Biomolecules & biomedicine最新文献

The prognostic value of systemic inflammatory and nutritional biomarkers in patients with locally advanced rectal cancer (LARC) remains inadequately defined. This multicenter retrospective study comprehensively assessed the prognostic performance of twelve inflammation-based indices, aiming to identify the most informative biomarker for patients undergoing neoadjuvant chemoradiotherapy followed by surgery. We analyzed data from 427 patients with stage II-III LARC treated at three medical centers between 2010 and 2021. Twelve biomarkers, derived from routine pretreatment blood parameters-including hemoglobin, albumin, neutrophils, lymphocytes, monocytes, and platelets-were evaluated for their association with overall survival (OS) and disease-free survival (DFS). The prognostic performance was measured using the concordance index (C-index), time-dependent area under the receiver operating characteristic curve (time-AUC), and Brier score. Among the evaluated biomarkers, the hemoglobin-albumin-lymphocyte-platelet (HALP) score exhibited robust and consistent prognostic performance. For OS, HALP achieved a C-index of 0.687 and a time-AUC of 0.668, along with the lowest Brier score (0.134); similar results were observed for DFS (C-index 0.675, time-AUC 0.665). Patients with low HALP scores had significantly worse OS and DFS compared to those with high HALP scores. Multivariate Cox regression analysis confirmed low HALP as an independent risk factor for OS (HR = 3.937, 95% CI: 2.445-6.329; p < 0.001) and DFS (HR = 2.212, 95% CI: 1.577-3.096; p < 0.001). Nomograms integrating HALP with key clinicopathological variables provided incremental prognostic value, demonstrating good discrimination and calibration at 12, 36, and 60 months. These findings indicate that HALP is a simple and cost-effective biomarker for prognostic stratification in LARC.

Nutritional status significantly influences treatment tolerance and long-term outcomes in patients with locally advanced rectal cancer (LARC); however, individual nutritional markers may not fully capture overall nutritional reserves. This study aimed to evaluate the prognostic value of a comprehensive nutritional index (CNI), derived from principal component analysis, in patients with LARC undergoing neoadjuvant chemoradiotherapy (NCRT) followed by surgical intervention. We conducted a retrospective analysis of 336 patients with LARC who received NCRT followed by surgery between 2014 and 2019. The CNI was constructed using body mass index, usual body weight percentage, total lymphocyte count, serum albumin, and hemoglobin levels. Patients were categorized into low- and high-CNI groups based on an outcome-oriented cut point, and survival outcomes were assessed through Kaplan-Meier analysis and Cox regression. Patients with lower CNI scores exhibited significantly poorer overall survival and disease-free survival compared to those with higher CNI scores. Furthermore, CNI remained independently associated with both endpoints after adjusting for established pathological factors, including tumor regression grade and ypN stage. A nomogram that integrates CNI, tumor regression grade, and ypN stage demonstrated favorable discrimination and calibration during internal validation. These findings support the use of pretreatment CNI as a practical nutritional composite associated with prognosis in LARC patients treated with NCRT, and the proposed nomogram may enhance individualized risk estimation.

Progesterone and adiponectin receptor 3 (PAQR3) is a Golgi-localized seven-transmembrane protein that anchors rapidly accelerated fibrosarcoma kinase (Raf) and suppresses rat sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) signaling, thereby influencing cellular proliferation, differentiation, and metastasis. This review aims to summarize the expression patterns, regulatory mechanisms, key downstream pathways, and clinical significance of PAQR3 in cancer. We synthesized findings from published clinical and experimental studies, including in vitro assays and nude mouse xenograft models, that evaluate PAQR3 expression, function, and signaling interactions across various tumor types. Overall, PAQR3 is frequently downregulated in many cancers, potentially due to promoter methylation, and low expression levels are associated with adverse clinicopathologic features and reduced survival. Functionally, PAQR3 overexpression inhibits proliferation, colony formation, migration, invasion, and tumor growth, primarily through the inhibition of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways and modulation of epithelial-mesenchymal transition (EMT). Additionally, PAQR3 is linked to nuclear factor kappa B/tumor protein p53 (NF-κB/p53), epidermal growth factor/beta-catenin (EGF/β-catenin) signaling, autophagy, and nuclear factor erythroid 2-related factor 2/ferroptosis (Nrf2/ferroptosis). These effects are modulated by upstream regulators, including microRNA-543 (miR-543), circular RNA 0043280/microRNA-203a-3p (circ_0043280/miR-203a-3p), microRNA-15b (miR-15b), human epidermal growth factor receptor 2 (HER2), 5-aza-2'-deoxycytidine (5-Aza-CdR), autophagy-related 7 (ATG7), and damage-specific DNA binding protein 2 (DDB2). In conclusion, PAQR3 functions as a tumor suppressor and holds potential as a prognostic biomarker. Targeting PAQR3-related pathways may provide new therapeutic opportunities.

