Espressione del recettore α degli estrogeni sulla membrana plasmatica dei linfociti: implicazioni nella patogenesi del Lupus Eritematoso Sistemico

Numerose evidenze epidemiologiche, immunologiche e cliniche suggeriscono che gli ormoni sessuali, in modo particolare gli estrogeni, svolgono un ruolo importante nell’insorgenza e nel decorso delle malattie autoimmuni. In particolare è stato dimostrato che gli estrogeni ed il loro recettore α (ERα) sono implicati nella patogenesi del lupus eritematoso sistemico (LES). Nel LES è stata dimostrata una profonda alterazione dell’omeostasi linfocitaria che porta alla produzione di differenti autoanticorpi IgG patogenetici, inclusi autoanticorpi anti-ER. Lo studio del possibile ruolo degli anticorpi anti-ER nel modulare l’omeostasi linfocitaria attraverso il legame a recettori di membrana potrebbe aprire nuove prospettive alla comprensione della patogenesi del LES. Per tale motivo abbiamo inizialmente verificato l’espressione e la funzionalità di ER a livello della membrana plasmatica linfocitaria. Successivamente, abbiamo indagato la presenza di anticorpi anti-ER nel siero dei pazienti con LES ed analizzato il loro ruolo nell’omeostasi T linfocitaria. Abbiamo dimostrato la presenza di anticorpi anti-ERα nel siero del 45% dei pazienti con LES. Questi anticorpi sono in grado di indurre apoptosi e attivazione dei linfociti T “resting” ed, inoltre, di aumentare la proliferazione dei linfociti T stimolati con anti-CD3. Abbiamo, anche, osservato che i livelli di anticorpi anti-ERα sono associati, significativamente, all’attività della malattia, i.e.“Systemic Lupus Erythematosus Disease Activity Index”, SLEDAI. In conclusione, i risultati ottenuti, evidenziano un ruolo patogenetico degli anticorpi anti-ERα nel LES. Quindi, una terapia mirata a modulare le risposte immunitarie mediate dagli anticorpi anti-ERα potrebbe essere utile a contrastare l’attività della malattia

Low expression of estrogen receptor β in T lymphocytes and high serum levels of anti-estrogen receptor α antibodies impact disease activity in female patients with systemic lupus erythematosus

BACKGROUND: Current evidence indicates that estrogens, in particular 17β-estradiol (E2), play a crucial role in the gender bias of autoimmune diseases although the underlying molecular mechanisms have not yet been fully elucidated. Immune cells have estrogen receptors (ERs), i.e., ERα and ERβ, that play pro- and anti-inflammatory functions, respectively, and the presence of one estrogen receptor (ER) subtype over the other might change estrogen effects, promoting or dampening inflammation. In this study, we contributed to define the influences of E2 on T cells from female patients with systemic lupus erythematosus (SLE), a representative autoimmune disease characterized by a higher prevalence in women than in men (female/male ratio 9:1). Particularly, our aim was to evaluate whether alterations of ERα and ERβ expression in T cells from female SLE patients may impact lymphocyte sensitivity to E2 and anti-ERα antibody (anti-ERα Ab) stimulation interfering with cell signaling and display a direct clinical effect. METHODS: Sixty-one premenopausal female patients with SLE and 40 age-matched healthy donors were recruited. Patients were divided into two groups based on the SLE Disease Activity Index 2000 (SLEDAI-2K) (i.e., <6 and ≥6). ER expression was evaluated in T lymphocytes by flow cytometry, immunofluorescence, and Western blot analyses. Serum anti-ERα Ab levels were analyzed by enzyme-linked immunosorbent assay (ELISA). ER-dependent signaling pathways were measured by a phosphoprotein detection kit. RESULTS: Intracellular ERβ expression was significantly lower in T cells from patients with SLEDAI-2K ≥6 as compared with healthy donors and patients with SLEDAI-2K <6 and negatively correlated with disease activity. The expression of intracellular and membrane-associated-ERα was similar in SLE and control T cells. ER-dependent signaling pathways were activated in T cells from SLE patients with SLEDAI-2K ≥6, but not with SLEDAI-2K <6, when both membrane and intracellular ERs were stimulated by co-treatment with E2 and anti-ERα Abs. CONCLUSIONS: Our results demonstrate an altered ER profile in SLE patients, possibly contributing to SLE pathogenesis and interfering with clinical activity, and highlight the potential exploitation of T cell-associated ERβ as a biomarker of disease activity

