Biomolecules & biomedicine最新文献

Coronary heart disease (CHD) is a leading cause of morbidity and mortality; patients with type 2 diabetes mellitus (T2DM) are at particularly high risk, highlighting the need for reliable biomarkers for early detection and risk stratification. We investigated whether combining the stress hyperglycemia ratio (SHR) and systemic inflammation response index (SIRI) improves CHD detection in T2DM. In this retrospective cohort of 943 T2DM patients undergoing coronary angiography, associations of SHR and SIRI with CHD were evaluated using multivariable logistic regression and restricted cubic splines; robustness was examined with subgroup and sensitivity analyses. Discriminative performance was assessed by receiver operating characteristic (ROC) analysis and reclassification metrics (integrated discrimination improvement [IDI], net reclassification improvement [NRI]). Internal validation used bootstrapping, with calibration and discrimination yielding apparent and bias-corrected estimates. Of 943 patients, 600 had CHD. Multivariable models showed SHR (OR=1.68; 95% CI, 1.14-2.46; p=0.008) and SIRI (OR=2.17; 95% CI, 1.54-3.05; p<0.001) were independently associated with CHD, with nonlinear relationships (p for nonlinearity <0.05). Findings were consistent across subgroups and sensitivity analyses. The combined SHR-SIRI model achieved an AUC of 0.813 (95% CI, 0.783-0.843), outperforming SHR alone (AUC=0.773; 95% CI, 0.740-0.805) and SIRI alone (AUC=0.745; 95% CI, 0.713-0.778), and significantly improved NRI and IDI (p <0.05). All models showed strong discrimination and calibration. In conclusion, SHR and SIRI are independently associated with CHD in T2DM, and their combination enhances early identification of high-risk individuals.

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which dysregulated interferon regulatory factor 5 (IRF5) may amplify pro-inflammatory pathways; prior genetic studies of IRF5 single-nucleotide variants (SNVs) in RA are inconsistent across populations and have not included mestizo Mexicans or evaluated rs59110799 in RA. We aimed to test whether four IRF5 SNVs (rs2004640G/T, rs2070197T/C, rs10954213G/A, rs59110799G/T) confer susceptibility to RA in women from Central Mexico. In a case-control study of 239 women with RA and 231 female controls (all self-identified Mexican-Mestizos, ≥3 generations), genotyping was performed by real-time PCR with TaqMan® probes; 80% of samples were duplicated (100% concordance) and control genotypes conformed to Hardy-Weinberg equilibrium. Association was assessed under allelic and multiple genetic models using logistic regression adjusted for age and birthplace, with Bonferroni correction for 23 tests (α=0.0022). Haplotype and linkage disequilibrium (LD) were analyzed with Haploview; putative functional effects were explored in silico (SNPinfo; GTEx). The minor alleles rs2004640T [OR=1.69, 95% CI 1.29-2.21; p=1.2×10⁻⁴], rs2070197C [OR=1.85, 1.39-2.46; p=2.0×10⁻⁵], and rs10954213A [OR=1.47, 1.12-1.93; p=0.002] were associated with increased RA risk after correction. Genotype-based associations were observed for rs2004640 (codominant and recessive) and rs2070197 (codominant, dominant, recessive). rs59110799G/T showed no significant association after correction (dominant model OR=1.69, 1.15-2.48; p=0.007). Nine haplotypes were identified; the haplotype carrying all four risk alleles (TCAT) was not associated, and two haplotypes with nominal signals (GCAG, TTGT) had control frequencies <1% and were excluded; variants were not in strong LD (r²<0.80). Our findings-providing the first evaluation of these IRF5 variants in Mexican women and the first report of rs59110799 in RA-support a role for IRF5 (rs2004640, rs2070197, rs10954213) in RA susceptibility in this Latin American population. Given the female-only design and moderate statistical power, replication and functional studies are warranted.

Neoadjuvant stereotactic radiosurgery (SRS) has emerged as a promising strategy for managing brain metastases, offering several advantages over traditional postoperative approaches. By delivering targeted radiation prior to surgical resection, neoadjuvant SRS aims to enhance local tumor control, reduce the risk of leptomeningeal dissemination, and optimize treatment efficiency. Recent findings suggest that neoadjuvant SRS provides comparable, if not superior, local control compared to postoperative SRS, while exhibiting lower rates of radiation necrosis and leptomeningeal disease. However, uncertainties persist regarding optimal dosing regimens, treatment timing, and patient selection criteria, as factors such as tumor size, volume, and histology may significantly influence clinical outcomes. Additionally, while neoadjuvant SRS addresses challenges related to target delineation and delays associated with postoperative treatment, its long-term efficacy and integration with systemic therapies require further investigation. This review consolidates evidence from recent retrospective and prospective studies, focusing on key outcomes such as local control rates, radiation toxicity profiles, and overall survival.

