Circulating long noncoding RNAs H19 and GAS5 are associated with type 2 diabetes but not with diabetic retinopathy: A preliminary study

Recently, a wide range of biological and pathological roles of long noncoding RNAs (lncRNAs) have been discovered. However, the potential role of circulating lncRNAs H19 and GAS5 in type 2 diabetes mellitus (T2DM) and diabetic retinopathy (DR) is not clear. Here, we assessed the plasma levels of H19 and GAS5 lncRNAs in T2DM patients with/without DR and evaluated if H19 and GAS5 pre-treatment plasma levels are a predictor of early response to a single aflibercept dose in DR subgroup. Plasma lncRNA expression profiles of 119 T2DM patients (66 with DR and 53 without DR) and 110 healthy controls were determined by quantitative reverse transcription PCR. The association of lncRNA expression profiles with clinical features and aflibercept early response in DR patients was investigated. Relative H19 expression levels were significantly increased in T2DM group (including DR and non-DR subgroups) vs. controls, while GAS5 levels were decreased in T2DM group (p < 0.001). There was no significant difference in H19 and GAS5 expression levels between DR and non-DR subgroups. H19 and GAS5 expression profiles were not significantly correlated with clinical parameters or response to aflibercept therapy in DR subgroup. Our findings indicate that the circulating lncRNAs H19 and GAS5 may be associated with T2DM prevalence but may not have an important diagnostic/prognostic role in DR or early response to aflibercept intravitreal injection in DR patients. Large-scale transcriptomic studies are warranted to validate our results and investigate other lncRNA candidates in T2DM

Increased Risk of Hypoglycemia Following Roux-en-Y Gastric Bypass Surgery in Patients Without Diabetes: a Propensity Score-Matched Analysis.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is an effective treatment for obesity. However, the incidence and long-term risk of hypoglycemia after surgery in patients without diabetes remains unclear. This study aimed to investigate the prevalence of hypoglycemia following RYGB surgery in patients with obesity and without diabetes. METHODS: A retrospective cohort study was conducted using the TriNetX database. The study population included 15,085 patients with obesity (BMI ≥ 30 kg/m2) who underwent RYGB surgery and 3,200,074 non-surgical controls, all without a history of diabetes or GLP-1 receptor agonist use. Propensity score matching was performed to balance baseline characteristics. The primary outcome was the incidence of hypoglycemia, defined by ICD-10-CM codes or laboratory values (glucose ≤ 70 mg/dL). Cox regression analysis was employed to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: In the overall study population, the risk of hypoglycemia was significantly higher in the RYGB group (18.70%, n = 2,810) compared to the control group (3.80%, n = 120,923; HR 4.3, 95% CI 4.14-4.46, p < 0.001). After propensity score matching (n = 14,916 per group), RYGB patients maintained an elevated risk (18.70%, n = 2,795) compared to matched controls (5.0%, n = 749; HR 3.7, 95% CI 3.44-4.05, p < 0.001). Time-series analysis revealed consistently higher hypoglycemia risk in the RYGB group, with hazard ratios ranging from 5.37 (95% CI 4.09-7.03) at 1 week to 3.75 (95% CI 3.45-4.06) at 10 years post-surgery (all p < 0.001). Subgroup analysis of RYGB patients who developed hypoglycemia showed a 30-day hospitalization rate of 21.3% and a mortality rate of 0.71%. CONCLUSION: RYGB surgery is associated with a significantly increased risk of hypoglycemia in patients with obesity and without diabetes, both in the short-term and long-term follow-up. These findings underscore the importance of monitoring and managing hypoglycemia in patients undergoing RYGB surgery, even in the absence of preexisting diabetes

Differential Effects of GLP-1 Receptor Agonists on Cancer Risk in Obesity: A Nationwide Analysis of 1.1 Million Patients.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated significant efficacy in obesity treatment beyond their original development for type-2 diabetes management. This comprehensive study investigated the relationship between GLP-1RA use and cancer incidence in individuals with obesity across a 5-year follow-up period. Methods: We conducted a large-scale cohort study using the TriNetX US Collaborative Network database (2013-2023) examining adult patients with obesity. The study utilized propensity score matching to pair GLP-1RA-treated patients with controls (1:1) using the nearest neighbor method. Cancer incidence served as the primary outcome measure over the 5-year follow-up, with subgroup analyses considering individual GLP-1RA agents, patient sex, and BMI categories. Results: Analysis revealed significant cancer-risk reductions associated with GLP-1RA use across multiple cancer types compared to matched controls. Notable risk reductions were observed in gastrointestinal (HR 0.67, 95% CI 0.59-0.75), skin (HR 0.62, 95% CI 0.55-0.70), breast (HR 0.72, 95% CI 0.64-0.82), female genital (HR 0.61, 95% CI 0.53-0.71), prostate (HR 0.68, 95% CI 0.58-0.80), and lymphoid/hematopoietic cancers (HR 0.69, 95% CI 0.60-0.80). Semaglutide demonstrated superior protective effects, particularly in gastrointestinal cancers (HR 0.45, 95% CI 0.37-0.53). Conversely, liraglutide showed increased risks for thyroid (HR 1.70, 95% CI 1.03-2.82) and respiratory cancers (HR 1.62, 95% CI 1.13-2.32). Conclusions: This research provides compelling evidence for GLP-1RAs potential role in cancer-risk reduction, with semaglutide showing particularly promising results. The differential effects observed among GLP-1RA agents emphasize the importance of personalized medicine approaches. These findings suggest significant implications for clinical practice and future research in both obesity management and cancer prevention

