Ovarian cancer (OvCa) remains a leading cause of gynecological cancer mortality, particularly due to its aggressive peritoneal metastasis. Conventional treatments, including surgery and paclitaxel-based chemotherapy, are often limited by poor drug penetration into solid tumors, multidrug resistance, and the highly immunosuppressive tumor microenvironment. To overcome these challenges, we engineered a novel bacteria membrane-fused biomimetic paclitaxel liposome (PLip@DMV) by incorporating bacteria membrane-derived vesicles from attenuated Salmonella VNP20009. Administered via intraperitoneal injection, PLip@DMV not only delivered paclitaxel effectively but also leveraged the immunomodulatory properties of the Salmonella membrane. This led to significant antitumor immune activation within the metastatic tumor microenvironment, synergistically enhancing therapeutic efficacy and markedly prolonging the survival of tumor-bearing mice. Furthermore, the enhanced delivery efficiency and sustained-release characteristics of PLip@DMV resulted in significantly reduced systemic toxicity and tissue accumulation compared to free paclitaxel. Our findings demonstrate that PLip@DMV represents a more efficient, safer, and immunologically potentiated strategy for treating peritoneal metastatic ovarian cancer. This novel biomimetic nanocarrier holds significant promise for improving clinical outcomes in advanced OvCa.

ABSTRACT Background Pathological intramuscular lipid deposition (myosteatosis) and exercise intolerance are hallmarks of metabolic disorders, including diabetes and metabolic dysfunction‐associated steatotic liver disease (MASLD), yet their underlying mechanisms remain unclear. Our previous work has confirmed that hypertriglyceridemia‐driven kallistatin (KAL) elevation is present in the peripheral blood of patients with MASLD and diabetes and is a causative factor in hepatic steatosis and MASH pathogenesis. Here, we aim to evaluate this elevated KAL on myosteatosis and exercise function. Methods We first established rat models of myosteatosis via a high‐fat diet or high‐fructose water intake and measured serum KAL levels by immunoblotting. KAL transgenic (KAL‐TG) mice were generated and subjected to longitudinal analyses, including Oil Red O staining for lipid deposition, exercise tolerance tests, indirect calorimetry for energy expenditure, mitochondrial DNA copy number quantification, ATP measurement, immunoblotting and quantitative PCR. For mechanistic analyses, mouse C2C12 myotubes were treated with recombinant KAL or KAL adenovirus, with or without co‐treatment with AICAR, AdipoRon or AdipoR1 siRNA. Additionally, we evaluated the potential ameliorative effects of KAL knockout and target agonists on myosteatosis. Results Serum KAL levels were significantly elevated in rat models of myosteatosis. Conversely, genetic ablation of KAL ameliorated diet‐induced muscle lipid deposition. KAL‐TG mice developed myosteatosis (muscle TG [μmol/g]: WT: 54.26 ± 14.56 [95% CI: 38.99–69.54]; KAL‐TG: 85.13 ± 11.53 [95% CI: 73.03–97.24], p < 0.01) and exhibited exercise intolerance (p < 0.05 for all) from 6 months of age. Mechanistically, KAL bound to sarcolemmal adiponectin receptor 1 (AdipoR1), suppressing AMPK activity. This led to reduced phosphorylation of acetyl‐CoA carboxylase (ACC) (p < 0.05), enhancing lipogenesis and downregulated the PGC‐1α/NRF1 axis (p < 0.05), impairing mitochondrial biogenesis and reducing ATP production (p < 0.05). Pharmacological activation of AdipoR1 (AdipoRon) and fenofibrate attenuated myosteatosis and restored exercise capacity in KAL‐TG mice (p < 0.05). Conclusions Abnormal elevation of KAL drives metabolic myopathy and exercise intolerance by antagonizing the AdipoR1‐AMPK axis. Our findings offer dual strategies: repurposing AdipoR1 agonists (e.g., AdipoRon) or reducing circulating KAL (e.g., via genetic ablation or triglyceride‐lowering agents such as fenofibrate), both applicable to diabetes/MASLD‐related metabolic myopathy.

