miR-214 coordinates melanoma progression by upregulating ALCAM through TFAP2 and miR-148b downmodulation

Malignant melanoma is one of the most aggressive human cancers, but the mechanisms governing its metastatic dissemination are not fully understood. Upregulation of miR-214 and ALCAM and the loss of TFAP2 expression have been implicated in this process, with TFAP2 a direct target of miR-214. Here, we link miR-214 and ALCAM as well as identify a core role for miR-214 in organizing melanoma metastasis. miR- 214 upregulated ALCAM, acting transcriptionally through TFAP2 and also posttranscriptionally through miR-148b (itself controlled by TFAP2), both negative regulators of ALCAM. We also identified several miR-214–mediated prometastatic functions directly promoted by ALCAM. Silencing ALCAM in miR-214–overexpressing melanoma cells reduced cell migration and invasion without affecting growth or anoikisin vitro, and it also impaired extravasation and metastasis formation in vivo. Conversely, cell migration and extravasation was reduced in miR-214–overexpressing cells by upregulation of either miR 148b or TFAP2. These findings were consistent with patterns of expression of miR-214, ALCAM, and miR-148b in human melanoma specimens. Overall, our results define a pathway involving miR-214, miR-148b, TFAP2, and ALCAM that is critical for establishing distant metastases in melanoma

The role of HMG-CoA reductase inhibition in endothelial dysfunction and inflammation

Statin-induced inhibition of HMG-CoA reductase reduces cholesterol production and prevents the formation of many non-steroidal isoprenoid compounds, such as farnesylpyrophosphate and geranylgeranylpyrophosphate, that act as lipid attachments for the post-translational modification of various proteins, including the G-proteins and transcription factors involved in a number of cell processes. However, the blockade of isoprenylation elicited by statin treatment also has biological effects on cell function that go beyond the decrease in cholesterol synthesis: these are the so-called “pleiotropic” effects that mainly relate to vascular function. Endothelial dysfunction is an independent predictor of cardiovascular events that correlates with inflammation markers/mediators and robust predictors of cardiovascular diseases such as increased high-sensitivity C-reactive protein levels. The results of in vivo and in vitro studies indicate that the statins have beneficial effects unrelated to cholesterol lowering, such as improving endothelial function, increasing myocardial perfusion, and enhancing the availability of nitric oxide. This review describes the pleiotropic effects of statins that may be involved in modulating/preventing endothelial dysfunction and inflammatory processes, as well as the cellular and molecular mechanisms through which they improve endothelial function

Assembly and functional analysis of an S/MAR based episome with the cystic fibrosis transmembrane conductance regulator gene

Improving the efficacy of gene therapy vectors is still an important goal toward the development of safe and efficient gene therapy treatments. S/MAR (scaffold/matrix attached region)-based vectors are maintained extra-chromosomally in numerous cell types, which is similar to viral-based vectors. Additionally, when established as an episome, they show a very high mitotic stability. In the present study we tested the idea that addition of an S/MAR element to a CFTR (cystic fibrosis transmembrane conductance regulator) expression vector, may allow the establishment of a CFTR episome in bronchial epithelial cells. Starting from the observation that the S/MAR vector pEPI-EGFP (enhanced green fluorescence protein) is maintained as an episome in human bronchial epithelial cells, we assembled the CFTR vector pBQ-S/MAR. This vector, transfected in bronchial epithelial cells with mutated CFTR, supported long term wt CFTR expression and activity, which in turn positively impacted on the assembly of tight junctions in polarized epithelial cells. Additionally, the recovery of intact pBQ-S/MAR, but not the parental vector lacking the S/MAR element, from transfected cells after extensive proliferation, strongly suggested that pBQ-S/MAR was established as an episome. These results add a new element, the S/MAR, that can be considered to improve the persistence and safety of gene therapy vectors for cystic fibrosis pulmonary disease

Electrical Power Subsystem for the Euclid Spacecraft

European Space Agency in the frame of Cosmic Vision 2015-2025 program [ 1 ]. It is a cosmology mission whose prime objective is to study the geometry and the nature of the dark matter and the dark energy with unprecedented accuracy. The spacecraft will be launched in 2020 by a Soyuz launcher, to perform a six-year survey of the extragalactic sky from a large-amplitude orbit around Lagrange point L2 of the Sun-Earth system. This paper outlines the Euclid Electrical Power Subsystem (EPS) design, providing a description of the major design drivers and resulting configuration, with a view to highlight aspects that could be considered for future designs

The COVID-19 Pandemic and Its Impact on Families' Mental Health: The Role Played by Parenting Stress, Parents' Past Trauma, and Resilience

International research has evidenced the psychological impact of the COVID-19 pandemic on families, and the key role played by parenting stress levels. Although significant associations with parents' past trauma and resilience have been shown, this study aimed to explore their complex interplay on the relationship between parents' peritraumatic distress due to COVID-19, parenting stress, and children's psychopathological difficulties. We recruited 353 parents with children aged two to 16 years via an online survey during the Italian second wave of COVID-19. Parents' peritraumatic distress due to COVID-19, parenting stress, past trauma and resilience, and children's psychological difficulties were assessed through self-report and report-form questionnaires. Parents' past traumas significantly predicted peritraumatic distress due to COVID-19 and children's psychological difficulties. The relationship between past traumas and children's psychological difficulties was serial mediated by parents' peritraumatic distress and parenting stress. Direct and total effects of parent's resilience on parent's peritraumatic distress were not significant, but there were significant indirect effects via parenting stress and via parents' peritraumatic distress and parenting stress, indicating inconsistent mediation. This study evidenced the key risk and protective role played by, respectively, parents' past traumas exposure and resilience on the relationship between parents' psychological difficulties due to COVID-19, parenting stress, and children's psychological difficulties, with important clinical implications

