Η συμβολή των μεγάλων μη-κωδικών (long non-coding) RNAs στην αιτιοπαθογένεια των ΙΦΝΕ

Ένας αυξανόμενος αριθμός μελετών ευρέως γονιδιώματος (Genome Wide Association Studies, GWAS) έχει αναδείξει εκατοντάδες πολυμορφισμούς που σχετίζονται με τον κίνδυνο εκδήλωσης ιδιοπαθών φλεγμονωδών νόσων του εντέρου (ΙΦΝΕ), όπως η νόσος Crohn (NC) και η ελκώδης κολίτιδα (ΕΚ). Πρόσφατα, έχει δειχθεί ότι τα μεγάλα μη-κωδικά RNA μετάγραφα (large non-coding RNA transcripts, LncRNAs) διαδραματίζουν ρυθμιστικό ρόλο σε ποικίλα νοσήματα, μεταβάλλοντας το επίπεδο έκφρασης των γονιδίων προκαλώντας εναλλακτικό μάτισμα ή επιδρώντας στη δευτεροταγή δομή τους, συμπεριλαμβανομένων των ΙΦΝΕ. Ωστόσο, η παθογένεση των ΙΦΝΕ παραμένει έως σήμερα ασαφής και υπάρχουν περιορισμένα δεδομένα σχετικά με το ρόλο των lncRNAs σε αυτές τις παθήσεις. Επομένως, στόχος της παρούσας μελέτης είναι να εκτιμήσει τη συσχέτιση μεταξύ πολυμορφισμών σε lncRNA γονίδια και την εκδήλωση ΙΦΝΕ στον ελληνικό πληθυσμό και να συμβάλει στην αποσαφήνιση της παθοφυσιολογίας των ΙΦΝΕ. Πραγματοποιήθηκε μελέτη πληθυσμού ασθενών-μαρτύρων και γονοτύπηση των πολυμορφισμών μονού νουκλεοτιδίου (single nucleotide polymorphisms, SNPs) rs1476514, rs3757247 και rs597325 σε δείγμα ορού αίματος από 242 ασθενείς με NC, 185 ασθενείς με ΕΚ και 220 υγιείς μάρτυρες. Βρέθηκε ότι η συχνότητα του αλληλόμορφου Α του SNP rs1476514 επικρατή στον υγιή πληθυσμό. Επιπροσθέτως, σχετικά με τον SNP rs3757247, η συχνότητα του αλληλόμορφου G είναι υψηλότερη στους υγιείς μάρτυρες σε σύγκριση με του ασθενείς με ΕΚ ενώ σε όλα τα υπό μελέτη δείγματα διαπιστώθηκε ετεροζυγωτία για τον SNP rs597325. Συμπερασματικά, η κατανόηση των μηχανισμών που συμμετέχουν στην εκδήλωση των ΙΦΝΕ είναι επί του παρόντος περιορισμένη και η αιτιολογία τους παραμένει άγνωστη. Καθώς όμως συσσωρεύονται δεδομένα που υποδεικνύουν ότι υπάρχει συσχέτιση ορισμένων SNPs σε lncRNAs με τις ΙΦΝΕ, θα χρειαστούν μελέτες με μεγαλύτερο πληθυσμό ώστε να επιβεβαιωθούν τα αποτελέσματα και να αναζητηθεί ο ρόλος των απορρυθμισμένων lncRNAs στην παθογένεση των ΙΦΝΕ.A number of Genome Wide Association Studies (GWAS) indicates hundreds of polymorphisms associated with Inflammatory Bowel Disease (IBD) risk, such as Crohn’s disease (CD) and ulcerative colitis (UC). In recent years, it has been shown that large non-coding RNA transcripts (LncRNAs) appear to have a regulatory role by altering the expression levels of genes causing alternative splicing or affecting their secondary structure in various diseases, including IBD. However, the pathogenesis of the IBD remains unclear so far and the there is scarce data about the role of lncRNAs in these diseases. Thus, we aimed to evaluate the correlation between polymorphisms at lncRNAs and the pathophysiology of IBD in Greek population. Genotyping of rs1476514, rs3757247 and rs597325 single nucleotide polymorphisms (SNPs) was carried out in a population-based case-control study including 242 patients with NC, 185 with EC and 220 healthy controls. According the results, the frequency of allele A of rs1476514, appears to prevail in healthy population. As far as rs3757247 is concerned, the frequency of G allele is higher in healthy controls in comparison to UC whereas all samples tested for rs597325 were found heterozygous. In conclusion, the understanding of the mechanisms of IBD presentation is limited so far and the etiology is basically still unknown. However, as accumulating evidence suggest that there is a correlation between selected lncRNA SNPs and IBDs, larger studies are needed in order to confirm our results and research further the role of dysregulated lncRNA polymorphisms in IBD pathogenesis

