By inhibiting dipeptidyl peptidase-4 (DPP-4), teneligliptin provides a therapeutic option for type 2 diabetes mellitus (T2DM) that is widely used in Asia. A generic product could lessen treatment costs, provided that its systemic availability is equivalent to that of the branded formulation. Such comparative information remains scarce for Chinese recipients of teneligliptin hydrobromide. We therefore investigated a new generic tablet as the test product and Tenelia^® as the reference product in fasted and fed settings.

A total of 52 healthy Chinese adults participated in a randomized, open-label crossover investigation involving one dose, two sequences, and two periods; 26 participants were assigned to each sequence. The test and reference products were each administered at 40 mg in the fasting and fed studies, and administrations were 7 days apart. A validated LC-MS/MS assay yielded plasma teneligliptin concentrations. After logarithmic transformation, AUC_0-t, AUC_0-∞, and C_max were subjected to analysis of variance (ANOVA). Equivalence required the 90% confidence interval (CI) of each test/reference geometric mean ratio (GMR) to fall completely between 80% and 125%. CTCAE v5.0 was used to grade adverse events (AEs).

In each dietary setting, the two products produced similar teneligliptin exposure. For AUC_0-t, AUC_0-∞, and C_max, every test/reference GMR had a 90% CI between the predefined boundaries of 80% and 125%. Serious adverse events (SAEs) did not occur.

Whether administered in the fasting or fed state, the generic tablet met the regulatory requirements for bioequivalence with Tenelia^®. The pharmacokinetic comparison consequently supports the generic product as an equivalent alternative.

The study was registered retrospectively in the Chinese Clinical Trial Registry (ChiCTR2500112749; November 19, 2025). Ethical approval was obtained from the Ethics Committee of The Affiliated Panyu Central Hospital, Guangzhou Medical University (PYZXYYEC [2025-013 (YW)]-01).

To evaluate whether abdominal magnetic resonance imaging (MRI)-derived metabolic phenotypes improve the opportunistic prediction of incident type 2 diabetes (T2D) beyond clinical risk models.

This study included 36,833 UK Biobank participants who underwent abdominal MRI and were free of T2D at imaging baseline. The original Cambridge Diabetes Risk Score (CDRS) was evaluated, and glycated haemoglobin (HbA1c) was added to form the clinical CDRS model. MRI phenotypes were selected using a LASSO-based selection-frequency analysis and added to construct the clinical CDRS-MRI model. Model performance was assessed in an internal validation set using Harrell's C-index, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI).

During a median follow-up of 7.38 years, 570 participants developed incident T2D. The selection-frequency analysis retained four MRI phenotypes: liver proton density fat fraction, liver volume, visceral fat volume, and pancreas volume. In the internal validation set, C-indices were 0.765 (95% CI, 0.731-0.800) for the original CDRS model, 0.820 (95% CI, 0.786-0.849) for the clinical CDRS model, and 0.849 (95% CI, 0.818-0.877) for the clinical CDRS-MRI model. The clinical CDRS-MRI model improved the C-index by 0.084 versus the original CDRS model and by 0.029 versus the clinical CDRS model, with a continuous NRI of 56.2% (95% CI, 40.6%-70.0%) and an IDI of 0.022 (95% CI, 0.010-0.037).

Abdominal MRI-derived phenotypes improved the prediction of incident T2D beyond established clinical risk models. These findings support secondary use of available abdominal MRI data for metabolic risk stratification, pending external validation.

Diabetic foot ulcer (DFU) is a severe complication of diabetes, characterized by chronic, difficult‑to‑heal foot wounds. It has been hypothesized that miR‑222‑3p may influence wound healing via the regulation of angiogenesis. To elucidate the underlying mechanism, experimental investigations were conducted in vitro using human dermal microvascular endothelial cells (HMEC‑1) and in vivo in a mouse model of streptozotocin‑induced diabetes. Methylglyoxal (MGO), a glycolytic intermediate, is known to contribute to diabetic vascular complications. The results demonstrated that MGO‑treated HMEC‑1 cells exhibited an increased expression of miR‑222‑3p and impaired microvascular endothelial cell function. The overexpression of miR‑222‑3p in MGO‑treated HMEC‑1 cells further suppressed cell proliferation, migration and tube formation, while it enhanced apoptosis. Moreover, the upregulation of miR‑222‑3p reduced the expression of apelin (APLN), and dual‑luciferase reporter assays confirmed APLN as a direct downstream target of miR‑222‑3p. The silencing of APLN markedly impaired HMEC‑1 cell function. Notably, both the exogenous supplementation with Apelin‑13 and the overexpression of APLN significantly reversed endothelial dysfunction caused by the upregulation of miR‑222‑3p. In vivo, in both normal and diabetic mice, the elevated expression of miR‑222‑3p in skin wounds reduced APLN levels in the peri‑wound tissue and impaired wound healing. However, the overexpression of APLN or the inhibition of miR‑222‑3p with an antagomiR reversed this impairment. Collectively, these results suggest that miR‑222‑3p impairs microvascular endothelial cell function by targeting APLN, thereby contributing to delayed wound healing in diabetic skin.

