SEOM clinical guideline in ovarian cancer (2020)

Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor.

BACKGROUND: Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined. METHODS: TRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred. RESULTS: We describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity. CONCLUSION: This study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies

Repeatedly Northwards and Upwards: Southern African Grasslands Fuel the Colonization of the African Sky Islands in Helichrysum (Compositae)

The Afromontane and Afroalpine areas constitute some of the main biodiversity hotspots of Africa. They are particularly rich in plant endemics, but the biogeographic origins and evolutionary processes leading to this outstanding diversity are poorly understood. We performed phylogenomic and biogeographic analyses of one of the most species-rich plant genera in these mountains, Helichrysum (Compositae-Gnaphalieae). Most previous studies have focused on Afroalpine elements of Eurasian origin, and the southern African origin of Helichrysum provides an interesting counterexample. We obtained a comprehensive nuclear dataset from 304 species (≈50% of the genus) using target-enrichment with the Compositae1061 probe set. Summary-coalescent and concatenation approaches combined with paralog recovery yielded congruent, well-resolved phylogenies. Ancestral range estimations revealed that Helichrysum originated in arid southern Africa, whereas the southern African grasslands were the source of most lineages that dispersed within and outside Africa. Colonization of the tropical Afromontane and Afroalpine areas occurred repeatedly throughout the Miocene-Pliocene. This timing coincides with mountain uplift and the onset of glacial cycles, which together may have facilitated both speciation and intermountain gene flow, contributing to the evolution of the Afroalpine flora.This work received financial support from the Spanish Ministry of Science, Innovation and Universities (PID2019-105583GB-C22/AEI/10.13039/501100011033) and the Catalan government (“Ajuts a grups consolidats” 2021SGR00315 and FI grant to C.B.-G. 2022FI_B 00150). The Ph.D. thesis was carried out under the Ph.D. program “Plant Biology and Biotechnology” of the Autonomous University of Barcelona (UAB). Additional support was provided by the Czech Science Foundation GAČR project no. 20-10878S to R.S. and F.K. and long-term research development project (RVO 67985939) of the Czech Academy of Sciences. Additional funds were obtained from the Norwegian Programme for Development, Research and Higher Education (NUFU; project AFROALP-II, no 2007/1058) and the Research Council of Norway (project SpeciationClock, no 274607) to C.B.Abstract 1. Introduction 2. Materials and Methods 2.1. Taxon Sampling 2.2. DNA Extraction, Library Preparation, Target Capture, and Sequencing 2.3. Molecular Data Processing and Phylogenetic Analyses 2.4. Divergence Time Estimation 2.5. Ancestral Range Estimation 3. Results 3.1. Alignment Processing and Filtering 3.2. Phylogenetic Analyses 3.3. Divergence Time and Ancestral Range Estimation 3.4. Number, Type, and Directionality Estimation of Biogeographical Events 4. Discussion 4.1. Utility of Target-Enrichment Strategies in Reconstructing the Radiation of Helichrysum 4.2. The Early History of Helichrysum and Colonization of Madagascar 4.3. Repeatedly Northwards 4.4. Repeatedly Upwards 5. Conclusions Supplementary Materials Author Contributions Funding Data Availability Statement Acknowledgments Conflicts of Interest Reference

Pre-exposure prophylaxis with hydroxychloroquine for COVID-19 : a double-blind, placebo-controlled randomized clinical trial

Background: Pre-exposure prophylaxis (PrEP) is a promising strategy to break COVID-19 transmission. Although hydroxychloroquine was evaluated for treatment and post-exposure prophylaxis, it is not evaluated for COVID-19 PrEP yet. The aim of this study was to evaluate the efficacy and safety of PrEP with hydroxychloroquine against placebo in healthcare workers at high risk of SARS-CoV-2 infection during an epidemic period. Methods: We conducted a double-blind placebo-controlled randomized clinical trial in three hospitals in Barcelona, Spain. From 350 adult healthcare workers screened, we included 269 participants with no active or past SARS-CoV-2 infection (determined by a negative nasopharyngeal SARS-CoV-2 PCR and a negative serology against SARS-CoV-2). Participants allocated in the intervention arm (PrEP) received 400 mg of hydroxychloroquine daily for the first four consecutive days and subsequently, 400 mg weekly during the study period. Participants in the control group followed the same treatment schedule with placebo tablets. Results: 52.8% (142/269) of participants were in the hydroxychloroquine arm and 47.2% (127/269) in the placebo arm. Given the national epidemic incidence decay, only one participant in each group was diagnosed with COVID-19. The trial was stopped due to futility and our study design was deemed underpowered to evaluate any benefit regarding PrEP efficacy. Both groups showed a similar proportion of participants experiencing at least one adverse event (AE) (p=0.548). No serious AEs were reported. Almost all AEs (96.4%, 106/110) were mild. Only mild gastrointestinal symptoms were significantly higher in the hydroxychloroquine arm compared to the placebo arm (27.4% (39/142) vs 15.7% (20/127), p=0.041). Conclusions: Although the efficacy of PrEP with hydroxychloroquine for preventing COVID-19 could not be evaluated, our study showed that PrEP with hydroxychloroquine at low doses is safe. Trial registration: ClinicalTrials.govNCT04331834. Registered on April 2, 2020