Sepsis is a complex systemic disease in which systemic toxicity-arising from inflammation-immune dysregulation, oxidative stress, programmed cell death (apoptosis, pyroptosis, ferroptosis), and metabolic reprogramming-drives multi-organ injury. The aim of this review was to synthesize how signaling pathways evolve within and between key organs (lungs, liver, kidneys, heart) and to evaluate whether multi-omics integration and network modeling can identify critical toxic nodes and predict disease progression. We conducted a narrative review of English-language mechanistic studies published between 2015 and 2025 in PubMed, Web of Science, and Scopus, supplemented by bibliography screening, while excluding case reports, conference abstracts, and non-mechanistic work. The evidence depicts a high-dimensional systemic network that remodels over time, with early pro-inflammatory modules transitioning toward immunosuppression and organ-specific injury patterns, while inter-organ propagation is mediated by damage-associated molecular patterns (DAMPs), exosomes, and metabolites. Oxidative stress and mitochondrial dysfunction, via reactive oxygen species (ROS), couple to pyroptosis and ferroptosis to reinforce toxicity loops, and computational approaches such as dynamic Bayesian networks (DBN) and graph neural networks (GNN) delineate regulatory hubs and support forecasting. Therapeutic progress has concentrated on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), the NOD-, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome, and glutathione peroxidase 4 (GPX4), alongside artificial intelligence (AI)-assisted personalized toxicity maps and dynamic early-warning systems, though challenges remain in specificity, safety, and resistance. In conclusion, sepsis can be conceived as a temporally staged systemic toxicity network, and when combined with multi-omics, DBN/GNN modeling, and AI-enabled decision support, this framework offers a path toward individualized, mechanism-based care, while requiring rigorous validation to ensure clinical durability.

Secreted Frizzled-Related Protein 4 (sFRP4), the largest member of the Secreted Frizzled-Related Protein (sFRP) family, contains two functional domains: a cysteine-rich domain (CRD) homologous to the Wnt-binding region of Frizzled (FZD) receptors and a netrin-like (NTR) domain structurally similar to axonal guidance proteins. By modulating the Wingless/Integrated (Wnt) signaling pathway, sFRP4 regulates essential cellular processes including proliferation, differentiation, apoptosis, and tissue homeostasis. This review aims to provide a comprehensive overview of the dualistic roles of sFRP4 in cancer, highlighting its tumor-suppressive and tumor-promoting functions, underlying molecular mechanisms, and therapeutic potential. A systematic literature search was conducted in PubMed and Web of Science databases (1996-2025) using predefined keywords, and from 277 identified publications, 47 studies were included that comprised clinical data, in vitro cell models, and in vivo experimental systems. Findings demonstrate that sFRP4 frequently acts as a tumor suppressor by sequestering Wnt ligands, suppressing cancer stem cell-like properties, reprogramming tumor metabolism, inhibiting angiogenesis, and enhancing chemosensitivity. Its downregulation is often driven by promoter hypermethylation or repression mediated by microRNAs (miRNAs). Conversely, in gastrointestinal and prostate cancers, sFRP4 is frequently upregulated, where it promotes Wnt pathway activation, invasion, stemness, chemoresistance, and reshaping of the tumor immune microenvironment. Mechanistic insights indicate that post-translational modifications and nuclear localization of sFRP4 further contribute to its paradoxical context-dependent functions. In conclusion, sFRP4 exerts dual roles in tumorigenesis, acting either as a tumor suppressor or promoter depending on tissue type, tumor microenvironment, and regulatory mechanisms. This complexity underscores both the challenges and opportunities of targeting sFRP4 in oncology, and future therapeutic strategies incorporating recombinant proteins, synthetic peptides, and nanoparticle-based delivery systems hold promise for harnessing its anti-tumor potential while overcoming resistance mechanisms.

