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Yinghao Sun and colleagues report a genome-wide association study for prostate cancer in Han Chinese men. They identify two new risk-associated loci at chromosomes 9q31 and 19q13. Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10 −14 ) and 19q13.4 (rs103294, P = 5.34 × 10 −16 ) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3 , a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells ( P < 1 × 10 −4 ). These findings may advance the understanding of genetic susceptibility to prostate cancer.

William Isaacs and colleagues report evidence for a second prostate cancer risk locus in the HNF1B gene at 17q12, ∼26 kb from the previously reported risk locus in this region. The two loci are separated by a recombination hot spot and contribute independently to prostate cancer risk. We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, ∼26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 × 10 −9 for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.

Here we conducted an evidence-based study in developing and validating a urinary biomarker combination of gene methylation assays in patients with hematuria. A number of 99 urine samples were obtained and detected from Chinese patients with hematuria. The Cancer Genome Atlas cohort with methylation (HM450) beta-values and clinical data of 412 bladder cancer and 21 matching normal tissue was included as a validation series. A risk score formula was then developed and calculated by the targeted genes, weighted by their estimated regression coefficients from the multivariable binary logistic regression analyses, and evaluated by receiver operating characteristic (ROC) curves analysis. The combination assay of HOXA9, ONECUT2, PCDH17, PENK, TWIST1, VIM and ZNF154 was singled out according to the results of multivariate logistic regression analysis. The higher probability of DNA methylation of all the selected 7 genes was found in bladder cancer group than the control group. Remarkable higher DNA methylation beta-values of all the selected 7 genes were also displayed in bladder cancer tissues compared with their matching normal bladder tissues. And the AUC value of our risk score model were 0.894 and 0.851 in respective cohort, revealing highlighted predictive value of our risk score model on bladder cancer diagnosis. In conclusions, a urinary combined methylation assay of HOXA9, ONECUT2, PCDH17, PENK, TWIST1, VIM and ZNF154 displayed accurate prediction of bladder cancer in hematuria patients, which provided the guidance for the patients at early stage tumor and during the follow-up after operation. Of course, prospective study based on a hematuria cohort with a large sample size should be conducted to validate these findings in the future.

Polymorphisms of genes involved in the pharmacokinetic and pharmacodynamic processes underlie the divergent drug responses among individuals. Despite some successes in identifying these polymorphisms, the candidate gene approach suffers from insufficient gene coverage whereas the genome-wide association approach is limited by less than ideal coverage of SNPs in some important genes. To expand the potential of the candidate approach, we aim to delineate a comprehensive network of drug-response genes for in-depth genetic studies. Pharmacologically important genes were extracted from various sources including literatures and web resources. These genes, along with their homologs and regulatory miRNAs, were organized based on their pharmacological functions and weighted by literature evidence and confidence levels. Their coverage was evaluated by analyzing three commercial SNP chips commonly used for genome-wide association studies: Affymetrix SNP array 6.0, Illumina HumanHap1M and Illumina Omni. A panel of drug-response genes was constructed, which contains 923 pharmacokinetic genes, 703 pharmacodynamic genes and 720 miRNAs. There are only 16.7% of these genes whose all known SNPs can be directly or indirectly (r(2) > 0.8) captured by the SNP chips with coverage of more than 80%. This is possibly because these SNPs chips have notably poor performance over rare SNPs and miRNA genes. We have compiled a panel of candidate genes that may be pharmacologically important. Using this knowledgebase, we are able to systematically evaluate genes and their variants that govern an individual's response to a given pharmaceutical therapy. This approach can serve as a necessary complement to genome-wide associations.

Aims: Polymorphisms of genes involved in the pharmacokinetic and pharmacodynamic processes underlie the divergent drug responses among individuals. Despite some successes in identifying these polymorphisms, the candidate gene approach suffers from insufficient gene coverage whereas the genome-wide association approach is limited by less than ideal coverage of SNPs in some important genes. To expand the potential of the candidate approach, we aim to delineate a comprehensive network of drug-response genes for in-depth genetic studies. Materials & methods: Pharmacologically important genes were extracted from various sources including literatures and web resources. These genes, along with their homologs and regulatory miRNAs, were organized based on their pharmacological functions and weighted by literature evidence and confidence levels. Their coverage was evaluated by analyzing three commercial SNP chips commonly used for genome-wide association studies: Affymetrix SNP array 6.0, Illumina HumanHap1M and Illumina Omni. Results: A panel of drug-response genes was constructed, which contains 923 pharmacokinetic genes, 703 pharmacodynamic genes and 720 miRNAs. There are only 16.7% of these genes whose all known SNPs can be directly or indirectly (r.sup.2 > 0.8) captured by the SNP chips with coverage of more than 80%. This is possibly because these SNPs chips have notably poor performance over rare SNPs and miRNA genes. Conclusion: We have compiled a panel of candidate genes that may be pharmacologically important. Using this knowledgebase, we are able to systematically evaluate genes and their variants that govern an individual'âs response to a given pharmaceutical therapy. This approach can serve as a necessary complement to genome-wide associations.

