Blood-based analysis of type-2 diabetes mellitus susceptibility genes identifies specific transcript variants with deregulated expression and association with disease risk

Despite significant progress by genome-wide association studies, the ability of genetic variants to conduce to the prediction or prognosis of type-2 diabetes (T2D) is weak. Expression analysis of the corresponding genes may suggest possible links between single-nucleotide polymorphisms and T2D phenotype and/or risk. Herein, we investigated the expression patterns of 24 T2D-susceptibility genes, and their individual transcript variants (tv), in peripheral blood of T2D patients and controls (CTs), applying RNA-seq and real-time qPCR methodologies, and explore possible associations with disease features. Our data revealed the deregulation of certain transcripts in T2D patients. Among them, the down-regulation of CAPN10 tv3 was confirmed as an independent predictor for T2D. In patients, increased expression of CDK5 tv2, CDKN2A tv3 or THADA tv5 correlated positively with serum insulin levels, of CDK5 tv1 positively with % HbA1c levels, while in controls, elevated levels of TSPAN8 were associated positively with the presence of T2D family history. Herein, a T2D-specific expression profile of specific transcripts of disease-susceptibility genes is for the first time described in human peripheral blood. Large-scale studies are needed to evaluate the potential of these molecules to serve as disease biomarkers

Increasing incidence of zoonotic visceral leishmaniasis on Crete, Greece

To determine whether the incidence of canine leishmaniasis has increased on Crete, Greece, we fitted infection models to serodiagnostic records of 8,848 dog samples for 1990–2006. Models predicted that seroprevalence has increased 2.4% (95% confidence interval 1.61%–3.51%) per year and that incidence has increased 2.2- to 3.8-fold over this 17-year period

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

AdS/CFT: dictionary and applications

This thesis discusses two separate questions within the field of gauge/gravity dualities. The first is what is the gravity dual of a CFT state and it is based on work done in collaboration with my advisor, Prof. Skenderis, and which was presented in [1]. In particular, we develop a systematic perturbative construction of bulk solutions that are dual to CFT excited states. The second question concerns four dimensional theories that admit charged planar AdS black hole solutions carrying axionic charge and which can support additional scalar hair. More specifically, we discuss a number of analytic solutions in which the axions have a linear profile in the boundary directions and the additional scalar field satisfies mixed boundary conditions. We focus on the effect of these features on the thermodynamics and dynamic stability of the solutions and we use our results to study phase transitions between solutions with the same asymptotic charges and which satisfy the same boundary conditions. These results are based on work done in collaboration with M. Caldarelli, I. Papadimitriou and K. Skenderis and which was presented in [2]

New clinical approaches and emerging evidence on immune-checkpoint inhibitors as anti-cancer therapeutics: CTLA-4 and PD-1 pathways and beyond

The development of immune checkpoint blockers, primarily comprising the anti-PD-1/anti-PD-L1 and anti-CTLA-4 monoclonal antibodies, has formed the therapeutic landscape of quite a few different cancer types. In spite of the great clinical results produced by some inhibitors in some cases, most cancer patients still present de novo or adaptive resistance, and thus, the overall efficacy of this type of immunotherapy is not sufficient. Here, we explore emerging immune checkpoint molecules apart from anti-PD-1/anti-PD-L1 and anti-CTLA-4, presently being used in the clinical setting as mono-or combinatorial therapy against various cancer types. Methods Primary publications with results between January 2014 and December 2019 were investigated on PubMed. ClinicalTrials.gov was screened for finding phase I/II/III cancer trials on the use of new immune checkpoint targets, including LAG-3, TIM-3, TIGIT, and VISTA, which are active (recruiting or not) or completed. Results We recapitulate the clinical data associated with these immune checkpoint inhibitors and analyze their application prospects. The investigation about such emerging molecules has produced encouraging outcomes in preclinical studies and/or clinical trials. Conclusions Although monotherapy treatment has yielded impressive results in some cases, the current attempts emphasize more the design of combinatorial immune checkpoint inhibition that targets non-redundant pathways to achieve a synergistic effect against cancer cells. It seems that such new combinatorial checkpoint inhibition schemes will achieve better outcomes for the patients than the ones witnessed with CTLA-4 or PD-1/PD-L1 blockers.The authors acknowledge the clinicaltrials.gov database and the various researchers whose research and clinical studies or published reports were used in the present review. They would also like to apologize to colleagues whose works were not cited due to space limitations.Scopu