Deltaic and Coastal Sediments as Recorders of Mediterranean Regional Climate and Human Impact Over the Past Three Millennia

This work was financially supported by the MISTRALS/PaleoMex program and by the Project of Strategic Interest NextData PNR 2011–2013 (www. nextdataproject.it). Lionel Savignan is thanked for his participation in the biomarker analysis. Radiocarbon datings for core KESC9-14 have been funded by Institut Carnot Ifremer-EDROME (grant A0811101). We also thank the Holocene North-Atlantic Gyres and Mediterranean Overturning dynamic through Climate Changes (HAMOC) project for financial support. The biomarker data presented here are available in the supporting information.Peer reviewedPublisher PD

Deltaic and Coastal Sediments as Recorders of Mediterranean Regional Climate and Human Impact Over the Past Three Millennia

International audienc

Research-policy partnerships - experiences of the Mental Health and Poverty Project in Ghana, South Africa, Uganda and Zambia

Background: Partnerships are increasingly common in conducting research. However, there is little published evidence about processes in research-policy partnerships in different contexts. This paper contributes to filling this gap by analysing experiences of research-policy partnerships between Ministries of Health and research organisations for the implementation of the Mental Health and Poverty Project in Ghana, South Africa, Uganda and Zambia. Methods: A conceptual framework for understanding and assessing research-policy partnerships was developed and guided this study. The data collection methods for this qualitative study included semi-structured interviews with Ministry of Health Partners (MOHPs) and Research Partners (RPs) in each country. Results: The term partnership was perceived by the partners as a collaboration involving mutually-agreed goals and objectives. The principles of trust, openness, equality and mutual respect were identified as constituting the core of partnerships. The MOHPs and RPs had clearly defined roles, with the MOHPs largely providing political support and RPs leading the research agenda. Different influences affected partnerships. At the individual level, personal relationships and ability to compromise within partnerships were seen as important. At the organisational level, the main influences included the degree of formalisation of roles and responsibilities and the internal structures and procedures affecting decision-making. At the contextual level, political environment and the degree of health system decentralisation affected partnerships. Conclusions: Several lessons can be learned from these experiences. Taking account of influences on the partnership at individual, organisation and contextual/system levels can increase its effectiveness. A common understanding of mutually-agreed goals and objectives of the partnership is essential. It is important to give attention to the processes of initiating and maintaining partnerships, based on clear roles, responsibilities and commitment of parties at different levels. Although partnerships are often established for a specific purpose, such as carrying out a particular project, the effects of partnership go beyond a particular initiative

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

MUSiC : a model-unspecific search for new physics in proton-proton collisions at root s=13TeV

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.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

Measurement of prompt open-charm production cross sections in proton-proton collisions at root s=13 TeV

The production cross sections for prompt open-charm mesons in proton-proton collisions at a center-of-mass energy of 13TeV are reported. The measurement is performed using a data sample collected by the CMS experiment corresponding to an integrated luminosity of 29 nb(-1). The differential production cross sections of the D*(+/-), D-+/-, and D-0 ((D) over bar (0)) mesons are presented in ranges of transverse momentum and pseudorapidity 4 < p(T) < 100 GeV and vertical bar eta vertical bar < 2.1, respectively. The results are compared to several theoretical calculations and to previous measurements.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