Endothelial dysfunction is a critical and initiating factor of the vascular complications of diabetes. Inflammation plays an important role in endothelial dysfunction regulated by epigenetic modifications. N6-methyladenosine (m⁶A) is one of the most prevalent epigenetic modifications in eukaryotic cells. In this research, we identified an m⁶A demethylase, fat mass and obesity-associated protein (FTO), as an essential epitranscriptomic regulator in diabetes-induced vascular endothelial dysfunction. We showed that enhanced FTO reduced the global level of m⁶A in hyperglycemia. FTO knockdown in endothelial cells (ECs) resulted in less inflammation and compromised ability of migration and tube formation. Compared with EC Fto^fl/fl diabetic mice, EC-specific Fto-deficient (EC Fto^Δ/Δ) diabetic mice displayed less retinal vascular leakage and acellular capillary formation. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with RNA-Seq indicated that Tnip1 served as a downstream target of FTO. Luciferase activity assays and RNA pull-down demonstrated that FTO repressed TNIP1 mRNA expression by erasing its m⁶A methylation. In addition, TNIP1 depletion activated NF-κB and other inflammatory factors, which aggravated retinal vascular leakage and acellular capillary formation, while sustained expression of Tnip1 by intravitreal injection of adeno-associated virus alleviated endothelial impairments. These findings suggest that the FTO-TNIP1-NF-κB network provides potential targets to treat diabetic vascular complications.

Background: Diabetic vascular complications share common pathophysiological mechanisms, but the relationship between diabetes‐related macrovascular complications (MacroVCs) and incident diabetic microvascular complications remains unclear. We aimed to investigate the impact of MacroVCs on the risk of microvascular complications. Methods and Results: There were 1518 participants with type 1 diabetes (T1D) and 20 802 participants with type 2 diabetes from the UK Biobank included in this longitudinal cohort study. MacroVCs were defined by the presence of macrovascular diseases diagnosed after diabetes at recruitment, including coronary heart disease, peripheral artery disease, stroke, and ≥2 MacroVCs. The primary outcome was incident microvascular complications, a composite of diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy. During a median (interquartile range) follow‐up of 11.61 (5.84–13.12) years and 12.2 (9.50–13.18) years, 596 (39.3%) and 4113 (19.8%) participants developed a primary outcome in T1D and type 2 diabetes, respectively. After full adjustment for conventional risk factors, Cox regression models showed significant associations between individual as well as cumulative MacroVCs and the primary outcome, except for coronary heart disease in T1D (T1D: diabetes coronary heart disease: 1.25 [0.98–1.60]; diabetes peripheral artery disease: 3.00 [1.86–4.84]; diabetes stroke: 1.71 [1.08–2.72]; ≥2: 2.57 [1.66–3.99]; type 2 diabetes: diabetes coronary heart disease: 1.59 [1.38–1.82]; diabetes peripheral artery disease: 1.60 [1.01–2.54]; diabetes stroke: 1.50 [1.13–1.99]; ≥2: 2.66 [1.92–3.68]). Subgroup analysis showed that strict glycemic (glycated hemoglobin <6.5%) and blood pressure (<140/90 mm Hg) control attenuated the association. Conclusions: Individual and cumulative MacroVCs confer significant risk of incident microvascular complications in patients with T1D and type 2 diabetes. Our results may facilitate cost‐effective high‐risk population identification and development of precise prevention strategies.

Purpose: To investigate the prevalence of diabetic retinopathy (DR) and vision-threatening DR (VTDR) in patients with type 2 diabetes mellitus (T2DM) stratified by the duration of diabetes and to identify the clinical variations and risk factors for VTDR occurring at different stages of T2DM.Methods: This was a retrospective comparative study. Patients were divided into short- (≤3 years), intermediate- (3–7 years), and long-duration (>7 years) groups. All patients were followed-up for DR and VTDR development. Risk factors were explored using logistic regression analysis.Results: A total of,2961 patients were included; among them, 1,036 (35.0%) patients developed DR, and 293 (9.9%) had VTDR. The frequency of VTDR in patients who developed DR in the short-duration group was significantly higher than that in the intermediate-duration group (25.7% vs. 15.0%; p = 0.019), but comparable with that of the long-duration group (25.7% vs. 31.8%; p = 0.138). Patients who developed VTDR within the first 3 years of T2DM were more likely to have a family history of diabetes (p = 0.024), had higher glycated hemoglobin (p = 0.025), were males (p = 0.042), and were notably older at the onset of diabetes (p <0.001) but younger when diagnosed with DR (p <0.001). Moreover, higher glycated hemoglobin (OR = 1.14; 95% CI: 1.00–1.29; p = 0.043) and diabetic nephropathy (DN) (OR = 2.31; 95% CI: 1.08–4.91; p = 0.030) were independent risk factors for developing VTDR during the first 3 years of T2DM.Conclusion: The risk of DR is not high in persons with ≤3 years’ duration of T2DM, however, if afflicted, the risk of VTDR should never be neglected. More frequent retinal screening is warranted in patients with newly diagnosed T2DM.