This study aims to investigate the genetic correlation and potential causal relationship between diabetes mellitus (DM) and Hashimoto thyroiditis (HT), and to assess the effects of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) on HT risk, with the goal of informing thyroid-function monitoring in patients with DM and improving HT management. We used linkage disequilibrium score regression (LDSC) to estimate the genetic correlation between DM and HT. We then performed two-sample Mendelian randomization (TSMR) using data from genome-wide association studies (GWAS) to evaluate potential causal effects of DM subtypes on HT. We selected single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) and applied the inverse-variance weighted (IVW) method along with complementary sensitivity analyses to estimate causal effects. We assessed heterogeneity using Cochran's Q test and identified outlier SNPs with MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier). We used the MR-Egger intercept to test for directional pleiotropy. Finally, we performed a leave-one-out analysis to evaluate whether any single SNP unduly influenced the MR estimates. LDSC showed a significant negative genetic correlation between DM and HT (rG = -0.3285, SE = 0.062, P = 1.20 × 10-7), with evidence of nonzero SNP heritability (h2P < .005). In two-sample MR analyses of DM overall, the IVW estimate suggested increased HT risk in UK Biobank (OR = 7.26, 95% CI = 1.95-27.11, P < .05) and was directionally consistent in FinnGen (OR = 1.08, 95% CI = 1.02-1.14, P < .05). Subtype-specific MR analyses supported a causal effect of T2DM on HT (OR = 1.10, 95% CI = 1.05-1.16, P < .05), whereas there was no evidence for a causal effect of T1DM (OR = 1.04, 95% CI = 0.97-1.12, P > .05). We provide genetic support for a causal relationship between T2DM liability and higher HT risk, with no evidence of a direct causal effect for T1DM. These findings motivate periodic thyroid-function assessment and integrated endocrine-metabolic care in T2DM, and warrant multi-ancestry and mechanistic studies to refine risk prediction and identify actionable biology.

Previous Mendelian randomization (MR) studies have linked obesity and type 2 diabetes (T2D) liability to osteomyelitis and skin or soft-tissue infection, but the reproducibility of these associations across independent outcome biobanks remains uncertain. We conducted cross-biobank univariable MR and multivariable MR analyses using European-ancestry genome-wide association study summary statistics. FinnGen Release 13 osteomyelitis (2519 cases and 471,012 controls) was designated as the primary clinical outcome, whereas cellulitis (10,223 cases and 468,418 controls) served as a comparative infection outcome; UK Biobank (UKB)-derived outcomes were used for replication. Exposure instruments containing UKB participants were restricted to FinnGen analyses, while separate non-UKB instruments were used for replication and cross-biobank pooling. Inverse-variance weighting was the primary estimator, with instrument-strength, pleiotropy, directionality, influential-variant, and multivariable conditional-strength analyses used to assess robustness. In FinnGen, each 1-standard-deviation increase in genetically predicted body mass index (BMI) on the source-GWAS standardized scale was associated with osteomyelitis (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.33-1.93) and cellulitis (OR 1.50, 95% CI 1.37-1.63), while T2D liability was associated with osteomyelitis (OR 1.41, 95% CI 1.24-1.61). Using non-UKB instruments, BMI-osteomyelitis estimates were directionally consistent across FinnGen and UKB (pooled OR 1.38, 95% CI 1.13-1.67; I2 = 0%), whereas BMI-cellulitis was positive in both biobanks despite heterogeneity in magnitude (I2 = 78.1%). T2D liability was associated with osteomyelitis in FinnGen but was not supported in UKB univariable MR, with substantial cross-biobank heterogeneity (I2 = 84.8%); the corresponding UKB multivariable MR estimate was nominal. In multivariable analyses, BMI-cellulitis remained supported across datasets, whereas BMI-osteomyelitis estimates attenuated after adjustment for T2D liability. BMI-cellulitis showed the greatest reproducibility. For osteomyelitis, BMI showed a reproducible total association but weaker evidence after adjustment for T2D liability, whereas T2D liability was consistently associated with osteomyelitis in FinnGen but was not robustly replicated in UKB. These findings emphasize the importance of external replication and evidence grading when interpreting metabolic-infection MR associations.