Objective:The dysbiosis of the gut microbiota is a well-known correlate in the pathogenesis of inflammatory bowel disease (IBD). However, the microbiome characteristics of patients with IBD who also have non-alcoholic fatty liver disease (NAFLD) are understudied, particularly the potential pathogenic mechanisms of the gut virome. Materials and Methods:In this study, we conducted a comprehensive gut virome correlation study, along with serum metabolomics analysis, by performing virus-like particle (VLP) and metagenomic sequencing on fecal samples from patients with inflammatory bowel disease and non-alcoholic fatty liver disease (IBD-NAFLD) and NAFLD (MASLD) controls without gastrointestinal diseases. Results:The results showed that changes in the fecal virome were associated with IBD-NAFLD (MASLD), particularly with an increase in the abundance of Caudovirales in IBD-NAFLD (MASLD) patients. Subsequent analysis of the gut virome identified Bacteroides as the top predicted host for the viruses. Additionally, we identified the pathways involved in all differential metabolites through KEGG annotation analysis, with the highest correlation being the galactose metabolism pathway. Conclusion:In conclusion, by using a customized integrated gut virome catalog tailored for IBD, we revealed the fundamental changes in the gut virome of IBD-NAFLD (MASLD) patients. This study is the first to uncover the specificity of the gut virome in IBD-NAFLD (MASLD) patients and predict Bacteroides as a potential host, suggesting a microbial signature primarily influenced by intestinal inflammation.

Background:Evidence-based treatment for unresectable combined hepatocellular-cholangiocarcinoma (cHCC-CCA) has not been established. This study aimed to assess the effectiveness and safety of interventional treatment combined with immunotargeted therapy (IIT) in unresectable cHCC-CCA patients. Methods:Patients with a histological diagnosis of unresectable cHCC-CCA who received IIT therapy from January 2019 to March 2024 were retrospectively enrolled. The study evaluated overall survival (OS), progression-free survival (PFS), tumor responses and safety. Results:A total of 242 cHCC-CCA patients were screened and 51 patients were enrolled for analysis. The median follow-up duration was 15.8 months (95% CI: 12.0-19.7 months). The median OS was 17.8 months (95% CI: 12.4-23.2 months) and the median PFS was 8.9 months (95% CI: 5.8-12.0 months). For overall response, the objective response rate was 41.2% and 56.9% based on RECIST 1.1 and mRECIST, respectively. Patients with primary cHCC-CCA showed significantly prolonged OS (median OS: 21.4 months vs. 11.4 months, p = 0.011) and PFS (median PFS: 9.5 months vs. 4.1 months, p = 0.036) compared to those with recurrent cHCC-CCA. Patients with dominant HCC did not show significant differences for OS (p = 0.835) and PFS (p = 0.553) compared to those with dominant iCCA. Six patients (11.8%) experienced grade ≥3 adverse events, including leukopenia (n=1, 2.0%), neutropenia (n=1, 2.0%), thrombocytopenia (n=2, 3.9%), elevated alanine transaminase (ALT) (n=2, 3.9%), elevated aspartate aminotransferase (AST) (n=2, 3.9%), hypoalbuminemia (n=2, 3.9%), and hyperbilirubinemia (n=1, 2.0%). Immunotherapy was discontinued for two patients due to grade ≥3 elevations in ALT and AST. Conclusion:The triple combination of interventional treatment, PD-(L)1 inhibitor, and targeted therapy is an effective and safe approach for unresectable cHCC-CCA patients.

Maintenance of glutamate homeostasis is essential for synaptic plasticity and cognition. Disrupted glutamate-glutamine cycling causes chronic excitotoxicity, a key driver of cognitive deficits in Alzheimer's disease (AD), though regulatory mechanisms remain unclear. Pigment epithelium-derived factor (PEDF), a neuroprotective protein declining with age, is demonstrated here to play a novel role in synaptic glutamate clearance. Analysis of peripheral blood samples from 19 patients with AD and 75 non-dementia control subjects revealed lower levels of PEDF in patients, and loss of PEDF correlates with cognitive decline. PEDF-deficient mice exhibit defective learning and memory, and higher susceptibility to AD. Furthermore, PEDF deficiency impaired synaptic plasticity and dendritic spine morphology. Mechanistically, PEDF inhibits ubiquitin-proteasome-dependent degradation of astrocytic glutamate transporter-1 (GLT-1) and normally guarantees elimination of synaptic glutamate by modulating the protein kinase C signaling pathway. Strikingly, restoring PEDF rescued cognitive deficits in a mouse model of AD, and upregulation of GLT-1 rescued cognitive impairment in PEDF-deficient mice. Collectively, these findings reveal PEDF is a physiologic regulator of synaptic glutamate homeostasis. Targeting PEDF deficiency-induced neural impairment may provide a novel avenue for the development of new therapeutic applications for neurodegenerative diseases associated with glutamate-induced excitotoxicity.