Prediabetes, characterized by intermediate hyperglycemia, is increasingly prevalent worldwide. While diabetes has been associated with a heightened risk of various cancers, the relationship between prediabetes and thyroid cancer remains ambiguous. This meta-analysis sought to assess whether prediabetes correlates with an elevated incidence of thyroid cancer. A systematic literature search was conducted across PubMed, Embase, Web of Science, Wanfang, and CNKI to identify longitudinal studies that compared the incidence of thyroid cancer in individuals with prediabetes to those with normoglycemia. Risk ratios (RRs) with 95% confidence intervals (CIs) were aggregated using a random-effects model. Subgroup and sensitivity analyses were performed to identify potential effect modifiers. Six prospective cohort studies, encompassing 5,743,849 participants, were included in the analysis. Overall, prediabetes was not significantly correlated with thyroid cancer incidence (RR = 1.04; 95% CI: 0.98-1.11; p = 0.23; I² = 53%). Subgroup analyses revealed no significant variations based on age, sex, region, follow-up duration, or definition of prediabetes. Notably, a significant association was identified in studies utilizing cancer registries or validated clinical diagnoses (RR = 1.29; 95% CI: 1.04-1.60), in contrast to studies relying solely on ICD-10 codes (RR = 1.01; 95% CI: 0.98-1.05; p for subgroup difference = 0.03). In conclusion, prediabetes was not linked to a significantly increased risk of thyroid cancer overall. However, a potential association was noted in studies employing clinically validated cancer diagnoses. These findings, derived from observational cohorts, should be interpreted cautiously, and further prospective research is necessary to elucidate any causal relationship.

Molecular classification has emerged as a critical tool for guiding personalized treatment in endometrial cancer (EC) and atypical endometrial hyperplasia (AEH). This retrospective study aimed to assess the impact of molecular classification on fertility-sparing treatment outcomes in patients diagnosed with EC and AEH who underwent fertility preservation therapy between 2006 and 2021. Patients were categorized into four molecular subtypes using immunohistochemistry (IHC) and Sanger sequencing, based on the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE): POLE-ultramutated, mismatch repair (MMR) deficient (MMRd), p53 abnormal (p53abn), and p53 wild-type (p53wt). All patients were evaluated for oncological prognosis and fertility outcomes, with a total of 103 patients included in the analysis. Recurrence rates exhibited significant differences among the molecular classifications, with the lowest recurrence rate observed in the p53wt subtype (19.7%), followed by MMRd (30.4%), POLE-ultramutated (66.7%), and p53abn (71.4%) subtypes. Multivariate Cox regression analysis indicated that the p53abn subtype was a significant risk factor for recurrence following conservation therapy when compared to the p53wt subtype. Additionally, there was a notable disparity in standard surgical treatment due to treatment failure, with operation rates of 7.5%, 19.2%, 66.7%, and 57.1% for the p53wt, MMRd, POLE-ultramutated, and p53abn subtypes, respectively. Regarding fertility outcomes, the p53wt group demonstrated the highest pregnancy rate after achieving a complete response compared to the other subtypes; however, no significant differences were observed in overall pregnancy outcomes. The ProMisE molecular classification holds significant prognostic value for patients with EC and AEH undergoing fertility-sparing treatment. Among the molecular subtypes, p53wt appears to be the most favorable for fertility-preserving interventions. This study provides essential insights into reproductive outcomes for this patient population.

Small-cell lung cancer (SCLC) is a tobacco-associated neuroendocrine tumor comprising ~15% of lung cancers (~150,000 cases/year). For decades, outcomes stagnated: most patients present with extensive-stage disease, screening rarely detects early tumors, surgery is seldom feasible, and platinum–etoposide remained the first-line standard with median overall survival (OS) <12 months. Radiotherapy (including consolidative thoracic RT) and prophylactic cranial irradiation or MRI surveillance offered incremental gains. Two shifts have begun to change the field. First, four transcriptional subtypes (SCLC-A, -N, -P, and inflammatory SCLC-I) support a more personalized approach, with SCLC-I appearing more responsive to immune checkpoint inhibitors (ICI). Second, adding atezolizumab or durvalumab to chemotherapy in extensive-stage SCLC produced a modest median OS gain but, crucially, a tail of long-term survivors. Subsequent trials extended these advances: IMforte suggested benefit from lurbinectedin maintenance with atezolizumab in ES-SCLC, and ADRIATIC demonstrated a landmark OS improvement (~22 months) with durvalumab consolidation after concurrent chemoradiotherapy in limited-stage SCLC. Targeted strategies are now emerging. Delta-like ligand 3 (DLL3), overexpressed in >80% of SCLC, enables T-cell–redirecting therapy: the bispecific T-cell engager (BiTE®) tarlatamab improved OS to 13.6 vs 8.3 months over standard second-line chemotherapy, with manageable cytokine release syndrome and occasional ICANS. B7 homolog 3 (B7-H3, CD276), uniformly expressed across SCLC subtypes and linked to poor prognosis, is another compelling target: the antibody–drug conjugate ifinatamab deruxtecan achieved a 54.8% response rate and meaningful survival in heavily pretreated patients, earning FDA Breakthrough designation. Together, DLL3- and B7-H3–directed therapies (with additional ADCs against Trop-2 and SEZ6 in development) are redefining second-line and later care. Key next steps include optimizing sequencing/combination strategies, managing BiTE® specific toxicities, and developing predictive biomarkers. After decades of futility, SCLC is transitioning from uniform chemotherapy to a precision-medicine paradigm with cautious optimism.