Treatment response in unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is highly variable due to marked intratumoral heterogeneity, while existing predictive biomarkers lack accuracy. We aimed to develop and validate a pretreatment ¹⁸F-FDG positron emission tomography (PET)-computed tomography (CT)-derived spatiotemporal heterogeneity model to predict treatment response and prognosis in unresectable LA-NSCLC, and to explore its biological underpinnings.

In a multicenter cohort of 434 patients with unresectable LA-NSCLC (training: n = 215; internal validation: n = 93; external validation: n = 126), treatment response was classified as responsive or nonresponsive based on initial assessment. Four distinct habitats (PEThigh-CThigh, PETlow-CTlow, PETlow-CThigh, and PEThigh-CTlow) were generated via the Otsu algorithm. Temporal heterogeneity was quantified using metabolic hotspot displacement (normalized distance from the hotspot to the tumor centroid and normalized distance from the hotspot to the tumor periphery) and integrated with spatial radiomics to build a multidimensional spatiotemporal model. Model performance was evaluated against conventional metrics, with interpretability enhanced via nomogram and SHapley Additive exPlanations analysis. Survival outcomes were assessed using Kaplan-Meier curves, and public transcriptomic data were analyzed to characterize underlying pathways.

The spatiotemporal model accurately predicted treatment response with AUCs of 0.822 (training), 0.821 (internal validation), and 0.810 (external validation), significantly outperforming conventional whole-tumor PET-CT models. It maintained robust generalizability across treatment subgroups and effectively stratified patients by progression-free survival and overall survival (P < .01). PEThigh-CThigh habitat volume fraction correlated with treatment resistance, whereas PETlow-CTlow habitat correlated with better response. Exploratory pathway analysis highlighted key pathways involving drug metabolism, glycolytic reprogramming, and immune microenvironment remodeling.

This study establishes a noninvasive spatiotemporal heterogeneity biomarker based on ¹⁸F-FDG PET-CT that reliably predicts treatment response and prognostic outcomes in unresectable LA-NSCLC. It offers valuable insights for personalized clinical decision making and supports precision oncology.

Molecular classifications have advanced prognostic stratification in endometrial carcinoma (EC), but they do not explicitly account for cause-specific mortality (CSM) and host-clinical context. We aimed to derive a clinically accessible classification that links demographic/clinicopathologic features, CSM, and molecular landscapes and to test whether it refines molecular-based survival stratification.

We conducted latent class analysis (LCA) on 46,772 cases of primary EC from the SEER program to identify latent characteristic lineages. The resulting LCA scheme was mapped to The Cancer Genome Atlas (TCGA) data. Cumulative incidence functions and Fine-Gray competing risks regression were used to estimate CSM. The Fisher test was employed to evaluate its association with TCGA subtypes. Transcriptomic differential expression analysis and pathway enrichment analysis were performed where data were accessible. Likelihood ratio tests assessed treatment-LCA interactions.

Five clinically interpretable classes emerged. Class 4 had significantly increased subdistribution hazard for CSM (1.34, P = .031); classes 3/5 trended higher. Classes were associated with TCGA subtypes (P < .001). Specifically, class 3 was associated with copy number (CN)-high enriched sybtype and class 1 was associated with CN-low subtype. Incorporating LCA labels into molecular survival models increased C-index and robustness of prognostic discrimination. Transcriptomics revealed class specific signatures implicating metabolic reprogramming, DNA repair, and immune pathways. Treatment benefit varied by class: compared with surgery alone, class 3 demonstrated the most significant survival advantage with surgery-radiotherapy-chemotherapy. Class 4 exhibited sensitivity to radiotherapy, while class 5 benefited exclusively from the triple therapy. Conversely, class 1/2 did not benefit from combined treatment.

LCA of routine clinical variables identifies subgroups susceptible to CSM and complements TCGA molecular classification, improving survival stratification.

