Examining how hypoglycemic medications affect brain function is one of the best approaches to addressing cognitive impairment. In this study, trelagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, w Show more
Examining how hypoglycemic medications affect brain function is one of the best approaches to addressing cognitive impairment. In this study, trelagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, was utilized to assess memory loss in diabetic rats through fear conditioning tests. Trelagliptin restored fear memory in diabetic rats that had been disrupted over a relatively long period (24 h) or extended period (5 days). Moreover, trelagliptin treatment reduced the higher incidence of neuronal cell death in the cerebral cortex, as observed via Nissl or hematoxylin and eosin staining. Subsequent analyses revealed that diabetic rats exhibited elevated levels of inflammatory cytokines (p-IKKα and p-NFκB) and a trend toward oxidative damage, indicated by malondialdehyde (MDA), superoxide dismutase 2 (SOD2), and glutathione peroxidase 4 (GPX4) detection. However, administration of trelagliptin reversed these markers to baseline levels. Additionally, trelagliptin activated p-AMPK, p-AKT, and p-GSK-3β. Notably, trelagliptin upregulated the expression of postsynaptic density protein 95 (PSD95) and synaptotagmin 1 (SYT1) while downregulating amyloid precursor protein (APP) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). These findings suggest that trelagliptin alleviates cognitive impairment in diabetic rats, likely through AMPK-AKT-GSK-3β-mediated mitigation of oxidative stress, enhancement of synaptic plasticity, and reduction of Aβ accumulation. Show less
Biochemical items play a significant role in clinical decision-making, so this study aims to evaluate the performance of different biochemical platforms. We collected 1,524 serum samples that were cen Show more
Biochemical items play a significant role in clinical decision-making, so this study aims to evaluate the performance of different biochemical platforms. We collected 1,524 serum samples that were centrifuged, and plasma was analyzed for HDL-C, LDL-C, Apo A1, Apo B, PA, and Fs-CRP with the Mindray BS2000M and Roche Cobas 8000 platforms. The results were evaluated by a non-parametric two-related sample test, Passing-Bablok regression analysis, Weighted Least Square analysis (WLS), and Bland-Altman analysis according to CLSI EP09-A3, EP5-A2, and EP15-A3. Between the two systems, there were statistically significant differences in the average bias of LDL-C, Apo A1, Apo B, PA, and Fs-CRP ( These findings suggest that the two platforms have good correlation and consistency in high-concentration medical decision levels in HDL-C, LDL-C, Apo A1, Apo B, and Fs-CRP, and all levels of PA in the two platforms are interchangeable and can replace each other. Show less
Jia Min Chen, Yan Wang, Yan Shi · 2025 · Clinical, cosmetic and investigational dermatology · added 2026-04-24
Omega-3 polyunsaturated fatty acids (PUFAs) are potential targets for the treatment of skin diseases due to their anti-inflammatory and immunomodulatory effects. By leveraging a genetic approach known Show more
Omega-3 polyunsaturated fatty acids (PUFAs) are potential targets for the treatment of skin diseases due to their anti-inflammatory and immunomodulatory effects. By leveraging a genetic approach known as Mendelian randomization (MR), we sought to determine the causal impact of PUFAs on the likelihood of developing skin diseases among individuals of European ancestry. We integrated GWAS data from the CHARGE consortium and UK Biobank to identify genetic instruments for omega-3 PUFAs and desaturase activity, using two-sample MR to assess their associations with six skin diseases. Elevated levels of omega-3 fatty acids were found to substantially lower the probability of experiencing atopic dermatitis (0.92, [0.85,0.98]), while increased DPA levels correlated with a substantial increase in the probability of squamous cell carcinoma occurrence (2.25, [1.29,3.92]). Increased DHA levels were also associated with a reduced risk of atopic dermatitis (0.90, [0.84,0.96]) but increased the risk of solar dermatitis (1.38, [1.09,1.73]). In addition, tissue-type specific MR analysis revealed that elevated FADS1 expression in fibroblasts significantly inhibited atopic dermatitis development (β = -0.181, [-0.276,-0.0853]), while elevated FADS2 expression in non-sun-exposed skin tissues was associated with a reduced risk of squamous cell carcinoma (β = -0.562, [-0.833,-0.029]). Conversely, heightened FADS2 expression was strongly linked to a greater likelihood of developing atopic dermatitis in both sun-exposed and sun-protected skin areas (β = 0.107, [0.0348,0.179]; β = 0.192, [0.114,0.0270], respectively). This study reveals the causal role of omega-3 PUFAs and FADS expression in specific tissues and blood in skin diseases. These findings underscore the potential of PUFA biosynthesis pathways as therapeutic targets for skin disease interventions. Show less
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANG Show more