Postoperative delirium (POD) is a prevalent and serious complication in adults undergoing surgery with general anesthesia. Remimazolam, an innovative ultra-short-acting benzodiazepine, has been identified as a potential alternative to propofol due to its advantageous pharmacological properties. However, its impact on POD remains uncertain. This study conducted a systematic review and meta-analysis following PRISMA guidelines. A comprehensive search of the PubMed, Embase, Cochrane Library, Web of Science, CNKI, and Wanfang databases was performed up to March 29, 2025. Randomized controlled trials (RCTs) comparing remimazolam and propofol in adult surgical patients under general anesthesia, specifically reporting on POD incidence, were included. A random-effects model was utilized to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs), accounting for heterogeneity. The analysis included seventeen RCTs encompassing 3,133 patients. Overall, remimazolam significantly decreased the risk of POD compared to propofol (OR: 0.71, 95% CI: 0.52-0.97, p = 0.03; I² = 36%). Sensitivity analyses, which involved excluding one study at a time, yielded consistent results, reinforcing the robustness of the findings. Subgroup analyses revealed uniform effects across different study designs (single-blind vs. double-blind; OR: 0.73 vs. 0.64; p = 0.71) and age groups (adults vs. elderly; OR: 0.64 vs. 0.72; p = 0.79). A trend toward greater benefit was observed in studies with longer follow-up periods (7 days: OR: 0.42) and in those employing the CAM or CAM-ICU for POD diagnosis, although subgroup differences were not statistically significant. In conclusion, remimazolam is associated with a significantly reduced risk of POD compared to propofol in adults undergoing general anesthesia.

Decitabine (DAC), a DNA methyltransferase inhibitor (DNMTi), is clinically effective in hematological malignancies such as myelodysplastic syndrome and acute myeloid leukemia, but its precise antineoplastic mechanisms remain incompletely understood. Beyond promoter demethylation, DAC is known to activate endogenous retroviruses (ERVs) and trigger type I interferon (IFN-I) responses, a phenomenon known as viral mimicry. The aim of this study was to investigate the roles of the mouse mammary tumor virus (MMTV) and interferon-β (IFN-β) in DAC-mediated tumor suppression. We employed two murine tumor models-4T1 mammary carcinoma and MC38 colon adenocarcinoma-in syngeneic immunocompetent mice, immunodeficient nude mice, and in vitro cultures. RNA and protein expression were assessed by quantitative PCR and immunoblotting, while functional contributions of MMTV and IFN-β were tested using short hairpin RNA (shRNA) knockdowns. DAC treatment suppressed tumor growth and pulmonary metastasis in vivo and inhibited cancer cell proliferation in vitro. It induced transcription of MMTV and expression of IFN-β, with a strong negative correlation between MMTV Env protein levels and tumor mass. Knockdown of either MMTV or IFN-β conferred resistance to DAC, confirming their functional roles. Reciprocal regulation was observed: MMTV knockdown reduced IFN-β expression, while IFN-β knockdown increased MMTV Env accumulation. Furthermore, DAC upregulated interferon regulatory factor 7 (IRF7), but this effect declined during prolonged treatment, suggesting a temporally restricted therapeutic window. In conclusion, our findings provide in vivo support for the viral mimicry hypothesis and demonstrate that MMTV and IFN-β contribute to DAC-mediated tumor suppression. The observed IRF7 downregulation and potential induction of immune checkpoints highlight the importance of therapeutic strategies combining DNMTis with immune checkpoint blockade to sustain antineoplastic efficacy.