Clinical And Experimental Medicine[JOURNAL]
Sun
200 papers
Artificial intelligence in immunotherapy: revolutionizing diagnostic and therapeutic applications in cancer and autoimmune diseases.
Alshorman J, Mehran MJ, Bahrami Y … +10 more , Mohammadzadeh S, Barzigar R, Morshedi M, Haider KH, Tembo KM, Rong SJ, Jadgal N, Altahla R, Bolideei M, Wang Y
Clin Exp Med · 2026 Mar · PMID 41787197 · Full text
Artificial intelligence (AI) is increasingly advancing precision immunotherapy by integrating high-dimensional biomedical data to support diagnosis, treatment selection, and longitudinal monitoring in both cancer and aut...
Artificial intelligence (AI) is increasingly advancing precision immunotherapy by integrating high-dimensional biomedical data to support diagnosis, treatment selection, and longitudinal monitoring in both cancer and autoimmune diseases. This review summarizes AI applications in biomarker discovery, prediction of immune checkpoint inhibitor (ICI) response and toxicity, neoantigen prioritization, CAR-T cell optimization, and therapeutic antibody engineering. In oncology, multimodal models combining multi-omics, medical imaging, and clinical variables improve patient stratification and non-invasive response assessment, with several imaging- and pathology-based prediction tasks reporting clinically meaningful performance (frequently AUC ~ 0.70–0.95 across tumor types and endpoints). In autoimmune diseases, AI enables earlier diagnosis, molecular subtyping, treatment-response prediction, and real-time disease activity tracking using EHR, laboratory, imaging, and wearable data—supporting precision management in conditions such as rheumatoid arthritis and type 1 diabetes. Key challenges include data heterogeneity, model interpretability, and governance; however, explainable AI, federated learning, and digital twin frameworks offer practical routes toward trustworthy clinical translation. Overall, AI is emerging as a foundational technology for next-generation, patient-specific immunotherapy across oncology and autoimmune medicine.
Immunotherapy in hepatocellular carcinoma: translating mechanistic insights into clinical advances.
Khorasani SK, Boroumandi S, Darzi A … +5 more , Shokouhfar M, Abdali P, Eini P, Vanan AG, Bahrami N
Clin Exp Med · 2026 Mar · PMID 41784912 · Full text
Hepatocellular carcinoma is the most common primary liver cancer and a leading cause of cancer-related mortality worldwide. Traditional systemic therapies, such as tyrosine kinase inhibitors, offer limited survival benef...
Hepatocellular carcinoma is the most common primary liver cancer and a leading cause of cancer-related mortality worldwide. Traditional systemic therapies, such as tyrosine kinase inhibitors, offer limited survival benefits, prompting the emergence of immunotherapy as a transformative approach. This review synthesizes mechanistic insights into the tumor microenvironment of hepatocellular carcinoma with clinical evidence from pivotal trials on immune checkpoint inhibitors. It summarizes outcomes from monotherapy and combination regimens incorporating antiangiogenic agents, tyrosine kinase inhibitors, radiotherapy, and locoregional therapies like transarterial chemoembolization or hepatic arterial infusion chemotherapy. Emerging modalities, including therapeutic vaccines, oncolytic viruses, Toll-like receptor agonists, and adoptive cell therapies, are also examined. Immune checkpoint inhibitors targeting programmed cell death protein 1, its ligand, and cytotoxic T-lymphocyte-associated protein 4 elicit durable responses in subsets of patients, though monotherapy provides modest overall benefits. Combination strategies, such as atezolizumab plus bevacizumab, tremelimumab–durvalumab (STRIDE), and nivolumab plus ipilimumab (CheckMate-9DW), have set new standards of care by significantly extending overall survival with acceptable toxicity. Resistance mechanisms involve tumor-intrinsic factors like beta-catenin signaling and antigen presentation defects, alongside microenvironmental elements including regulatory T cells, myeloid-derived suppressor cells, and cytokine networks. Effective management of immune-related adverse events, particularly hepatic toxicities, is critical. Immunotherapy has revolutionized hepatocellular carcinoma treatment, fostering multimodal and personalized strategies. Future directions emphasize validated biomarkers, optimized sequencing, and randomized trials to broaden long-term survival gains.
Metabolic dysfunction-associated fatty liver disease and risk of knee osteoarthritis: A prospective cohort study.
Zhang Y, Jiang L, Teng X … +3 more , Xia C, Zhou H, Wang F
Clin Exp Med · 2026 Mar · PMID 41784857 · Full text
Knee osteoarthritis (KOA) is a leading cause of chronic pain and disability. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a systemic metabolic disorder that influences extra-hepatic conditions. Althoug...
