Αναστολείς PD-1/PD-L1 στην θεραπεία των ασθενών με προχωρημένο/μεταστατικό ή υποτροπιάζοντα καρκίνο του τραχήλου της μήτρας

Ο καρκίνος του τραχήλου της μήτρας είναι ένα μείζονος σημασίας πρόβλημα δημόσιας υγείας, καθώς ευθύνεται για περίπου 311.000 θανάτους ετησίως. Παγκοσμίως αποτελεί τον τέταρτο πιο συχνά εμφανιζόμενο καρκίνο στον γυναικείο πληθυσμό, ενώ είναι δεύτερος σε συχνότητα στις αναπτυσσόμενες χώρες. Οι μισές περίπου γυναίκες διαγιγνώσκονται με τη νόσο σε προχωρημένο ή μεταστατικό στάδιο. Η ενδεδειγμένη θεραπεία για αυτά τα στάδια της νόσου είναι ο συνδυασμός σισπλατίνης και πακλιταξέλης ή σισπλατίνης και πακλιταξέλης και μπεβασιζουμάμπης επιφέροντας μέση επιβίωση της τάξης του ενός και του 1,5 έτους αντίστοιχα. Λαμβάνοντας υπόψιν ότι οι πλειονότητα των γυναικών που προσβάλλονται από καρκίνο του τραχήλου της μήτρας διανύουν μόλις την τέταρτη ή την πέμπτη δεκαετία της ζωής τους, προκύπτει επιτακτική ανάγκη για ανακάλυψη νέων και αποτελεσματικών θεραπειών. Σκοπός: Η παρούσα συστηματική ανασκόπηση έχει ως στόχο να αξιολογήσει την αποτελεσματικότητα και την ασφάλεια μίας νέας ομάδας παραγόντων, των αναστολέων PD-1/PD-L1 στον προχωρημένο/μεταστατικό ή υποτροπιάζοντα καρκίνο του τραχήλου της μήτρας. Οι μελέτες οι οποίες επιλέχθηκαν προέκυψαν έπειτα από αναζήτηση της υπάρχουσας βιβλιογραφίας για την περίοδο 01.01.2000 έως 28.02.2021. Η παρούσα εργασία διενεργήθηκε σύμφωνα με τις αρχές του PRISMA και χρησιμοποιήθηκε ένας προκαθορισμένος αλγόριθμος αναζήτησης. Κριτήρια επιλογής: Όλες οι κλινικές μελέτες φάσης Ι/ΙΙ με αποτελέσματα στην αξιολόγηση της αποτελεσματικότητας και της ασφάλειας των αναστολέων PD-1/PD-L1 στους ασθενείς με προχωρημένο/μεταστατικό ή υποτροπιάζοντα καρκίνο του τραχήλου της μήτρας. Συλλογή δεδομένων: Συνολικά συμπεριλήφθηκαν 10 κλινικές μελέτες φάσης Ι/ΙΙ εκ των οποίων οι τέσσερις περιλαμβάνουν δεδομένα για την αποτελεσματικότητα και ασφάλεια της πεμπρολιζουμάμπης, τρεις της νιβολουμάμπης, και από μία για την σεμιπλιμάμπη, ατεζολιζουμάμπη και δουρβαλουμάμπη. Συμπεράσματα: Η πεμπρολιζουμάμπη και η νιβολουμάμπη εμφανίζουν αισιόδοξα αποτελέσματα όσον αφορά την αποτελεσματικότητα και την ασφάλεια. Η σεμιπλιμάμπη φαίνεται να προκαλεί μεγαλύτερη τοξικότητα σε σύγκριση με τους άλλους παράγοντες και χαμηλή ανταπόκριση της νόσου. Η ατεζολιζουμάμπη δεν κατάφερε μέχρι σήμερα να επιφέρει σημαντικά αποτελέσματα ενώ η δουρβαλουμάμπη φαίνεται να είναι ένας ασφαλής παράγοντας με ενθαρρυντικά αρχικά αποτελέσματα ως προς την αποτελεσματικότητα.Cervical cancer consists a major global public health issue, accounted for approximately 311.000 deaths every year. Despite the comprehensive cervical cancer control including primary prevention and secondary prevention, cervical cancer remains the fourth most common cancer in women worldwide and the second in developing countries. Almost half of the women are diagnosed at an advanced or metastatic stage of disease. The standard treatment for recurrent/metastatic cervical cancer is a combination of paclitaxel and cisplatin or paclitaxel and cisplatin and bevacizumab, associated with a median survival of one to one and a half years respectively. Taking into consideration that cervical cancer concerns young women, there is an urgent need for the discovery of new efficient treatments. Objectives: This systematic review aims to evaluate the efficacy and safety of an emerging group of agents, PD-1/PD-L1 inhibitors, in reccurent/metastatic cervical cancer patients. Eligible articles were identified by a search of existing literature for the period 01/01/2000–28/02/2021. This study was performed in accordance with PRISMA guidelines and a specified algorithm was used in identifying eligible studies. Selection criteria: All phase I/II clinical trials evaluating the efficacy and safety of PD-1/PD-L1 inhibitors in recurrent/advanced/metastatic cervical cancer patients. Data collection: Overall, 10 phase I/II clinical trials were retrieved of which four studies explored the efficacy and safety of pembrolizumab, three studies of nivolumab, one of cemiplimab, one of atezolizumab, one of durvalumab in recurrent/advanved/metastatic cervical cancer. Conclusions: Pembolizumab exhibited promising results in terms of safety and efficacy as also did nivolumab. Patients under cemiplimab treatment developed more adverse events compared with other agents and low response to therapy. Atezolizumab could not meet the expected efficacy leading in zero response. Durvalumab has a manageable safety profile with promising preliminary results in terms of efficacy