A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study

[Purpose]: To evaluate the efficacy and safety of lapatinib (L) and trastuzumab (T) combination in HER2-positive metastatic breast cancer (MBC) patients previously treated with T and/or L.[Materials and methods]: We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L–T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed.[Results]: One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1–43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%).[Conclusion]: The combination of L–T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L–T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.This work was supported by GlaxoSmithKline plc (GSK) through a contract with Medica Scientia Innovation Research (MedSIR), an academic research organization focused on independent clinical research development

Thermal architecture for the QUBIC cryogenic receiver

QUBIC, the QU Bolometric Interferometer for Cosmology, is a novel forthcoming instrument to measure the B-mode polarization anisotropy of the Cosmic Microwave Background. The detection of the B-mode signal will be extremely challenging; QUBIC has been designed to address this with a novel approach, namely bolometric interferometry. The receiver cryostat is exceptionally large and cools complex optical and detector stages to 40 K, 4 K, 1 K and 350 mK using two pulse tube coolers, a novel 4He sorption cooler and a double-stage 3He/4He sorption cooler. We discuss the thermal and mechanical design of the cryostat, modelling and thermal analysis, and laboratory cryogenic testing.Fil: May, A. J.. University of Manchester; Reino UnidoFil: Chapron, C.. Astroparticule et Cosmologie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Coppi, G.. University of Manchester; Reino UnidoFil: D’Alessandro, G.. Università di Roma; ItaliaFil: de Bernardis, P.. Università di Roma; ItaliaFil: Masi, S.. Università di Roma; ItaliaFil: Melhuish, S.. University of Manchester; Reino UnidoFil: Piat, M.. Astroparticule et Cosmologie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Piccirillo, L.. University of Manchester; Reino UnidoFil: Schillaci, A.. Università di Roma; ItaliaFil: Thermeau, J. P.. Astroparticule et Cosmologie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Bonaparte, J.. Comisión Nacional de Energía Atómica; ArgentinaFil: Di Donato, Andrés Leonardo. Comisión Nacional de Energía Atómica; ArgentinaFil: Fasciszewski Zeballos, Alejandro Miguel. Comisión Nacional de Energía Atómica; ArgentinaFil: Gamboa Lerena, Martín Miguel. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Garcia, Beatriz Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Etchegoyen, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Gomez Berisso, Mariano. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: González, M.. Comisión Nacional de Energía Atómica; ArgentinaFil: Harari, Diego Dario. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kristukat, C.. Universidad Nacional de San Martín; ArgentinaFil: Medina, Maria Clementina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Ringegni, P.. Universidad Nacional de la Plata. Facultad de Ingeniería. Uidet Grupo de Ensayos Mecanicos Aplicados.; ArgentinaFil: Romero, Gustavo Esteban. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Suarez, C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Mundo, Luis Mariano. Universidad Nacional de la Plata. Facultad de Ingeniería. Uidet Grupo de Ensayos Mecanicos Aplicados.; ArgentinaFil: Watson, B.. University of Manchester; Reino UnidoFil: Wicek, F.. Laboratoire de l’Accélérateur Linéaire; FranciaFil: Zannoni, M.. Università degli Studi di Milano; ItaliaFil: Zullo, A.. Istituto Nazionale Di Fisica Nucleare; ItaliaMillimeter, Submillimeter, and Far-Infrared Detectors and Instrumentation for Astronomy IXEstados UnidosSociety of Photographic Instrumentation Engineer

Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients

Non-perturbative effects and wall-crossing from topological strings

We argue that the Gopakumar-Vafa interpretation of the topological string partition function can be used to compute and resum certain non-perturbative brane instanton effects of type II CY compactifications. In particular the topological string A-model encodes the non-perturbative corrections to the hypermultiplet moduli space metric from general D1/D(-1)-brane instantons in 4d N=2 IIB models. We also discuss the reduction to 4d N=1 by fluxes and/or orientifolds and/or D-branes, and the prospects to resum brane instanton contributions to non-perturbative superpotentials. We argue that the connection between non-perturbative effects and the topological string underlies the continuity of non-perturbative effects across lines of BPS stability. We also confirm this statement in mirror B-model matrix model examples, relating matrix model instantons to non-perturbative D-brane instantons. The computation of non-perturbative effects from the topological string requires a 3d circle compactification and T-duality, relating effects from particles and instantons, reminiscent of that involved in the physical derivation of the Kontsevich-Soibelmann wall-crossing formula.Comment: 44 pages, 5 figures. Major revisions, new results added, previous results unchanged, refs adde