Knee osteoarthritis (KOA) is a leading cause of chronic pain and disability. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a systemic metabolic disorder that influences extra-hepatic conditions. Although cross-sectional studies link MAFLD to KOA, prospective evidence remains limited. This study aimed to investigate the longitudinal association between MAFLD, and KOA and assess the mediating role of inflammation. This study included 303,604 participants from the UK Biobank without baseline osteoarthritis. MAFLD was defined using the fatty liver index alongside metabolic criteria, fibrosis severity was assessed using the Fibrosis-4 score, and MAFLD subtypes were categorized. Incident KOA was identified through linked health records. Cox proportional hazard regression model was used to estimate hazard ratios (HR) and 95% confidence interval (CI) for the association. Mediation analysis evaluated the potential role of high-sensitivity C-reactive protein (hs-CRP). Over a median follow-up of 13.67 years, 17,137 KOA cases occurred. MAFLD was associated with an 18% higher risk of KOA (HR 1.18, 95% CI 1.13-1.24), with risk increasing by fibrosis severity (P for trend < 0.001). Among subtypes, MAFLD-overweight/obesity showed a significant association with KOA (HR 1.19, 95% CI 1.14-1.25), while MAFLD-diabetes (HR 1.05, 95% CI 0.96-1.16) and MAFLD-lean (HR 1.23, 95% CI 0.93-1.62) did not reach statistical significance. Additionally, hs-CRP explained 8.94% of the association between MAFLD and KOA. MAFLD was independently associated with higher KOA risk; inflammation partially mediates this association. These findings suggest MAFLD as a systemic metabolic condition affecting musculoskeletal health, supporting integrated management strategies.
Mechanistic insights into atorvastatin-induced hepatotoxicity: molecular pathways, clinical relevance, and strategies for safer personalized therapy.
Abdel-Rasol MA, El-Sayed WM
Clin Exp Med · 2026 Mar · PMID 41784742 · Full text
Atorvastatin, a chemically defined HMG-CoA reductase inhibitor, is widely prescribed for hyperlipidemia and cardiovascular disease prevention. However, it has been implicated in hepatotoxic effects ranging from transient...
Atorvastatin, a chemically defined HMG-CoA reductase inhibitor, is widely prescribed for hyperlipidemia and cardiovascular disease prevention. However, it has been implicated in hepatotoxic effects ranging from transient transaminase elevations to rare but severe liver injury. This review critically examines the molecular and biochemical mechanisms underlying atorvastatin-induced hepatotoxicity, emphasizing translational relevance and human health risk assessment. A structured literature search (2000-2025) integrated evidence from clinical reports, experimental models, and pharmacogenomic studies. Key pathways analyzed included mitochondrial dysfunction, oxidative stress, bile acid dysregulation, and inflammatory signaling, with special attention to genetic polymorphisms (SLCO1B1, CYP3A4, UGT1A1) and drug-drug interactions. Atorvastatin-induced hepatotoxicity results from interconnected molecular events. Mitochondrial dysfunction impairs electron transport chain activity, causing ATP depletion and excessive ROS production. Oxidative stress drives lipid peroxidation, protein modification, and DNA injury, while inhibition of bile acid transporters (BSEP, NTCP, MRP2) promotes cholestatic damage. ROS and bile acid accumulation activate Kupffer cells and the NLRP3 inflammasome, amplifying inflammatory cascades (e.g., TNF-α, IL-1β). Pharmacogenomic variations in SLCO1B1, CYP3A4/5, and UGT1A1 modulate atorvastatin disposition and susceptibility, contributing to idiosyncratic injury. Drug-drug interactions further intensify hepatotoxic risk. Mechanistic insights support preventive strategies such as genotype-guided dosing, structured liver function monitoring, and adjunctive therapies targeting oxidative stress, mitochondrial stabilization, or bile acid homeostasis. Defining these mechanistic pathways provides a framework for integrating pharmacogenomic data and mechanistic biomarkers into clinical practice, enabling safer, more personalized statin therapy and improving risk stratification in drug-induced liver injury.
Efficacy and safety of denosumab biosimilars in the treatment of postmenopausal osteoporosis: A systematic review of randomized clinical trials.
Shakibaei F, Malekshahi S, Heidari N … +1 more , Heidari A
Clin Exp Med · 2026 Mar · PMID 41784728 · Full text
Denosumab biosimilars were developed to provide cost-effective alternatives to the reference monoclonal antibody for postmenopausal osteoporosis (PMO). This review assessed their efficacy, safety, and immunogenicity in t...
Denosumab biosimilars were developed to provide cost-effective alternatives to the reference monoclonal antibody for postmenopausal osteoporosis (PMO). This review assessed their efficacy, safety, and immunogenicity in the treatment of PMO. A systematic search of PubMed/Medline, Ovid-Embase, and Web of Science (to April 2025) identified randomized controlled trials comparing denosumab biosimilars with either the originator (Prolia) or placebo. Data on bone mineral density (BMD), bone turnover markers, adverse events, and immunogenicity were synthesized descriptively. In addition, the National Institutes of Health (NIH) Quality Assessment Tool was employed to evaluate the risk of bias across all eligible studies. Eleven RCTs met the inclusion criteria. Biosimilars showed therapeutic equivalence to the reference product, with comparable BMD gains at the lumbar spine, total hip, and femoral neck, and similar reductions in CTX and P1NP. In placebo-controlled trials, biosimilars significantly increased BMD and reduced bone turnover by more than 70%. Safety and immunogenicity profiles were comparable to the originator, with no new safety signals or neutralizing antibodies. Denosumab biosimilars demonstrate efficacy and safety equivalent to Prolia, offering an accessible, cost-efficient option for PMO management. Long-term data are needed to confirm sustained antifracture benefits.
Immune checkpoint inhibitors in bladder cancer: from mechanistic insights to emerging combination frontlines.
Ajalli MM, Sansebli Y, Ekrami D … +5 more , Alaeenejad F, Abbasi A, Eini P, Hassanzadeh F, Bahrami N
Clin Exp Med · 2026 Mar · PMID 41784671 · Full text
Bladder cancer (BC), primarily urothelial carcinoma, remains one of the most common and lethal genitourinary malignancies worldwide, with limited long-term outcomes from standard treatments such as chemotherapy and radic...