Efficacy of Infliximab after Failure of Subcutaneous Anti-TNF Agents in Patients with Moderate to Severe Ulcerative Colitis

Aim: To assess the efficacy of infliximab in ulcerative colitis (UC) patients who had failed therapy with adalimumab or golimumab. Methods: Retrospective analysis of prospectively acquired data of all anti-TNF naive patients with moderate to severe UC who received adalimumab or golimumab in 4 tertiary referral centres. Patients with primary non response or secondary loss of response to adalimumab or golimumab received therapy with infliximab. Clinical response and remission rates were assessed at week 14 and 54 after initiation of infliximab. Results: Between September 2015 and September 2017, 29 of 58 (50%) anti-TNF naive patients with moderate to severe UC failed therapy with adalimumab (n=38) or golimumab (n=20). Twenty one of 29 (72.4%) patients were primary non responders and 8 (27.6%) patients lost response to adalimumab or golimumab. All these 29 patients received infliximab, while 15 (51.7%) were on concomitant azathioprine therapy. Eighteen (62.1%) and 10 (34.5%) patients showed clinical response and clinical remission at week 14 respectively, while 14 (48.3%) patients were on clinical remission at week 54 after initiation of infliximab. Azathioprine co-administration at the start of infliximab was associated with a greater proportion of patients achieving clinical remission at week 54 (10 of 15 patients on combination therapy vs 4 of 14 patients on infliximab monotherapy, p=0.04). Conclusions: A significant proportion of anti-TNF naive patients with moderate to severe UC who have failed 1st course therapy with subcutaneous anti-TNF agents can achieve clinical response and/or remission with 2nd course therapy with infliximab

Comparison between tofacitinib and ustekinumab as a third-line therapy in refractory ulcerative colitis: multicenter international study

Background: Ustekinumab and tofacitinib have recently been approved for the management of moderate to severe ulcerative colitis (UC). However, there is no evidence on how they should be positioned in the therapeutic algorithm. The aim of this study was to compare tofacitinib and ustekinumab as third-line therapies in UC patients in whom anti-TNF and vedolizumab had failed. Methods: This was a multicenter retrospective observational study. The primary outcome was disease progression, defined as the need for steroids, therapy escalation, UC-related hospitalization and/or surgery. Secondary outcomes were clinical remission, normalization of C-reactive protein, endoscopic remission, treatment withdrawal, and adverse events. Results: One-hundred seventeen UC patients were included in the study and followed for a median time of 11.6 months (q₁–q₃, 5.5-18.7). Overall, 65% of patients were treated with tofacitinib and 35% with ustekinumab. In the entire study cohort, 63 patients (54%) had disease progression during the follow-up period. Treatment with ustekinumab predicted increased risk of disease progression compared to treatment with tofacitinib in Cox regression analysis (HR: 1.93 [95% CI: 1.06-3.50] p = 0.030). Twenty-eight (68%) patients in the ustekinumab group and 35 (46%) in the tofacitinib group had disease progression over the follow-up period (log-rank test, p < 0.054). No significant differences were observed for the secondary outcomes. Six and 22 adverse events occurred in the ustekinumab and tofacitinib groups, respectively (15% vs. 31%, p = 0.11). Conclusions: Tofacitinib was more efficacious in reducing disease progression than ustekinumab in this cohort of refractory UC patients. However, prospective head-to-head clinical trials are needed as to confirm these data.ACKNOWLEDGMENTS: The authors received no financial support for the research, authorship, and/or publication of this article. Open access funding provided by BIBLIOSAN

Patients with inflammatory bowel disease are not at increased risk of COVID-19 : a large multinational cohort study

