Notch signaling deregulation in multiple myeloma: A rational molecular target

Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches.     

Self-reported influenza vaccination uptake in people with chronic diseases: data from Progressi delle Aziende Sanitarie per la Salute in Italia (PASSI)

BackgroundInfluenza is an important public health problem, with potential severe consequences among people with chronic diseases. The aim of this study was to obtain reliable measures of seasonal influenza vaccine uptake in this population, otherwise not available in Italy.MethodsProgressi delle Aziende Sanitarie per la Salute in Italia (PASSI) is a nationwide surveillance system of health-related behaviours and acceptance of preventive interventions (including influenza immunisation) offered by the Italian National Health Service. Data are collected with telephone interviews at local health unit level for supporting local activities. The survey sample is randomly selected from local health unit lists of adult residents. The trend of annual vaccine coverage since 2008 was estimated for people aged 18–64 years who reported having at least one chronic disease. To obtain a sufficient sample size in subgroups, we analysed the characteristics of vaccinated people in the 2010–13 cumulative dataset. Univariate, multivariate, and logistic regression analyses were undertaken.FindingsIn 2008–13, 13 659 individuals with at least one chronic disease were interviewed. Vaccination coverage fell significantly from 29·7% (95% CI 27·2–32·4) in 2007–08 to 19·9% (18·0–22·1) in 2012–13. During 2010–13, the overall proportion of vaccinated people with a chronic disease was 25·6% (24·5–26·7). Vaccine coverage of people with diabetes (34·3%, 31·7–36·9) or cardiovascular diseases (31·8%, 29·6–34·2) was greater than that of people affected by renal failure, respiratory diseases, tumours, or chronic liver diseases (26·5% [22·5–30·7], 24·9% [23·2–26·7], 22·2% [20·0–24·6], and 20·6% [17·5–24·6], respectively). Vaccination coverage increased with age (from 13·1% [11·0–15·5] in the 18–34 year age group to 33·4% [31·9–35·1] in people aged 50–64 years); it was higher among people with a low educational level than among those with a high educational level, higher in those having economic difficulties than in those with no economic difficulties, and higher among Italian citizens than among non-citizens.InterpretationIn the past few years, prevalence of influenza vaccination in Italian adults with at least one chronic disease was well below the Ministry of Health's goal (75% minimum) and showed a downward trend. A major reason of this evolution is probably the changing public perception of the benefits and risks of vaccines. PASSI is a source of useful data not otherwise available for public health intervention.FundingItalian Ministry of Health.     

Metabolic Syndrome Does Not Improve the Prediction of 5-Year Cardiovascular Disease and Total Mortality Over Standard Risk Markers. Prospective Population Based Study

Metabolic syndrome (MS) is widely believed to be an important risk factor for cardiovascular disease (CVD). We assessed whether a model based on MS improved prediction of CVD and total mortality over the Framingham''s general CVD system (FRS) and whether MS was better than its individual components.Prospective cohort study of 855 participants randomly selected from the general population. Cox proportional hazards models were used to estimate the hazard ratios selecting a composite endpoint of CVD and total mortality. The performance of the FRS was compared with that of 4 MS-based models that differed in their use of individual components of MS as well as in the use of optimized cut-points of MS. The assessment included metrics of discrimination, calibration, and risk reclassification.Of all the models, only the model containing the 5 optimized components of MS improved model fit (deviance 10.7, P = 0.005), discrimination (difference of areas under the receiving operating curves 0.018), and risk reclassification in participants without events (net reclassification index 5.97, P = 0.01). The addition of optimized waist circumference to the FRS model improved the performance more than any other MS-based model. Every model containing the dichotomous definition of MS failed to improve model fit, discrimination, and risk reclassification.MS did not contribute predictive information over the FRS for the 5-year risk of CVD and total mortality. Some individual components of MS, in particular waist circumference, might play a role as part of the FRS provided their cut-off points are optimized.     

How is the quality of the available evidence on molar-incisor hypomineralization treatment? An overview of systematic reviews

Clinical Oral Investigations - This overview analyzed the quality of the systematic reviews (SRs) available on treatments for molar-incisor hypomineralization (MIH). Six electronic databases were...     

Relationship between European Mitochondrial Haplogroups and Chronic Renal Allograft Rejection in Patients with Kidney Transplant

Mitochondrial DNA variants may contribute to differences in mitochondrial function, leading to an altered immune system. The aim of this study was to analyze the relationship between mtDNA haplogroups and the development of chronic allograft dysfunction in patients with kidney transplant. A retrospective observational study was carried out on 261 patients who received kidney transplant (114 had stable transplant and 147 patients developed chronic allograft dysfunction). DNA samples were genotyped for 14 mtDNA polymorphisms by using Sequenom''s MassARRAY platform (San Diego, CA, USA). Only European white patients within the N macro-cluster were included. Patients with haplogroups V (odds ratio (OR)=0.32; p=0.037) and J (OR=0.36; p=0.038) showed lower odds for developing CRAD than patients with haplogroup H. After adjusting for the most significant variables, haplogroups V and J tended to statistical significance (p=0.091 and p=0.067 respectively). This is a preliminary study in which mtDNA haplogroups seem to be implicated in susceptibility or protection for developing chronic allograft dysfunction.