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANGPTL4 levels are observed in diabetic and obese individuals. However, the potential link between ANGPTL4 and diabetes- or obesity-related complications remains uncertain. This study aimed to explore whether plasma ANGPTL4 level could serve as a predictor of cancer mortality, cardiovascular mortality, and all-cause mortality in a community-based cohort. A community-based cohort study was conducted, where fasting plasma ANGPTL4 concentrations were measured at baseline, and vital status was ascertained through linkage with the National Health Insurance Research Database in Taiwan. During a 10.46-year follow-up period, 29 (2.49%) of the 1163 participants died. Subjects within the highest tertile of plasma ANGPTL4 levels exhibited the lowest survival rate. In unadjusted models, plasma ANGPTL4 significantly predicted all-cause mortality, cancer mortality, and cardiovascular or cancer-related mortality. Upon adjustment for confounders including age, sex, smoking, body mass index (BMI), hypertension, diabetes mellitus (DM), and renal function, each standard deviation increase in plasma ANGPTL4 was associated with HRs of 1.35 (95% CI: 1.01-1.80, Plasma ANGPTL4 emerges as a promising biomarker capable of predicting 10-year mortality and enhancing risk prediction beyond established risk factors. Show less
Ambient fine particulate matter (PM2.5) has emerged as a critical environmental threat to ocular health; however, the underlying molecular mechanisms affecting the retinal pigment epithelium (RPE) rem Show more
Ambient fine particulate matter (PM2.5) has emerged as a critical environmental threat to ocular health; however, the underlying molecular mechanisms affecting the retinal pigment epithelium (RPE) remain largely uncharacterized. This study aimed to investigate transcriptomic alterations in RPE cells following PM2.5 exposure and to identify key regulatory pathways involved. Next-generation sequencing (NGS) was used to investigate differential gene expression in ARPE-19 cells upon PM2.5 exposure. Bioinformatic analyses, including pathway enrichment and gene set enrichment analysis (GSEA), were performed to identify affected signaling cascades. Functional assays-including cell viability, wound healing, and Transwell migration-were conducted to evaluate phenotypic changes. Quantitative RT-PCR (Reverse Transcription Polymerase Chain Reaction) and ELISA (Enzyme-Linked Immunosorbent Assay) validated gene expression and transforming growth factor-beta (TGF-β) secretion. TGF-β stimulation and receptor inhibition were applied to dissect pathway involvement. Comprehensive analysis revealed substantial changes in gene expression profiles, with pathway enrichment highlighting the activation of cell migration-related pathways such as focal adhesion, regulation of actin cytoskeleton, extracellular matrix (ECM)-receptor interaction, tight junction, and adherens junction. Notably, the TGF-β, MAPK (Mitogen-Activated Protein Kinase), and PI3K/AKT (Phosphoinositide 3-Kinase / Protein Kinase B) pathways were significantly modulated. Functional assays showed that PM2.5 exposure enhanced ARPE-19 cell viability and migratory capacity. Among the differentially expressed genes, angiopoietin-like 4 (ANGPTL4) was markedly upregulated following PM2.5 stimulation. Pharmacological inhibition of TGF-β signaling abrogated PM2.5-induced ANGPTL4 expression, suggesting a pivotal role of the TGF-β pathway in mediating these effects. These findings demonstrate that PM2.5 induces transcriptomic reprogramming and activates the TGF-β signaling cascade in RPE cells, thereby enhancing cellular migration. Specifically, ANGPTL4 was identified as a key downstream effector of this pathway. This study provides novel insights into the molecular mechanisms by which air pollution contributes to retinal disease pathogenesis and suggests potential therapeutic targets for preventing PM2.5-induced retinal injury. Show less
Early identification of individuals with low advance care planning (ACP) engagement remains a critical component of clinical care. However, we know little about the heterogeneity of ACP engagement at Show more
Early identification of individuals with low advance care planning (ACP) engagement remains a critical component of clinical care. However, we know little about the heterogeneity of ACP engagement at the individual level. This study identified latent subgroups of ACP engagement using latent profile analysis (LPA), and explored their associations with death attitudes. This study recruited 302 end-stage renal disease (ESRD) patients undergoing dialysis. Data included sociodemographic characteristics, the Advance Care Planning Engagement Survey (ACPES; Chinese version), and the Death Attitude Profile-Revised (DAP-R). Based on multidimensional indicators, LPA was employed to identify distinct ACP engagement profiles. Model fit and classification quality in LPA were evaluated based on class sizes and entropy values. All analyses were completed in SPSS 26.0 and Mplus 8.3, with R3STEP and BCH methods employed to uncover underlying patterns and relationships. Among dialysis-dependent ESRD patients, ACP engagement was categorized into two latent profiles: a "low-ACP Engagement" profile (n = 162, 53.6%) and a "high-ACP Engagement" profile (n = 140, 46.4%), with good classification quality (entropy = 0.909). The profile membership was significantly associated with dialysis vintage, and educational level (both This study identifies two distinct ACP engagement profiles among dialysis-dependent ESRD patients. Findings emphasize the need for tailored interventions, particularly for patients with shorter dialysis vintage and lower education level, and highlight the role of death attitudes in shaping ACP engagement. These findings should be interpreted with caution due to the cross-sectional design and single-center setting. Show less
