Hypermethylation of genomic 3.3-kb repeats is frequent event in HPV-positive cervical cancer

Background: Large-scale screening methods are widely used to reveal cancer-specific DNA methylation markers. We previously identified non-satellite 3.3-kb repeats associated with facioscapulohumeral muscular dystrophy (FSHD) as hypermethylated in cervical cancer in genome-wide screening. To determine whether hypermethylation of 3.3-kb repeats is a tumor-specific event and to evaluate frequency of this event in tumors, we investigated the 3.3-kb repeat methylation status in human papilloma virus (HPV)-positive cervical tumors, cancer cell lines, and normal cervical tissues. Open reading frames encoding DUX family proteins are contained within some 3.3-kb repeat units. The DUX mRNA expression profile was also studied in these tissues. Methods: The methylation status of 3.3-kb repeats was evaluated by Southern blot hybridization and bisulfite genomic sequencing. The expression of DUX mRNA was analyzed by RT-PCR and specificity of PCR products was confirmed by sequencing analysis. Results: Hypermethylation of 3.3-kb repeats relative to normal tissues was revealed for the first time in more than 50% (18/34) of cervical tumors and in 4 HPV-positive cervical cancer cell lines. Hypermethylation of 3.3-kb repeats was observed in tumors concurrently with or independently of hypomethylation of classical satellite 2 sequences (Sat2) that were hypomethylated in 75% (15/20) of cervical tumors. We have revealed the presence of transcripts highly homologous to DUX4 and DUX10 genes in normal tissues and down-regulation of transcripts in 68% of tumors with and without 3.3-kb repeats hypermethylation. Conclusion: Our results demonstrate that hypermethylation rather than hypomethylation of 3.3-kb repeats is the predominant event in HPV-associated cervical cancer and provide new insight into the epigenetic changes of repetitive DNA elements in carcinogenesis

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Factors affecting diabetic patient’s long-term quality of life after simultaneous pancreas-kidney transplantation: a single-center analysis

[EN]Pancreas transplantation (PT) is one of the few ways to restore euglycemia within diabetic patients; however, the high morbidity caused by surgical complications and the need for immunosuppressive therapy has raised controversy about PT improving the health-related quality-of-life (HRQoL). The aim of this study is to assess the long-term (≥ 5 years after PT) HRQoL and to identify the factors affecting it. A single-center, cross-sectional study of 49 sequential PT was performed. All patients conducted a telephone interview to fulfill the modification of Medical Outcome Health Survey Short Form questionnaire (SF-36v2) and were compared to similar post-PT studies from the literature. Patients with a history of replacement renal therapy (RRT) or neuropathy undergoing a PT were associated to a worse bodily pain (P = 0.03) and physical function (P = 0.04), respectively, whereas those with retinopathy showed an improved Role Emotional (P = 0.04). Multivariate analysis revealed the presence of RRT as the only independent prognostic factor for a worse bodily pain [relative risk = 3.9; 95% confidence interval (1.1-14.6)], (P = 0.04). Furthermore, nearly all PT recipients (91.8%) claimed an overall better health than prior to PT. Our study confirms that PT recipients' HRQoL improves after PT, showing similar HRQoL scores across different populations and suggests that patients in predialysis could benefit from an improved HRQoL if transplanted on the early stages of the disease

Does Hepatocellular Carcinoma Surveillance Increase Survival in At-Risk Populations? Patient Selection, Biomarkers, and Barriers

Hepatocellular carcinoma (HCC) is a highly morbid and prevalent cancer globally. While high quality evidence for mortality benefit of HCC surveillance is lacking, early detection of HCC is likely beneficial as prognosis is highly correlated with tumor stage. High risk populations, including patients with cirrhosis and subgroups with Hepatitis B, should undergo surveillance with ultrasound ± alpha-fetoprotein (AFP) at 6-month intervals. In addition, emerging data suggest that patients with Hepatitis C cirrhosis who achieve sustained virologic response should continue surveillance. Further research is needed to determine the value of surveillance in patients with nonalcoholic fatty liver disease in the absence of cirrhosis or with advanced fibrosis of other etiologies. Newer biomarkers and models such as Lens culinaris agglutinin-reactive fraction of AFP, des-γ-carboxy prothrombin, and the GALAD score are increasingly utilized in the diagnosis and prognostication of HCC. The role of these biomarkers in surveillance is still under investigation but may potentially offer a more practical alternative to traditional image-based surveillance. Despite recommendations from multiple professional society guidelines, many at-risk patients do not receive HCC surveillance due to barriers at the patient, clinician, and health care system levels. Strategies such as implementing patient navigation services, educating clinicians about surveillance guidelines, and creating automated outreach systems, may improve surveillance rates and ultimately reduce morbidity and mortality from HCC