Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p

The Sign of the V: Papers in Honour of Sten Vikner

‘The Sign of the V’ is a festschrift in honour of Sten Vikner, written by friends, colleagues, and collaborators, present and past, to celebrate both his 60th birthday and his contribution to the field of linguistics. The papers cover a wide range of topics in theoretical and empirical linguistic research, from phonetics and phonology, through morphology, semantics, and syntax, to pragmatics, as well as language acquisition, second-language learning, language processing, language teaching, language contact, historical linguistics, and language variation and change. Many different languages are featured, including the Scandinavian languages (i.e. Danish, Faroese, Icelandic, Norwegian and Swedish), Catalan, Dutch, English, Finnish, West Flemish, French, German, Greek, Italian, Scots, and Yiddish. The scope and depth of the chapters in this anthology is a clear indication of the scope and depth of Sten Vikner’s own comparative research well as his impact on the field of linguistics.‘The Sign of the V’ is a festschrift in honour of Sten Vikner, written by friends, colleagues, and collaborators, present and past, to celebrate both his 60th birthday and his contribution to the field of linguistics. The papers cover a wide range of topics in theoretical and empirical linguistic research, from phonetics and phonology, through morphology, semantics, and syntax, to pragmatics, as well as language acquisition, second-language learning, language processing, language teaching, language contact, historical linguistics, and language variation and change. Many different languages are featured, including the Scandinavian languages (i.e. Danish, Faroese, Icelandic, Norwegian and Swedish), Catalan, Dutch, English, Finnish, West Flemish, French, German, Greek, Italian, Scots, and Yiddish. The scope and depth of the chapters in this anthology is a clear indication of the scope and depth of Sten Vikner’s own comparative research well as his impact on the field of linguistics

The Sign of the V: Papers in Honour of Sten Vikner

‘The Sign of the V’ is a festschrift in honour of Sten Vikner, written by friends, colleagues, and collaborators, present and past, to celebrate both his 60th birthday and his contribution to the field of linguistics. The papers cover a wide range of topics in theoretical and empirical linguistic research, from phonetics and phonology, through morphology, semantics, and syntax, to pragmatics, as well as language acquisition, second-language learning, language processing, language teaching, language contact, historical linguistics, and language variation and change. Many different languages are featured, including the Scandinavian languages (i.e. Danish, Faroese, Icelandic, Norwegian and Swedish), Catalan, Dutch, English, Finnish, West Flemish, French, German, Greek, Italian, Scots, and Yiddish. The scope and depth of the chapters in this anthology is a clear indication of the scope and depth of Sten Vikner’s own comparative research well as his impact on the field of linguistics.‘The Sign of the V’ is a festschrift in honour of Sten Vikner, written by friends, colleagues, and collaborators, present and past, to celebrate both his 60th birthday and his contribution to the field of linguistics. The papers cover a wide range of topics in theoretical and empirical linguistic research, from phonetics and phonology, through morphology, semantics, and syntax, to pragmatics, as well as language acquisition, second-language learning, language processing, language teaching, language contact, historical linguistics, and language variation and change. Many different languages are featured, including the Scandinavian languages (i.e. Danish, Faroese, Icelandic, Norwegian and Swedish), Catalan, Dutch, English, Finnish, West Flemish, French, German, Greek, Italian, Scots, and Yiddish. The scope and depth of the chapters in this anthology is a clear indication of the scope and depth of Sten Vikner’s own comparative research well as his impact on the field of linguistics