Beyond the Burn: Leukemia Threats Following Radioactive Iodine Ablation Therapy for Thyroid Cancer.

Background: Radioactive iodine (RAI) ablation therapy is a common minimally invasive treatment for patients diagnosed with differentiated thyroid cancer (DTC). Although previous studies have identified a link between RAI and the mortality from secondary solid cancers, the connection between RAI and leukemia remains under-researched. This study investigated the differential risk of leukemia and its subtypes in DTC patients following RAI treatment. Methods: DTC patients from the Surveillance, Epidemiology, and End Results (SEER) Registry 17 (2000-2019) were analyzed. The standard incidence ratio (SIR) and excess risk (ER) compared to the reference population were calculated. Results: Out of 196,569 DTC patients, 1381 patients developed various types of hematological malignancies. Leukemia was diagnosed in 508 of these patients, and it had the highest risk among the malignancies studied, with an SIR of 1.74 (95%CI: 1.59-1.9). The RAI group had an SIR of 2.12 (95%CI: 1.87-2.39), while the non-RAI group had an SIR was 1.45 (95%CI: 1.37-1.52) (p < 0.001). Those diagnosed before the age of 55 years had a conspicuously elevated risk (SIR 2.74) compared to those diagnosed at 55 years or older (SIR 1.53). American Indian/Alaska Native survivors manifested a pronounced leukemia risk with an SIR of 7.63 (95%CI: 2.46-17.8). Conclusions: RAI treatment increased the risk of developing leukemia when serving as adjuvant therapy in surgical patients (SIR 2.12). There exists a significant association between RAI treatment in DTC patients and the incidence of leukemia. This susceptibility seems to be modulated by factors including time since diagnosis, age, gender, and racial background

MicroRNA-34a: A Key Regulator in the Hallmarks of Renal Cell Carcinoma

Renal cell carcinoma (RCC) incidence has increased over the past two decades. Recent studies reported microRNAs as promising biomarkers for early cancer detection, accurate prognosis, and molecular targets for future treatment. This study aimed to evaluate the expression levels of miR-34a and 11 of its bioinformatically selected target genes and proteins to test their potential dysregulation in RCC. Quantitative real-time PCR for miR-34a and its targets; MET oncogene; gene-regulating apoptosis (TP53INP2 and DFFA); cell proliferation (E2F3); and cell differentiation (SOX2 and TGFB3) as well as immunohistochemical assay for VEGFA, TP53, Bcl2, TGFB1, and Ki67 protein expression have been performed in 85 FFPE RCC tumor specimens. Clinicopathological parameter correlation and in silico network analysis have also implicated. We found RCC tissues displayed significantly higher miR-34a expression level than their corresponding noncancerous tissues, particularly in chromophobic subtype. MET and E2F3 were significantly upregulated, while TP53INP2 and SOX2 were downregulated. ROC analysis showed high diagnostic performance of miR-34a (AUC = 0.854), MET (AUC = 0.765), and E2F3 (AUC = 0.761). The advanced pathological grade was associated with strong TGFB1, VEGFA, and Ki67 protein expression and absent Tp53 staining. These findings indicate miR-34a along with its putative target genes could play a role in RCC tumorigenesis and progression

Beyond Glycemic Control: GLP-1 Receptor Agonists and Their Impact on Calcium Homeostasis in Real-World Patients.