Immunotherapy, a therapeutic strategy aimed at modulating the host immune system, has undergone rapid evolution over recent decades, particularly in oncology. Advanced methodologies, including immune checkpoint inhibition, cytokine therapy, chimeric antigen receptor T-cell therapy (CAR-T), and tumor-infiltrating lymphocyte therapies, have significantly transformed cancer treatment. This review summarizes recent advancements in immunotherapy and examines its expanding applications across a range of diseases, such as autoimmune disorders, infectious diseases, transplant rejection, and allergic conditions. A structured literature search was conducted using PubMed and Google Scholar, prioritizing studies published from 2015 to 2026. The findings underscore the efficacy of monoclonal antibodies, adoptive cell therapies, cytokine modulation, and checkpoint-targeted strategies beyond oncology. However, challenges remain, including variable patient responses, immune-related adverse events, and treatment costs. This review also explores the emerging role of artificial intelligence (AI) in enhancing personalized immunotherapy through patient stratification, biomarker identification, and predictive modeling. The integration of multi-omics data with AI presents promising opportunities for improving treatment efficacy and safety, although issues related to data quality, interpretability, regulatory frameworks, and ethical considerations must be addressed. In conclusion, immunotherapy is rapidly extending beyond cancer, and AI-supported personalized approaches offer a promising pathway to safer, more effective, and broadly applicable treatments.

The escalating crisis of antimicrobial resistance (AMR) among Gram-negative pathogens, particularly Klebsiella pneumoniae (KP), necessitates innovative strategies to enhance the efficacy of existing antibiotics. Synergistic drug combinations present a promising approach to improve therapeutic outcomes and delay the emergence of resistance. This study investigates the synergistic interaction between the natural alkaloid berberine chloride and the repurposed antibiotic rifaximin against KP. Integrated in vitro and in silico analyses reveal significant bactericidal synergy between the two agents, mediated through concurrent inhibition of the transcriptional anti-termination factor RfaH, a key regulator of virulence and capsule biosynthesis. Molecular docking and dynamics simulations demonstrate that both compounds cooperatively bind to the RfaH pocket, stabilizing an inactive ternary complex without major structural disruption. Functional assays confirm that the combination effectively suppresses RfaH-dependent capsule production at lower concentrations compared to monotherapy. These findings suggest that RfaH is a viable target for combinatorial inhibition and provide a plausible mechanistic foundation for the berberine-rifaximin synergy. This work supports the rational development of dual-targeting anti-virulence strategies to combat multidrug-resistant KP infections.

Fecal DNA methylation of the syndecan-2 (SDC2) gene is being explored as a noninvasive biomarker for colorectal cancer (CRC) detection. However, its diagnostic performance necessitates thorough evaluation. A systematic search of PubMed, Embase, and Web of Science was conducted to identify studies investigating fecal SDC2 methylation (mSDC2) for CRC diagnosis. Eligible studies included adult CRC patients with histological confirmation and controls with either normal mucosa or benign colorectal lesions. Pooled sensitivity and specificity were synthesized using a Reitsma bivariate random-effects model, and summary receiver operating characteristic (SROC) curves with corresponding area under the curve (AUC) values were derived from this hierarchical model. Twenty-five studies encompassing 3,427 CRC patients, 3,267 individuals with benign lesions, and 5,372 with normal mucosa were included. For the comparison of CRC versus normal mucosa (24 studies), the pooled sensitivity and specificity were 0.86 (95% confidence interval [CI]: 0.82-0.89; I² = 88%) and 0.93 (95% CI: 0.90-0.95; I² = 95%), respectively. The pooled diagnostic odds ratio (DOR) was 81.73 (95% CI: 51.60-129.46), with an AUC of 0.95 (95% CI: 0.93-0.97). In the comparison against benign lesions (22 studies), the sensitivity was 0.85 (95% CI: 0.81-0.89; I² = 87%), specificity was 0.66 (95% CI: 0.59-0.71; I² = 91%), DOR was 11.10 (95% CI: 7.61-16.19), and AUC was 0.83 (95% CI: 0.80-0.86). Deeks' funnel plot asymmetry tests indicated no statistically significant publication bias (p = 0.48 and 0.54). In conclusion, fecal mSDC2 testing demonstrates high diagnostic accuracy for CRC detection when compared to individuals with normal mucosa and moderate performance against benign colorectal lesions. These findings suggest that mSDC2 may serve as a promising noninvasive biomarker to complement existing CRC screening methodologies.

The relationship between prediabetes and chronic kidney disease (CKD) remains ambiguous, with varying results across cohort studies. This meta-analysis aimed to assess whether prediabetes is linked to an increased risk of developing incident CKD in the general adult population. A comprehensive search was conducted in PubMed, Embase, and Web of Science from inception to September 28, 2025, for longitudinal observational studies that evaluated CKD risk in individuals with prediabetes compared to those with normoglycemia. Prediabetes was defined by impaired fasting glucose (IFG), impaired glucose tolerance (IGT), elevated glycated hemoglobin (HbA1c), or a combination of these criteria. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Fifteen cohorts comprising 2,854,724 participants were included in the analysis. The results indicated that prediabetes was significantly associated with an increased risk of incident CKD (RR: 1.21, 95% CI: 1.12-1.31; I² = 90%). Subgroup analyses revealed that the association was not significantly influenced by the definitions of prediabetes, study design, demographic characteristics of the population, follow-up duration, or study quality scores (p for subgroup difference all > 0.05). Meta-regression analysis suggested that a higher mean age of the population was inversely correlated with the observed effect size for the relationship between prediabetes and CKD risk (coefficient = -0.030, p = 0.004; adjusted R² = 67%). In conclusion, prediabetes is associated with a modestly elevated risk of developing CKD in the general population, with a potentially stronger correlation observed in younger individuals. These findings indicate an association rather than causality and suggest that early glycemic dysregulation may be linked to subsequent renal risk prior to the onset of overt diabetes.

