase in childhood exposure to traffic-related total NO x was associated with a BMI increase of 0.71 (95% CI, 0.29-1.13) at 13 years of age and adult HOMA-IR increase of 0.55 (95% CI, 0.23-0.87). An estimated mediation effect identified BMI at 13 years of age combined with accelerated BMI growth as accounting for 41.8% of the estimated total effect (β, 0.23; 95% bootstrap CI, 0.01-0.52) between total NO x and HOMA-IR. Similar patterns were observed when exploring traffic density as an exposure or HbA 1c level as an outcome. Conclusions and Relevance In this cohort study of young adults, the long-term association between TRAP and insulin resistance may be partially explained by higher BMI and accelerated BMI growth from early adolescence into young adulthood. These findings highlight the importance of weight management in children, particularly those residing in highly polluted areas.
Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model
Authors: Shuo Wang, Chuangye Qi, Chetan Rajpurohit, Baijayanti Ghosh, Wen Xiong, Baiping Wang, Yanyan Qi, Sung Hee Hwang, Bruce D Hammock, Hongjie Li, Li Gan, Hui Zheng
Journal: Molecular Neurodegeneration (2025)

Abstract Background The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer’s disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood. Methods Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice. This was followed by single-nucleus RNA-sequencing (snRNA-seq), biochemical and immunohistochemical analysis, and behavioral assessments. Additionally, we examined the effects of the sEH-EET pathway in primary microglia cultures and human induced pluripotent stem cell (iPSC)-derived neurons exhibiting seeding-induced Tau inclusions. Results sEH inhibition improved cognitive function, rescued neuronal cell loss, and reduced Tau pathology and microglial reactivity. snRNA-seq revealed that TPPU treatment upregulated genes involved in actin cytoskeleton and excitatory synaptic pathways. Treatment of human iPSC-derived neurons with TPPU enhanced synaptic density without affecting Tau accumulation, suggesting a cell-autonomous neuroprotective effect of sEH blockade. Furthermore, sEH inhibition reversed disease-associated and interferon-responsive microglial states in PS19 mice, while EET supplementation promoted Tau phagocytosis and clearance in primary microglia cultures. Conclusion These findings demonstrate that sEH blockade or EET augmentation confers therapeutic benefit in neurodegenerative tauopathies by simultaneously targeting neuronal and microglial pathways.