The effectiveness of immunotherapy in hepatocellular carcinoma (HCC) is limited, however, the molecular mechanism remains unclear. In this study, we identified baculoviral IAP repeat-containing protein 2 (BIRC2) as a key regulator involved in immune evasion of HCC. Genome-wide CRISPR/Cas9 screening was conducted to identify tumor-intrinsic genes pivotal for immune escape. In vitro and in vivo models demonstrated the role of BIRC2 in protecting HCC cells from immune killing. Then the function and relevant signaling pathways of BIRC2 were explored. The therapeutic efficacy of BIRC2 inhibitor was examined in different in situ and xenograft HCC models. Elevated expression of BIRC2 correlated with adverse prognosis and resistance to immunotherapy in HCC patients. Mechanistically, BIRC2 interacted with and promoted the ubiquitination-dependent degradation of NFκB-inducing kinase (NIK), leading to the inactivation of the non-canonical NFκB signaling pathway. This resulted in the decrease of major histocompatibility complex class I (MHC-I) expression, thereby protecting HCC cells from T cell-mediated cytotoxicity. Silencing BIRC2 using shRNA or inhibiting it with small molecules increased the sensitivity of HCC cells to immune killing. Meanwhile, BIRC2 blockade improved the function of T cells both in vitro and in vivo. Targeting BIRC2 significantly inhibited tumor growth, and enhanced the efficacy of anti-programmed death protein 1 (PD-1) therapy. Our findings suggested that BIRC2 blockade facilitated immunotherapy of HCC by simultaneously sensitizing tumor cells to immune attack and boosting the anti-tumor immune response of T cells.

Radioresistance represents a substantial challenge in cancer treatment, particularly in esophageal squamous cell carcinoma (ESCC), where the underlying molecular mechanisms remain incompletely understood. Small nucleolar RNAs (snoRNAs), primarily located in the nucleolus, are noncoding RNAs whose roles in ESCC radiotherapy are unclear. In this study, an upregulated snoRNA, SNORA58 is identified in ESCC via a snoRNA PCR array. Furthermore, based on multicenter data, SNORA58 is established as a promising biomarker for predicting response to neoadjuvant chemoradiotherapy (nCRT). Patients with high SNORA58 expression levels presented a lower likelihood of achieving a complete response to nCRT and poorer clinical outcomes. Functionally, SNORA58 enhances cancer cell resistance to radiotherapy without affecting chemotherapeutic sensitivity. Mechanistically, SNORA58 stabilizes CTCF by inhibiting its ubiquitin-mediated degradation, leading to JNK1 downregulation and subsequent inactivation of the JNK signaling pathway; this disrupts intracellular iron homeostasis, thereby alleviating radiotherapy-induced ferroptosis. Notably, the administration of a JNK signaling activator significantly restored the radiosensitivity of high-SNORA58 ESCC cells both in vitro and in vivo. These findings elucidate the first demonstration of SNORA58 as a critical regulator of radioresistance in ESCC and reveal a novel link between snoRNAs and ferroptosis in this specific context, suggesting potential therapeutic strategies for managing ESCC.

Tumors are diseases caused by abnormal cell division and growth, which can be life-threatening if not treated properly. Serpin inhibitors play a crucial role in regulating pathophysiological process and are promising drug targets. Kallistatin (SERPINA4) and Pigment Epithelium-Derived Factor (PEDF, SERPINF1) are two serpins that lack protease inhibitory activity but are abundant in blood. They exhibit anti-angiogenic effects and are involved in tumorigenesis. The pathogenic role and mechanism of Kallistatin and pigment epithelium-derived factor (PEDF) have been extensively studied for their potential use in cancer therapy. Kallistatin and PEDF play significant roles in controlling tumor growth and progression. While they share some common mechanisms of action, such as promoting apoptosis and inhibiting angiogenesis, they also have distinct differences in effectiveness and range of anti-tumor activities. This review compares and contrasts the expression patterns, structural features, expression regulation, disease roles, signaling pathways, and potential clinical value of Kallistatin and PEDF, aiming to provide a comprehensive understanding of their biomedical and clinical potential.

Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer’s disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechanism is uncertain. Here, the present investigation identified significantly elevated serum Kallistatin levels in AD patients concomitant with hyperglycemia and hypertriglyceridemia, suggesting potential crosstalk between neuroendocrine regulation and metabolic dysregulation in AD pathophysiology. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by downregulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, the experiments clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD.

Ovarian cancer (OC) is a highly fatal and refractory malignancy affecting women, and platinum resistance remains a major clinical dilemma. Compared with other OC subtypes, ovarian clear cell carcinoma (OCCC) frequently exhibits increased platinum refractoriness, accompanied by increased glycogen levels, which promotes clear-cell morphology, and wild-type p53. However, the roles of these factors in platinum resistance of OCCC are unclear. Here, we investigated whether glycogen promotes OCCC resistance to platinum agents and reported that GYS1, a rate-limiting enzyme in glycogen synthesis, is clinically associated with poor prognosis and chemoresistance in OCCC. Mechanistically, p53 promotes GYS1 breakdown via the upregulation of RNF144a, whereas GYS1 induces the reversal of p53 ubiquitination and degradation by competitively binding to USP14, forming a positive feedback circuit. Under platinum stress, the accumulated glycogen is mobilized by the p53/GYS1 feedback circuit, which fuels energetic NADPH production, resulting in resistance to disulfidptosis and increased platinum resistance in OCCC. Collectively, our findings identify glycogen as a contributor to OCCC platinum resistance and elucidate the underlying mechanisms, highlighting a crucial p53/GYS1 positive feedback loop.

Type 2 diabetes mellitus (T2DM) is a major global public health burden. The mechanisms through which glucose-stimulated insulin secretion (GSIS) can be suppressed in individuals with obesity-derived type 2 diabetes mellitus (T2DM) have not been elucidated. Compared to normal subjects, the expression of pigment epithelium-derived factor (PEDF) is upregulated in the islets of patients with obesity and T2DM. However, the role of PEDF in β-cells is unclear. This study employed male PEDF transgenic and knockout mice to assess β-cell function through oral glucose tolerance tests and GSIS assays. Complementary cell line experiments elucidated underlying mechanisms, collectively demonstrating the role of PEDF in regulating insulin secretion. PEDF suppressed GSIS by downregulating the SNARE complex, which suppresses the PI3K/Akt signaling pathway. Thus, targeting PEDF is a potential therapeutic strategy for treating T2DM. PEDF impairs insulin secretion in β-cells by downregulating the SNARE complex, thereby suppressing the PI3K/Akt signaling pathway, suggesting that PEDF is a therapeutic target for T2DM.

Lymph node metastasis (LNM) is significantly associated with distant metastasis and poor prognosis in patients with breast cancer (BC). However, the mechanism underlying LNM in BC remains unclear, limiting the development of effective anti-metastatic strategies. Given the lipid-enriched lymphatic microenvironment, we identify the fatty acid transporter cluster of differentiation 36 (CD36) via TCGA-based screening. Aberrant expression of CD36 is positively correlated with LNM and poor prognosis in clinical specimens. BC cells with high expression of CD36 confers anoikis-resistance exposed to lymph or palmitic acid treatment. Furthermore, CD36 drives LNM in both popliteal LNM and orthotopic BC mouse models through yes-associated protein (YAP)-TEADs signaling pathway. Elevated CD36 faciliates the uptake of fatty acids and induces the PPARα-CYP7A1-bile acid biosynthesis pathway, leading to the nucleus translocation and activation of YAP by suppressing the YAP phosphorylation at Ser127. Activated YAP-TEADs complexes directly bind to the BCL2 promoter to upregulate Bcl-2 expression. Collectively, our findings identify CD36 as a critical regulator of LNM in BC and reveal a CD36-PPARα-CYP7A1-YAP regulatory axis that may provide an effective therapeutic window for preventing metastasis in BC. CD36 drives lymph node metastasis in breast cancer by activating YAP signaling-mediated anoikis resistance via inducing the PPARα-CYP7A1 bile acid biosynthesis pathway.

