Cellular senescence is a hallmark for cancers, particularly in lung adenocarcinoma (LUAD). This study developed a risk model using senescence signature genes for LUAD patients. Based on the RNA-seq, c Show more
Cellular senescence is a hallmark for cancers, particularly in lung adenocarcinoma (LUAD). This study developed a risk model using senescence signature genes for LUAD patients. Based on the RNA-seq, clinical information and mutation data of LUAD patients collected from the TCGA and GEO database, we obtained 102 endotheliocyte senescence-related genes. The "ConsensusClusterPlus" R package was employed for unsupervised cluster analysis, and the "limma" was used for the differentially expressed gene (DEG) analysis. A prognosis model was created by univariate and multivariate Cox regression analysis combined with Lasso regression utilizing the "survival" and "glmnet" packages. KM survival and receiver operator characteristic curve analyses were conducted applying the "survival" and "timeROC" packages. "MCPcounter" package was used for immune infiltration analysis. Immunotherapy response analysis was performed based on the IMvigor210 and GSE78220 cohort, and drug sensitivity was predicted by the "pRRophetic" package. Cell invasion and migration were tested by carrying out Transwell and wound healing assays. According to the results, a total of 32 genes related to endotheliocyte senescence were screened to assign patients into C1 and C2 subtypes. The C2 subtype showed a significantly worse prognosis and an overall higher somatic mutation frequency, which was associated with increased activation of cancer pathways, including Myc_targets2 and angiogenesis. Then, based on the DEGs between the two subtypes, we constructed a five-gene RiskScore model with a strong classification effectiveness for short- and long-term OS prediction. High- and low-risk groups of LUAD patients were classified by the RiskScore. High-risk patients, characterized by lower immune infiltration, had poorer outcomes in both training and validation datasets. The RiskScore was associated with the immunotherapy response in LUAD. Finally, we found that potential drugs such as Cisplatin can benefit high-risk LUAD patients. In-vitro experiments demonstrated that silencing of Angiopoietin-like 4 (ANGPTL4), Gap Junction Protein Beta 3 (GJB3), Family with sequence similarity 83-member A (FAM83A), and Anillin (ANLN) reduced the number of invasive cells and the wound healing rate, while silencing of solute carrier family 34 member 2 (SLC34A2) had the opposite effect. This study, collectively speaking, developed a prognosis model with senescence signature genes to facilitate the diagnosis and treatment of LUAD. Show less
Maternal circulating lipid concentrations impact the risk of pregnancy complications and infant health outcomes. The associations between physical activity and circulating lipids during pregnancy rema Show more
Maternal circulating lipid concentrations impact the risk of pregnancy complications and infant health outcomes. The associations between physical activity and circulating lipids during pregnancy remain inadequately understood. A study was conducted from July 2024 to March 2025, involving the recruitment of 520 pregnant women in Wuhan, China. The Pregnancy Physical Activity Questionnaire (PPAQ) scores were evaluated in trimesters. Circulating lipid profiles, including total triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), apolipoprotein A1 (APOA1) and apolipoprotein B (APOB) concentrations, were assessed at each trimester. The daily energy expenditure of physical activity (EEPA) during the first, second, and third trimesters was recorded as 11.35, 9.07, and 9.48 metabolic equivalents-hour/day (METs-h/d). The EEPA in the first trimester was significantly greater than that in the second ( This study suggests that increased physical activity during pregnancy is associated with lower lipid levels. Moreover, maternal age appears to have a significant impact on physical activity and the metabolism of circulating lipids during pregnancy. Show less
Periodontitis (PD) is a chronic inflammatory disease in which oxidative stress plays a crucial role in its progression. Mitophagy eliminates damaged mitochondria and alleviates oxidative stress; howev Show more