Bladder cancer (BC), primarily urothelial carcinoma, remains one of the most common and lethal genitourinary malignancies worldwide, with limited long-term outcomes from standard treatments such as chemotherapy and radical cystectomy. These conventional modalities often fail to achieve durable responses and can severely affect patients’ quality of life, underscoring the need for more effective and targeted therapeutic strategies. Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte–associated protein 4 (CTsLA-4) have revolutionized BC therapy by restoring antitumor immune function. Nevertheless, treatment resistance, immune-related adverse events, and patient heterogeneity continue to limit their universal efficacy. This review provides an in-depth overview of ICI mechanisms and highlights evolving therapeutic approaches, including combination strategies with chemotherapy, radiotherapy, Bacillus Calmette–Guérin (BCG), and antibody–drug conjugates (ADCs). It also discusses emerging biomarkers such as PD-L1 expression, tumor mutational burden (TMB), and DNA damage repair (DDR) deficiency as predictive tools for treatment selection. Overall, this study underscores the pivotal role of immunotherapy in reshaping bladder cancer management and outlines future directions toward safe, personalized, and biomarker-driven therapeutic paradigms.
Identification and validation of lymphangiogenesis-related genes for predicting acute myeloid leukemia prognosis: insights from bulk RNA sequencing and single-cell RNA sequencing analyses.
Qu W, Wang R, Zhao M … +3 more , Zhang T, Shi X, Zhao M
Clin Exp Med · 2026 Mar · PMID 41772327 · Full text
Acute myeloid leukemia (AML) is a hematologic malignancy, and lymphangiogenesis can affect the proliferation, invasion, and other biological behaviors of leukemia cells. This study explored lymphangiogenesis-associated m...
Acute myeloid leukemia (AML) is a hematologic malignancy, and lymphangiogenesis can affect the proliferation, invasion, and other biological behaviors of leukemia cells. This study explored lymphangiogenesis-associated mechanisms in AML. AML datasets were downloaded from public databases. Differential expression analysis, univariate Cox regression, and machine learning were used to identify prognostic lymphangiogenesis-related genes (LYMRGs) and build a risk model. Prognostic analyses included enrichment pathway, genetic mutation, immune microenvironment, and drug sensitivity analyses. Dataset GSE116256 explored LYMRG expression in key cells; GSE142698 and RT-qPCR verified prognostic LYMRG expression. A 6-LYMRG (ANGPT1, HGF, MAPK8, PCNA, TBL1XR1, TLR4) risk model was the optimal prognostic signature. Moreover, pathways like cytokine-cytokine receptor interaction and immune cells such as macrophages were found to be associated with risk stratification in AML patients. Mutational patterns differed between different risk AML patients. High-risk AML patients showed greater sensitivity to UMI.77, vorinostat, BI.2536, tozasertib, daporinad, carmustine, MIM1, and WEHI.539. Furthermore, significant changes in prognostic LYMRG expression were observed during key cell (including progenitor cells, monocyte-derived dendritic cells, and erythroblasts) differentiation. Importantly, GSE142698 and RT-qPCR confirmed that HGF, MAPK8, PCNA, and TBL1XR1 were abundantly expressed, while TLR4 showed low expression in AML patients. This study identified ANGPT1, HGF, MAPK8, PCNA, TBL1XR1, and TLR4 as the key prognostic indicators for AML. The lymphangiogenesis-associated risk model provided an efficient tool for predicting patient survival and might facilitate the development of personalized treatment strategies for AML.
Impaired central sensitivity to thyroid hormones is associated with increased liver fibrosis degree in the euthyroid population.
Li Y, Huang J, Wang F … +1 more , Gan H
Clin Exp Med · 2026 Mar · PMID 41770430 · Full text
To analyse the relationship between central sensitivity to thyroid hormones (THs) and liver fibrosis in a euthyroid population. Central TH sensitivity indices, including the thyroid feedback quantile-based index (TFQI),...
To analyse the relationship between central sensitivity to thyroid hormones (THs) and liver fibrosis in a euthyroid population. Central TH sensitivity indices, including the thyroid feedback quantile-based index (TFQI), thyroid stimulating hormone index (TSHI), and thyrotropin thyroxine resistance index (TT4RI), were calculated according to TH levels. Liver stiffness measurement (LSM) values were determined by liver shear wave quantification ultrasonography, and statistical analysis of the above data was conducted. Compared with those in the LSM < 7.3 kPa group, the TFQI, TSHI, and TT4RI in the LSM ≥ 7.3 kPa group significantly increased (P < 0.001). Trend tests of multiple regression equations indicated that the LSM was positively correlated with the TT4RI (β = 0.413, P < 0.001). In the sex subgroups, the LSM was positively correlated with the TT4RI (β = 0.425, P = 0.03) and TSHI (β = 0.015, P = 0.027) in females; in the age subgroups, the LSM was positively correlated with the TT4RI (inflection point: 8.4 kPa, β = 0.324, P = 0.01) and TSHI (inflection point: 8.3 kPa, β = 0.01, P = 0.022) before the inflection points in the age < 65 years group; and in the BMI subgroups, the LSM was positively correlated with the TT4RI (inflection point: 5.9 kPa, β = 0.437, P = 0.008), TSHI (inflection point: 6.8 kPa, β = 0.013, P = 0.008) and TFQI (inflection point: 6.8 kPa, β = 0.007, P = 0.045) in the BMI < 30 kg/m group. Central TH sensitivity decreases as the degree of fibrosis increases in the euthyroid population, particularly among females, individuals aged < 65 years, and those with a BMI < 30 kg/m within certain ranges.