Stroke is a leading cause of mortality and disability globally, with post-stroke depression and post-stroke anxiety being common and significant complications that hinder recovery and adversely affect Show more
Stroke is a leading cause of mortality and disability globally, with post-stroke depression and post-stroke anxiety being common and significant complications that hinder recovery and adversely affect quality of life. Although these conditions frequently co-occur, their heterogeneity remains poorly understood. This study integrates the Health Ecology Model (HEM) and employs Latent Profile Analysis (LPA) to identify distinct psychological profiles of depression and anxiety among patients with acute ischemic stroke (AIS), as well as to investigate their multilevel determinants. Patients with AIS from a tertiary hospital in Guangdong Province, China, from January to November 2024 were included. Within one week of stroke onset, the data of sociodemographic, clinical characteristics, swallowing function, stroke severity, activities of daily living, resilience and social support were collected according to the HEM guidelines. The Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7 were used to assess the depression and anxiety symptoms of the patients three months after stroke onset. LPA was employed to identify distinct psychological profiles, and variables with a A total of 551 patients with AIS were included in the study, 49 were lost to follow-up or withdrew, resulting in a final analytic sample of 502 participants (91.11%). Three distinct psychological profiles were identified: no depression-anxiety (67.93%), high-risk depression-anxiety (21.12%) and major depression-anxiety (10.95%). In the multivariate analysis, the results indicated that occupation (OR = 0.61, 95% CI [0.40-0.93]), National Institutes of Health Stroke Scale (NIHSS, OR = 1.60, 95% CI [1.06-2.42]), Barthel Index (BI, OR = 1.67, 95% CI [1.27-2.19]) and hypertension (OR = 2.37, 95% CI [1.29-4.35]) were independent predictors of the high-risk depression-anxiety profile, while NIHSS (OR = 2.33, 95% CI [1.42-3.85]), BI (OR = 2.65, 95% CI [1.62-4.35]) and resilience (OR = 0.92, 95% CI [0.87-0.98]) were significantly associated with the major depression-anxiety profile. This study reveals significant heterogeneity in psychological distress among AIS survivors. Key predictors of post-stroke emotional comorbidity include occupation, hypertension, stroke severity, activities of daily living and low resilience. Early identification of high-risk individuals can significantly enhance screening and intervention strategies, particularly by focusing on symptoms such as anhedonia and nervousness. Future research should focus on longitudinal designs and objective biomarkers to better understand the mechanisms behind post-stroke emotional comorbidity. Show less
Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute Show more
Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute lung injury (ALI) and their relationship to injury remain unclear. Transcriptomic and lipidomic analyses revealed downregulation of PUFA synthesis pathways, particularly omega-3 PUFAs, in pulmonary ECs during LPS-induced ALI. Activation of the PUFA metabolic pathway, through FADS1/2 overexpression or omega-3 fatty acid supplementation, protected ECs from ferroptosis and restored barrier function. In vivo, pulmonary EC-specific overexpression of FADS1/2 contributed to the alleviation of ALI. Overexpression of whole lung FADS1/2, combined with alpha-linolenic acid (ALA) supplementation, also significantly mitigated ALI. PARK7 is identified as an endogenous regulator of FADS1/2, acting through the BMP-BMPR-SMAD1/5/9 signaling. Driven by histone H3K14 lactylation, which is also promoted by the downregulation of FADS1/2, PARK7 upregulation restored FADS1/2 expression and counteracted ferroptosis, thereby forming a protective feedback loop. This study elucidates a novel regulatory axis involving the two major metabolic changes-downregulation of PUFA synthesis and upregulation of histone lactylation-in ALI pathogenesis, which are interconnected through the PARK7-BMP signaling pathway. Targeting this axis offers potential therapeutic strategies for mitigating endothelial dysfunction and ferroptosis in ARDS/ALI. Show less
Background Myeloid/lymphoid neoplasm with eosinophilia and rearrangement of FGFR1(MLN-FGFR1), also referred to as 8p11 myeloproliferative syndrome (EMS), arises from aberrant FGFR1 gene rearrangement Show more