The impact of COVID-19 on inflammatory bowel disease (IBD) patients under pharmacological immunosuppression is still not clearly understood. We investigated the incidence of COVID-19 and the impact of immunosuppression and containment measures on the risk of SARS-CoV-2 infection in a large IBD cohort, from a multicenter cohort from 21st of February to 30th of June, 2020. Ninety-seven patients with IBD (43 UC, 53 CD, one unclassified IBD) and concomitant COVID-19 over a total of 23,879 patients with IBD were enrolled in the study. The cumulative incidence of SARS-CoV-2 infection in patients with IBD vs. the general population was 0.406% and 0.402% cases, respectively. Twenty-three patients (24%) were hospitalized, 21 (22%) had pneumonia, four (4%) were admitted to the Intensive Care Unit, and one patient died. Lethality in our cohort was 1% compared to 9% in the general population. At multivariable analysis, age > 65 years was associated with increased risk of pneumonia and hospitalization (OR 11.6, 95% CI 2.18–62.60; OR 5.1, 95% CI 1.10–23.86, respectively), treatment with corticosteroids increased the risk of hospitalization (OR 7.6, 95% CI 1.48–40.05), whereas monoclonal antibodies were associated with reduced risk of pneumonia and hospitalization (OR 0.1, 95% CI 0.04–0.52; OR 0.3, 95% CI 0.10–0.90, respectively). The risk of COVID-19 in patients with IBD is similar to the general population. National lockdown was effective in preventing infection in our cohort. Advanced age and treatment with corticosteroids impacted negatively on the outcome of COVID-19, whereas monoclonal antibodies did not seem to have a detrimental effect.peer-reviewe

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Measurement of the W gamma Production Cross Section in Proton-Proton Collisions at root s=13 TeV and Constraints on Effective Field Theory Coefficients

A fiducial cross section for W gamma production in proton-proton collisions is measured at a center-of-mass energy of 13 TeV in 137 fb(-1) of data collected using the CMS detector at the LHC. The W -> e nu and mu nu decay modes are used in a maximum-likelihood fit to the lepton-photon invariant mass distribution to extract the combined cross section. The measured cross section is compared with theoretical expectations at next-to-leading order in quantum chromodynamics. In addition, 95% confidence level intervals are reported for anomalous triple-gauge couplings within the framework of effective field theory.Peer reviewe

Probing effective field theory operators in the associated production of top quarks with a Z boson in multilepton final states at root s=13 TeV

Peer reviewe

Performance of the CMS muon trigger system in proton-proton collisions at √s = 13 TeV

The muon trigger system of the CMS experiment uses a combination of hardware and software to identify events containing a muon. During Run 2 (covering 2015-2018) the LHC achieved instantaneous luminosities as high as 2 × 10 cm s while delivering proton-proton collisions at √s = 13 TeV. The challenge for the trigger system of the CMS experiment is to reduce the registered event rate from about 40 MHz to about 1 kHz. Significant improvements important for the success of the CMS physics program have been made to the muon trigger system via improved muon reconstruction and identification algorithms since the end of Run 1 and throughout the Run 2 data-taking period. The new algorithms maintain the acceptance of the muon triggers at the same or even lower rate throughout the data-taking period despite the increasing number of additional proton-proton interactions in each LHC bunch crossing. In this paper, the algorithms used in 2015 and 2016 and their improvements throughout 2017 and 2018 are described. Measurements of the CMS muon trigger performance for this data-taking period are presented, including efficiencies, transverse momentum resolution, trigger rates, and the purity of the selected muon sample. This paper focuses on the single- and double-muon triggers with the lowest sustainable transverse momentum thresholds used by CMS. The efficiency is measured in a transverse momentum range from 8 to several hundred GeV

Measurements of Higgs boson production cross sections and couplings in the diphoton decay channel at root s=13 TeV

Measurements of Higgs boson production cross sections and couplings in events where the Higgs boson decays into a pair of photons are reported. Events are selected from a sample of proton-proton collisions at root s = 13TeV collected by the CMS detector at the LHC from 2016 to 2018, corresponding to an integrated luminosity of 137 fb(-1). Analysis categories enriched in Higgs boson events produced via gluon fusion, vector boson fusion, vector boson associated production, and production associated with top quarks are constructed. The total Higgs boson signal strength, relative to the standard model (SM) prediction, is measured to be 1.12 +/- 0.09. Other properties of the Higgs boson are measured, including SM signal strength modifiers, production cross sections, and its couplings to other particles. These include the most precise measurements of gluon fusion and vector boson fusion Higgs boson production in several different kinematic regions, the first measurement of Higgs boson production in association with a top quark pair in five regions of the Higgs boson transverse momentum, and an upper limit on the rate of Higgs boson production in association with a single top quark. All results are found to be in agreement with the SM expectations.Peer reviewe