Exosomal bioactive molecules: molecular regulation, functional heterogeneity, and translational implications in disease diagnostics and therapeutics.
Chigozie VU
Clin Exp Med · 2026 Feb · PMID 41748937 · Full text
Exosomes are nanoscale extracellular vesicles that play a pivotal role in cell-to-cell communication by transporting a rich cargo of bioactive molecules, including proteins, lipids, and diverse nucleic acids. Recent disc...
Exosomes are nanoscale extracellular vesicles that play a pivotal role in cell-to-cell communication by transporting a rich cargo of bioactive molecules, including proteins, lipids, and diverse nucleic acids. Recent discoveries have uncovered the complex molecular machinery behind exosome biogenesis and cargo loading, highlighting the roles of Endosomal Sorting Complex Required for Transport (ESCRT) complexes, lipid domains, RNA-binding proteins, and post-translational modifications. This review presents a comprehensive synthesis of the molecular pathways that regulate exosomal heterogeneity, with a focus on how these mechanisms govern the selective enrichment of biologically active cargo. We also discuss state-of-the-art technologies and omics platforms—such as ExoCarta and machine learning–based classifiers—used to decode exosomal content for diagnostic purposes. The clinical relevance of exosomes is examined through their roles in liquid biopsies for cancer, metabolic, and neurodegenerative diseases, emphasizing biomarker performance in terms of sensitivity and specificity. Furthermore, we explore the therapeutic potential of both native and engineered exosomes for targeted drug delivery, wound healing, and neuroregeneration, and provide insights into ongoing clinical trials. Despite growing interest, translational challenges persist, including standardization of isolation protocols, variability in cargo, targeting specificity, and regulatory constraints. Emerging strategies—ranging from synthetic exosome mimetics to AI-driven diagnostic algorithms—are rapidly reshaping the landscape of exosome-based precision medicine. This review consolidates current knowledge while proposing a forward-looking framework that integrates basic biology, engineering innovation, and clinical application, positioning exosomes as powerful agents in the future of diagnostics and therapeutics.
Evaluating deep learning models for pancreatic cancer diagnosis.
Li D, He H, Hu J … +3 more , Ding Y, Kong L, Hu A
Clin Exp Med · 2026 Feb · PMID 41746513 · Full text
Pancreatic cancer is a highly aggressive and often fatal disease, with early detection being a key factor for improving patient survival. Recent advances in artificial intelligence (AI), particularly deep learning, have...
Pancreatic cancer is a highly aggressive and often fatal disease, with early detection being a key factor for improving patient survival. Recent advances in artificial intelligence (AI), particularly deep learning, have demonstrated significant potential in disease diagnosis based on histopathological images. This study investigates the effectiveness of two deep learning models, residual neural network (ResNet) and visual geometry group network (VGG), in distinguishing pancreatic cancer tissue from normal pancreatic tissue using histological images. A total of 3,000 hematoxylin and eosin (H&E) stained pathological images were collected for both normal pancreatic tissue and pancreatic cancer tissue. The images were acquired using a microscopic slide scanning system in our laboratory. After preprocessing steps such as cropping, resizing, and normalization, the images were input into two deep neural networks, ResNet and VGG, for training and testing. The deep learning models were implemented using the PyTorch framework and tested on a CUDA10 parallel computing platform. ResNet achieved an accuracy of 92.27% and an F1-score of 0.92, outperforming VGG, which achieved an accuracy of 86.01% and an F1-score of 0.86. K-fold cross-validation was performed to evaluate the generalization ability of the models. The results showed that deep learning models, particularly ResNet, offer substantial promise for improving the accuracy of pancreatic cancer diagnosis, potentially facilitating earlier and more accurate detection in clinical settings.
CD44 is associated with papillary thyroid carcinoma metastasis via potential modulation of the immunosuppressive tumor microenvironment.
Adeerjiang Y, Huo MH, Ma L … +15 more , Li XX, Tian Y, Bai C, Wang BW, Qu X, Yao XY, Ma LL, Gan XX, Kuang JY, Liang HZ, Qiang BR, Wang R, Bao JL, Jiang S, Du GL
Clin Exp Med · 2026 Feb · PMID 41739250 · Full text
To investigate the role of CD44 in papillary thyroid carcinoma (PTC) lymph node metastasis and its connotation with Treg-mediated immunosuppression through TGF-β and IL-10 signaling. Eighty-two benign thyroid nodule pati...