Background Myeloid/lymphoid neoplasm with eosinophilia and rearrangement of FGFR1(MLN-FGFR1), also referred to as 8p11 myeloproliferative syndrome (EMS), arises from aberrant FGFR1 gene rearrangement in bone marrow hematopoietic stem cells, resulting in the transformation of myeloid/lymphoid cells into neoplastic growths. The clinical and laboratory features of affected individuals are influenced by the specific partner genes. Purpose This article aims to report a case of MLN-FGFR1 involving a novel CNTRL::FGFR1 splicing variant and to discuss its clinicopathological characteristics and treatment challenges. Methods/Results We report a case of MLN-FGFR1 in a 35-year-old male patient presenting with leukocytosis, lymphadenopathy, hepatosplenomegaly, and a mixed population of B lymphoblasts, T lymphoblasts, and monoblasts in the bone marrow and lymph nodes. Comprehensive molecular profiling, including chromosomal karyotyping, fluorescence in situ hybridization (FISH), targeted transcriptome sequencing, reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing, identified a novel splicing variant of the CNTRL::FGFR1 fusion, resulting from a t(8;9)(p11;q33) translocation. This novel splicing variant involves an in-frame fusion between exon 38 of CNTRL and exon 11 of FGFR1, retaining the kinase domain of FGFR1 and leading to its constitutive activation. Despite multiple treatment regimens, the patient failed to achieve complete remission (CR). Conclusion The findings highlight the urgent need for targeted therapies, such as FGFR inhibitors, to improve outcomes in patients with FGFR1-rearranged malignancies. Show less
Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CA Show more
Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CAFs) contribute to immunosuppression in osteosarcoma are not fully understood. We performed single-cell RNA sequencing (scRNA-seq) on osteosarcoma tissues from patients treated with neoadjuvant chemotherapy and anti-PD-1 therapy to investigate the tumor microenvironment. Cellular composition, gene expression programs, and signaling pathways were analyzed. Functional assays, pull-down and PLA-flow binding validation, and in vivo mouse models were used to dissect the mechanisms by which CAF-derived factors influence CD8⁺ T cell function and contribute to immunotherapy response. We identified a subpopulation of CD36⁺ CAFs, characterized by adaptive uptake of oxidized low-density lipoprotein (OxLDL) and activation of the PPARG-FABP4 axis. This metabolic program promoted ANGPTL4 secretion, which bound integrin on CD8⁺ T cells and activated the JAK2-STAT3 pathway, leading to T cell exhaustion and impaired effector function. In vivo, administration of VitE effectively scavenged OxLDL, reprogrammed the TME, enhanced CD8⁺ T cell infiltration, and synergized with PD-1 blockade to improve tumor control. CD36⁺ CAFs drive immunosuppressive metabolic reprogramming via the OxLDL-PPARG-ANGPTL4 axis, promoting CD8⁺ T cell exhaustion and resistance to immunotherapy in osteosarcoma. Targeting this pathway with VitE alleviated CAF-mediated immune suppression and enhanced PD-1 blockade responses in preclinical models, providing a rationale for metabolism-based combinatorial strategies in osteosarcoma. Show less
Evidence of the benefits of cordycepin (Cpn) for treating obesity is accumulating, but detailed knowledge of its therapeutic targets and mechanisms remains limited. This study aimed to systematically Show more
Evidence of the benefits of cordycepin (Cpn) for treating obesity is accumulating, but detailed knowledge of its therapeutic targets and mechanisms remains limited. This study aimed to systematically identify Cpn's therapeutic targets and pathways in Western diet (WD)-induced obesity using integrated network pharmacology, transcriptomics, and experimental validation. A Western diet (WD)-induced mice model was used to evaluate the effectiveness of Cpn in ameliorating obesity. A network pharmacology analysis was then employed to identify the potential anti-obesity targets of Cpn. GO functional enrichment and KEGG pathway analysis were performed to elucidate the potential functions of the identified targets, followed by constructing a protein-protein interaction network to screen the core targets. Meanwhile, quantitative transcriptomics was conducted to validate and broaden the network pharmacology findings. Finally, molecular docking and quantitative real-time PCR assay were used for the core target validation. Cpn treatment effectively alleviated obesity-related symptoms in WD-induced mice. The metabolic pathway, insulin signaling pathway, HIF-1 signaling pathway, FoxO signaling pathway, lipid and atherosclerosis pathway, and core targets including CPS1, HRAS, MAPK14, PAH, ALDOB, AKT1, GSK3B, HSP90AA1, BHMT2, EGFR, CASP3, MAT1A, APOM, APOA2, APOC3, and APOA1 are involved in regulating the therapeutic effect of Cpn. This study comprehensively uncovers the potential mechanism of Cpn against obesity based on network pharmacology and quantitative transcriptomics, which provides evidence for revealing the pathogenesis of obesity, suggesting that Cpn is a possible lead compound for anti-obesity treatment. Show less
Inflammation is a complex factor in the pathogenesis of intracranial aneurysms (IA), but its specific cellular inflammatory factors remain uncertain. We collected two cohorts and measured the represen Show more
