Systemic lupus erythematosus: immunopathogenesis and novel therapeutic targets

Systemic lupus erythematosus (SLE) is the prototype of autoimmune diseases with multiorgan involvement. SLE presents many genetic and epigenetic associations and the pathogenesis is characterized by a complex network of alterations affecting both adaptative and innate immunity. The disclosure of novel mechanisms of SLE pathogenesis suggested new therapeutic targets, based on interference with the cytokine pathways or on depletion of the immune cells

Glioblastoma and glioblastoma stem cells are dependent on functional MTH1

Glioblastoma multiforme (GBM) is an aggressive form of brain cancer with poor prognosis. Cancer cells are characterized by a specific redox environment that adjusts metabolism to its specific needs and allows the tumor to grow and metastasize. As a consequence, cancer cells and especially GBM cells suffer from elevated oxidative pressure which requires antioxidant-defense and other sanitation enzymes to be upregulated. MTH1, which degrades oxidized nucleotides, is one of these defense enzymes and represents a promising cancer target. We found MTH1 expression levels elevated and correlated with GBM aggressiveness and discovered that siRNA knock-down or inhibition of MTH1 with small molecules efficiently reduced viability of patient-derived GBM cultures. The effect of MTH1 loss on GBM viability was likely mediated through incorporation of oxidized nucleotides and subsequent DNA damage. We revealed that MTH1 inhibition targets GBM independent of aggressiveness as well as potently kills putative GBM stem cells in vitro. We used an orthotopic zebrafish model to confirm our results in vivo and light-sheet microscopy to follow the effect of MTH1 inhibition in GBM in real time. In conclusion, MTH1 represents a promising target for GBM therapy and MTH1 inhibitors may also be effective in patients that suffer from recurring disease

Thrombosis in vasculitis: from pathogenesis to treatment

In recent years, the relationship between inflammation and thrombosis has been deeply investigated and it is now clear that immune and coagulation systems are functionally interconnected. Inflammation-induced thrombosis is by now considered a feature not only of autoimmune rheumatic diseases, but also of systemic vasculitides such as Behçet’s syndrome, ANCA-associated vasculitis or giant cells arteritis, especially during active disease. These findings have important consequences in terms of management and treatment. Indeed, Behçet’syndrome requires immunosuppressive agents for vascular involvement rather than anticoagulation or antiplatelet therapy, and it is conceivable that also in ANCA-associated vasculitis or large vessel-vasculitis an aggressive anti-inflammatory treatment during active disease could reduce the risk of thrombotic events in early stages. In this review we discuss thrombosis in vasculitides, especially in Behçet’s syndrome, ANCA-associated vasculitis and large-vessel vasculitis, and provide pathogenetic and clinical clues for the different specialists involved in the care of these patients

CLINICAL OUTCOMES OF SELF-EXPAMDABLE METALLIC STENTS IN PALLIATION OF MALIGNANT ANASTOMOTIC STRICTURES: A SINGLE CENTER EXPERIENCE

Background: self-expandable metallic stents (SEMS) are employed as the preferred non surgical palliative treatment for gastric outlet obstruction due to malignancies. Metallic stents are often employed to treat malignant anastomotic obstructions after surgicsl interventions as esophagojejunostomy, gastrojejunostomy and esophagogastrojejunostomy. Methods: this case series reports prospectively the clinical outcomes of SEMS in the palliative care of malignant anastomotic strictures caused by the recurrence gastric cancer follwing gastric surgery as oncological curative treatment, in a series of nine consecutive patients, treated between January 2009 and december 2012 in our center. Results: Nine patients (M:F=8:1) were enrolled in the study. The operation was a total gastrectomy with esophagogastrojejunostomy (n=4), subtotal gastrectomy with Bilroth-II reconstruction (n=4), subtotal gastrectomy with Billroth-II reconstruction (n=3), and subtotal gastrectomy with esophagogastrostomy (n=2). The technical success rate was 88,9%, and the clinical success rate was 88.9%. The reostruction of the stent, due to the ingrowth of the tumor, occurred in 1 patient (11,1%) within 1 month after stent placement. the migration of the stent occurred after the placement of a covered stent in 1 patient who underwent a subtotal gastrectomy (with Billroth-II reconstruction). A case o partial stent dislodgement was treated with the placement of a second stent. The median survival period was 180 days (range, 30-240 days) and the median stent patency was 45 days 8range, 30-90 days). Conclusions: Although the number of the patients treated with SEMS results, in this series, almost small to certainly judge the safety and feasibility of SEMS, we believe that the endoscopic insertion of SEMS seems to be a safe, easily feasible, and effective treatment in the palliative care of malignant anastomotic strictures caused by the recurrence of gastric cancer following gastric surgery. The technical and clinical success, and the onset of complications of this procedure are influenced by several factors, such as the type of anastomosis, the technical features of the stent, and the extent of the underlying tumor

Illness perceptions of COVID-19 in Europe: Predictors, impacts and temporal evolution