Periodontitis (PD) is a chronic inflammatory disease in which oxidative stress plays a crucial role in its progression. Mitophagy eliminates damaged mitochondria and alleviates oxidative stress; however, its specific regulatory mechanisms in PD remain unclear. This study utilized single-cell and bulk RNA sequencing data to identify core genes and investigate their potential roles. We utilized single-cell RNA sequencing data and applied 4 algorithms - area under the curve cell level enrichment, U-statistics-based single-cell signature scoring, single-sample gene set scoring, and AddModuleScore - to assess mitophagy activity and identify candidate genes. Subsequently, based on bulk RNA-seq data, 5 machine learning algorithms, including Least Absolute Shrinkage and Selection Operator Regression, random forest, Boruta, gradient boosting machine, and eXtreme Gradient Boosting, were employed to further screen core genes from the candidate gene set. Finally, immune infiltration analysis, cell communication analysis, and gene interaction network construction were integrated to systematically elucidate the regulatory mechanisms of core genes in the progression of PD. Single-cell RNA sequencing combined with multiple algorithms revealed significantly elevated mitophagy activity in PD tissues, particularly in monocytes/macrophages and endothelial cells. Additionally, we identified 4 core genes: BNIP3L, VPS13C, CTTN, and MAP1LC3B. BNIP3L and CTTN were downregulated in periodontitis, correlating negatively with disease prevalence, immune infiltration, and inflammatory pathways, whereas VPS13C and MAP1LC3B were upregulated, showing positive correlations. CellChat analysis highlighted monocytes/macrophages and endothelial cells with high core gene expression as key mediators of intercellular communication. This study identified BNIP3L, VPS13C, CTTN, and MAP1LC3B as core mitophagy-related genes associated with PD, and highlighted the pivotal roles of monocytes/macrophages and endothelial cells in disease progression. These findings provide new insights into the pathogenesis of PD and offer a theoretical foundation for mitophagy-targeted diagnosis, biomarker identification, and precision therapy. Show less
Activation of cancer-associated fibroblasts (CAFs) plays an important role in tumor metastasis. The purpose of this study is to investigate the role of POU6F2 in conversion of hepatic stellate cells ( Show more
Activation of cancer-associated fibroblasts (CAFs) plays an important role in tumor metastasis. The purpose of this study is to investigate the role of POU6F2 in conversion of hepatic stellate cells (HSCs) into CAFs in liver metastasis of gastric adenocarcinoma (GAC). POU6F2 expression was examined by real-time PCR, Western blot and immunohistochemical staining. The functional roles of POU6F2 in GAC liver metastasis were investigated both cellular experiments in vitro and in vivo using a mouse model of subcutaneous splenic injection. ChIP and ELISA assays were used to explore the underlying molecular mechanism of POU6F2 in liver metastasis of GAC. Here we reported that POU6F2 was upregulated in GAC tissue with liver metastasis, which predicted poor early liver metastasis. Upregulating POU6F2 promoted EMT, invasion and migration of GAC cells in vitro, and the liver metastasis of GAC cells in vivo. Mechanic investigation further revealed that upregulating POU6F2 promoted the invasion and metastasis of GAC by transcriptional upregulation of EMT-inducer SNAI1, and promoting the conversion of HSCs into CAFs dependent on transcriptional upregulation of IGF2-induced activation of PI3K/AKT signaling. Our findings uncover a novel dual mechanism by which POU6F2 promotes liver metastasis of GAC. Show less
Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiolo Show more
Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiology-based therapies are lacking. To comprehensively identify the metabolic causal factors and potential drug targets for PCOS. This genetic association study was conducted using bidirectional two-sample Mendelian Randomization (MR), multivariable MR (MVMR) and drug-target MR. Considering metabolic sexual dimorphism, female-specific genome-wide association studies (GWASs) for metabolic factors were obtained. To ensure the robustness of the findings, an additional independent PCOS GWAS dataset was utilized for replication. The PCOS cohort included 10,074 PCOS cases (mean age 28 to 45 years) and 103,164 controls (mean age 27 to 60 years) of European ancestry. All participants were female. Employing two-sample MR analysis, we found that genetically proxied body mass index (BMI) (OR = 3.40 [95 % CI, 2.65-4.36]), triglyceride (TG) (OR = 1.54 [95 % CI, 1.17-2.04]), low-density lipoprotein cholesterol (LDL-c) (OR = 1.37 [95 % CI, 1.07-1.76]), and type 2 diabetes (T2D) (OR = 1.24 [95 % CI, 1.09-1.41]) were significantly associated with an increased risk of PCOS, whereas genetically predicted high-density lipoprotein cholesterol (HDL-c) (OR = 0.61 [95 % CI, 0.47-0.80]) decreased the odds of PCOS. Stepwise MVMR established a hierarchy of interactions among these metabolic factors, identifying BMI and HDL-c as the most prominent causal factors. Notably, drug-target MR analysis identified incretin-based therapeutics, PCSK9 inhibitors, LPL gene therapy, sulfonylureas, and thiazolidinediones as potential therapeutics for PCOS. All these findings were validated in an independent dataset. This study offered insights into the roles of obesity, diabetes, and dyslipidemia in PCOS etiology and therapeutics, underscoring the necessity for managing metabolic health in women and paving the way for tailored therapeutic strategies for PCOS based on its metabolic underpinnings. 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
Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate Show more
Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate injection, which results in rapid elimination and poor patient compliance. Consequently, oral delivery strategies capable of targeting atherosclerotic plaques are imperative for nucleic acid therapeutics. Herein we report the development of yeast-derived capsules (YCs) packaging an antisense oligonucleotide (AM33) targeting microRNA-33 (miR-33) for the oral treatment of atherosclerosis. YCs provide stability for AM33, preventing its premature release in the gastrointestinal tract. AM33-containing YCs, defined as YAM33, showed high transfection in macrophages, thus promoting cholesterol efflux and inhibiting foam cell formation by regulating the target genes/proteins of miR-33. Orally delivered YAM33 effectively accumulated within atherosclerotic plaques in Show less
Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensiv Show more
Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensively studied. This study aimed to explore clinical characteristics and the usage of electrolytes and AAs in children with PCMs. Children diagnosed with PCMs who had genetic test reports were included. Relevant information was collected and processed, and clinical characteristics and mutated genes were clarified. Gene databases were searched to explore related electrolytes and AAs in the treatment of PCMs. The effect of calcium was explored in children with DCM. Paired samples T tests and nonparametric Wilcoxon signed-rank tests were performed for comparison between before and after using calcium. In this study, 27 children with gene test results were enrolled to perform gene-related analysis. The median age was 2.5 years old. Mutated genes were collected, including pathogenic, likely pathogenic, uncertain significance, and other mutations. The most frequently mutated genes related to dilated cardiomyopathy (DCM) were For children with DCM, calcium supplements may be beneficial. AAs, including serine, cysteine, and arginine, could be used for supplementary treatment in children with DCM and HCM. Show less
D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported the diverse effects of D-2HG in pathophysiological processes, yet its role in Show more
D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported the diverse effects of D-2HG in pathophysiological processes, yet its role in breast cancer remains largely unexplored. We applied an advanced biosensor approach to detect the D-2HG levels in breast cancer samples. We then investigated the biological functions of D-2HG through multiple in vitro and in vivo assays. A joint MeRIP-seq and RNA-seq strategy was used to identify the target genes regulated by D-2HG-mediated N6-methyladenosine (m We found that D-2HG accumulated in triple-negative breast cancer (TNBC), exerting oncogenic effects both in vitro and in vivo by promoting TNBC cell growth and metastasis. Mechanistically, D-2HG enhanced global m Our study unveils a previously unrecognized role for D-2HG-mediated RNA modification in TNBC progression and targeting the D-2HG/FTO/m Show less
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mech Show more
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms, with a particular focus on mitochondrial function and apoptosis. Differential expression analyses were performed across three datasets-The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (LIHC), GSE36076, and GSE95698-to identify overlapping differentially expressed genes (DEGs). A prognostic risk model was then constructed. Cysteine/serine-rich nuclear protein 1 ( A six-gene prognostic model was established, comprising downregulated genes ( Show less
Osteoarthritis (OA) is a common progressive joint disorder marked by synovial inflammation, cartilage degeneration, the formation of osteophytes, though its underlying molecular mechanisms remain uncl Show more