Inflammation is a complex factor in the pathogenesis of intracranial aneurysms (IA), but its specific cellular inflammatory factors remain uncertain. We collected two cohorts and measured the representation of vascular inflammation-related proteins using the Olink CVD II Vascular Inflammation Panel. We subsequently validated our findings using ELISA and RT-qPCR. Our proteomic analysis identified 11 vascular inflammation-related markers that were significantly differentially represented between the IA and control groups. These markers were implicated in leukocyte migration, immune response, triglyceride and lipoprotein metabolism, acute phase response, T cell regulation, and several key biological pathways, including PPAR, HIF-1, cytokine-cytokine interactions, and PI3K-AKT signaling. Further validation with ELISA and RT-qPCR confirmed the differential representation of IL6, PTX3, LPL, and OLR1 between the two groups. Notably, a combination marker incorporating these four factors demonstrated high diagnostic potential for the early detection of IA. Our study has identified a set of informative biomarkers (IL6, PTX3, LPL, and OLR1) that could be valuable for the early diagnosis of IA. Importantly, this is the first report of significantly elevated OLR1 representation in the plasma of IA patients. Further investigation into the role of OLR1 in the pathogenesis of IA is warranted. SIGNIFICANCE: This study significantly advances our understanding of the molecular mechanisms underlying intracranial aneurysm (IA) pathogenesis. By identifying a panel of novel biomarkers, including the previously unreported elevated expression of OLR1 in IA patients, we provide crucial insights into the inflammatory processes involved in aneurysm formation and development. These findings have important clinical implications, as the identified biomarkers could serve as valuable tools for early diagnosis and potentially targeted therapeutic interventions. Furthermore, the study highlights the complex interplay of inflammatory pathways in IA, suggesting that a multi-faceted approach may be necessary for effective management. Show less
Calcific aortic valve stenosis (CAVS) is steadily rising worldwide with no effective pharmacological agents available. Observational studies implicated dyslipidaemia as a risk factor for CAVS. Whether Show more
Calcific aortic valve stenosis (CAVS) is steadily rising worldwide with no effective pharmacological agents available. Observational studies implicated dyslipidaemia as a risk factor for CAVS. Whether dyslipidaemia is causative for CAVS and the therapeutic potential of different lipid-modifying drug targets for CAVS treatment remains unclear. We appraised the relationship of genetically-proxied lipid traits and 12 lipid-modifying drug targets with CAVS risk using Mendelian randomization (MR). Genetic variants associated with lipid traits and variants in genes encoding lipid-modifying drug targets were retrieved from GLGC. Summary-level data for CAVS were obtained from the TARGET consortium and FinnGen. Validation analyses were performed using genetic instruments retrieved from liver-derived gene expression and circulation plasma levels of targets. Colocalisation and mediation analyses were performed to evaluate the robustness of our findings and explore potential mediators (i.e., lipoprotein a (Lp(a)), body mass index, apolipoprotein B (ApoB)). The MR analyses supported that total cholesterol and LDL-cholesterol level were independent causal risk factors. The drug-target MR analysis suggested that genetic mimicry of PCSK9 inhibition should reduce CAVS risk (OR = 0.63, 95% CI = 0.56-0.70), which was corroborated by colocalisation analysis. Secondary analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.94 per SD reduction in PCSK9 expression, 95% CI = 0.88-1.00) and circulating plasma levels of PCSK9 (OR = 0.86 per SD reduction in PCSK9 protein, 95% CI = 0.83-0.88) on CAVS risk. ApoB and Lp(a) mediated 55.9% and 4.5%, respectively, of the total effect of PCSK9 on CAVS risk. Multiple sensitivity analyses supported this observation. Our study supports total cholesterol, LDL-cholesterol as a causal factor for CAVS, and genetically proxied inhibition of PCSK9 may reduced its risk. Show less
This study aimed to identify heterogeneous patterns of medical coping modes (MCM) and to examine the moderating role of social support in the relationship between these patterns and social disability Show more
This study aimed to identify heterogeneous patterns of medical coping modes (MCM) and to examine the moderating role of social support in the relationship between these patterns and social disability in young and middle-aged patients after percutaneous coronary intervention (PCI). A cross-sectional study was conducted among 129 post-PCI patients from a single center in China. Participants completed the Medical Coping Modes Questionnaire (MCMQ), the Social Support Rating Scale (SSRS), and the Social Disability Screening Schedule (SDSS). Latent profile analysis (LPA) was used to identify distinct coping patterns. The moderation effect of social support was tested using the Johnson-Neyman technique. Two distinct coping profiles were identified via LPA: "Adaptive Copers" (55.1%), characterized by higher confrontation and lower avoidance/resignation, and "Maladaptive Copers" (44.9%), showing the opposite pattern. A counterintuitive finding emerged, with the Maladaptive Copers reporting significantly lower social disability scores. Furthermore, beyond this profile differentiation, social support demonstrated a significant U-shaped moderating effect in the coping-disability relationship. Its moderating role was statistically significant only at very low (<39.884) and very high (>52.924) levels of support. This study reveals two key findings: first, post-PCI patients are heterogeneous in coping, comprising adaptive and maladaptive subgroups; second, the impact of these coping styles on social disability is non-linearly moderated by social support. Clinicians should assess both coping profiles and social support levels to tailor interventions effectively. Show less