Objective: Illness perceptions (IP) are important predictors of emotional and behavioral responses in many diseases. The current study aims to investigate the COVID-19-related IP throughout Europe. The specific goals are to understand the temporal development, identify predictors (within demographics and contact with COVID-19) and examine the impacts of IP on perceived stress and preventive behaviors. Methods: This was a time-series-cross-section study of 7, 032 participants from 16 European countries using multilevel modeling from April to June 2020. IP were measured with the Brief Illness Perception Questionnaire. Temporal patterns were observed considering the date of participation and the date recoded to account the epidemiological evolution of each country. The outcomes considered were perceived stress and COVID-19 preventive behaviors. Results: There were significant trends, over time, for several IP, suggesting a small decrease in negativity in the perception of COVID-19 in the community. Age, gender, and education level related to some, but not all, IP. Considering the self-regulation model, perceptions consistently predicted general stress and were less consistently related to preventive behaviors. Country showed no effect in the predictive model, suggesting that national differences may have little relevance for IP, in this context. Conclusion: The present study provides a comprehensive picture of COVID-19 IP in Europe in an early stage of the pandemic. The results shed light on the process of IP formation with implications for health-related outcomes and their evolution. © Copyright © 2021 Dias Neto, Nunes da Silva, Roberto, Lubenko, Constantinou, Nicolaou, Lamnisos, Papacostas, Höfer, Presti, Squatrito, Vasiliou, McHugh, Monestès, Baban, Alvarez-Galvez, Paez-Blarrina, Montesinos, Valdivia-Salas, Ori, Lappalainen, Kleszcz, Gloster, Karekla and Kassianos

Yeast two-hybrid junk sequences contain selected linear motifs

Yeast two-hybrid (Y2H) screenings result in identification of many out-of-frame (OOF) clones that code for short (2-100 amino acids) peptides with no sequence homology to known proteins. We hypothesize that these peptides can reveal common short linear motifs (SLiMs) responsible for their selection. We present a new protocol to address this issue, using an existing SLIM detector (TEIRESIAS) as a base method, and applying filters derived from a mathematical model of SLiM selection in OOF clones. The model allows for initial analysis of likely presence of SLiM(s) in a collection of OOF sequences, assisting investigators with the decision of whether to invest resources in further analysis. If SLiM presence is detected, it estimates the length and number of amino acid residues involved in binding specificity and the amount of noise in the Y2H screen. We demonstrate that our model can double the prediction sensitivity of TEIRESIAS and improve its specificity from 0 to 1.0 on simulated data and apply the model to seven sets of experimentally derived OOF clones. Finally, we experimentally validate one SLiM found by our method, demonstrating its utility

Patterns of psychological responses among the public during the early phase of COVID-19: A cross-regional analysis

This study aimed to compare the mediation of psychological flexibility, prosociality and coping in the impacts of illness perceptions toward COVID-19 on mental health among seven regions. Convenience sampled online survey was conducted between April and June 2020 from 9130 citizens in 21 countries. Illness perceptions toward COVID-19, psychological flexibility, prosociality, coping and mental health, socio-demographics, lockdown-related variables and COVID-19 status were assessed. Results showed that psychological flexibility was the only significant mediator in the relationship between illness perceptions toward COVID-19 and mental health across all regions (all ps = 0.001–0.021). Seeking social support was the significant mediator across subgroups (all ps range = <0.001–0.005) except from the Hong Kong sample (p = 0.06) and the North and South American sample (p = 0.53). No mediation was found for problem-solving (except from the Northern European sample, p = 0.009). Prosociality was the significant mediator in the Hong Kong sample (p =0.016) and the Eastern European sample (p = 0.008). These findings indicate that fostering psychological flexibility may help to mitigate the adverse mental impacts of COVID-19 across regions. Roles of seeking social support, problem-solving and prosociality vary across regions. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Mental Health Status of Healthcare Workers During the COVID-19 Outbreak An International Study

Background: The COVID-19 pandemic is a massive health crisis that has exerted enormous physical and psychological pressure. Mental healthcare for healthcare workers (HCWs) should receive serious consideration. This study served to determine the mental-health outcomes of 1,556 HCWs from 45 countries who participated in the COVID-19 IMPACT project, and to examine the predictors of the outcomes during the first pandemic wave. Methods: Outcomes assessed were self-reported perceived stress, depression symptom, and sleep changes. The predictors examined included sociodemographic factors and perceived social support. Results: The results demonstrated that half of the HCWs had moderate levels of perceived stress and symptoms of depression. Half of the HCWs (n = 800, 51.4%) had similar sleeping patterns since the pandemic started, and one in four slept more or slept less. HCWs reported less perceived stress and depression symptoms and higher levels of perceived social support than the general population who participated in the same project. Predictors associated with higher perceived stress and symptoms of depression among HCWs included female sex, not having children, living with parents, lower educational level, and lower social support. Discussion: The need for establishing ways to mitigate mental-health risks and adjusting psychological interventions and support for HCWs seems to be significant as the pandemic continues