Non-alcoholic fatty liver disease (NAFLD) and diabetic retinopathy (DR) are common clinical complications of metabolic syndrome in different organ systems. However, the relationship between NAFLD and DR remains controversial, and more high-level evidence is needed to clarify the causal link between them. We aimed to investigate the causal relationship between NAFLD and DR across its progression stages, and to identify circulating proteins may mediate this association.

Based on genetic tools, a multi-stage network MR framework was constructed, integrating NAFLD/DR genome-wide association study data and three blood proteome-wide datasets. Causal effects of NAFLD on DR were assessed using inverse-variance weighted regression and multimodal models. Proteome-wide MR identified DR-associated proteins. Bidirectional two-sample MR and mediation models quantified regulatory weights in NAFLD-protein-DR pathways. In addition, the transcriptional expression levels of the identified mediator proteins in the liver were verified through single-cell transcriptome sequencing. The levels of the mediator protein in the serum samples of clinical patients were detected by ELISA. The levels of mediator proteins in the aqueous humor and vitreous humor samples of clinical patients were detected by Luminex liquid-phase protein chip.

NAFLD increased DR risk (OR = 1.04, 95% CI: 1.01-1.08) and specifically promoted non-proliferative DR (NPDR) progression (OR = 1.26, 95% CI: 1.05-1.52). Four proteins were identified as candidate mediators of NAFLD-DR association, among them, LTB (lymphotoxin-β, a TNF superfamily member involved in immune regulation and inflammatory responses) showed the strongest effect. In the liver of NAFLD model mice, the expression of the LTB gene was mainly elevated in T cells and B cells. The levels of LTB protein in the aqueous humor, vitreous humor and serum of NAFLD patients with DR were all higher than those of NAFLD patients without DR.

NAFLD is causally associated with an increased risk of DR development, particularly during early NPDR stages. LTB may mediate the biological process by which NAFLD promotes DR. T cells and B cells in the liver of patients with NAFLD produce higher levels of LTB protein. In NAFLD patients with DR, LTB protein levels were elevated in serum, aqueous humor, and vitreous humor compared to NAFLD patients without DR, suggesting that LTB may play a role in the link between these two conditions.

The prevalence of Type 2 Diabetes (T2D) has increased over the years. However, the current diagnostic markers such as fasting blood glucose and HbA1c come with certain limitations. Hence, there is a need for a more robust minimally invasive biomarker. This study aimed to identify sets of dysregulated miRNAs in plasma small extracellular vesicles (sEVs) as biomarkers for T2D diagnosis.

This study was part of the Rice Intervention for Chronic Health (RICH) trial. Plasma sEVs were isolated from T2D and control subjects and characterized. The sEVs-miRNAs expressions were compared using next generation sequencing and validated using digital PCR. Bioinformatic analyses were performed to study the roles of dysregulated miRNAs. Plasma proteins were profiled to study the systemically dysregulated T2D pathways.

The levels of miR-142-3p and miR-454-3p were increased in plasma sEVs of T2D subjects. Among a subgroup of T2D subjects in whom glycemic control improved (n = 13), these two upregulated miRNAs also decreased. The combination of sEVs-miR-142-3p, waist circumference, and BMI demonstrated high diagnostic values (AUC-ROC=0.985, p < 0.001) to distinguish between T2D and control subjects. The integrated results from miRNA bioinformatics analysis and plasma proteomics profiling suggested association between the predicted targets of miRNA and systemic dysregulated pathways in T2D.

This study identified the potential of sEV-miR-142-3p as biomarkers for T2D diagnosis when used in combination with waist circumference and BMI. This study provided preliminary evidence of sEVs-miRNAs in future clinical use for T2D management.

This study aimed to examine the associations of maternal first-trimester atherogenic index of plasma (AIP) with gestational diabetes mellitus (GDM) and birth weight outcomes, and the mediating role of second-trimester blood glucose.

This prospective cohort study included 5,706 pregnant women without pre-existing diabetes or other chronic diseases. AIP was calculated as log₁₀[TG (mg/dL)/HDL-C (mg/dL)] from fasting lipid profiles. Generalized linear models and mediation analysis were used to assess the relationships between AIP and outcomes, and the mediating effects of blood glucose.