Spinal cord ischemia-reperfusion injury (SCII) often causes neurological damage and devastating sensory and motor dysfunction. Identifying key genes and signaling pathways in SCII progression may provide novel therapeutic targets. Two gene expression datasets (GSE138966 and GSE167274) were obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using R software, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Hub genes were screened via Venn analysis, and a protein-protein interaction (PPI) network was constructed using Cytoscape software. Key hub genes were validated by qRT-PCR in a rat SCII model. A total of 99 hub genes were identified, including 60 up-regulated and 39 down-regulated genes. KEGG analysis revealed significant enrichment in MAPK, cAMP, and Rap1 signaling pathways. PPI network analysis highlighted Ccl2 , Mmp9 , Itgb1 , Timp1 , Myd88 , and Lgals3 as central nodes. qRT-PCR validation showed persistent up-regulation of Tnc , Thbs2 , and S100a10 at 1 h, 24 h, and 48 h post-SCII; early up-regulation of Msn , Lcp1 , Lcn2 , and Akap12 at 1 h; and delayed up-regulation of Itga5 at 48 h ( P  < 0.05). This study identifies novel, key SCII-related genes that have been largely overlooked and, for the first time, defines their time-dependent expression patterns via in vivo experimental validation. Our findings provide crucial mechanistic insights and nominate promising therapeutic targets for SCII.

Background: To overcome the gastrointestinal and hepatic toxicity of oral pirfenidone (PFD) in the treatment of idiopathic pulmonary fibrosis (IPF), this study systematically constructed a minimal-component, buffer-free pirfenidone aerosol inhalation solution (PFD-AIS), achieving lung-targeted delivery, reduced systemic exposure, and maintained antifibrotic efficacy. Methods: Analytical methods for PFD-AIS, covering content, related substances, aerodynamic particle size distribution (APSD), and delivered dose uniformity, were established. The prescription and preparation process of the formulation was optimized by evaluating its key quality attributes. Pharmacodynamic and pharmacokinetic evaluations of PFD-AIS were performed in a mouse lung-fibrosis model and SD rats. Results: The final specification of PFD-AIS was set to 40 mg:4 mL, containing 40 mg of PFD, 28 mg of sodium chloride, and 4 mL of injection water with a preparation process of 40 °C for 60 min and a pH range of 4–8. The PFD-AIS exhibited a fine particle fraction (FPF) of 56.1%, meeting the requirements for deep lung deposition. The delivered dose and delivery rate were 17.52 mg and 2.48 mg/min, respectively, both complying with inhalation formulation standards. In the bleomycin-induced IPF mouse model, the PFD-AIS markedly improved pulmonary fibrosis pathology, reduced the lung coefficient, and significantly lowered serum ALT/AST levels, indicating hepatic protection. In the SD rats, compared with oral dosing, PFD-AIS administration resulted in significantly lower AUC0−t (−63%) and AUC0–∞ (−67%) values, demonstrating a substantial reduction in systemic drug exposure. Conclusion: This work presents a complete, systematic chain—from formulation, process, and quality control to pharmacodynamics and pharmacokinetics—of a PFD-AIS. The PFD-AIS is effective and feasible, featuring a stable preparation process and controllable quality. Lung-directed drug delivery enhances PFD’s therapeutic efficacy, reduces systemic exposure and liver toxicity, and offers significant clinical advantages.