Autoimmune polyglandular syndrome type 4: experience from a single reference center

Purpose: To characterize patients with APS type 4 among those affected by APS diagnosed and monitored at our local Reference Center for Autoimmune Polyglandular Syndromes. Methods: Monocentric observational retrospective study enrolling patients affected by APS diagnosed and monitored in a Reference Center. Clinical records were retrieved and analyzed. Results: 111 subjects (51 males) were affected by APS type 4, mean age at the onset was 23.1 ± 15.1 years. In 15 patients the diagnosis of APS was performed during the first clinical evaluation, in the other 96 after a latency of 11 years (range 1-46). The most frequent diseases were type I diabetes mellitus and celiac disease, equally distributed among sexes. Conclusions: The prevalence of APS type 4 is 9:100,000 people. Type I diabetes mellitus was the leading indicator of APS type 4 in 78% subjects and in 9% permitted the diagnosis occurring as second manifestation of the syndrome. Our data, showing that 50% of patients developed APS type 4 within the first ten years, don't suggest any particular follow-up time and, more importantly, don't specify any particular disease. It is important to emphasize that 5% of women developed premature ovarian failure

Loss of PML Nuclear Bodies in Familial Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share genetic causes and pathogenic mechanisms. The critical genetic players of ALS and FTD are the TARDBP, FUS and C9orf72 genes, whose protein products, TDP-43, FUS and the C9orf72-dipeptide repeat proteins, accumulate in form of cytoplasmic inclusions. The majority of the studies focus on the understanding of how cells control TDP-43 and FUS aggregation in the cytoplasm, overlooking how dysfunctions occurring at the nuclear level may influence the maintenance of protein solubility outside of the nucleus. However, protein quality control (PQC) systems that maintain protein homeostasis comprise a cytoplasmic and a nuclear arm that are interconnected and share key players. It is thus conceivable that impairment of the nuclear arm of the PQC may have a negative impact on the cytoplasmic arm of the PQC, contributing to the formation of the cytoplasmic pathological inclusions. Here we focused on two stress-inducible condensates that act as transient deposition sites for misfolding-prone proteins: Promyelocytic leukemia protein (PML) nuclear bodies (PML-NBs) and cytoplasmic stress granules (SGs). Upon stress, PML-NBs compartmentalize misfolded proteins, including defective ribosomal products (DRiPs), and recruit chaperones and proteasomes to promote their nuclear clearance. SGs transiently sequester aggregation-prone RNA-binding proteins linked to ALS-FTD and mRNAs to attenuate their translation. We report that PML assembly is impaired in the human brain and spinal cord of familial C9orf72 and FUS ALS-FTD cases. We also show that defective PML-NB assembly impairs the compartmentalization of DRiPs in the nucleus, leading to their accumulation inside cytoplasmic SGs, negatively influencing SG dynamics. Although it is currently unclear what causes the decrease of PML-NBs in ALS-FTD, our data highlight the existence of a cross-talk between the cytoplasmic and nuclear PQC systems, whose alteration can contribute to SG accumulation and cytoplasmic protein aggregation in ALS-FTD

Integration of mental health comorbidity in medical specialty programs in 20 countries

Methods A systematic analysis was performed of the medical specialization academic programs of 20 different countries to establish which medical specialties take into account mental health issues in the specialty curricular design and which mental health content these programs address. The criteria that were explored in the educational programs include: 1) name of the medical specialties that take into account mental health content in curriculum design, 2) name of the mental health issues addressed by these programs. After independent review and data extraction, paired investigators compared the findings and reached consensus on all discrepancies before the final presentation of the data. Descriptive statistics evaluated the frequency of the data presented. Results Internal medicine, family medicine, neurology, pediatrics and geriatrics were the specialties that included mental health topics in their programs. In four countries: Bangladesh, Serbia, the Netherlands and France, 50%of all graduate specialty training programs include mental health content. In ten countries: Germany, Sweden, the United Kingdom, Mexico, Belgium, India, Russia, Canada, Israel and Spain, between 20% and 49% of all graduate specialty training programs include mental health content. In six countries - Brazil, Chile, Colombia, Croatia, Kenya, and the United States-less than 20% of all graduate specialty training programs include mental health content. Discussion The proposal that we have made in this article should be taken into account by decision-makers, in order to complement the different postgraduate training programs with mental health issues that are frequently present with other physical symptoms. It is not our intention that the different specialists know how to treat psychiatric comorbidities, but rather pay attention to their existence and implications in the diagnosis, evolution and prognosis of many other diseases. The current fragmentation of medicine into ever finer specialties makes the management of comorbidity ever more difficult: a reorientation of post- graduate training might improve the situation