Adenosine 5'-diphosphate ribosylation factor-like 8B (ARL8B), a small GTPase, is involved in lysosome motility. Our study investigates the role of ARL8B in hepatocellular carcinoma (HCC) using in vitro and in vivo experiments, bioinformatics, and clinical data. We found that ARL8B expression is abnormally elevated in HCC and correlates with poor prognosis. ARL8B knockdown triggered lysosomal dysfunction-manifesting as abnormal morphology, decreased pH, reduced hydrolase activity, and impaired autophagic degradation-which subsequently led to cell cycle arrest and reduced cell viability. Additionally, tumors with high ARL8B expression (ARL8Bhigh) exhibited notable differences in tumor microenvironment composition compared to those with low ARL8B expression (ARL8Blow). ARL8Bhigh HCCs had significantly increased infiltration of NFKBIZ+/HIF1A+ and VEGFA+/SPP1+ neutrophils. EcoTyper analysis indicated that ARL8Bhigh HCCs had a lower proportion of carcinoma ecotype 6, a cellular ecosystem common in normal tissues but rare in tumors. Bioinformatics and real-world analysis showed a positive correlation between ARL8B and PD-L1 expression. Patients with high ARL8B expression exhibited increased sensitivity to sorafenib and immune checkpoint blockade therapy. In conclusion, our findings identify ARL8B as a key lysosomal regulator associated with tumor microenvironment composition in HCC, suggesting its potential as both a therapeutic target and a biomarker for predicting treatment response.

Primary objective was to evaluate the association between post-surgical MRD detected by a tumor-informed personalized panel (brPROPHET) and CRC recurrence, Secondary objectives were to determine the optimal timepoint for MRD assessment, and compare the performance of different MRD detection methods, including brPROPHET, a tumor-informed fixed panel (TIFP) and a tumor-naïve fixed panel (TNFP). Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) has emerged as a pivotal marker in colorectal cancer (CRC), but optimal detection timing and methods remain unclear. This study included patients with resectable stage I-IV CRC. Tumor tissues were obtained at surgery, and blood samples were collected preoperatively, on post-surgical days 7 and 30 (D7/D30), and every 3–6 months. MRD was assessed using the above three methods. A total of 214 patients were included in the analysis, with imaging follow-up available for 196 patients (median follow-up: 18.2 months), among whom 24 (12.2%) experienced recurrence. MRD positivity at D7/D30 associated with significantly reduced disease-free survival (DFS). Longitudinal ctDNA-MRD positivity and MTM levels >0.01/mL were also associated with recurrence. Adjuvant chemotherapy was associated with better DFS in patients with positive MRD at D7 (HR=0.26, 95% CI 0.07–0.98, P =0.03) instead of those with negative MRD at D7. Among the 168 patients assessed with all three methods, the brPROPHET assay demonstrated better association of DFS at D7. ctDNA-based MRD detected by brPROPHET associates with recurrence in CRC. Day 7 is an effective alternative landmark to Day 30 for MRD assessment and brPROPHET outperforms TIFP and TNFP in the association of DFS. ClinicalTrials.gov number: NCT06143644.

Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment.

Erectile dysfunction, a precursor to cardiovascular diseases, is linked to metabolic disorders like gout. However, whether hyperuricemia plays a direct causative role in erectile dysfunction is unclear. Here we show that clinical data from young patients (24-49 years) reveal an over 2.5-fold increased erectile dysfunction risk with elevated serum uric acid. In spontaneous hyperuricemia rats with Urate oxidase gene knockout, hyperuricemia impairs erectile function early (20 weeks) without other metabolic comorbidities. Mechanistically, uric acid enters corpus cavernosum smooth muscle cells, interacting with MLCK at N803 to inhibit its ubiquitination by E3 ligase NEDD4L, stabilizing MLCK and increasing MLC2 phosphorylation, and leading to corpus cavernosum contraction. Pharmacological uric acid-lowering (febuxostat, benzbromarone, 3170) or MLCK inhibition (ML-7) restores erectile function in rats. Our findings reveal the key molecules and mechanisms of hyperuricemia-induced erectile dysfunction, which provides evidence for hyperuricemia or gout patients to control uric acid levels and prevent erectile dysfunction.