Participants had a mean maternal age of 29.3 years, a mean first-trimester AIP of 0.28 ± 0.19, GDM prevalence of 20.64%, and mean neonatal birth weight of 3314.05 ± 442.11 g. A 1-unit increase in first-trimester AIP was associated with greater birth weight (β: 93.12 g, 95% CI: 39.38-146.87), elevated GDM risk (RR: 2.08, 95% CI: 1.52-2.85), and higher risk of large-for-gestational-age infants (RR: 1.67, 95% CI: 1.09-2.58). A nonlinear association was identified between first-trimester AIP and birth weight, with a 158.95 g (β: 158.95 g, 95% CI: 90.70-227.20) rise per 1-unit elevation in AIP above 0.14. Fasting plasma glucose (FPG) mediated 28.35% of the association between AIP and birth weight, rising to 60.04% among women with GDM. The third-trimester rise in AIP was significantly smaller in women with GDM.

First-trimester AIP appears to correlate with GDM and birth weight. Second-trimester FPG mediates this association, particularly in mothers with GDM. These findings support the clinical value of early lipid monitoring in prenatal care.

Persistent inflammation, defective angiogenesis, and metabolic dysfunction impede diabetic wound repair. Although Zilian ointment (ZLO) is clinically applied to wounds, its activity in diabetic wounds and the associated molecular basis remain incompletely understood. We therefore assessed the reparative effects of ZLO and examined the signaling events potentially involved.

UHPLC-MS was used to characterize the chemical profile of ZLO, and network pharmacology was integrated to identify potential molecular targets and pathways. A diabetic wound model was applied to assess the reparative effects of ZLO on wound closure and tissue regeneration. Histological and immunohistochemical approaches were used to evaluate angiogenesis, macrophage polarization, and the expression of hypoxia/glycolysis-associated proteins, including HIF-1α, GLUT1, LDHA, PKM2, and VEGFA. AKT/HIF-1α pathway activation was further examined by western blotting.

ZLO-treated db/db mice displayed a smaller residual wound area and more complete histological repair, including greater epithelial coverage, granulation tissue formation, and collagen accumulation. Treatment was accompanied by stronger CD31 and VEGFA signals, together with a macrophage profile characterized by more F4/80⁺CD206⁺ cells and fewer F4/80⁺iNOS⁺ cells. KEGG enrichment and PPI network analyses highlighted HIF-1 signaling and AKT1, respectively. In wound sections, ZLO increased the expression of HIF-1α, GLUT1, PKM2, and VEGFA. Immunoblotting further revealed an elevated p-AKT/AKT ratio and recovery of HIF-1α and VEGFA protein levels.

ZLO facilitates diabetic wound repair, with its therapeutic effects potentially associated with AKT/HIF-1α-linked metabolic regulation and enhanced angiogenic responses.

This network meta-analysis (NMA) intends to fully assess the value of contrast-enhanced ultrasound (CEUS) combined with other imaging techniques in the diagnosis of thyroid nodules (TNs), and provide clinical guidance.

We systematically searched PubMed, Web of Science, Embase, and Cochrane up to October 15, 2025, and assessed study quality by the QUADAS-2 tool. The combination of CEUS and CEUS with other techniques was assessed for accuracy by R4.5.1 and ANOVA-based NMA.

Twenty-six original studies were included, encompassing 5022 TNs from 4484 patients. CEUS-ultrasound elastography (UE) demonstrated favorable diagnostic performance in differentiating benign and malignant TNs (superiority index [SI]: 3.47, 95%CI 0.2-7). The pooled sensitivity (SE) and specificity (SP) of CEUS-UE were 0.92 (95%CI 0.88-0.95, SUCRA 80.0%) and 0.83 (95%CI 0.75-0.89, SUCRA 60.7%), respectively. CEUS-artificial intelligence (AI) was generally effective in identifying high-risk TNs (SI: 3.81, 95%CI 0.33-9), with pooled SE and SP of 0.95 (95%CI 0.91-0.98, SUCRA 90.0%) and 0.81 (95%CI 0.68-0.91, SUCRA 49.6%), respectively. CEUS-conventional ultrasound (US) showed favorable diagnostic performance in identifying non-risk-stratified TNs (SI: 5.29, 95%CI 0.33-9), with pooled SE and SP of 0.89 (95% CI 0.74-0.97, SUCRA 61.4%) and 0.88 (95%CI 0.69-0.97, SUCRA 76.9%), respectively.

CEUS-UE demonstrates favorable overall diagnostic performance in differentiating benign and malignant TNs. CEUS-AI may offer additional value in identifying high-risk TNs with multiple suspicious features. CEUS-US is effective in identifying non-risk-stratified TNs. However, these subgroup findings require further validation in larger, diverse external cohorts.

https://www.crd.york.ac.uk/PROSPERO/myprospero, identifier CRD420251169562.

Immune regulatory networks contribute to colorectal cancer (CRC) progression, but most clinical studies focus on tissue immune-cell abundance or static inflammatory mediators. We investigated cytokine-response patterns in cultures derived from peripheral-blood CD14+ cells and local immune-cell composition in tumor-adjacent and resection-margin mucosa.