Osteoarthritis (OA) is a common progressive joint disorder marked by synovial inflammation, cartilage degeneration, the formation of osteophytes, though its underlying molecular mechanisms remain unclear. This study integrated bioinformatics and experimental validation to identify key genes in OA synovium and their association with immune infiltration. Analysis of the GSE82107 dataset (10 OA, 7 controls) revealed 909 differentially expressed genes (525 upregulated, 384 downregulated). WGCNA identified the "midnightblue" module, and its intersection with DEGs yielded 122 genes enriched in cytokine-cytokine receptor interaction, JAK-STAT signaling, and autophagy pathways. Protein-protein interaction analysis highlighted FLT3LG, MC4R, CXCL10, CARTPT, and LHX2 as core genes (AUC 0.743-0.871). Immune infiltration analysis showed elevated M0 macrophages in OA, with CXCL10 showing a strong positive correlation with M1 macrophage infiltration (r = 0.74), and MC4R correlating with the presence of follicular helper T cells (r = 0.85). In vitro, OA-derived fibroblast-like synoviocytes exhibited CXCL10 upregulation, MC4R downregulation, and increased IL-6, IL-8, and TNF-α secretion, which were markedly reduced by CXCL10 knockdown or MC4R overexpression. Synovial tissue assays confirmed these expression patterns. CXCL10 and MC4R may represent promising diagnostic markers and therapeutic targets, offering new insights into OA immunopathogenesis and precision intervention. Show less
Cardiovascular-kidney-metabolic (CKM) syndrome significantly increases cancer and mortality risks, but the combined effects of CKM syndrome and physical activity (PA) on these outcomes remain poorly u Show more
Cardiovascular-kidney-metabolic (CKM) syndrome significantly increases cancer and mortality risks, but the combined effects of CKM syndrome and physical activity (PA) on these outcomes remain poorly understood. This prospective study included 66,650 UK Biobank participants with accelerometry data. CKM syndrome was classified into five stages based on metabolic, kidney, and cardiovascular health. PA was categorized by intensity into light (LPA), moderate (MPA), vigorous (VPA), and moderate-to-vigorous (MVPA) levels, and further divided into tertiles by daily duration. Multivariable Cox models were used to estimate hazard ratios. Over a median follow-up of 8.03 years, 4,301 incident cancer cases and 2,442 deaths occurred. Advancing CKM stages were associated with elevated risks of both cancer incidence and all cause mortality, while increasing PA levels reduced these risks. Significant interactions were observed between CKM syndrome and both MPA and MVPA on cancer and mortality risks (P interaction < 0.05). In participants with the lowest tertile of MPA or MVPA, those in stages 2 and 4 had higher cancer risk, while in the highest tertile, this risk was no longer elevated. For all-cause mortality, in participants with the lowest tertile of MPA or MVPA, CKM stage 3 exhibited higher risks, while those in the highest tertile did not. CKM stage 4 remained associated with higher mortality across all PA intensity levels, but risks decreased with increasing MVPA levels. Higher levels of MPA and MVPA may mitigate the elevated risks of both cancer incidence and all-cause mortality associated with CKM stages 2 to 4. Show less
While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as Show more
While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as no recurrence through 5-year follow-up, helps identify potentially cured patients, yet predictive clinicopathologic features in stage I invasive NSCLC need clarification. This study sought to identify such features to enable risk-adapted surveillance. We analyzed a prospectively collected dataset of patients with stage I invasive NSCLC who underwent R0 resection between 2008 and 2015. Cox regression analysis was used to evaluate the association between clinicopathologic features and disease recurrence, aiming to identify independent prognostic factors. A total of 1,817 patients met the inclusion criteria. The 5-year cumulative incidence of recurrence was 14.6%. Female sex, tumor size ≤2 cm, lepidic-predominant adenocarcinoma (LPA) histologic type, presence of a ground-glass opacity (GGO) component, and solid component size ≤10 mm were identified as independent prognostic factors. A risk stratification system was subsequently developed, classifying patients into two groups: a low-risk group (with ≥4 factors; n=341) and an elevated-risk group (with <4 factors; n=1,476). Kaplan-Meier analysis revealed statistically significant differences in recurrence-free survival (RFS), overall survival (OS), and lung cancer-specific survival (LCSS) between the two groups (P<0.001). The low-risk group is considered to represent the population within the surgical curative time window. Patients with stage I invasive NSCLC who meet at least four of the following five criteria-female sex, tumor size ≤2 cm, solid component ≤10 mm, presence of a GGO component, and LPA histologic type-may be considered within the "surgical curative time window" and may therefore qualify for reduced surveillance intensity. Show less
Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic dr Show more
Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic drivers of 20 GI diseases. Focusing on colorectal (CC) and esophageal cancer (EC), we identified five metabolites (e.g., 1,2-di-palmitoyl-sn-glycero-3-phosphocholine) and arachidonic acid ethyl ester as causal drivers. Summary-data-based MR and colocalization analysis (PP.H4 > 0.75) revealed FADS1 as a master regulator of these metabolites, with genetic variants exhibiting tissue-specific lipidomic effects. Functional validation using FADS1-knockout cell lines and mouse models demonstrated that FADS1 inhibition suppresses tumor cell proliferation, migration, and invasion while promoting apoptosis. In vivo, FADS1 deletion reduced chemically induced CC/EC tumor burden by 62-75%, accompanied by decreased Ki-67/MMP-9 expression and inflammatory infiltration. Mechanistically, FADS1 ablation disrupted lipid metabolism (reduced linoleic acid and arachidonic acid) and attenuated PI3K/AKT and MAPK signaling. Multi-omics integration further corroborated FADS1-mediated epigenetic regulation (e.g., mQTL-driven DNA methylation). This study establishes FADS1 as a pivotal orchestrator of GI carcinogenesis via metabolic reprogramming and signaling dysregulation, offering a compelling therapeutic target for precision oncology in CC and EC. Regulatory mechanisms of FADS1 in CC and EC. Show less
Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in inn Show more
Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in innate immunity, play pivotal regulatory roles in sepsis pathogenesis. While Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, is traditionally believed to exert immunosuppressive effects through membrane anchoring, its involvement in macrophage polarization during sepsis remains unclear. This study investigated the spatial distribution of PD-L1 in macrophages and its regulatory effects on inflammatory responses during sepsis. This study investigated PD-L1’s regulatory role in macrophage polarization through RNA sequencing, Immunoprecipitation-mass spectrometry, molecular docking, and site-directed mutagenesis, with preliminary validation in C57BL/6 mice. Using GEO database analysis combined with qRT-PCR and Western blotting, we confirmed elevated PD-L1 expression in sepsis and M1-polarized macrophages. Laser scanning confocal microscopy demonstrated dual localization of PD-L1, appearing both on the plasma membrane and intracellularly within M1 macrophages. RNA sequencing revealed PD-L1’s promotion of M1 polarization through enhanced AIM2 expression in the NOD-like receptor pathway. Integrated analyses employing mass spectrometry, molecular docking, site-directed mutagenesis, and Western blotting demonstrated PD-L1 binding to AIM2, which augmented expression of downstream effector molecules (IL-18 and IFN-γ) and potentiated STAT1 activation. Silencing AIM2 by siRNA or IL-18 antagonism reversed PD-L1-induced M1 markers (IL-27, IL-6, iNOS/NO). PD-L1 was further shown to exacerbate pathological progression in septic mouse models. Our study demonstrated that sepsis-induced PD-L1 overexpression in macrophages exacerbates pathological progression by upregulating AIM2 expression, binding to AIM2 to enhance IL-18 production, which activates STAT1 to drive M1 polarization. The online version contains supplementary material available at 10.1186/s12964-025-02578-1. Show less
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles Show more
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles in biological processes. This study aims to explore the impact and mechanisms of circRNA505 on antler chondrocytes. Functional experiments demonstrated that m5C-modified circRNA505 inhibits antler chondrocyte proliferation, enhances osteogenic differentiation, and facilitates cellular glycolysis. Mechanistically, dual luciferase and AGO2-RIP assays revealed a direct binding relationship between circRNA505, miR-127, and p53. Rescue assays further showed that circRNA505 affects cell proliferation and differentiation through the miR-127/p53 axis. Meanwhile, RNA Antisense Purification (RAP) screening and analysis of related proteins binding to circRNA505 demonstrated that circRNA505 binds to LDHA and increases the level of LDHA phosphorylation through FGFR1 to promote cellular glycolysis by FISH-IF, RIP, and Western blot experiments. Additionally, Me-RIP assays confirmed the m5C methylation modification of circRNA505. NSUN2 mediates the m5C modification of circRNA505, affecting its stability, while the m5C reader ALYREF promotes the nuclear export of circRNA505 in an ALYREF-dependent manner. This study provides new insights into the regulatory mechanisms underlying rapid antler development. Show less