To investigate the role of CD44 in papillary thyroid carcinoma (PTC) lymph node metastasis and its connotation with Treg-mediated immunosuppression through TGF-β and IL-10 signaling. Eighty-two benign thyroid nodule patients were compared with 122 PTC patients. Differentially expressed proteins (DEPs) were identified in both tissue and serum. CD44 expression was validated by ELISA, IHC and flow cytometry. The proportion of Treg and cytokines were analyzed in parallel. The tumor microenvironment architecture was examined using 3D tissue clearing and whole-mount imaging. The functional role of CD44 was further explored using TPC-1 human PTC cell line through gain-of-function and loss-of-function assays in vitro. Proteomic analysis identified 34 tissue and 17 serum DEPs involved in metastasis. CD44 levels in serum were significantly higher in PTC patients than in controls (345.45 ± 44.88 pg/mL vs. 73.33 ± 25.64 pg/mL, P < 0.001). Furthermore, CD44 expression in the serum of CLNM patients was further elevated (782.01 ± 168.38 pg/mL vs. 248.77 ± 55.33 pg/mL, P < 0.001). Multivariate analysis identified CD44 as an independent risk factor for PTC (OR = 5.271, 95% CI: 1.741 ~ 15.959) and CLNM (OR = 3.995, 95% CI: 1.298 ~ 12.298). CD44 levels showed positive correlations with increased TGF-β, IL-10 levels, and Treg frequency. CD44 levels were connected with amplified TGF-β, IL-10, and Treg frequency. IHC and 3D imaging also demonstrated colocalization of CD44⁺ tumor cells and Tregs in H&E sections and whole-mount. Importantly, CD44 knockdown suppressed, while CD44 overexpression enhanced, TPC-1 cell proliferation in vitro, suggesting a direct role of CD44 in promoting tumor cell growth. Our data suggest that CD44 may contribute to PTC metastasis by modulating the immunosuppressive microenvironment through TGF-β/IL-10 mediated Treg accumulation and by directly driving tumor cell proliferation. These findings highlight a potential pathogenic role of CD44 in PTC progression.
Exploring immune-inflammatory cross-talk in atherosclerosis using AI-enhanced multi-omics approaches.
Zhao Z, Zhao Z, Jia H … +3 more , Qin Y, Xiahou Z, Li W
Clin Exp Med · 2026 Feb · PMID 41739231 · Full text
Atherosclerosis is a complex chronic inflammatory disease characterized by lipid accumulation, vascular smooth muscle cell (VSMCs) proliferation, and immune cell infiltration. However, the heterogeneity and functional dy...
Atherosclerosis is a complex chronic inflammatory disease characterized by lipid accumulation, vascular smooth muscle cell (VSMCs) proliferation, and immune cell infiltration. However, the heterogeneity and functional dynamics of VSMCs in atherosclerotic lesions have not been systematically elucidated. In this study, we integrated single-cell transcriptomics with spatial transcriptomics analysis to delineate the developmental trajectories and functional states of VSMC subsets. Our analysis identified a distinct LUM + VSMCs subpopulation residing at an early stage of differentiation, marked by elevated cellular plasticity, stemness features, and strong activation of pro-inflammatory signaling pathways. Spatial transcriptomics and in vitro functional assays—including EdU incorporation, apoptosis quantification, and cell viability assays—further validated LUM as a key regulator promoting VSMC proliferation and inflammation. Importantly, the C0 LUM + VSMCs were predicted to interact extensively with endothelial cells and macrophages through CD99, MIF, and CCL-mediated signaling axes, underscoring their role as dedifferentiated, pro-inflammatory effector cells contributing to disease progression. These findings highlight the power of big data-enabled single-cell approaches in identifying cell-type–specific mechanisms and offer new avenues for precision diagnostics and biomarker discovery in inflammatory vascular diseases.
Clinical characteristics and therapies of multi-organ immune related adverse events.
Wang D, Zhou Y, Li H … +12 more , Xin Y, Yuan M, Mu W, Qu X, Liu Y, Shen L, Liu Y, Wang X, Xiao Y, Song Y, Yu K, Wang C
Clin Exp Med · 2026 Feb · PMID 41731215 · Full text
Immune checkpoint inhibitors (ICIs) activate the immune system by blocking PD-1, CTLA-4, and PD-L1, thereby inducing autoimmune-mediated adverse reactions known as immune-related adverse events (irAEs). When two or more...
Immune checkpoint inhibitors (ICIs) activate the immune system by blocking PD-1, CTLA-4, and PD-L1, thereby inducing autoimmune-mediated adverse reactions known as immune-related adverse events (irAEs). When two or more organs are involved, this condition is defined as multi-organ immune-related adverse events (multi-organ irAEs). Patients with multi-organ irAEs account for approximately 20%-30% of all irAE cases; however, clinical research focusing on this subset remains limited. The purpose of this study is to analyze the clinical characteristics, optimal therapeutic approaches, and mortality-related risk factors of multi-organ irAEs. We searched all case reports of irAEs associated with ICIs in the PubMed, Web of Science, Cochrane Library, and Embase databases from their inception to January 2022. Search terms included "Immune Checkpoint Inhibitors", "Checkpoint Inhibitors, Immune", "Immune Checkpoint Blockers", "PD-L1", "CTLA-4 Inhibitor", "PD-1", and "Case report". After removing duplicate literature and applying strict inclusion/exclusion criteria, a total of 2,740 articles were included, encompassing 2,964 patients (782 with multi-organ irAEs and 2,182 with single-organ irAEs). Patients were stratified by the number of affected organs to compare clinical characteristics between multi-organ and single-organ irAE groups. For patients with multi-organ irAEs, subgroup analyzes were performed based on glucocorticoid dosage to identify optimal treatment strategies, and further stratified by survival status to explore potential mortality risk factors. No statistically significant differences in age or sex were observed between patients with multi-organ irAEs and those with single-organ irAEs (P > 0.05). However, the multi-organ irAE group exhibited significantly higher proportions of cardiovascular toxicity, thyroid toxicity, skin toxicity, and severe adverse reactions (P < 0.05), as well as a significantly elevated mortality rate (P < 0.05). Among patients with severe multi-organ irAEs, there were no significant differences in sex or age between high-dose and low-dose glucocorticoid subgroups (P > 0.05); notably, the high-dose glucocorticoid group had a significantly higher mortality rate (P < 0.05). For patients with non-severe multi-organ irAEs, no statistically significant differences in sex, age, mortality, or prognosis were detected between high-dose and low-dose glucocorticoid groups (P > 0.05). Multivariate logistic regression analysis revealed that cardiovascular toxicity, pulmonary toxicity, hepatotoxicity, and myositis were positively correlated with mortality in patients with multi-organ irAEs (OR > 1, P < 0.05). The most common organ combinations in multi-organ irAEs are "cardiac + neurological, cardiac + pulmonary, thyroid + pituitary, cardiac + hepatic, and gastrointestinal + skin". Multi-organ irAEs are generally more severe and associated with poorer outcomes compared to single-organ irAEs. High-dose glucocorticoids did not demonstrate superior prognostic outcomes and may be associated with an increased mortality risk in severe irAEs.clinical decisions regarding glucocorticoid dosing should be individualized based on the severity of irAEs and the specific organs involved.Cardiovascular toxicity, pulmonary toxicity, hepatotoxicity, and myositis are potential mortality risk factors for multi-organ irAEs induced by ICIs.
