The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A

Methylmercury (MeHg) exposure has been related to amyotrophic lateral sclerosis (ALS) pathogenesis and molecular mechanisms of its neurotoxicity has been associated to an overexpression of the Restrictive Element 1 Silencing Transcription factor (REST). Herein, we evaluated the possibility that MeHg could accelerate neuronal death of the motor neuron-like NSC34 cells transiently overexpressing the human Cu2+/Zn2+superoxide dismutase 1 (SOD1) gene mutated at glycine 93 (SOD1-G93A). Indeed, SOD1-G93A cells exposed to 100 nM MeHg for 24 h showed a reduction in cell viability, as compared to cells transfected with empty vector or with unmutated SOD1 construct. Interestingly, cell survival reduction in SOD1-G93A cells was associated with an increase of REST mRNA and protein levels. Furthermore, MeHg increased the expression of the transcriptional factor Sp1 and promoted its binding to REST gene promoter sequence. Notably, Sp1 knockdown reverted MeHg-induced REST increase. Co-immunoprecipitation experiments demonstrated that Sp1 physically interacted with the epigenetic writer Lysine-Methyltransferase-2A (KMT2A). Moreover, knocking-down of KMT2A reduced MeHg-induced REST mRNA and protein increase in SOD1-G93A cells. Finally, we found that MeHg-induced REST up-regulation triggered necropoptotic cell death, monitored by RIPK1 increased protein expression. Interestingly, REST knockdown or treatment with the necroptosis inhibitor Necrostatin-1 (Nec) decelerated MeH-induced cell death in SOD1-G93A cells. Collectively, this study demonstrated that MeHg hastens necroptotic cell death in SOD1-G93A cells via Sp1/KMT2A complex, that by epigenetic mechanisms increases REST gene expression

Workaholism and Technostress During the COVID-19 Emergency: The Crucial Role of the Leaders on Remote Working

Although remote working can involve positive outcomes both for employees and organizations, in the case of the sudden and forced remote working situation that came into place during the COVID-19 crisis there have also been reports of negative aspects, one of which is technostress. In this context of crisis, leadership is crucial in sustainably managing and supporting employees, especially employees with workaholic tendencies who are more prone to developing negative work and health outcomes. However, while research on the role of the positive aspects of leadership during crises does exist, the negative aspects of leadership during the COVID-19 crisis have not yet been studied. The present study aimed to explore the role of authoritarian leadership in a sample of 339 administrative university employees who worked either completely from home or from home and the workplace. The study examined the moderating effect of a manager on this relationship and the connections between workaholism and technostress through conditional process analysis. Results pointed out that high authoritarian leadership had an enhancing effect, whereas low authoritarian leadership had a protective effect on the relationship between workaholism and technostress, only in the group of complete remote workers. Thus, authoritarian leadership should be avoided and training leaders to be aware of its effect appears to be essential. Limitations, future directions for the study, and practical implications are also discussed

Interobserver reproducibility in pathologist interpretation of columnar-lined esophagus

Confirmation of endoscopically suspected esophageal metaplasia (ESEM) requires histology, but confusion in the histological definition of columnar-lined esophagus (CLE) is a longstanding problem. The aim of this study is to evaluate interpathologist variability in the interpretation of CLE. Thirty pathologists were invited to review three ten-case sets of CLE biopsies. In the first set, the cases were provided with descriptive endoscopy only; in the second and the third sets, ESEM extent using Prague criteria was provided. Moreover, participants were required to refer to a diagnostic chart for evaluation of the third set. Agreement was statistically assessed using Randolph’s free-marginal multirater kappa. While substantial agreement in recognizing columnar epithelium (K = 0.76) was recorded, the overall concordance in clinico-pathological diagnosis was low (K = 0.38). The overall concordance rate improved from the first (K = 0.27) to the second (K = 0.40) and third step (K = 0.46). Agreement was substantial when diagnosing Barrett’s esophagus (BE) with intestinal metaplasia or inlet patch (K = 0.65 and K = 0.89), respectively, in the third step, while major problems in interpretation of CLE were observed when only cardia/cardia-oxyntic atrophic-type epithelium was present (K = 0.05–0.29). In conclusion, precise endoscopic description and the use of a diagnostic chart increased consistency in CLE interpretation of esophageal biopsies. Agreement was substantial for some diagnostic categories (BE with intestinal metaplasia and inlet patch) with a well-defined clinical profile. Interpretation of cases with cardia/cardia-oxyntic atrophic-type epithelium, with or without ESEM, was least consistent, which reflects lack of clarity of definition and results in variable management of this entity

Thyroid cancers: From surgery to current and future systemic therapies through their molecular identities

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor

Targeting PI3K/AKT/mTOR Pathway in Breast Cancer: From Biology to Clinical Challenges

Breast cancer (BC) is the most common women cancer and cause of cancer death. Despite decades of scientific progress in BC treatments, the clinical benefit of new drugs is modest in several cases. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway mutations are frequent in BC (20-40%) and are significant causes of aggressive tumor behavior, as well as treatment resistance. Improving knowledge of the PI3K/AKT/mTOR pathway is an urgent need. This review aims to highlight the central role of PI3K-mTORC1/C2 mutations in the different BC subtypes, in terms of clinical outcomes and treatment efficacy. The broad base of knowledge in tumor biology is a key point for personalized BC therapy in the precision medicine era

A See-Saw S4S_4 model for fermion masses and mixings

We present a supersymmetric see-saw $S_4$ model giving rise to the most general neutrino mass matrix compatible with Tri-Bimaximal mixing. We adopt the $S_4\times Z_5$ flavour symmetry, broken by suitable vacuum expectation values of a small number of flavon fields. We show that the vacuum alignment is a natural solution of the most general superpotential allowed by the flavour symmetry, without introducing any soft breaking terms. In the charged lepton sector, mass hierarchies are controlled by the spontaneous breaking of the flavour symmetry caused by the vevs of one doublet and one triplet flavon fields instead of using the Froggatt-Nielsen U(1) mechanism. The next to leading order corrections to both charged lepton mass matrix and flavon vevs generate corrections to the mixing angles as large as ${\cal O}(\lambda_C^2)$. Applied to the quark sector, the symmetry group $S_4\times Z_5$ can give a leading order $V_{CKM}$ proportional to the identity as well as a matrix with ${\cal O}(1)$ coefficients in the Cabibbo $2\times 2$ submatrix. Higher order corrections produce non vanishing entries in the other $V_{CKM}$ entries which are generically of ${\cal O}(\lambda_C^2)$.Comment: 30 pages, 3 figures, minor changes to match the published versio