Objective:The purpose of the study was to develop and validate the psychometric properties of the Colorectal Cancer and Colonoscopy Screening Health Beliefs Scale for First-Degree Relatives (CCHBS-FDR) instrument for the first-degree relatives (FDRs) of people with colorectal cancer (CRC) in China. Methods:This study was conducted in two phases: scale development and psychometric testing. In the scale development phase, a preliminary item pool was established based on a systematic review, qualitative interviews (n ​= ​42), and the Revised Colorectal Cancer Perception and Screening (RCRCPS) instrument. The scale was then refined through expert consultation and laymen review. Psychometric properties were tested by item analysis, validity assessment and reliability evaluation on a convenience sample of 258 Chinese FDRs of patients with CRC. Results:A preliminary 37-item scale with six dimensions, perceived severity, perceived susceptibility, perceived benefits, barriers-priority, barriers-concerns and barriers-knowledge, was developed in the first phase. The content validity index of the CCHBS-FDR was satisfactory (I-CVI ​= ​0.86-1, S-CVI/UA ​= ​0.89, S-CVI/Ave ​= ​0.98). Cronbach's α coefficient for overall scale was 0.863, and subscales ranged from 0.689 to 0.939. Confirmatory factor analysis results suggested that the CCHBS-FDR conformed to the six-factor model (χ 2/df ​= ​2.075, RMSEA ​= ​0.065, CFI ​= ​0.892, TLI ​= ​0.880, and SRMR ​= ​0.077). Conclusions:The CCHBS-FDR demonstrated acceptable reliability and validity as a culturally specific instrument for assessing health beliefs among FDRs with CRC. It can serve as a valuable tool for providing a more precise assessment of health beliefs and helping healthcare professionals develop and evaluate tailored communication interventions to promote colonoscopy screening among FDRs.

Colorectal cancer (CRC) diagnosis is challenging due to generalized symptoms. Various biomarker models exist, but their clinical application is limited by low sensitivity and heterogeneous cutoff values. This study aimed to develop and validate a diagnostic model for CRC. Data from 489 patients-337 with CRC and 152 with benign disease-were included. Patients were randomly assigned to training (n = 342) and validation (n = 147) cohorts. Logistic regression identified age (OR 1.06), CA153 (OR 0.26), CEA (OR 4.49), CYFRA 21-1 (OR 5.88), ferritin (OR 0.15), and hs-CRP (OR 0.05) as independent risk factors. Sensitivity and specificity were 88.61% and 82.86% in the training cohort and 90.00% and 76.60% in the validation cohort. Cutoff values for the biomarkers were: CA199, 9.809 U/mL; CA125, 7.743 U/mL; CA153, 6.295 U/mL; CEA, 3.982 ng/mL; CYFRA 21-1, 1.769 ng/mL; ferritin, 163.361 mg/L; hs-CRP, 0.196 mg/L; and serum albumin, 55.966 g/L. The model showed higher sensitivity for early-stage CRC (95.45%, 95% CI 87.2-98.6%) than late-stage CRC (87.27%, 95% CI 76.4-93.5%; P = 0.08). AUCs were 0.907 (training) and 0.872 (validation). The model demonstrated higher sensitivity for early-stage CRC (95.45%) than late-stage CRC (87.27%), underscoring its utility in early detection.

Background:HHLA2, a member of the B7 family, is extensively expressed in various cancers and plays a pivotal role in modulating the immune microenvironment. However, its prognostic significance in hepatocellular carcinoma (HCC) remains poorly understood. This study aims to elucidate the expression patterns of HHLA2 and PD-L1 in HCC, their associations with tumor-infiltrating lymphocytes (TILs), and their impact on clinical outcomes. Methods:Immunohistochemistry (IHC) was employed to evaluate HHLA2 and PD-L1 expression in 547 HCC tissue samples. PD-L1 positivity was defined as ≥1% membranous or cytoplasmic staining. Hematoxylin and eosin (H&E) staining was utilized to quantify TILs (percentage/area), while IHC was used to measure the densities of CD3+, CD4+, and CD8+ TILs (cells/mm²). Results:HHLA2 and PD-L1 exhibited similar positivity rates. HHLA2 positivity was associated with older age, lower alpha-fetoprotein (AFP) levels, well-differentiated tumors, and improved overall survival (OS). HHLA2 expression was inversely correlated with stromal TIL density. In contrast, tumor cell (TC)-PD-L1 and inflammatory cell (IC)-PD-L1 positivity were positively correlated with higher stromal TIL density and increased levels of CD3+, CD4+, and CD8+ TILs. Patients with HHLA2(+)/PD-L1(-) status demonstrated the longest OS. A novel classification system based on HHLA2/PD-L1 expression identified distinct immune profiles and prognostic subgroups. Conclusion:HHLA2 significantly influences the immune microenvironment of HCC and serves as an independent prognostic marker. The combined assessment of HHLA2 and PD-L1 expression facilitates risk stratification, providing a framework to optimize immunotherapy strategies. These findings contribute to the advancement of precision medicine in the management of HCC.