With the increasing prevalence of human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC), there is a need for efficient, minimally invasive methods to evaluate p16 status. This study aimed to assess the concordance of p16 status between ultrasound (US)-guided core needle biopsy (CNB) of cervical lymph nodes and surgical specimens, and to describe the numbers of CNB and surgical sessions required to establish the histopathologic diagnosis. This retrospective study included 39 patients diagnosed with OPSCC or head and neck squamous cell carcinoma of unknown primary (SCCUP) at a single tertiary hospital between March 2019 and March 2024. All included patients underwent US-guided CNB of cervical lymph nodes and a surgical procedure (biopsy or resection), and had evaluable p16 immunohistochemistry (IHC) results on both specimen types. The concordance rate for p16 status between US-guided CNB and surgical specimens was 100.0% (39/39; 95% CI, 91.0-100.0%; 35 p16-positive and 4 p16-negative cases). Sensitivity was 100.0% (35/35; 95% CI, 90.0-100.0%) and specificity was 100.0% (4/4; 95% CI, 39.8-100.0%). In all 39 included patients, a diagnosis of metastatic squamous cell carcinoma and an evaluable p16 result were obtained at the first CNB session. Among the 35 patients with OPSCC, 10 (28.6%) required more than 1 surgical session at the primary tumor site. No immediate complications were observed following US-guided CNB. In this cohort, US-guided CNB of cervical lymph nodes showed complete observed concordance with surgical specimens for p16 status, and a diagnosis with an evaluable p16 result was obtained at the first CNB session in all patients. Prospective, multicenter validation including more p16-negative cases is required before wider adoption.

This study aimed to systematically investigate the epidemiological distribution characteristics and disease burden of cervical cancer (CC) in Asian populations, and to assess the causal relationship between smoking, a key modifiable risk factor, and the incidence of CC based on genetic evidence, thereby providing a scientific basis for targeted prevention and control strategies in Asia. This study first used the GBD 2021 database to analyze trends in CC incidence, prevalence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2021 across global, Asian, and East Asian regions, along with age distribution and attributable risk factors. It then applied 2-sample Mendelian randomization (MR) using genome-wide association study (GWAS) data from East Asian populations, with multiple smoking-related behaviors (e.g., current smoking, cigarettes per day, household smoking exposure) as exposures and CC as the outcome. GBD analysis revealed that in 2021, Asia accounted for over half of the global CC disease burden. Although point estimates suggested a potential upward trend in CC burden across Asia from 1990 to 2021, statistical significance was not reached for the overall Asian population. Despite a general decline in the global incidence rate, the incidence in Japan exhibited a statistically supported upward trend, while point estimates in several other East Asian countries also suggested an increase. The peak disease burden was concentrated among women aged 55 to 59 years. Risk attribution analysis indicated that unsafe sexual behavior was the primary attributable factor for CC-related DALYs, while the attributable burden of smoking was significantly higher in Japan than in other regions. However, MR analysis did not identify statistically significant causal associations between any smoking-related exposure factors and CC risk (P-FDR ≥ .05 after false discovery rate correction). Sensitivity analyses revealed no substantial heterogeneity or pleiotropy bias. Asia, particularly East Asia, faces a substantial and potentially growing burden of CC. Causal inference based on genetic data from East Asian populations did not confirm a direct causal relationship between smoking and the incidence of cervical cancer. Future studies with larger genetic samples are needed to further elucidate the precise role of smoking.

Adding pembrolizumab to standard concurrent chemoradiotherapy (CCRT) has shown substantial survival benefits in newly diagnosed, high-risk locally advanced cervical cancer (LACC), but its economic value in Saudi Arabia has not been established. This study assessed the cost-effectiveness of pembrolizumab plus CCRT versus placebo plus CCRT as first-line treatment for high-risk LACC from the perspective of the Saudi Arabian healthcare payer.

A partitioned survival analysis model was developed to project lifetime costs and quality-adjusted life-years (QALYs) for a hypothetical cohort of women with high-risk LACC in the Saudi public healthcare sector, using resource use patterns consistent with major tertiary care and specialized cancer centers. Clinical efficacy data were obtained from the KEYNOTE-A18 trial. Costs were sourced from official Saudi price lists, local hospital data, and a formal Structured Expert Elicitation process, and were reported in 2025 United States dollars. Health state utilities were derived from the literature. The primary outcome was the incremental cost-effectiveness ratio. Future costs and QALYs were discounted at an annual rate of 3%. Comprehensive deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty.

Adding pembrolizumab to CCRT resulted in an incremental gain of 3.51 life-years and 2.93 QALYs at an additional cost of $242,043 compared with placebo plus CCRT. At its current list price, the regimen yielded an incremental cost-effectiveness ratio of $82,626 per QALY. At a willingness-to-pay threshold of $90,000 per QALY, the probability of the pembrolizumab regimen being cost-effective was 67%.

Pembrolizumab in combination with CCRT provides substantial clinical benefits in patients with high-risk LACC in Saudi Arabia. At the current price, this regimen is likely to be considered cost-effective. The analysis provides a strong, evidence-based rationale for significant price negotiations to ensure that the regimen delivers value to the Saudi healthcare system.