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection te Show more
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure. Show less
Dysregulated fibroblast growth factor receptor (FGFR) signaling - driven by amplifications, mutations, or fusions - represents a clinically validated oncogenic driver across diverse malignancies. Pan- Show more
Dysregulated fibroblast growth factor receptor (FGFR) signaling - driven by amplifications, mutations, or fusions - represents a clinically validated oncogenic driver across diverse malignancies. Pan-FGFR-selective inhibitors (erdafitinib, pemigatinib, and futibatinib) have been developed in clinical practice. However, their therapeutic efficacy is substantially limited by inevitable on-target resistance mutations and toxicities via FGFR1/4 inhibition. Next-generation FGFR isoform-selective small-molecule inhibitors are emerging and represent active research frontiers. FGFR2-selective inhibitor lirafugratinib, FGFR3-selective inhibitors LOXO-435 and TYRA-300, FGFR2/3-selective inhibitor ABSK061, and FGFR4-selective inhibitors are in clinical development. Additionally, novel isoform-selective FGFR-targeting degraders, FGFR2b/FGFR3-selective antibodies, and de novo-designed 'c' isoform-selective proteins provide novel treatment strategies. This review provides an overview of the current FGFR-targeted therapeutics and limitations and evaluates next-generation inhibitor development to guide future research. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health issue due to its high prevalence, yet the impact of accelerometer-measured physical activity on clinical outcomes re Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health issue due to its high prevalence, yet the impact of accelerometer-measured physical activity on clinical outcomes remains unclear. This study aims to examine the associations of physical activity with the risk of liver cirrhosis, cancer, cardiovascular disease (CVD) incidence and mortality. 32 681 MASLD participants with accelerometer-derived physical activity data from the UK Biobank were analysed. Physical activity intensity was categorised into light (LPA), moderate (MPA) and vigorous (VPA) intensity. Cox proportional hazard and acceleration failure models were employed to assess associations between physical activity duration and outcomes. During a median follow-up of 7.5-7.9 years, 1883 deaths, 151 liver cirrhosis, 3312 cancers and 6657 CVD events were recorded. Physical activity, regardless of intensity, was consistently associated with a reduced risk of liver cirrhosis, CVD and all-cause mortality. Compared with non-MASLD individuals, our analysis indicates that longer duration of physical activity, specifically >1945 min/week of LPA or >383 min/week of MPA may theoretically eliminate the excess risk of mortality associated with MASLD. Among MASLD individuals, longer physical activity duration, regardless of intensity, was associated with reduced risks of liver cirrhosis and mortality. MPA and VPA were associated with lower CVD risk, while VPA was associated with reduced cancer risk, highlighting the potential benefits of increasing the intensity and duration of physical activity in MASLD management. Show less
Breast cancer has seriously affected women's physical and mental health. This investigation aims at screening differentially expressed genes (DEGs) in breast cancer and illuminating the potential biol Show more
Breast cancer has seriously affected women's physical and mental health. This investigation aims at screening differentially expressed genes (DEGs) in breast cancer and illuminating the potential biological functions of Leiomodin 1 (LMOD1) and its behind mechanisms against breast cancer. The common DEGs (co-DEGs) between the GSE22820 and GSE29431 data sets and pivotal genes were screened out using bioinformatics methods. The biological roles of LMOD1 overexpression on malignant phenotypes were validated by functional assays and the impact on fatty acid synthesis was also elucidated in breast cancer cell lines. Additionally, colivelin, a STAT3 activator, was applied for further investigating the role of LMOD1 on the JAK2/STAT3 pathway in vitro. A total of 208 co-DEGs and 5 focal genes were screened through bioinformatics analysis, and 5 focal genes were downregulated in breast cancer cell lines. LMOD1 overexpression retarded proliferative, migratory, invasive capabilities of breast cancer cells. LMOD1 overexpression suppressed fatty acid synthesis. Furthermore, the inhibitory effects on malignant phenotypes of breast cancer cells with LMOD1 overexpression were partially abolished after colivelin treatment. Additionally, LMOD1 could impede fatty acid synthesis in breast cancer cells. Our study highlighted LMOD1 exerted as a tumor-suppressive role in breast cancer, which was correlated with restraining the JAK2/STAT3 pathway activation. Show less
Atherosclerosis (AS) is the leading cause of global mortality and morbidity. Despite the elevated expression of sodium-hydrogen exchanger 1 (NHE1) and olfactory receptor 2 (Olfr2) in plaque macrophage Show more
Atherosclerosis (AS) is the leading cause of global mortality and morbidity. Despite the elevated expression of sodium-hydrogen exchanger 1 (NHE1) and olfactory receptor 2 (Olfr2) in plaque macrophages, their interactions within the AS context remain poorly understood. In this study, ApoE Show less