Inherited retinal diseases (IRDs) represent a genetically diverse group of disorders that result in the progressive degeneration of photoreceptors and/or retinal pigment epithelium (RPE), ultimately leading to significant vision loss and diminished quality of life. Symptoms vary widely, encompassing night blindness, peripheral vision loss, central vision impairment, and total blindness, with disease progression influenced by the specific genetic mutation and inheritance pattern. This narrative review synthesizes recent findings on the pathogenesis of IRDs and examines stem cell-based interventions across preclinical models and early clinical trials. Mutations in genes such as RPE65, ABCA4, and USH2A disrupt critical retinal pathways, contributing to oxidative stress, inflammation, and apoptosis. Stem cell strategies, including pluripotent stem cell-derived RPE/photoreceptor precursors, mesenchymal stem cells, and retinal progenitor cells, offer potential mechanisms for limited cellular replacement and synaptic integration, as well as paracrine neuroprotection and immunomodulation. Current research indicates feasible delivery methods (intravitreal, subretinal, or suprachoroidal) with generally acceptable safety profiles; however, functional improvements in vision are often inconsistent and temporary, and durable vision restoration remains unproven. Significant challenges persist, including immune rejection, tumorigenicity risks, weak engraftment, technical complexity, and regulatory barriers. These issues underscore the necessity for standardized manufacturing processes and well-controlled, long-term clinical trials to advance the field of IRD treatment.

Psoriasis is a chronic systemic inflammatory disease primarily affecting the skin, yet it is increasingly recognized for its systemic implications, particularly its strong association with type 2 diabetes mellitus (T2DM). This review synthesizes recent mechanistic and clinical evidence to elucidate the shared pathways linking psoriasis and T2DM, as well as to explore therapeutic strategies for this comorbidity. We conducted a narrative review of studies published between January 2020 and October 2025, encompassing preclinical models, clinical trials, and high-quality reviews that address pathogenesis and treatment. Key findings indicate that shared genetic loci and molecular pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, the IL-23/Th17 axis, and mitochondrial dysfunction associated with the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, contribute to both cutaneous inflammation and systemic metabolic dysregulation. Additionally, adipokine imbalances and chronic low-grade inflammation exacerbate insulin resistance and psoriatic skin pathology. Therapeutically, IL-17/IL-23 inhibitors, metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, and other immunomodulatory strategies demonstrate potential in addressing both dermatologic and metabolic features. These insights reinforce the notion of psoriasis as a systemic disorder with significant metabolic consequences, highlighting the need for integrated, multidisciplinary management. Future research should concentrate on precise gene-environment interactions, biomarker validation, and the development of treatments that simultaneously target both skin and metabolic pathology to advance precision medicine for patients with psoriasis-T2DM comorbidity.

Coronary artery disease (CAD) represents a complex interplay of genetic, environmental, and lifestyle factors. In this study, we utilized whole-exome sequencing (WES) on 28 patients with obstructive CAD to identify rare variants that may influence clinical outcomes beyond conventional atherosclerotic risk. We examined 74 genes curated from the Genomics England PanelApp, focusing on familial hypercholesterolemia (FH), cardiac arrhythmias (CA), and pulmonary arterial hypertension (PAH), ultimately detecting 8,251 variants. After applying a stringent filtering process with a population maximum allele frequency (PopMax AF) threshold of <0.1%, we identified 68 candidate variants across 23 genes. The majority were associated with CA (47/68, 69%), followed by PAH (12/68, 18%) and FH (9/68, 13%). Notably, 30 variants (44%) were novel, and 18 were categorized as high-impact frameshift mutations. The highest burden of candidate variants was found in the sodium voltage-gated channel alpha subunit 10 (SCN10A), followed by the ryanodine receptor 2 (RYR2), mitochondrial seryl-tRNA synthetase 2 (SARS2), A-kinase anchoring protein 9 (AKAP9), and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4). Clinical evaluation revealed a pathogenic variant in the low-density lipoprotein receptor (LDLR) and likely pathogenic variants in sodium voltage-gated channel alpha subunit 5 (SCN5A) and potassium voltage-gated channel subfamily Q member 1 (KCNQ1); additionally, nine other variants were predicted to be deleterious, including five novel SCN10A variants. Functional annotation using Gene Ontology (GO) and Human Phenotype Ontology (HPO) highlighted mechanisms impacting cardiac structure, electrical conduction, and lipid homeostasis.