Itsuki Kageyama

ABSTRACT We examined the association between serum uric acid (UA) levels and cancer incidence through a conventional observational and two‐sample Mendelian randomization (MR) study in the same population (triangulation). We followed 13,695 individuals aged 35–69 years for cancer incidence (total, gastric, colorectal, lung, prostate, and breast cancers) over a median period of 10.6 years. The conventional observational dataset consisted of two subsets sampled from the full cohort using different sampling procedures. Odds ratios were computed using logistic regression for one type of single‐nucleotide polymorphism (SNP) array, and hazard ratios were computed using the Cox proportional hazards model for another type of SNP array, combining them to calculate conventional relative risks (RRs). For two‐sample MR, 42 UA‐related SNPs were identified from Biobank Japan genome‐wide association study data (109,029 participants). Associations between these SNPs and cancer were estimated using J‐MICC Study data. MR RRs of cancer incidence per one standard deviation (SD) increase in genetically predicted UA were predicted using the inverse variance weighted (IVW) method and other MR approaches. In the conventional analysis, the highest UA concentration group (≥ 6.4 mg/dL) showed a decreased risk of lung cancer (RR: 0.64, 95% confidence interval [CI]: 0.41–0.98) compared with the lowest UA concentration group (< 4.0 mg/dL). The two‐sample MR (IVW method) also suggested that UA was inversely (although marginally) associated with lung cancer risk (RR per one SD: 0.65, 95% CI: 0.40–1.05). In conclusion, lower, rather than higher, UA concentrations may be associated with an increased risk of lung cancer.

ABSTRACT Early detection of pancreatic cancer remains challenging, and reliable circulating biomarkers are needed to enable earlier diagnosis and improve clinical outcomes. We conducted a plasma proteomics study using the Olink Explore HT platform to identify novel biomarker candidates for early‐stage pancreatic cancer. The study included 42 patients with stage I–II pancreatic cancer and 43 matched controls. Plasma protein levels were quantified using the Olink Proximity Extension Assay, and differential abundance was assessed using Welch's t ‐test with correction for multiple testing. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC). Among 5419 proteins analyzed, 982 showed significant differences between cases and controls. Carboxylesterase 3 (CES3) was the most significantly decreased protein, whereas leukocyte immunoglobulin‐like receptor B4 (LILRB4) was the most significantly increased protein; both demonstrated excellent diagnostic performance (AUC = 0.91). In addition, pancreatic polypeptide (PPY) showed markedly reduced levels in patients with tumors arising in the head of the pancreas, suggesting anatomical specificity. This comprehensive Olink‐based proteomic analysis identifies CES3 and LILRB4 as promising plasma biomarkers for early‐stage pancreatic cancer and highlights PPY as informative for tumor localization. These findings provide a valuable resource for biomarker discovery and support further validation of these candidates for noninvasive early detection and risk stratification.

OBJECTIVES: Mitochondrial dysfunction has been implicated in neurodegenerative diseases, but evidence regarding its association with cognitive performance in the general population remains limited. This study aimed to examine the association between peripheral blood mitochondrial DNA copy number (mtDNA-CN) and cognitive function in the general Japanese population. METHODS: We conducted a cross-sectional analysis of 282 participants (134 men and 148 women) from the Yakumo Study, a population-based health examination in Hokkaido, Japan. Peripheral blood mtDNA-CN was measured by quantitative real-time PCR and categorized into tertiles. Cognitive function was assessed using the short version of the Mini-Mental State Examination (SMMSE), the Logical Memory Test (LMT), and the Digit Cancellation Test (D-CAT). Logistic regression analyses were performed to evaluate the association between mtDNA-CN levels and cognitive performance, with adjustments for relevant demographic and clinical factors. RESULTS: Lower mtDNA-CN was significantly associated with poorer SMMSE scores in women and with reduced D-CAT3 performance-reflecting attention and executive function-in men. No significant associations were observed for LMT scores in either sex. These domain- and sex-specific associations remained consistent after adjustment for potential confounders. CONCLUSIONS: Lower mtDNA-CN was associated with poorer cognitive performance in the general Japanese population, in a cognitive domain- and sex-specific manner. mtDNA-CN thus has potential as a non-invasive biomarker for the early identification of individuals at increased risk of cognitive decline. Longitudinal studies are necessary to evaluate its predictive utility and potential application in dementia prevention strategies.