Family caregivers ('carers') bear the highest care burden during the postoperative survivorship period of pancreatic cancer, given its poor prognosis. Most carers report unmet needs when taking on car Show more
Family caregivers ('carers') bear the highest care burden during the postoperative survivorship period of pancreatic cancer, given its poor prognosis. Most carers report unmet needs when taking on caregiving responsibilities during this period. Thoroughly investigating carers' needs is essential for helping families address practical care challenges. However, this important topic remains underexplored. To assess the need levels and identify need subgroups among carers of patients with pancreatic cancer 6 months after surgery and demographic predictors contributing to heterogeneity. Cross-sectional study. Participants were recruited from the pancreas centres of four tertiary A-level comprehensive hospitals in Jiangsu Province, China. 240 patients with pancreatic cancer and their carers ('dyads') participated in the survey. Carers completed the Comprehensive Needs Assessment Tool in Cancer for Carers, the Activities of Daily Living Scale for patients, and the General Demographic Information Questionnaire for dyads. Latent profile analysis (LPA) was used to categorise carers' needs. Non-parametric and chi-square tests were used to examine differences in need scores and sociodemographic characteristics among subgroups. Multiple logistic regression (MLR) was used to analyse sociodemographic impacts. Six months post-surgery, the total carers' need score was 41.83 ± 22.65 points, indicating a moderate level, with the highest needs reported for healthcare personnel, information and knowledge, and facilities and services. The LPA results revealed that carers were divided into five distinct subgroups based on differing levels of need across the domains assessed by the Comprehensive Needs Assessment Tool in Cancer for Carers, with proportions of 8.8 %, 22.5 %, 8.3 %, 55 %, and 5.4 %. Subgroup membership was predicted by four factors: carers' sex (odds ratio [OR]: 11.08, 95 % confidence interval [CI]: 1.64, 74.99, We have highlighted the complex individualised needs of carers of patients with pancreatic cancer. Through LPA and MLR, we identified distinct need subgroups and their predictors. Healthcare professionals may be able to improve dyads' health by tailoring support to each subgroup's specific needs and issues. Registration number: ChiCTR2400079415, registered 03/01/2024, first recruitment 04/02/2024. Show less
Accelerating ammonium metabolism of hepatocyte like cells (HLCs) is critical for various functions of hepatocytes. The aim of the present study was to investigate whether Farnesoid X receptor (FXR) ag Show more
Accelerating ammonium metabolism of hepatocyte like cells (HLCs) is critical for various functions of hepatocytes. The aim of the present study was to investigate whether Farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), accelerated ammonium metabolism of HLCs, which was derived from adipose derived mesenchymal stem cells (ADSCs). Human ADSCs were seed in flat bottom plate, then our differentiation protocol was used for 21 days. OCA treatment had been performed in Step3 for 10days. Then, 1) hepatic maturation, 2) urea cycle genes, 3) urea production, and 4) ammonium metabolism was compared depend on the presence or absence of OCA. HLCs had been successfully produced for 21 days. HLCs with OCA showed significantly higher mRNA expressions of AAT than those without OCA. HLCs with OCA showed significantly higher mRNA expressions of urea cycle genes such as SLC25A13, CPS1, and OTC. Urea production was also tended to be upregulated by OCA addition. HLCs with OCA showed significantly higher clearance of NH4Cl at 6hr and 24 hr after addition of NH4Cl. FXR agonist, OCA, accelerates ammonium metabolism of ADSCs derived HLCs. HLCs could be one of treatment options of hepatic encephalopathy of patients with liver failure or urea cycle disorder in the future. J. Med. Invest. 72 : 54-59, February, 2025. Show less
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported Show more
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations. Show less
Little is known about the association between physical activity and the risk of pre-sarcopenic obesity (pre-SO) among adolescents. Hence, this study aimed to examine the association between physical a Show more