Objectives: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and immune infiltration plays a crucial role in the prognosis of UM. This study aimed to generate an immunological marker-based predictive signature for the overall survival (OS) of UM patients.Methods: Single-sample gene-set enrichment analysis (ssGSEA) was used to profile immune cell infiltration in 79 patients with UM from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate least absolute shrinkage and selection operator (LASSO) Cox regressions were used to determine the prognostic factors for UM and construct the predictive immunosignature. Receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves were performed to evaluate the clinical ability and accuracy of the model. In addition, the predictive accuracy was compared between the immunosignature and the Tumor, Node, Metastasis (TNM) staging system of American Joint Committee on Cancer (AJCC). We further analyzed the differences in clinical characteristics, immune infiltrates, immune checkpoints, and therapy sensitivity between high- and low-risk groups characterized by the prognostic model.Results: Higher levels of immune cell infiltration in UM were related to a lower survival rate. Matrix metallopeptidase 12 (MMP12), TCDD inducible poly (ADP-ribose) polymerase (TIPARP), and leucine rich repeat neuronal 3 (LRRN3) were identified as prognostic signatures, and an immunological marker-based prognostic signature was constructed with good clinical ability and accuracy. The immunosignature was developed with a concordance index (C-index) of 0.881, which is significantly better than that of the TNM staging system (p< 0.001). We further identified 1,762 genes with upregulated expression and 798 genes with downregulated expression in the high-risk group, and the differences between the high- and low-risk groups were mainly in immune-related processes. In addition, the expression of most of the immune checkpoint-relevant and immune activity-relevant genes was significantly higher in the high-risk group, which was more sensitive to therapy.Conclusion: We developed a novel immunosignature constructed by MMP12, TIPARP, and LRRN3 that could effectively predict the OS of UM.

Purpose: Local recurrence predicts dismal prognosis in eyelid sebaceous carcinoma (SC). Recurrence predictors vary across studies. Accurate recurrence estimation is essential for individualized therapy in eyelid SC. This study aims to identify recurrence predictors and develop a nomogram for personalized prediction in eyelid SC. Methods: We conducted a multicenter retrospective cohort study. Chart reviews were performed in 418 consecutive patients with eyelid SC. All patients were followed up after their initial surgery. Multivariate Cox regression was used to explore the independent predictors of recurrence. A nomogram for recurrence prediction was developed and validated with bootstrap resampling. The predictive accuracy and discriminative ability were compared with the Tumor, Node, Metastasis (TNM) staging system. Results: Over a median of 60-month follow-up, 167 patients (40%) had local recurrence. The median time from diagnosis to recurrence was 14 months. The 1-year cumulative recurrence rate was 18%. Diagnostic delay (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 1.00–1.01, P = 0.001), orbital involvement (HR = 4.47, 95% CI = 3.04–6.58, P < 0.001), Ki67 (HR = 1.01, 95% CI = 1.00–1.02, P = 0.008) and initial surgery of Mohs micrographic surgery with intraoperative frozen section control (HR = 0.53, 95% CI = 0.35–0.80, P = 0.003) were independent influencing factors of recurrence. A nomogram integrating these four factors combined with pagetoid spread displayed satisfactory discriminative ability (C-index = 0.80–0.83; area under the curve [AUC] = 0.82–0.84), which compared favorably than TNM staging (all P < 0.05). Conclusions: The recurrence rate is high in eyelid SC. Early detection and primary resection with Mohs micrographic surgery are recommended in controlling recurrence. Patients with orbital involvement, high Ki67 expression, and pagetoid spread may require adjuvant measures. This nomogram offers more accurate recurrence estimates, aiding in therapeutic decision making.

Purpose: To examine the association between tear glucose (TG) and the presence and severity of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods: A cross-sectional study. TG was examined by rapid qualitative test strip in 160 patients. The severity of DR was graded as mild DR and severe DR. The presence and severity of DR were compared between patients with positive and negative TG. The association of TG with the presence and the severity of DR was estimated by multivariable regression analysis and spearman’s rank correlation test, respectively. The performance of TG to detect DR was evaluated by the receiver operating characteristic (ROC) curve. Results: In this study, 160 patients were included, with a median age of 64.0 years, and 88 (55.0%) patients were males. A total of 91 (56.9%) patients had positive TG, and 69 (43.1%) patients had negative TG. In TG-positive group, 41 (45.1%) patients were diagnosed with DR, among them, 8 (19.5%) patients had mild DR, and 33 (80.5%) patients were afflicted with severe DR. Multivariable logistic regression indicated that the presence of DR positively correlated with the presence of positive TG (odds ratio [OR], 3.62; 95% confidence interval [CI], 1.56–8.40; p < 0.01), longer duration of diabetes (OR, 1.11; 95% CI 1.06–1.17; p < 0.01) and higher HbA1c (OR, 1.25; 95% CI 1.01–1.54; p = 0.03). Moreover, Spearman’s correlation analysis suggested that the grading of TG increased with the severity of DR (r_s = 0.28, p < 0.01). The area under the curve (AUC) of the model integrating TG, the duration of diabetes and HbA1c was 0.76 (95% CI 0.69–0.84), indicating a fair discriminative ability of DR. Conclusion: TG level was associated with the presence and the severity of DR. TG might be an easy-to-use, non-invasive parameter to the screening and monitoring of DR among patients with diabetes.