The aftermath of the Merck's HIV vaccine trial

The recently released results of the Merck's Phase IIb "test-of concept" vaccine trials have shown no protection from HIV-1 infection in the vaccinated group compared with a control group vaccinated with placebo. The study was designed to test the Merck's MRKAd5 trivalent candidate vaccine. The vaccine formulation was expected to stimulate a HIV-specific T cell immune response and to either prevent infection, or to reduce the levels of the viral load in vaccinated subjects. Upon the first evaluation of the interim data, the independent Data and Safety Monitoring Board (DSMB) underscored no protection from HIV-1 infection in the vaccine-inoculated volunteers compared with the control group; accordingly, the vaccine trial was stopped. This disappointing outcome warrants a critical analysis of the current vaccine studies and calls for a renewed effort toward a rational design of novel immunogens to be tested in large primate trials

Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration

Type 2 diabetes (T2D) is a disease characterized by impaired insulin secretion. The Wnt signaling transcription factor Tcf7l2 is to date the T2D-associated gene with the largest effect on disease susceptibility. However, the mechanisms by which TCF7L2 variants affect insulin release from \u3b2-cells are not yet fully understood. By taking advantage of a tcf7l2 zebrafish mutant line, we first show that these animals are characterized by hyperglycemia and impaired islet development. Moreover, we demonstrate that the zebrafish tcf7l2 gene is highly expressed in the exocrine pancreas, suggesting potential bystander effects on \u3b2-cell growth, differentiation and regeneration. Finally, we describe a peculiar vascular phenotype in tcf7l2 mutant larvae, characterized by significant reduction in the average number and diameter of pancreatic islet capillaries. Overall, the zebrafish Tcf7l2 mutant, characterized by hyperglycemia, pancreatic and vascular defects, and reduced regeneration proves to be a suitable model to study the mechanism of action and the pleiotropic effects of Tcf7l2, the most relevant T2D GWAS hit in human populations

Women's Cardiac Health in 2020: A Systematic Review

AbstractAlthough substantial progress has been made toward improving gender- and sex-specific cardiovascular disease (CVD) management and outcomes, contemporary reports indicate a persistent knowledge gap with regard to optimal risk-stratification and management in female cardiac heart disease (CHD) patients. Prominent patient and system delays in diagnosing CHD are, in part, due to the limited awareness for the latent CVD risk in women, a lack of sex-specific thresholds within clinical guidelines, and subsequent limited performance of contemporary diagnostic approaches in women. Several traditional risk factors for CHD affect both women and men. But other factors can play a bigger role in the development of heart disease in women. In addition, little is known about the influence of socioenvironmental and contextual factors on gender-specific disease manifestation and outcomes. It is imperative that we understand the mechanisms that contribute to worsening risk factors profiles in young women to reduce future atherosclerotic CVD morbidity and mortality. This comprehensive review focuses on the novel aspects of cardiovascular health in women and sex differences as they relate to clinical practice and prevention, diagnosis, and treatment of CVD. Increased recognition of the prevalence of traditional cardiovascular risk factors and their differential impact in women, as well as emerging nontraditional risk factors unique to or more common in women, contribute to new understanding mechanisms, leading to worsening outcome for women

Modeling Human Muscular Dystrophies in Zebrafish: Mutant Lines, Transgenic Fluorescent Biosensors, and Phenotyping Assays

: Muscular dystrophies (MDs) are a heterogeneous group of myopathies characterized by progressive muscle weakness leading to death from heart or respiratory failure. MDs are caused by mutations in genes involved in both the development and organization of muscle fibers. Several animal models harboring mutations in MD-associated genes have been developed so far. Together with rodents, the zebrafish is one of the most popular animal models used to reproduce MDs because of the high level of sequence homology with the human genome and its genetic manipulability. This review describes the most important zebrafish mutant models of MD and the most advanced tools used to generate and characterize all these valuable transgenic lines. Zebrafish models of MDs have been generated by introducing mutations to muscle-specific genes with different genetic techniques, such as (i) N-ethyl-N-nitrosourea (ENU) treatment, (ii) the injection of specific morpholino, (iii) tol2-based transgenesis, (iv) TALEN, (v) and CRISPR/Cas9 technology. All these models are extensively used either to study muscle development and function or understand the pathogenetic mechanisms of MDs. Several tools have also been developed to characterize these zebrafish models by checking (i) motor behavior, (ii) muscle fiber structure, (iii) oxidative stress, and (iv) mitochondrial function and dynamics. Further, living biosensor models, based on the expression of fluorescent reporter proteins under the control of muscle-specific promoters or responsive elements, have been revealed to be powerful tools to follow molecular dynamics at the level of a single muscle fiber. Thus, zebrafish models of MDs can also be a powerful tool to search for new drugs or gene therapies able to block or slow down disease progression

La sarcoidosi: vecchie certezze e nuove prospettive

Summary Introduction Sarcoidosis is the paradigm of the internistic disease. It virtually affects every organ and tissue and is characterized by the presence of noncaseating granulomas. A holistic view is needed for the diagnosis and treatment of the disease. The authors provide an overview on several recently published studies, which pose new perspectives on the approach to the disease. Materials and methods The authors reviewed the scientific literature focusing on new etiopathogenetic, diagnostic and therapeutic data. Results and discussion A multimodal approach is appropriate and effective in the diagnosis and treatment of systemic diseases such as sarcoidosis. In this context, the internist plays a key role more than any other specialist