Little is known about the association between physical activity and the risk of pre-sarcopenic obesity (pre-SO) among adolescents. Hence, this study aimed to examine the association between physical activity and pre-SO in a sample of 2143 adolescents aged 12 to 18 years from Yinchuan, China. The pre-SO was defined by three criteria: low skeletal muscle mass adjusted by weight (SMM/W) combined with body mass index (BMI), fat mass percentage (FMP), and waist circumference (WC). After adjusting for age, smoking, drinking, sleep time, and high-fat food consumption, participants with high physical activity (HPA) had a lower risk of pre-SO compared to those with low physical activity (LPA) according to the obesity criteria of FMP (OR 0.63, 95% CI, 0.48-0.83, P < 0.05), and WC (OR 0.71, 95% CI, 0.52-0.96, P < 0.05). Additionally, restricted cubic spline models showed a linear dose-response association between total physical activity (TPA) and pre-SO no matter what obesity criteria were adopted (all P overall trend < 0.05, all P non-linear > 0.50). Subgroup analyses revealed that individuals with higher TPA levels exhibited a decreased risk of pre-SO in boys according to the obesity criteria of FMP, and WC. In conclusion, HPA is associated with a reduced risk of pre-SO in adolescents, especially among boys. Show less
Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevale Show more
Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes of both coding and non-coding regions. However, the role of non-coding eccDNA regions that serve as enhancers has been largely overlooked. Here, genome-wide profiling of serum eccDNAs from donors and MM patients who responded well or poorly to bortezomib-lenalidomide-dexamethasone (VRd) therapy is characterized. A high copy number of eccDNA ANKRD28 (eccANKRD28) predicts poor therapy response and prognosis but enhanced transcriptional activity. Established VRd-resistant MM cell lines exhibit a higher abundance of eccANKRD28, and CRISPR/Cas9-mediated elevation of eccANKRD28 desensitizes bortezomib and lenalidomide treatment both in vitro and in vivo. Integrated multi-omics analysis (H3K27ac ChIP-seq, scRNA-seq, scATAC-seq, CUT&Tag, et al.) identifies eccANKRD28 as an active enhancer involved in drug resistance driven by the key transcription factor, POU class 2 homeobox 2 (POU2F2). POU2F2 interacts with sequence-specific eccANKRD28 as well as RUNX1 and RUNX2 motifs to form the protein complex, which activates the promoter of oncogenes, including IRF4, JUNB, IKZF3, RUNX3, and BCL2. This study elucidates the potential transcriptional network of enhancer eccANKRD28 in MM drug resistance from a previously unrecognized epigenetic perspective. Show less
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key u Show more
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE Show less
Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, over Show more
Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, overshadowing its influence on the biological effects of formulations. In this study, we reevaluated the delivery effect of CH using widely applied lipid microspheres (LM) as a model DDS. We conducted comprehensive investigations into the impact of CH on the distribution, cell uptake, and protein corona (PC) of LM at sites of cardiovascular inflammatory injury. The results demonstrated that moderate CH promoted the accumulation of LM at inflamed cardiac and vascular sites without exacerbating damage while partially mitigating pathological damage. Then, the slow cellular uptake rate observed for CH@LM contributed to a prolonged duration of drug efficacy. Network pharmacology and molecular docking analyses revealed that CH depended on LM and exerted its biological effects by modulating peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in vascular endothelial cells and estrogen receptor alpha (ERα) protein levels in myocardial cells, thereby enhancing LM uptake at cardiovascular inflammation sites. Proteomics analysis unveiled a serum adsorption pattern for CH@LM under inflammatory conditions showing significant adsorption with CH metabolism-related apolipoprotein family members such as apolipoprotein A-V (Apoa5); this may be a major contributing factor to their prolonged circulation Show less
Primary membranous nephropathy (pMN) often progresses to end-stage renal disease (ESRD) in the absence of immunosuppressive therapy. The immunological mechanisms driving pMN progression remain insuffi Show more