β-Hydroxybutyrate, a primary metabolite of ketogenic diets and its dual role in modulating colorectal cancer: from molecular mechanisms to therapeutic insights.
Rashidi P, Bagheri Z, Khodayar Z … +12 more , Tarkashvand S, Elahirad N, Akhoondi R, Moghaddam SH, Sanati M, Haghighatjou R, Yekani R, Mehboodi M, Banimahdidehkordi A, Rabiei S, Dinvari H, Maleki MH
Clin Exp Med · 2026 Feb · PMID 41731205 · Full text
Colorectal cancer (CRC) is a genetically varied malignancy noted for its metabolic flexibility, which enables cancer cells to adapt to different energy sources. Beta-hydroxybutyrate (BHB), a significant ketone body that...
Colorectal cancer (CRC) is a genetically varied malignancy noted for its metabolic flexibility, which enables cancer cells to adapt to different energy sources. Beta-hydroxybutyrate (BHB), a significant ketone body that is elevated during ketogenic diets, has attracted considerable attention for its potential therapeutic benefits. However, recent evidence indicates that BHB may paradoxically facilitate the advancement of CRC by acting as an alternative energy source, especially in cancer cells with mutations in critical genes such as APC, KRAS, and TP53. This review investigates the mechanisms through which CRC cells utilize BHB for their survival, focusing on enhanced metabolic plasticity, resistance to apoptosis, and modified responses to chemotherapy and immunotherapy. It also explores the interaction between BHB and the tumor microenvironment (TME), emphasizing how BHB can influence immune responses and tumor progression. Given the complexity of BHB’s role in CRC, the review underscores the necessity for personalized approaches that consider the tumor’s genetic and metabolic characteristics. Understanding the dual role of BHB in CRC is essential for devising more effective therapeutic strategies that can either harness or counteract its effects, thereby guiding the application of ketogenic diets and other metabolic interventions in the treatment of CRC.
NK cell-associated LncRNA signature predicts prognosis and immune landscape in hepatocellular carcinoma.
Li X, Li J, Li Y … +5 more , Fan Y, Tan W, Shi F, Zhu Y, Gong C
Clin Exp Med · 2026 Feb · PMID 41731179 · Full text
The purpose of this investigation was to develop and validate a risk model based on natural killer (NK) cell-associated lncRNAs to predict outcomes in individuals with hepatocellular carcinoma (HCC). To further explore t...
The purpose of this investigation was to develop and validate a risk model based on natural killer (NK) cell-associated lncRNAs to predict outcomes in individuals with hepatocellular carcinoma (HCC). To further explore the role of NK cells in the HCC tumor microenvironment, we leveraged single-cell RNA sequencing data and the TCGA-LIHC dataset to identify NK cell-associated lncRNAs. Using Cox regression and LASSO techniques, we pinpointed four key lncRNAs as prognostic markers for the model. The model demonstrated robust predictive power across the training set, validation set, and entire dataset. Additionally, we identified a synergistic interaction between NK cells and other immune cells, particularly CD8 + T cells, in HCC. Moreover, we uncovered novel molecular subgroups of HCC and their associations with the immune microenvironment and drug sensitivity. To further validate these findings, we performed experimental validation of the expression and function of the model lncRNAs in HCC. These results suggest that the NK cell-associated lncRNA model not only serves as an effective prognostic tool for HCC patient outcomes but also offers potential molecular targets for immunotherapy and targeted therapies.
Long noncoding RNA SRRM2-AS1 mediates coronary artery damage in Kawasaki disease by promoting endothelial-to-mesenchymal transition.
Song S, Zhang H, Lin R … +14 more , Zhang J, Zhang Q, Li C, Xia Y, Zeng J, Lu K, Ge D, Qiu H, Niu C, Jia C, Zhang C, He Y, Chu M, Rong X
Clin Exp Med · 2026 Feb · PMID 41731159 · Full text
Kawasaki disease (KD) is the leading cause of acquired heart disease in children, though its etiology and underlying mechanisms remain elusive. Emerging evidence indicates that long noncoding RNAs (lncRNAs) regulate endo...