The role of T-regulatory lymphocytes in autoimmune epithelitis - Sjogren syndrome

Autoimmune epithelitis or Sjogren syndrome (SS) is a common, chronic autoimmune disorder characterized by the destruction of the exocrine glands (mainly the salivary and lacrimal glands). The histopathologic lesions of the disease are associated with the presence of lymphocytic infiltrates that tend to develop around ductal epithelium. These infiltrates vary by severity extending from mild to severe degree of inflammation with concomitant loss of tissue architecture. They mainly consist of activated T- and B-lymphocytes, while classical antigen-presenting cells (macrophages and dendritic cells) are primarily reported in heavy infiltrates. Finally, it is not evident whether regulatory-T cells (Tregs), a subpopulation with suppressive capacity and pivotal implication in the regulation of autoimmune responses and, subsequently, of the autoimmune disorders, are involved in the inflammatory SS lesions. Although it has never been systematically studied, evidence suggests that the composition of the lymphocytic infiltrates varies according to lesion severity. A detailed analysis of the SS inflammatory lesions is of particular importance for the understanding of the disease pathogenesis, as well as for the choice of the appropriate therapeutic intervention (current therapeutic approaches are based on the depletion of specific cell types, such as B lymphocytes). In the current study, the variations in the composition of SS-salivary gland lesions of distinct severity were investigated. Thus, the incidence of the major lymphocytic populations [T cells and their subpopulation CD4+-T, CD8+-T and Tregs, B lymphocytes, macrophages (ΜΦ), interdigitating (iDC) and follicular (fDC) dendritic cells, and natural-killer cells (NK)] was analyzed in mild, intermediate or severe inflammatory lesions and possible correlations between the frequency of these lymphocytic populations and lesion severity, as well as clinical manifestations of the disease, were studied. Specifically, due to the key role of Tregs in the regulation of the autoimmune responses, their incidence and its variation with lesion severity were analyzed in the minor salivary glands and peripheral blood of SS patients, and compared to those in other non-SS inflammatory lesions of salivary glands or in salivary glands of controls without evidence of inflammation. This study reveals that the composition of the lymphocytic infiltrates in salivary glands of SS patients varies according to lesion severity. The incidence of total infiltrating T cells, CD4+-T- and B-lymphocytes, ΜΦ and iDCs was found to be significantly different among tissues with mild, intermediate or severe inflammatory lesions. T cells have been considered as the major population in the SS lymphocytic infiltrates, however, the findings of the current study indicate that this applies only for mild lesions, while B lymphocytes predominate in severe ones. The negative correlation between T-cell incidence and the grade of infiltration owes to the reduction of infiltrating CD4+-T-cell incidence, as CD8+-T-cell incidence remains unchanged. Similarly, iDCs that gather antigens from the periphery and then present them in the lymph nodes are negatively associated with biopsy