👤 Louis Vignati

(1) Background: The development of laryngeal cancer is a multistep process involving structural alterations of the epithelial mucosa, from dysplasia (LDy) to invasive carcinoma. In this study, we define new biomarkers, prognostic for malignant transformation, in patients affected by LDy. (2) Methods: We used targeted next-generation sequencing and immunohistochemical analysis to define the mutational and immunological landscape of 15 laryngeal dysplasia progressing to invasive cancer (progressing dysplasia), as well as 31 cases of laryngeal dysplasia that did not progress to carcinoma (non-progressing dysplasia). Two pathologists independently analyzed the presence of tumor-infiltrating lymphocytes in LDy pre-embedded paraffin-fixed specimens. The RNA-based next-generation sequencing panel OIRRA was used to evaluate the expression of 395 genes related to immune system activation. (3) Results: High TILs are significantly correlated with a higher risk of malignant transformation. The non-brisk pattern was significantly associated with an 86% reduced risk of malignant progression (OR = 0.16, 95% CI: 0.03-0.5, Show less

Unimolecular dual incretins derived from hybridized glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) sequences have demonstrated synergistic reduction of adiposity in animal models and reductions of hyperglycemia in short-duration human trials. Here, we extend the characterization of NNC0090-2746 (also known as RG7697), a fatty-acylated dual agonist possessing in vitro balanced GIPR and GLP-1R agonism. In this 12-week, randomized, placebo-controlled, double-blind phase 2a trial, patients with type 2 diabetes inadequately controlled with metformin received 1.8 mg of NNC0090-2746 or placebo subcutaneously once daily. Liraglutide 1.8 mg (Victoza), starting with 2-week dose escalation, was administered subcutaneously once daily as an open-label reference arm. Measurements were collected at regular intervals after randomization. NNC0090-2746 significantly improved glycemic control and reduced body weight compared with placebo. Total cholesterol, alone among a range of lipid parameters, and leptin were both significantly reduced compared with placebo. Treatment with NNC0090-2746 was generally safe and well tolerated. Show less

Hypertrophic cardiomyopathy (HCM) is a familial, genetically determined, primary cardiomyopathy caused by mutations in genes coding for proteins of the sarcomere, or, less frequently, genes involved in storage diseases. In pediatric settings, pure HCM has an estimated incidence of 4.7 per million children. The disease is often sub-clinical and goes unrecognized mainly because most patients with HCM have only mild symptoms, if any. However, sudden cardiac death, the most dramatic clinical occurrence and the primary concern for patients and physicians alike, may be the first manifestation of the disease. We describe a case of compound heterozygosity in the MYBPC3 gene (p.Glu258Lys and IVS25-1G>A) associated with biventricular hypertrophy, atrial enlargement and subsequent neonatal death 33 days postpartum. Other studies have reported compound and/or double heterozygosis in the same or different sarcomeric genes during childhood and adulthood, and neonatal presentations have also been described. Our observations show that the combination of a missense (p.Glu258Lys) and a splice-site mutation (IVS25-1G>A) profoundly affects the clinical course. In families in which parental mutations are known, preimplantation (where ethically and legally feasible) or prenatal genetic screening should be adopted because: (1) neonatal HCM in genetic heterozygosity is potentially lethal and (2) heart disease is the most common developmental malformation and the leading cause of neonatal mortality and morbidity. Show less