This single-center prospective observational study included 106 patients with colorectal adenocarcinoma and 20 comparison subjects with non-malignant surgical conditions. Peripheral-blood CD14+ cells were isolated, differentiated with M-CSF, and subjected to sequential LPS stimulation. IL-1β, IL-6, IL-8, and MCP-1 concentrations were measured, and cytokine-response indices were calculated. In CRC patients, CD4+, CD8+, CD20+, CD56+, and CD68+ cell densities were quantified immunohistochemically in paired mucosal compartments. Analyses addressed CRC-associated differences, local immune-cell organization, systemic-local associations, and an exploratory comparison between patients without distant metastases (n = 97) and patients with distant metastases (n = 9).

CRC was associated with selective remodeling of IL-1β and IL-6 response indices. Compared with the comparison group, CRC patients showed higher IL-1β post-washout persistence, lower shutdown efficiency and re-induction capacity, and a higher re-stimulation index. IL-6 responses were characterized by lower basal activity but higher basal drift, primary LPS response, and post-washout persistence. The exploratory comparison according to distant metastasis status identified additional differences in selected IL-1β and IL-6 indices, however, these findings are limited by the small number of patients with distant metastases. Locally, CD20+ cells were enriched in tumor-adjacent mucosa, whereas CD68+ cells were enriched in resection-margin mucosa. Matched immune-cell densities were positively correlated across compartments. The strongest systemic-local association was an inverse correlation between MCP-1 primary LPS response and CD68+ cell density in tumor-adjacent mucosa.

CRC is associated with altered cytokine responsiveness in M-CSF-differentiated cultures derived from blood CD14+ cells and with compartment-specific mucosal immune-cell organization. The observed systemic-local associations suggest partial coupling between these experimental and tissue-level immune features. Exploratory metastasis-associated patterns were identified but require validation in larger, adequately powered cohorts.

Single-isocenter stereotactic radiosurgery enables efficient treatment of multiple brain metastases (SI-MBM SRS), but demands high geometric accuracy. Plan complexity metrics are increasingly used as indicators for quality assurance (QA) performance, however their applicability to SRS remains uncertain, particularly in the context of multi-institutional variability.

This study evaluated the relationship between plan complexity, target geometry, and end-to-end dosimetric QA outcomes for SI-MBM SRS across multiple institutions.

Forty-two SI-MBM SRS plans from different centers and platforms were delivered to polymer gel phantoms, providing high-resolution 3D dose measurements. Gamma passing rates (GPRs) were calculated under 3%/2 mm, 5%/2 mm and 5%/1 mm criteria and were correlated with eleven established complexity metrics calculated per plan. Geometric factors, including target equivalent diameter and distance-to-isocenter, were analyzed. Receiver-operating-characteristic (ROC) analysis was performed to identify optimal thresholds for predicting QA pass/fail (≥90% GPR).

No statistically significant differences between the different linacs and treatment planning systems were found, nor strong or consistent correlations between complexity metrics and GPRs. In contrast, geometric parameters were more influential: off-axis distance and target size significantly affected QA performance, with the largest differences observed for far-off-axis lesions. ROC analysis identified optimal thresholds of 34.9 mm for distance-to-isocenter and 4.8 mm for equivalent diameter in predicting QA outcomes (AUC∼0.60-0.65), although the predictive performance remained modest.

In this multi-institutional, gel-based end-to-end study of SI-MBM SRS, target geometry was a stronger QA performance predictor than complexity metrics. These findings emphasize the importance of geometry-aware QA strategies and the need for further standardized, multi-institutional evaluations to clarify the interplay between complexity, geometry, and machine performance in SRS.

The objective of this systematic review and meta-analysis was to evaluate the validity of progression-free survival (PFS) and the objective response rate (ORR) as surrogate end points for overall survival (OS) in randomized controlled trials (RCTs) of metastatic renal cell carcinoma. The MEDLINE, Embase, and Cochrane CENTRAL databases were searched from inception to June 10, 2025. Associations between treatment effects on OS, PFS, and ORR were assessed using Pearson correlation coefficients (r). Surrogate threshold effect (STE) analyses determined the minimum PFS hazard ratio (HR) or ORR odds ratio (OR) required to predict OS benefit. Subgroup analyses were conducted by treatment class, line of therapy, and histology. Sixty-two randomized controlled trials comprising 24,518 patients were included. PFS-OS demonstrated a moderate correlation (r = 0.52; 95% confidence interval [CI], 0.38-0.66), with an STE (HR, 0.92; 95% CI, 0.79-1.09). ORR-OS demonstrated a moderate correlation (r = -0.59; 95% CI, -0.72, -0.45), with an STE (OR, 1.40; 95% CI, 0.99-1.89). Subgroup estimates varied across treatment settings and were frequently imprecise, particularly for ORR and in smaller treatment-class subgroups; limited representation of non-clear cell renal cell carcinoma precluded reliable histology-specific conclusions. Overall, PFS and ORR had moderate trial-level associations with OS in metastatic renal cell carcinoma, but the overall analyses did not demonstrate sufficiently consistent surrogacy to reliably predict OS benefit. These findings should be interpreted cautiously given the substantial heterogeneity of the included trials. Surrogate validity appears to be context-dependent, supporting continued reliance on OS and the need for more robust surrogate end points.

Ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy, is approved for relapsed/refractory multiple myeloma (RRMM).

Using the Center for International Blood and Marrow Transplant Research registry, this study evaluated outcomes of frail patients receiving commercial cilta-cel from March 2022 to December 2023. Frailty was defined by an adapted simplified score incorporating age, performance status, and comorbidities.

Among 541 patients with available frailty status, 183 (33.8%) were frail and 358 (66.2%) were nonfrail. Overall response rates were comparable (frail 82.8% vs. nonfrail 88.5%). However, frail patients had inferior progression-free survival (PFS) (12-month PFS, 62.7% [95% confidence interval (CI), 53.6%-71.3%] vs. 75.9% [95% CI, 70.4%-81.1%]; p < .01) and overall survival (OS) (12-month OS 72.8% [95% CI, 64.9%-80.0%] vs. 90.4% [95% CI, 86.6%-93.7%]; p < .01). Twelve-month treatment-related mortality in frail patients was 6.8% (95% CI, 3.4%-11.2%) versus 3.6% (95% CI, 1.8%-6.1%), p = .12. Cytokine release syndrome (grade ≥2) occurred in 22.4% of frail versus 17.9% of nonfrail patients (p = .05), and immune effector cell-associated neurotoxicity (ICANS) of any grade was reported in 32.2% versus 17.6% (p < .01). Rates of cranial nerve palsies and Parkinsonism were comparable. Prolonged cytopenia (>day 30) was more common in frail patients (30.6% vs. 21.2%; p < .01). On multivariable analysis, frailty independently predicted worse PFS (hazard ratio [HR], 1.67; 95% CI, 1.16-2.40), OS (HR, 2.46; 95% CI, 1.57-3.87), and higher odds of any-grade ICANS (odds ratio, 2.01; 95% CI, 1.32-3.08) (all p < .01).

Cilta-cel remains effective in frail RRMM, but frailty is associated with reduced survival and increased toxicity, supporting tailored CAR-T strategies.

Inotuzumab (InO)-based frontline regimens have significantly improved the survival of older patients with Philadelphia-negative (Ph-) B-cell acute lymphoblastic leukemia (B-ALL). Yet, outcome after relapse is not reported for this population.

The retrospective RELAPSINO study describes post-relapse outcome of 48 older patients treated front-line with a combination of InO and low-dose chemotherapy in the EWALL-INO trial (NCT03249870). At relapse (91% medullary), median age was 70 years and median duration of first complete remission (CR1) 15.2 months. CD19 or CD22 expression loss was observed in respectively 13% and 23% of evaluable cases. Most patients (85%) received salvage therapy (blinatumomab, low dose or intensive chemotherapy, in combination or not). There was no InO re-treatment.

Overall, CR2 was reached by 51% of the patients. Median event-free survivals (EFS, 3.2 months) and overall survivals (OS, 4.5 months) were dismal. For patients achieving CR2, 2-year OS was 46% and leukemia-free survival (LFS) was 36%. By multivariable analysis, not receiving intensive chemotherapy was associated with significantly lower EFS (hazard ratio [HR], 3.28; 95% confidence interval [CI], 1.43-7.53, p = .005), LFS (HR, 13.2; 95% CI, 2.46-70.88, p = .003), and OS (HR, 3.25; 95% CI, 1.39-7.59, p = .006). CR1 duration ≥12 months was significantly associated with better EFS (HR, 0.31; 95% CI, 0.14-0.67, p = .003), LFS (HR, 0.16; 95% CI, 0.04-0.72, p = .01), and OS (HR, 0.42; 95% CI, 0.20-0.89, p = .023). Not achieving CR2 was associated with lower OS (HR, 8.0; 95% CI, 3.25-20.1, p < .001). Receiving blinatumomab had no impact.

These results indicate that salvage regimen should be proposed in this context, allowing 50% of patients to achieve CR2 and have better survival.