Apolipoprotein C3 (APOC3) was found to induce inflammation in human monocytes. Jarisch-Herxheimer reaction (JHR) was perceived to be caused by immune reactions of dividing spirochaetes to penicillin t Show more
Apolipoprotein C3 (APOC3) was found to induce inflammation in human monocytes. Jarisch-Herxheimer reaction (JHR) was perceived to be caused by immune reactions of dividing spirochaetes to penicillin treatment. The aim of this study was to investigate the role of APOC3 in patients with syphilis and JHR. This prospective cohort study enrolled adult patients with active syphilis with/without JHR. Serum samples were collected before and after administration of the first dose of benzathine penicillin and the serum levels of APOC3 were determined by enzyme-linked immunosorbent assay (ELISA). The APOC3 level and changes in APOC3 level before and after benzathine penicillin treatment in different groups were compared with the Mann-Whitney U test or Kruskal-Wallis test. Forty adult patients with syphilis and 32 controls were enrolled. All 40 patients with syphilis were men who have sex with men, and 30 (75%) were people living with human immunodeficiency virus (HIV). Overall, 19 patients (47%) developed JHR. The active syphilis group had a significantly higher serum APOC3 level (median 38.3 µg/mL, interquartile range [IQR]: 34.5-48.0 µg/mL) than the controls ( p = 0.020). The serum levels of APOC3 were higher in the 21 patients without JHR before and after benzathine penicillin treatment compared with the controls (38.9 µg/mL [IQR: 34.5-66.7 µg/mL] and 39.4 µg/mL [IQR: 33.7-62.9] µg/mL vs 31.8 µg/mL [IQR: 27.5-42.2 µg/mL]). Receiving operating characteristic curve analysis showed that the best cutoff value of APOC3 to predict the absence of JHR before benzathine penicillin therapy compared to the controls was 34.2 µg/mL (area under the curve 0.695, p = 0.017, CI = 0.544-0.846, sensitivity = 0.81, specificity = 0.406). A high baseline serum APOC3 level can predict the absence of JHR in patients with syphilis treated with the first dose of benzathine penicillin. Show less
Despite the well-established association between the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratio and ischemic stroke, its specific relationship with the underlying vascular pathologies contr Show more
Despite the well-established association between the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratio and ischemic stroke, its specific relationship with the underlying vascular pathologies contributing to stroke remains poorly understood. This study aims to investigate the association between the apoB/apoA1 ratio and intracranial or extracranial atherosclerosis. We enrolled 408 patients with acute ischemic stroke who had never been treated with statins or fibrates. Based on the images from computed tomography angiography (CTA), the patients were categorized into four groups: intracranial atherosclerosis stenosis (ICAS, n = 136), extracranial carotid atherosclerosis stenosis (ECAS, n = 45), combined intracranial and extracranial atherosclerosis stenosis (COAS, n = 73), and non-cerebral atherosclerosis stenosis (NCAS, n = 154). Demographic characteristics, clinical factors, and serum lipid levels were collected and then compared across groups. The apoB/apoA1 ratio was significantly higher in patients with ICAS, ECAS and COAS compared to those in the NCAS group. Multivariable logistic regression analysis demonstrated that the ApoB/ApoA1 ratio was independently associated with ICAS, but not with ECAS. ROC curve analysis showed that the ApoB/ApoA1 ratio had a good diagnostic ability for ICAS, with an area under the curve (AUC) of 0.764, an optimal cut-off value of 0.8122, a sensitivity of 81.3%, and a specificity of 59.8%. An higher apoB/apoA1 ratio is associated with ICAS in ischemic stroke patients. Show less
Genome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been Show more
Genome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been limited by phenotyping challenges and small sample sizes. We test associations of rare and ultra-rare coding variants with proton density fat fraction (PDFF) and MASLD case-control status in 736,010 participants of diverse ancestries from the UK Biobank, All of Us, and BioMe and performed a trans-ancestral meta-analysis. We then developed models to accurately predict PDFF and MASLD status in the UK Biobank and tested associations with these predicted phenotypes to increase statistical power. The trans-ancestral meta-analysis with PDFF and MASLD case-control status identifies two single variants and two gene-level associations in APOB, CDH5, MYCBP2, and XAB2. Association testing with predicted phenotypes, which replicates more known genetic variants from GWAS than true phenotypes, identifies 16 single variants and 11 gene-level associations implicating 23 additional genes. Two variants were polymorphic only among African ancestry participants and several associations showed significant heterogeneity in ancestry and sex-stratified analyses. In total, we identified 27 genes, of which 3 are monogenic causes of steatosis (APOB, G6PC1, PPARG), 4 were previously associated with MASLD (APOB, APOC3, INSR, PPARG), and 23 had supporting clinical, experimental, and/or genetic evidence. Our results suggest that trans-ancestral association analyses can identify ancestry-specific rare and ultra-rare coding variants in MASLD pathogenesis. Furthermore, we demonstrate the utility of machine learning in genetic investigations of difficult-to-phenotype diseases in trans-ancestral biobanks. Show less