THE EFFECT OF A GREEK TRADITIONAL DANCE PROGRAM ON THE MOTOR COMPETENCE OF CHILDREN WITH AUTISM SPECTRUM DISORDER

It is usual for individuals with autism spectrum disorder (ASD) to demonstrate deficits in motor behavior. Participation in movement programs has been suggested to elicit improvements in their motor competence (MC) level. The aim of the present study was to examine the effect of a Greek traditional dance (GTD) program on the MC of 6-14-year-old children with ASD. The study design included eight participants (two girls, six boys), who were randomly allocated into two equal-sized groups, group A (its members participated only in the regular Physical Education lessons provided by their school) and group B (its members additionally followed an 8-week GTD program of two 40-min sessions per week). Children’s MC was assessed prior and immediately after the completion of the GTD program by the Bruininks- Oseretsky Test of Motor Proficiency (BOT-2 SF). Due to study’s small sample size and participants’ heterogenous ASD characteristics, the results will be interpreted as outcomes of multiple single case studies. Overall, it was observed that the MC of all participants was considerably poor; however, members of group B made greater improvements in both the total BOT-2 point score and most item raw scores compared to those of group A, with balance and body coordination skills presenting the greater improvements. Even though the results of this study stress the positive effect of GTD on the MC of children with ASD, future studies employing wider sample sizes and/or implementing longer programs are required to further confirm its merit. Article visualizations

Preparation and certification of 243Am spike reference material: IRMM-0243 : Certified reference material for the amount content of 243Am and n(241Am)7n(243Am) isotope amount ratio

This report describes the preparation and certification of IRMM-0243, a 243Am spike reference material. It is certified for the amount content of 243Am and the isotope amount ratios of n(241Am)/n(243Am) and n(242mAm)/n(243Am). Furthermore, the material is certified for the amount contents of 241Am and total Am, the mass fractions of 243Am, 241Am and total Am, the isotope amount and mass fractions (e.g. isotopic composition) and the molar mass of Am. The material was produced in compliance with ISO/IEC 17034:2016 and certified in accordance with ISO Guide 35:2006. The material was prepared by dilution of an americium starting solution in nitric acid and dispensing of the solution into glass ampoules. In total 587 units were produced. Between-unit homogeneity was quantified and stability during dispatch and storage were assessed in accordance with ISO Guide 35:2006. The characterisation of the amount content of 243Am was performed by Isotope Dilution Mass Spectrometry (IDMS) using a 241Am spike, produced from highly enriched 241Pu material. The isotope amount ratios of n(241Am)/n(243Am) and n(242mAm)/n(243Am) were measured by Thermal Ionisation Mass Spectrometry (TIMS). The certified values were verified by alpha particle spectrometry, alpha particle counting at a defined solid angle (DSA) and high-resolution gamma-ray spectrometry as independent verification methods. The uncertainties of the certified values were estimated in compliance with the Guide to the Expression of Uncertainty in Measurement (GUM) [ ] and include uncertainties related to possible inhomogeneity, instability and characterisation. The main purpose of this material is for use as a spike isotopic reference material for the quantification of americium by IDMS in unknown samples. A unit of IRMM-0243 consists of a glass ampoule with a screw cap containing about 3.5 mL nitric acid solution (c = 1 mol/L) with an americium mass fraction of about 1.5 μg/g solution. The material is a true solution; therefore there is no recommended minimum sample intake to be taken into account.JRC.G.2-Standards for Nuclear Safety, Security and Safeguard

Evaluating the glucose raising effect of established loci via a genetic risk score.

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with glucose levels. We tested the hypothesis here whether the cumulative effect of glucose raising SNPs, assessed via a score, is associated with glucose levels. A total of 1,434 participants of Greek descent from the THISEAS study and 1,160 participants form the GOMAP study were included in this analysis. We developed a genetic risk score (GRS), based on the known glucose-raising loci, in order to investigate the cumulative effect of known glucose loci on glucose levels. In the THISEAS study, the GRS score was significantly associated with increased glucose levels (mmol/L) (β ± SE: 0.024 ± 0.004, P = 8.27e-07). The effect of the genetic risk score was also significant in the GOMAP study (β ± SE: 0.011 ± 0.005, P = 0.031). In the meta-analysis of the two studies both scores were significantly associated with higher glucose levels GRS: β ± SE: 0.019 ± 0.003, P = 1.41e-09. Also, variants at the SLC30A8, PROX1, MTNR1B, ADRA2A, G6PC2, LPIN3 loci indicated nominal evidence for association with glucose levels (p < 0.05). We replicate associations of the established glucose raising variants in the Greek population and confirm directional consistency of effects (binomial sign test p = 6.96e-05). We also demonstrate that the cumulative effect of the established glucose loci yielded a significant association with increasing glucose levels

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.</p

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.</p

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.</p

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.</p