This study compared the efficacy of neoadjuvant immunochemotherapy (nICT) followed by surgery versus upfront surgery for locally advanced esophageal squamous cell carcinoma (ESCC). In this prospective controlled trial (2020-2025), 623 stage II-IIIB ESCC patients were included; 192 received nICT (cisplatin, nab-paclitaxel, sintilimab) before surgery, and 431 underwent direct surgery. Propensity-score matching (PSM) and overlap weighting were used to adjust for baseline confounders. After PSM (144 pairs), the nICT group showed significantly improved progression-free survival (PFS; HR = 0.31, p<0.001) and overall survival (OS; HR = 0.42, p=0.002) compared to the upfront surgery group. The nICT group also had higher 1-/3-year PFS (88.8%/84.3% vs. 68.1%/52.8%) and OS rates (94.8%/84.7% vs. 89.6%/65.2%). Sensitivity analysis using overlap weighting confirmed these robust findings (PFS: HR = 0.37, p<0.001; OS: HR = 0.62, p=0.033). For locally advanced ESCC, neoadjuvant immunochemotherapy significantly improves both PFS and OS compared to upfront surgery, establishing it as a highly effective treatment strategy.

Background: Cardiovascular diseases (CVDs) are the leading global cause of mortality and disability, with prevalence increasing due to aging and risk factors like obesity and hypertension. The retina, rich in microvasculature, provides a unique opportunity to investigate microvascular dysfunction linked to CVDs and other systemic vascular diseases. Method: This study used a multifaceted approach to assess the genetic correlation and causal relationship between retinal characteristics and CVDs. Linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) analyses were conducted using genome-wide association study (GWAS) data from the UK Biobank and FinnGen datasets. A cross-sectional study was also conducted to validate the findings, collecting optical coherence tomography (OCT) images from 124 eyes (89 with CVDs and 35 healthy controls). A prediction model is based on least absolute shrinkage and selection operator (LASSO) regression to assess the risk of CVD. Result: Using LDSC and two-sample MR, we found genetic evidence consistent with a causal effect whereby genetically proxied thinner retinal nerve fiber layer (RNFL) was associated with higher risks of hypertension and myocardial infarction (MI), while genetically proxied thicker photoreceptor inner segment/outer segment (PR-IS/OS) was associated with coronary heart disease and MI (false discovery rate [FDR] thresholds as reported). Genetically proxied thinner retinal pigment epithelium (RPE) showed an inverse association with stroke risk. Several circulating biomarkers—including lipoprotein(a) [Lp(a)], low-density lipoprotein cholesterol (LDL-C), and ApoB—exhibited MR evidence of association with multiple CVDs. In a cross-sectional cohort, retinal layer differences and their relationships with lipids were directionally consistent with the genetic findings. Conclusion: Retinal structural traits measured by OCT—particularly RNFL, PR-IS/OS, and RPE thickness—are best interpreted as non-invasive markers that reflect systemic vascular biology. Our MR analyses support shared etiologic pathways between retinal microstructure and CVDs rather than implying that retinal damage clinically causes cardiovascular events. Findings warrant validation in larger and more diverse populations and should not be considered definitive proof of causality.

The reduced-tillage (Rt) has been proposed as a strategy to improve soil organic carbon and soil total nitrogen pools. However, little is known of the role of the reduced-tillage compared with the organic (Org) and conventional (Con) management in the Songnen Plain of China. We studied the 4 yr effect of three management strategies (Con, Org and Rt management) on labile soil organic carbon (C) and nitrogen (N) pools, including variation in mineralizable carbon and nitrogen, microbial biomass carbon and nitrogen, dissolved organic carbon and nitrogen in the rotation of alfalfa-corn established in 2009. Soil characteristics including soil organic carbon (SOC), soil total nitrogen (STN), dissolved organic carbon (DOC), dissolved organic nitrogen (DON), microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN) were quantified in samples collected during the 9 yr rotation of 5yr-alfalfa ( Medicago sativa L.) followed by 4 yr corn ( Zea mays L.). The mineralizable C was increased in the four years, and although not statistically significant, 12% higher in the fourth year under reduced-tillage than conventional management (268 kg ha −1 ). Soil organic C was increased by 30% under reduced-tillage compared to conventional management (15.5 Mg ha −1 ). Three management strategies showed similar labile N pools in the Con and Org management, but differed in the Rt management. Org management showed significantly lesser mineralizable and inorganic N compared to other strategies, but soil microbial community and comparable crop yield across management strategy in year 4, indicating more efficient N use for organic than other management strategy. In our conditions, reduced-tillage for corn cropping after five years of alfalfa grassland can accumulate labile C and N and improve N utilization to for crop yields in the forage-based rotations. These findings suggest an optimal strategy for using Rt management to enhance soil properties and crop yield in plantation soils and provide a new perspective for understanding the potential role of Rt management in plantation soil.