Kawasaki disease (KD) is the leading cause of acquired heart disease in children, though its etiology and underlying mechanisms remain elusive. Emerging evidence indicates that long noncoding RNAs (lncRNAs) regulate endothelial-to-mesenchymal transition (EndMT), a cellular process implicated in vascular pathology. However, the specific involvement of lncRNAs in KD-associated coronary artery damage via EndMT remains undefined. Here, we show that the lncRNA SRRM2-AS1 is markedly elevated in the serum of children with KD and is internalized by coronary artery endothelial cells. Overexpression of SRRM2-AS1 in human coronary artery endothelial cells (HCAECs) increased cell migration and induced EndMT, as confirmed by elevated mesenchymal marker expression and morphological changes. Mechanistically, bioinformatics analysis, dual-luciferase reporter assays, and gene expression profiling revealed SRRM2 as a direct target of SRRM2-AS1. Our findings suggest that SRRM2 promotes EndMT through ubiquitin C (UBC) and the PI3K/Akt/GSK-3β/β-catenin signaling pathway. In a mouse model of KD, recombinant AAV9-mediated SRRM2-AS1 overexpression intensified coronary artery inflammation and increased vimentin expression, further supporting its role in EndMT. Collectively, these results demonstrate that SRRM2-AS1 drives EndMT in KD via the SRRM2/UBC/PI3K/Akt/GSK-3β/β-catenin axis, thereby contributing to coronary artery damage. Consequently, SRRM2-AS1 emerges as a promising therapeutic target for KD-associated vasculopathy, offering potential avenues to mitigate cardiovascular complications in affected children.
The clinical benefit of adding anlotinib to chemoradiothearpy in high-grade gliomas: a systematic review, meta-analysis, and specific analysis on glioblastoma.
Habibi MA, Hojjat SH, Hajikarimloo B … +9 more , Dashti M, Ghasemzadeh A, Tajvidi M, Bahri A, Shahir Eftekhar M, Safari Dehnavi N, Kamroo A, Mohammadzadeh I, Shafizadeh M
Clin Exp Med · 2026 Feb · PMID 41729324 · Full text
Anlotinib, a novel multi-target tyrosine kinase inhibitor, has shown promise in improving survival and managing associated complications. This systematic review and meta-analysis aimed to evaluate the efficacy and safety...
Anlotinib, a novel multi-target tyrosine kinase inhibitor, has shown promise in improving survival and managing associated complications. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of Anlotinib in patients with high-grade glioma, specifically glioblastoma (GBM). This study was conducted according to the PRISMA guidelines. A systematic search was conducted on PubMed, Embase, Web of Science, and Scopus up to 9 December 2024. The included studies were appraised and assessed for quality and potential bias and further statistical analyses were performed using STATA v.17. A total of 17 studies with 473 patients were recruited, which included 204 patients with GBM. The pooled analysis resulted in a 6-month OS of 67% (95% CI: 42-92%) and a 1-year OS equal to 50% (95% CI: 36-64%) from the Anlotinib treatment. Progression-free survival at 6 months was 61% (95% CI: 46-75%), and at 1 year was 27% (95% CI: 13-41%), also showing similar promising outcomes. The overall response rate (ORR) and disease control rate (DCR) were reported at 55% (95% CI: 44-67%) and 90% (95% CI: 87-94%), respectively. The sub-group analysis revealed that adding anlotinb to temozolomide (TMZ) and radiotherapy had superior outcomes regarding OS, PFS, and DCR. Moreover, the highest ORR and complete response rate were achieved by Anlotinib plus stereotactic radiosurgery. Anlotinib demonstrates considerable efficacy in extending survival and achieving disease control in high-grade glioma patients when added to radiotherapy and TMZ. These findings can support its inclusion in therapeutic regimens, warranting further investigation in large-scale randomized controlled trials.
Analysis of cancer stem cell mechanism and immune profiling in breast cancer of unknown primary.
Ren M, Chen C, Hu Z … +3 more , Yang Y, Wei P, Zhou X
Clin Exp Med · 2026 Feb · PMID 41729320 · Full text
Cancer of unknown primary (CUP) encompasses a highly heterogeneous group of cancers with limited therapeutic options and a dismal prognosis. To date, the pathogenesis and immune profiling of CUP have not been fully chara...
Cancer of unknown primary (CUP) encompasses a highly heterogeneous group of cancers with limited therapeutic options and a dismal prognosis. To date, the pathogenesis and immune profiling of CUP have not been fully characterized which could provide more therapeutic targets.Samples of thirteen breast CUPs and five known metastatic breast cancers were subjected to gene expression analysis. The identified cancer stem cell (CSC) phenotype induced by the overexpression of T-cell leukemia/lymphoma-1 A (TCL1A) was validated via cytological experiments.Compared with known metastatic breast cancers, breast CUPs presented various genetic abnormalities mainly involving pluripotency in stem cells and upregulation of immune-related signaling pathways. CUPs also had significantly greater immune cell infiltration and tumor inflammation signature scores, accompanied by a higher trend of PD-L1 expression and tumor-infiltrating lymphocytes. TCL1A, a gene associated with stem cell-like features, was more highly expressed in various types of CUP than in metastases with known primary sites. In triple-negative breast cancer cell lines, overexpression of TCL1A promoted cell proliferation, invasion, and sphere formation and inhibited apoptosis; it also markedly upregulated CSC and epithelial-mesenchymal transition marker expression. Analysis of the downstream signaling pathways affected by TCL1A revealed notable enrichment of the AKT pathway.Breast CUP is characterized by complex genomic alterations and an inflamed immune microenvironment. The significant overexpression of TCL1A and the enrichment of CSC signatures suggest that the TCL1A-AKT axis may serve as a potential therapeutic target, highlighting the CSC phenotype as a critical biological mechanism in the tumorigenesis and progression of CUP.
