Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome

<p>Abstract</p> <p>Background</p> <p>Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder characterized by defective function of Fas, autoimmune manifestations that predominantly involve blood cells, polyclonal accumulation of lymphocytes in the spleen and lymph nodes with lymphoadenomegaly and/or splenomegaly, and expansion of TCRαβ+ CD4/CD8 double-negative (DN) T cells in the peripheral blood. Most frequently, it is due to Fas gene mutations, causing ALPS type Ia (ALPS-Ia). However, other mutations, namely of the FasL gene (ALPS-Ib) and the caspase-10 gene (ALPS-II) are occasionally detected, whereas some patients do not present any known mutations (ALPS-III). Recently, mutations of the NRAS gene have been suggested to cause ALPS-IV.</p> <p>Results</p> <p>This work reports two patients that are combined heterozygous for single nucleotide substitutions in the Fas and caspase-10 genes. The first patient carried a splice site defect suppressing allele expression in the Fas gene and the P501L substitution in caspase-10. The second had a mutation causing a premature stop codon (Q47X) in the Fas gene and the Y446C substitution in caspase-10. Fas expression was reduced and caspase-10 activity was decreased in both patients. In both patients, the mutations were inherited from distinct healthy parents.</p> <p>Conclusion</p> <p>These data strongly suggest that co-transmission of these mutation was responsible for ALPS.</p

Influenza Vaccination Campaign during the COVID-19 Pandemic: The Experience of a Research and Teaching Hospital in Milan

Background: During the COVID-19 pandemic, more than ever, optimal influenza vaccination coverage among healthcare workers (HCWs) is crucial to avoid absenteeism and disruption of health services, as well as in-hospital influenza outbreaks. The aim of this study is to analyze the 2020 influenza vaccination campaign, comparing it with the previous year’s in a research and teaching hospital in Northern Italy. Methods: adopting an approach based on combined strategies, three interventions were deployed: a promotional and educational campaign, vaccination delivery through both ad hoc and on-site ambulatories, and a gaming strategy. Personal data and professional categories were collected and analyzed using univariate logistic regression. Vaccinated HCWs were asked to fill in a questionnaire to describe their reasons for vaccination adherence. Results: the vaccination coverage rate (VCR) was 43.1%, compared to 21.5% in 2019. The highest increase was registered among administrative staff (308.3%), while physicians represent the most vaccinated category (n = 600). Moreover, residents (prevalence ratio (PR): 1.12; 95% CI 1.04–1.20), as well as intensive care (PR: 1.44; 95% CI: 1.24–1.69) and newborn workers (PR: 1.41; 95% CI: 1.20–1.65) were, respectively, the categories most frequently vaccinated for the first time. Conclusion: the significant increase in vaccination coverage rate confirms the suitability of the combined strategy of delivering the flu vaccination campaign and represents a first step towards reaching WHO recommended vaccination rates

Adherence to Mediterranean Diet and Risk of Pancreatic Cancer: Systematic Review and Meta-Analysis

Pancreatic cancer (PC) represents the 6th cause of cancer death. Although the aetiology of PC is not completely understood, numerous risk factors have been identified in association with this cancer, among them diet. However, little is known about the association between the Mediterranean Diet (MedDiet) and the risk of PC. For this reason, we conducted a systematic review with meta-analysis according to the PRISMA guidelines, searching on three databases (PubMed/MEDLINE, Scopus, and EMBASE). The protocol was registered in PROSPERO. Both fixed and random effect models were performed. The Effect size was reported as a hazard ratio (HR) with a 95% Confidence Interval (CI). A total of eight articles were included. The methodological quality of the included meta-analyses was high. Our results show that a higher adherence to the MedDiet is associated with a lower risk of PC [HR:0.82 (0.76&ndash;0.88) p &lt; 0.001, based on 1,301,320 subjects]. The results were also confirmed in sensitivity and subgroups analyses (avoidance of potential overlapping effects, type of tools used to assess dietary intake and the diagnosis of PC, prevalence and incidence of PC risk, country where the studies took place, sex, and cancer site). Promoting a higher adherence to the MedDiet could be an effective approach to reduce the risk of PC

Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome-0

<p><b>Copyright information:</b></p><p>Taken from "Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome"</p><p>http://www.biomedcentral.com/1471-2172/8/28</p><p>BMC Immunology 2007;8():28-28.</p><p>Published online 13 Nov 2007</p><p>PMCID:PMC2211507.</p><p></p>omic DNA of Pt.1 and Pt.2. Circles represent females; squares, males; subjects carrying a CASP10 mutation are marked in black, those with a TNFRSF6 are marked with striped lines. Numbers indicate the cell survival upon Fas triggering by mAb in T cell lines generated form each subject; Fas function was defective in Pt.1 and borderline in the other subjects (normal values of cell survival: median 60%, 95percentile 82%

Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome-2

<p><b>Copyright information:</b></p><p>Taken from "Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome"</p><p>http://www.biomedcentral.com/1471-2172/8/28</p><p>BMC Immunology 2007;8():28-28.</p><p>Published online 13 Nov 2007</p><p>PMCID:PMC2211507.</p><p></p>in the panel. a) Western blot analysis of cell transfectant lysates performed with anti-caspase-10 antibody; expression of the transfected molecules was confirmed using anti-HA and -FLAG antibodies (data not shown). The white arrow shows the pro-caspase-10; black arrows indicate the cleaved forms. b) Fluorimetric enzyme assay of caspase-10 activity evaluated in the cell transfectant lysates 24 h after transfection; data are relative to those displayed by mock-transfected cells (indicated as 100%) and are the means ± SE of data from 6 independent experiments. The asterisks mark the data significantly different from those obtained with P501L-transfected cells (p < 0.01, Mann Whitney test)

Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome-3

<p><b>Copyright information:</b></p><p>Taken from "Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome"</p><p>http://www.biomedcentral.com/1471-2172/8/28</p><p>BMC Immunology 2007;8():28-28.</p><p>Published online 13 Nov 2007</p><p>PMCID:PMC2211507.</p><p></p>omic DNA of Pt.1 and Pt.2. Circles represent females; squares, males; subjects carrying a CASP10 mutation are marked in black, those with a TNFRSF6 are marked with striped lines. Numbers indicate the cell survival upon Fas triggering by mAb in T cell lines generated form each subject; Fas function was defective in Pt.1 and borderline in the other subjects (normal values of cell survival: median 60%, 95percentile 82%

DataSheet1_Neurodegeneration: can metabolites from Eremurus persicus help?.docx

The number of patients affected by neurodegenerative diseases is increasing worldwide, and no effective treatments have been developed yet. Although precision medicine could represent a powerful tool, it remains a challenge due to the high variability among patients. To identify molecules acting with innovative mechanisms of action, we performed a computational investigation using SAFAN technology, focusing specifically on HuD. This target belongs to the human embryonic lethal abnormal visual-like (ELAV) proteins and plays a key role in neuronal plasticity and differentiation. The results highlighted that the molecule able to bind the selected target was (R)-aloesaponol-III-8-methyl ether [(R)-ASME], a metabolite extracted from Eremurus persicus. Notably, this molecule is a TNF-α inhibitor, a cytokine involved in neuroinflammation. To obtain a suitable amount of (R)-ASME to confirm its activity on HuD, we optimized the extraction procedure. Together with ASME, another related metabolite, germichrysone, was isolated. Both ASME and germichrysone underwent biological investigation, but only ASME confirmed its ability to bind HuD. Given the multifactorial nature of neurodegenerative diseases, we decided to investigate ASME as a proteasome activator, being molecules endowed with this kind of activity potentially able to counteract aggregations of dysregulated proteins. ASME was able to activate the considered target both in enzymatic and cellular assays. Therefore, ASME may be considered a promising hit in the fight against neurodegenerative diseases.</p