Priorities for research in soil ecology

The ecological interactions that occur in and with soil are of consequence in many ecosystems on the planet. These interactions provide numerous essential ecosystem services, and the sustainable management of soils has attracted increasing scientific and public attention. Although soil ecology emerged as an independent field of research many decades ago, and we have gained important insights into the functioning of soils, there still are fundamental aspects that need to be better understood to ensure that the ecosystem services that soils provide are not lost and that soils can be used in a sustainable way. In this perspectives paper, we highlight some of the major knowledge gaps that should be prioritized in soil ecological research. These research priorities were compiled based on an online survey of 32 editors of Pedobiologia – Journal of Soil Ecology. These editors work at universities and research centers in Europe, North America, Asia, and Australia. The questions were categorized into four themes: (1) soil biodiversity and biogeography, (2) interactions and the functioning of ecosystems, (3) global change and soil management, and (4) new directions. The respondents identified priorities that may be achievable in the near future, as well as several that are currently achievable but remain open. While some of the identified barriers to progress were technological in nature, many respondents cited a need for substantial leadership and goodwill among members of the soil ecology research community, including the need for multi-institutional partnerships, and had substantial concerns regarding the loss of taxonomic expertise

Correction to: Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers.

After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Développement d'outils pour la prévision d'évènements météorologiques locaux

La prévision numérique du temps constitue l'un des enjeux majeurs de nos sociétés pour se prémunir contre les risques météorologiques et climatiques. L'augmentation de la population a pour conséquence d'augmenter la pression de cette dernière sur le territoire. De ce fait, elle est aujourd'hui davantage exposée et vulnérable à ces risques. Des prévisions précises permettent de sauver des vies, en avertissant à l'avance les autorités ou acteurs concernés de se préparer et de se prémunir des conséquences en mettant en place des mesures de protection. Cela permet de réduire les impacts et diminuer les pertes humaines économiques. Toutefois, les systèmes de prévisions opérationnels actuels peinent encore à répondre aux besoins des autorités et acteurs concernés à se préparer efficacement en minimisant les coûts associés à la mise en œuvre des mesures de protection. Pour répondre à cette problématique, deux outils sont développés et évalués dans ce travail de thèse. Le but étant de proposer des outils simples et peu gourmand en temps de calculs de sorte à fournir des prévisions plus précises que les modèles actuels à court et moyen terme. Pour cela, trois situations qui peinent encore aujourd'hui à être correctement simulées par les modèles de prévision ont été choisies: les évènements de précipitations d'origine convective dans les Préalpes bernoises, les évènements de précipitation d'origine orographique dans le Sud des Alpes et le risque de gel dans le vignoble bourguignon d'Aloxe-Corton. Le premier outil a été développé spécifiquement pour les évènements de fortes précipitations convectives dans les Préalpes bernoises. Il est basé sur un indice de convection composite, nommé Heavy Precipitation Index, réunissant les indices de convections les plus performants de la région d'étude. Cet indice a permis de capturer plus d'évènements de précipitations que le modèle à partir duquel il est calculé, au prix d'une surestimation des faux positifs. Le deuxième outil a été développé et évalué pour nos trois situations. Il s'agit d'un modèle "multi-colonnes" basé sur un assemblage de modèles colonne. Ce modèle quasi-3D, nommée FIZCR, consiste à appliquer un modèle colonne sur chaque cellule d'une maille de haute résolution (500 m), offrant ainsi une plus grande résolution spatiale que les modèles opérationnel utilisé actuellement. Pour chacune de ces cellules, des paramètres de surface et conditions initiales venant de bases de données de haute résolution, telles que les images satellite sont prises en compte. Le but est d'améliorer la prévision en considérant les phénomènes induits par l'hétérogénéité de la surface (i.e. topographie complexe, utilisation du sol, etc.). En effet, nous supposons que les processus "physiques" agissant dans la verticale sont plus déterminants dans le comportement de l'atmosphère à l'échelle locale que la dynamique. La prise en compte des paramètres de surface sous-maille, notamment les sources d'humidité pour les précipitations d'origine convective, et la topographie pour les précipitations d'origine orographique n'ont cependant pas permis d'améliorer la simulation de ces dernières. En revanche, pour le vignoble d'Aloxe-Corton, elle a permis d'obtenir des simulations de température de surface plus précises que le modèle régional climatique qui le pilote, malgré une sous-estimations de l'amplitude thermique journalière.</p