Early detection and risk stratification of insulin resistance in children and adolescents with excess weight: a sdLDL/oxLDL-Based model.
Zhao Y, Zhu Z, Hu W … +1 more , Li J
Clin Exp Med · 2026 Feb · PMID 41729314 · Full text
Childhood excess weight is a significant risk factor for insulin resistance (IR), a key precursor to metabolic syndrome and type 2 diabetes. In epidemiologic studies, IR is commonly assessed by the homeostatic model asse...
Childhood excess weight is a significant risk factor for insulin resistance (IR), a key precursor to metabolic syndrome and type 2 diabetes. In epidemiologic studies, IR is commonly assessed by the homeostatic model assessment for insulin resistance (HOMA-IR). This study aimed to develop a small dense low-density lipoprotein (sdLDL) and oxidized low-density lipoprotein (oxLDL)-based model for the early detection and risk stratification of HOMA-IR-defined IR in children and adolescents with excess weight. A total of 510 children and adolescents with excess weight (aged 7-17 years) were enrolled and stratified into IR (n = 173) and non-IR (n = 337) groups according to HOMA-IR. Comprehensive anthropometric and biochemical parameters were collected, including comparative analyses of sdLDL, oxLDL, and triglyceride to high-density lipoprotein cholesterol (TG/HDL) ratio. Independent risk factors were identified through univariate and multivariate logistic regression, followed by development of a nomogram prediction model incorporating three lipid parameters and adjusted for age and sex. Model performance was evaluated using receiver operating characteristic curves, calibration analysis with bootstrap internal validation and decision curve analysis (DCA). Univariate analysis identified significant associations between IR and mean arterial pressure, TG/HDL, total cholesterol to HDL (TC/HDL) ratio, LDL to HDL (LDL/HDL) ratio, oxLDL, and sdLDL (all P < 0.05). Multivariate analysis confirmed TG/HDL (adjusted odds ratio [aOR] = 5.61, 95% confidence interval [CI]: 3.060-10.639, P < 0.001), oxLDL (aOR = 1.092, 95% CI: 1.065-1.120, P < 0.001), and sdLDL (aOR = 1.109, 95% CI: 1.076-1.146, P < 0.001) as independent risk factors. The final age- and sex-adjusted nomogram demonstrated strong discrimination (AUC = 0.836), good calibration (bootstrap-corrected mean absolute error = 0.012), and clear net clinical benefit across a wide range of decision thresholds based on DCA. Probability-based stratification enabled both continuous scoring and visual classification of individual IR risk. The developed age- and sex-adjusted nomogram combining TG/HDL ratio, sdLDL, and oxLDL demonstrates superior performance for predicting IR in children and adolescents with excess weight. By integrating continuous risk scoring with clinically actionable risk stratification, this tool supports early identification and tiered management in both screening and clinical decision-making settings.
Safety profile of FLT3 inhibitors in acute myeloid leukemia: a systematic review and meta-analysis of adverse events.
Gaio M, Zinzi A, Liguori V … +5 more , Cagnotta C, Frasca M, Laino LV, Rossi F, Capuano A
Clin Exp Med · 2026 Feb · PMID 41729312 · Full text
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Approximately 30% of patients present alterations in the FMS-like receptor tyrosine kinase 3 (FLT3) gene, which are associated with poor prognosis...
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Approximately 30% of patients present alterations in the FMS-like receptor tyrosine kinase 3 (FLT3) gene, which are associated with poor prognosis. FLT3 inhibitors - midostaurin (first-generation), gilteritinib and quizartinib (second-generation) - have been developed to block FLT3 activation. Given the need of optimizing treatment in FLT3-mutated AML, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the safety profiles of FLT3 inhibitors. Following the PRISMA statement, we searched Embase, MEDLINE and Cochrane Library. The Cochrane Risk of Bias Tool for RCTs was used for quality assessment. Of 2132 references, seven RCTs, involving 2409 adult patients, met inclusion criteria: quizartinib and midostaurin in two trials each and gilteritinib in three. The most frequently reported adverse events (AEs) were classified under the System Organ Class (SOC) Blood and lymphatic system disorders (N = 5474, 58.4% of them related to FLT3 inhibitors). The most frequently observed non-hematological AEs were gastrointestinal disorders, pyrexia, elevated ALT/AST and headache. FLT3 inhibitors are not associated with a significant increase in the risk of AEs compared to standard treatments. No meaningful differences in AE risk were observed among the three drugs. The only exception was an higher risk of ALT increased with gilteritinib (RR = 2.40, 95% CI: 1.16-4.95). Future studies should stratify safety outcomes by demographic and clinical characteristics and incorporate long-term follow-up for a more comprehensive safety assessment in clinical practice.
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