focus score. On the other hand, ΜΦ increase with the infiltration grade, a finding implying their possible accumulation in heavy infiltrates in an effort to “clean up” the derivatives of the inflammation. .................H αυτοάνοση επιθηλιίτιδα ή σύνδρομο Sjogren (σS) αποτελεί μία συχνή, χρόνια αυτοάνοση νόσο που χαρακτηρίζεται από την καταστροφή των εξωκρινών (κυρίως των σιελογόνων και δακρυϊκών) αδένων. Οι ιστοπαθολογικές βλάβες της νόσου σχετίζονται με την παρουσία λεμφοκυτταρικών διηθήσεων που έχουν την τάση να αναπτύσσονται γύρω από το πορικό επιθήλιο. Οι διηθήσεις αυτές ποικίλουν ως προς τη δριμύτητα και εκτείνονται από ήπιου έως εκτεταμένου βαθμού με συνακόλουθη καταστροφή της αρχιτεκτονικής δομής του αδένα. Αποτελούνται ως επί το πλείστον από ενεργοποιημένα Τ- και Β-λεμφοκύτταρα, ενώ τα κλασσικά αντιγονοπαρουσιαστικά κύτταρα (μακροφάγα και δενδριτικά κύτταρα) αναφέρονται κυρίως στις βαριές βλάβες. Τέλος, δεν είναι γνωστό αν στις φλεγμονώδεις διηθήσεις του σS συμμετέχουν τα ρυθμιστικά-Τ (Τρυθ) κύτταρα, ένας υποπληθυσμός με κατασταλτικές ιδιότητες και σημαντικό ρόλο στη ρύθμιση των ανοσολογικών αποκρίσεων και κατ’ επέκταση των αυτοάνοσων νοσημάτων. Παρόλο που αρκετά στοιχεία υποδεικνύουν ότι η σύσταση των λεμφοκυτταρικών διηθήσεων μεταβάλλεται ανάλογα με το βαθμό δριμύτητας της βλάβης, η μεταβολή αυτή δεν έχει μελετηθεί. Η εν τω βάθει ανάλυση των φλεγμονωδών διηθήσεων του σS είναι ιδιαίτερα σημαντική για την κατανόηση της παθογένειας της νόσου, αλλά και για την επιλογή της κατάλληλης θεραπευτικής αγωγής (οι σύγχρονες θεραπευτικές προσεγγίσεις στοχεύουν στην εξάλειψη συγκεκριμένων τύπων λεμφοκυττάρων, όπως τα Β λεμφοκύτταρα). Στην παρούσα εργασία, μελετήθηκε η μεταβολή της σύστασης των λεμφοκυτταρικών διηθήσεων των σιελογόνων αδένων των ασθενών με σS σε σχέση με τη δριμύτητα της βλάβης. Για το σκοπό αυτό, αναλύθηκε η συχνότητα των κύριων λεμφοκυτταρικών πληθυσμών [Τ κυττάρων και των υποπληθυσμών τους CD4+-Τ, CD8+-Τ και Τρυθ κυττάρων, Β λεμφοκυττάρων, μακροφάγων (ΜΦ), διαπλεκόμενων (δΔΚ) και λεμφοζιδιακών (λΔΚ) δενδριτικών κυττάρων, και κυττάρων φυσικών-φονέων (ΦΦ)] σε ήπιες, ενδιάμεσες ή εκτεταμένες φλεγμονώδεις βλάβες και διερευνήθηκε η ύπαρξη πιθανών συσχετίσεων μεταξύ της επίπτωσής τους και της βαρύτητας της βλάβης, καθώς και κλινικών χαρακτηριστικών της νόσου. Ειδικότερα, λόγω της εξέχουσας σημασίας τους στη ρύθμιση των αυτοάνοσων αποκρίσεων, μελετήθηκαν, περαιτέρω, η ύπαρξη και η συχνότητα των Τρυθ κυττάρων στις λεμφοκυτταρικές διηθήσεις των σιελογόνων αδένων και στο περιφερικό αίμα ασθενών με σS και συγκρίθηκαν με τις αντίστοιχες σε φλεγμονώδεις βλάβες των σιελογόνων αδένων άλλης αιτιολογίας ή σε σιελογόνους αδένες μαρτύρων χωρίς φλεγμονώδη ευρήματα. Η μελέτη αυτή καταδεικνύει ότι η σύσταση των λεμφοκυτταρικών διηθήσεων των σιελογόνων αδένων των ασθενών με σS ποικίλει ανάλογα με τη δριμύτητα της βλάβης. Η συχνότητα του συνολικού πληθυσμού των Τ κυττάρων, των CD4+-Τ- και Β-λεμφοκυττάρων, των ΜΦ και των δΔΚ βρέθηκε ότι διαφέρει σημαντικά μεταξύ ιστών με ήπιες, ενδιάμεσες ή εκτεταμένες φλεγμονώδεις βλάβες. Παρόλο που τα Τ κύτταρα θεωρούνταν ο κυρίαρχος πληθυσμός των λεμφοκυτταρικών διηθήσεων του σS, τα ευρήματα της παρούσας εργασίας δείχνουν ότι αυτό ισχύει μόνο στις ήπιες βλάβες, ενώ στις εκτεταμένες διηθήσεις υπερτερούν τα Β λεμφοκύτταρα. ......

Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach

Type-2 diabetes mellitus (T2D) is a chronic metabolic disorder, associated with an increased risk of developing solid tumors and hematological malignancies, including acute myeloid leukemia (AML). However, the genetic background underlying this predisposition remains elusive. We herein aimed at the exploration of the genetic variants, related transcriptomic changes and disturbances in metabolic pathways shared by T2D and AML, utilizing bioinformatics tools and repositories, as well as publicly available clinical datasets. Our approach revealed that rs11709077 and rs1801282, on PPARG, rs11108094 on USP44, rs6685701 on RPS6KA1 and rs7929543 on AC118942.1 comprise common SNPs susceptible to the two diseases and, together with 64 other co-inherited proxy SNPs, may affect the expression patterns of metabolic genes, such as USP44, METAP2, PPARG, TIMP4 and RPS6KA1, in adipose tissue, skeletal muscle, liver, pancreas and whole blood. Most importantly, a set of 86 AML/T2D common susceptibility genes was found to be significantly associated with metabolic cellular processes, including purine, pyrimidine, and choline metabolism, as well as insulin, AMPK, mTOR and PI3K signaling. Moreover, it was revealed that the whole blood of AML patients exhibits deregulated expression of certain T2D-related genes. Our findings support the existence of common metabolic perturbations in AML and T2D that may account for the increased risk for AML in T2D patients. Future studies may focus on the elucidation of these pathogenetic mechanisms in AML/T2D patients, as well as on the assessment of certain susceptibility variants and genes as potential biomarkers for AML development in the setting of T2D. Detection of shared therapeutic molecular targets may enforce the need for repurposing metabolic drugs in the therapeutic management of AML

Altered SERCA Expression in Breast Cancer

Background and Objectives: Calcium (Ca2+) signaling is critical for the normal functioning of various cellular activities. However, abnormal changes in cellular Ca2+ can contribute to pathological conditions, including various types of cancer. The maintenance of intracellular Ca2+ levels is achieved through tightly regulated processes that help maintain Ca2+ homeostasis. Several types of regulatory proteins are involved in controlling intracellular Ca2+ levels, including the sarco/endoplasmic reticulum (SR/ER) Ca2+ ATPase pump (SERCA), which maintains Ca2+ levels released from the SR/ER. In total, three ATPase SR/ER Ca2+-transporting (ATP2A) 1-3 genes exist, which encode for several isoforms whose expression profiles are tissue-specific. Recently, it has become clear that abnormal SERCA expression and activity are associated with various types of cancer, including breast cancer. Breast carcinomas represent 40% of all cancer types that affect women, with a wide variety of pathological and clinical conditions. Materials and methods: Using cBioPortal breast cancer patient data, Kaplan–Meier plots demonstrated that high ATP2A1 and ATP2A3 expression was associated with reduced patient survival. Results: The present study found significantly different SERCA specific-type expressions in a series of breast cancer cell lines. Moreover, bioinformatics analysis indicated that ATP2A1 and ATP2A3 expression was highly altered in patients with breast cancer. Conclusion: Overall, the present data suggest that SERCA gene-specific expressioncan possibly be considered as a crucial target for the control of breast cancer development and progression