Primary membranous nephropathy (pMN) often progresses to end-stage renal disease (ESRD) in the absence of immunosuppressive therapy. The immunological mechanisms driving pMN progression remain insufficiently understood. We developed a single-cell transcriptomic profile of peripheral blood mononuclear cells (PBMCs) from 11 newly-diagnosed pMN patients and 5 healthy donors. Through correlation analysis, we identified potential biomarkers for disease stratification and poor prognosis. Expression levels of several proinflammatory factors were significantly increased in patients compared to healthy donors, such as interleukins ( Our study provides insight into the immunological mechanism of pMN and identifies numerous biomarkers and signaling pathways as potential therapeutic targets for managing the progression of high-risk pMN. Show less
Amyloid cerebrovascular disease, primarily driven by the accumulation of amyloid-beta (Aβ) peptides, is intricately linked to neurodegenerative disorders like Alzheimer's disease. BACE1 (beta-site amy Show more
Amyloid cerebrovascular disease, primarily driven by the accumulation of amyloid-beta (Aβ) peptides, is intricately linked to neurodegenerative disorders like Alzheimer's disease. BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) plays a critical role in the production of Aβ, making it a key therapeutic target. In the current work, a CNS library of ChemDiv database containing 44085 compounds was screened against the BACE1 protein. Initially, a structure-based pharmacophore hypothesis was constructed, followed by virtual screening, with the screened hits docked to the BACE1 protein to determine the optimal binding modes. The docking results were examined using the glide gscore and chemical interactions of the docked molecules. The cutoff value of -5 kcal/mol was used to select hits with high binding affinities. A total of seven hits were chosen based on the glide g score. Furthermore, the possible binding mechanisms of the docked ligands were investigated, and it was discovered that all seven selected ligands occupied the same site in the predicted binding pocket of protein. The bioactivity scores of the compounds demonstrated that the chosen compounds possess the features of lead compounds. The toxicity risks and ADMET features of the selected hits were anticipated, and four compounds, J032-0080, SC13-0774, V030-0915, and V006-5608 were chosen for stability analysis. The selected hits were extremely stable and strongly bound to the BACE1 pocket, and conformational changes caused by RMSD, RMSF, and protein-ligand interactions were assessed using MD modeling. Similarly, principal component analysis revealed a large static number of hydrogen bonds. The MM/GBSA binding free energies maps revealed a significant energy contribution in the binding of selected hits to BACE1. The binding free energy landscapes indicated that the hits were bound with a high binding affinity. Thus, the hits could serve as lead compounds in biophysical investigations to limit the biological activity of the BACE1 protein. Show less
Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its anti Show more
Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its antibacterial properties remain unknown. Here, we demonstrated that DZB displays broad-spectrum activity against Show less
The development of BACE-1 (β-site amyloid precursor protein cleaving enzyme 1) inhibitors is a crucial focus in exploring early treatments for Alzheimer's disease (AD). Recently, graph neural networks Show more
The development of BACE-1 (β-site amyloid precursor protein cleaving enzyme 1) inhibitors is a crucial focus in exploring early treatments for Alzheimer's disease (AD). Recently, graph neural networks (GNNs) have demonstrated significant advantages in predicting molecular activity. However, their reliance on graph structures alone often neglects explicit sequence-level semantic information. To address this limitation, we proposed a Graph and multi-level Sequence Fusion Learning (GSFL) model for predicting the molecular activity of BACE-1 inhibitors. Firstly, molecular graph structures generated from SMILES strings were encoded using GNNs with an atomic-level characteristic attention mechanism. Next, substrings at functional group, ion level, and atomic level substrings were extracted from SMILES strings and encoded using a BiLSTM-Transformer framework equipped with a hierarchical attention mechanism. Finally, these features were fused to predict the activity of BACE-1 inhibitors. A dataset of 1548 compounds with BACE-1 activity measurements was curated from the ChEMBL database. In the classification experiment, the model achieved an accuracy of 0.941 on the training set and 0.877 on the test set. For the test set, it delivered a sensitivity of 0.852, a specificity of 0.894, a MCC of 0.744, an F1-score of 0.872, a PRC of 0.869, and an AUC of 0.915. Compared to traditional computer-aided drug design methods and other machine learning algorithms, the proposed model can effectively improve the accuracy of the molecular activity prediction of BACE-1 inhibitors and has a potential application value. Show less