B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined r Show more
B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27-IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 interaction-mediated self-targeting, these cells promoted B cell PD-L1 expression and immune evasion. Mechanistically, Show less
Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) Show more
Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) such as dibasic calcium phosphate anhydrate (DCPA) are commonly employed for bone repair, their inadequate cellular immune responses significantly impede sustained degradation and optimal osteogenesis. In this study, drawing inspiration from the key structure of an acidic non-collagenous protein-CaP complex (ANCPs-CaP) essential for natural bone formation, we prepared biomimetic mineralized dibasic calcium phosphate (MDCPA). This preparation utilized plant-derived non-collagenous protein Zein as the organic template and acidic artificial saliva as the mineralization medium. Physicochemical property analysis revealed that MDCPA is a complex of Zein and DCPA, which mimics the composite of the natural ANCP-CaP. Moreover, MDCPA exhibited enhanced biodegradability and osteogenic potential. Mechanistic insight revealed that MDCPA can be phagocytized and degraded by macrophages via the FCγRIII receptor, leading to the release of interleukin 27 (IL-27), which promotes osteogenic differentiation by osteoimmunomodulation. The critical role of IL-27 in osteogenesis is further confirmed using IL-27 gene knockout mice. Additionally, MDCPA demonstrates effective healing of critical-sized defects in rat cranial bones within only 4 w, providing a promising basis and valuable insights for critical-sized bone defects regeneration. Show less
Asthma severity assessment is essential for asthma management. Transcriptomics contributes substantially to asthma pathogenesis. Then, this study aimed to explore asthma severity-associated transcript Show more
Asthma severity assessment is essential for asthma management. Transcriptomics contributes substantially to asthma pathogenesis. Then, this study aimed to explore asthma severity-associated transcriptomics profile and promising biomarkers for asthma severity prediction. In discovery cohort, induced sputum cells from 3 non-severe and 3 severe asthma patients were collected and analyzed using RNA-seq. Multivariate analysis was performed to explore asthma severity-associated transcriptomics profile and differential expressed genes (DEGs). The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were used for pathway enrichment analysis. Subsequently, based on the previous study and clinical experience, the mRNA expressions of 6 overlapped asthma severity-associated DEGs and Distinct asthma severity-associated transcriptomics profile was identified in induced sputum cells in discovery cohort. Then, 345 DEGs were found, of which 38 terms and 32 pathways were enriched using GO and KEGG, respectively. In validation cohort, the mRNA expressions of Collectively, this study provides the first identification of the association between induced sputum cells transcriptomics profile and asthma severity, indicating the potential value of transcriptomics for asthma management. The study also reveals the promising value of serum C3 for predicting asthma severity in clinical practice. Show less
Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining Show more
Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining heart health by draining fluids and immune cells. However, their involvement in HFpEF remains largely unexplored. We examined cardiac lymphatic alterations in mice with HFpEF with comorbid obesity and hypertension, and in heart tissues from patients with HFpEF. Using genetically engineered mouse models and various cellular and molecular techniques, we investigated the role of cardiac lymphatics in HFpEF and the underlying mechanisms. In mice with HFpEF, cardiac lymphatics displayed substantial structural and functional anomalies, including decreased lymphatic endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, and impaired capacity to drain fluids and immune cells. LEC numbers and marker expression levels were also decreased in heart tissues from patients with HFpEF. Stimulating lymphangiogenesis with an adeno-associated virus expressing an engineered variant of vascular endothelial growth factor C (VEGFC Our study provides evidence that cardiac lymphatic disruption, driven by impaired BCAA catabolism in LECs, is a key factor contributing to HFpEF. These findings unravel the crucial role of BCAA catabolism in modulating lymphatic biology, and suggest that preserving cardiac lymphatic integrity may present a novel therapeutic strategy for HFpEF. Show less
FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted Show more
FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring FGFR1/2 somatic alterations. Treatment of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/FGFR1-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing FGFR1 Show less