Background/Objectives: The effect of glucagon-like peptide-1 receptor (GLP-1R) agonists on calcium homeostasis is poorly understood. This study aimed to investigate the association between GLP-1R agonist use and the risk of hypocalcemia and/or hypercalcemia, as well as other clinical outcomes. Methods: A retrospective cohort study used de-identified patient data from the TriNetX Global Collaborative Network, including 15,655 adult patients prescribed GLP-1R agonists and 15,655 propensity-matched controls. Outcomes included hypocalcemia, hypercalcemia, emergency visits, hospitalizations, cardiovascular events, and all-cause mortality. Results: GLP-1R agonist use was associated with a reduced risk of hypocalcemia (2.7% vs. 5.5%, RR 0.49, 95% CI: 0.44-0.55) but an increased risk of hypercalcemia (2.3% vs. 1.1%, RR 2.02, 95% CI: 1.69-2.42). The effect on hypocalcemia was most pronounced during the first six months of treatment. Among individual agents, tirzepatide showed the most pronounced effect, reducing hypocalcemia risk by 63% while increasing hypercalcemia risk by 85%. Semaglutide demonstrated similar effects, while dulaglutide and liraglutide showed modest effects. Furthermore, GLP-1R agonist use was associated with reduced risks of emergency visits (RR 0.57, 95% CI: 0.54-0.60), hospitalizations (RR 0.40, 95% CI: 0.36-0.44), cardiovascular events, and all-cause mortality (HR 0.27, 95% CI: 0.21-0.36). Conclusions: GLP-1R agonists exhibit a complex influence on calcium homeostasis, reducing hypocalcemia risk while increasing hypercalcemia risk. Beyond calcium regulation, these medications significantly reduce healthcare utilization, improve cardiovascular outcomes, and decrease mortality. Further research is needed to elucidate the mechanisms behind the differential effects of individual GLP-1R agonists, particularly tirzepatide, to optimize personalized treatment approaches and long-term safety

The HCV-Melanoma Paradox: First Multi-Cohort and Molecular Net-Work Analysis Reveals Lower Incidence but Worse Outcomes-Integrating Clinical, Real-World, and In Silico Data.

Background and Objectives: The relationship between hepatitis C virus (HCV) infection and melanoma remains poorly understood. This study aimed to investigate the association between HCV and melanoma, assess outcomes in patients with both conditions, and explore potential molecular mechanisms connecting the two diseases. Materials and Methods: We conducted a retrospective cohort study of 142 melanoma patients, including 29 with HCV-related cirrhosis, and analyzed their clinical outcomes. For external validation, we used the TriNetX Global Collaborative Network database, comprising 219,960 propensity-matched patients per group. An in silico analysis was performed to identify the molecular pathways linking HCV and melanoma. Results: In the retrospective cohort, HCV-positive melanoma patients showed an increased risk of early relapse (41.4% vs. 18.6%, p = 0.014), recurrence (65.5% vs. 39.8%, p = 0.020), and mortality (65.5% vs. 23.0%, p < 0.001) compared to HCV-negative patients. TriNetX data analysis revealed that HCV-positive patients had a 53% lower risk of developing melanoma (RR = 0.470, 95% CI: 0.443-0.498, p < 0.001). However, HCV-positive melanoma patients had higher all-cause mortality (HR = 1.360, 95% CI: 1.189-1.556, p < 0.001). An in silico analysis identified key molecular players, including IL-6 and CTLA4, in the HCV-melanoma network. Conclusions: While HCV infection may be associated with a lower risk of melanoma development, HCV-positive patients who develop melanoma have poorer outcomes. The identified molecular pathways provide potential targets for future research and therapeutic interventions

Risk of Malignancy Following Radiofrequency Ablation of Thyroid Nodules

Radiofrequency ablation (RFA) is a safe and effective treatment of symptomatic benign thyroid nodules. However, some publications have cautioned against the use of RFA in Bethesda III, IV, and V thyroid nodules due to risk of developing follicular thyroid cancer. Unfortunately, these studies lack in statistical power due to small sample size. We aim to investigate the pathological changes following RFA of Bethesda III, IV, and V thyroid nodules. Patients treated by RFA with pre-operative and post-operative fine needle aspiration (FNA) were included. Nondiagnostic nodules were subsequently subjected to ThyGeNEXT and ThyraMIR testing. The FNA results following RFA were compared against the two FNA biopsies prior to ablation. The repeat FNA occurred between 1 and 24 months after ablation. Surgery was offered to patients when indicated and final pathology was recorded. A total of 74 thyroid nodules were included. At baseline, 21 nodules were nondiagnostic, 37 nodules were benign, and 16 nodules were either Bethesda III, IV, or V. Of the 37 benign nodules, 35 (94.6%) remained benign on repeat FNA and 2 (5.4%) became nondiagnostic with no mutation detected following molecular and genetic testing. Of the 21 baseline nondiagnostic nodules which were proven benign by ThyGeNEXT and ThyraMIR prior to ablation, 17 (81%) were benign on repeat FNA and 4 (19%) remained nondiagnostic with no mutation detected. Of the 16 Bethesda III, IV, and V nodules, 6 (37.5%) were benign on repeat FNA, 1 (6.3%) was nondiagnostic on repeat FNA, and 9 (56.2%) remained Bethesda III, IV, and V nodules with no mutation detected on molecular and genetic testing. Among the 5 patients with Bethesda III, IV, and V nodules who had surgery, 4 (80%) were benign and 1 (20%) was papillary thyroid carcinoma on surgical pathology. No patients had follicular carcinoma. Following RFA, the majority of nodules (98.6%) were benign by FNA or surgical pathology. RFA does not increase the risk of follicular carcinoma in Bethesda III, IV, and V thyroid nodules