Professional Exposure to Goats Increases the Risk of Pneumonic-Type Lung Adenocarcinoma: Results of the IFCT-0504-Epidemio Study

Pneumonic-type lung adenocarcinoma (P-ADC) represents a distinct subset of lung cancer with specific clinical, radiological, and pathological features. Given the weak association with tobacco-smoking and the striking similarities with jaagsiekte sheep retrovirus (JSRV)-induced ovine pulmonary adenocarcinoma, it has been suggested that a zoonotic viral agent infecting pulmonary cells may predispose to P-ADC in humans. Our objective was to explore whether exposure to domestic small ruminants may represent a risk factor for P-ADC. We performed a multicenter case-control study recruiting patients with P-ADC as cases and patients with non-P-ADC non-small cell lung cancer as controls. A dedicated 356-item questionnaire was built to evaluate exposure to livestock. A total of 44 cases and 132 controls were included. At multivariate analysis, P-ADC was significantly more associated with female gender (Odds-ratio (OR) = 3.23, 95% confidence interval (CI): 1.32–7.87, p = 0.010), never- smoker status (OR = 3.57, 95% CI: 1.27–10.00, p = 0.015), personal history of extra-thoracic cancer before P-ADC diagnosis (OR = 3.43, 95% CI: 1.10–10.72, p = 0.034), and professional exposure to goats (OR = 5.09, 95% CI: 1.05–24.69, p = 0.043), as compared to other subtypes of lung cancer. This case-control suggests a link between professional exposure to goats and P-ADC, and prompts for further epidemiological evaluation of potential environmental risk factors for P-ADC

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

Pleurésies malignes révélatrices d'un cancer (étiologies et discussion des investigations paracliniques)

Introduction : Les études s'intéressant aux pleurésies malignes sont nombreuses, les causes habituellement retrouvées : les cancers bronchiques, mammaires et les lymphomes malins. Beaucoup signent une complication métastatique d'un cancer connu mais certaines révèlent un cancer. Le but de cette étude est l'évaluation de la fréquence des étiologies. L'objectif secondaire est d'évaluer les investigations paracliniques utiles à la recherche du cancer primitif. Méthodologie : Nous avons réalisé une étude rétrospective à partir du fichier des pleurésies malignes répertoriées par le service d'anatomo-pathologie du CHU de Nantes durant la période de janvier 1999 à décembre 2001. L'analyse des éléments anamnésiques, histologiques, cliniques et paracliniques permet de définir deux groupes : les pleurésies métastatiques d'un cancer connu et celles qui révèlent un cancer. Une recherche des étiologies est menée. La présentation clinico-radiologique, les examens paracliniques engagés, la survie ainsi que les traitements menés chez les patients dont la pleurésie est la première manifestation du cancer sont analysés. Résultats : La pleurésie est révélatrice du cancer chez 85 patients sur 209 (40.7%). Les causes les plus fréquentes sont le cancer bronchique (36,5%), le mésothéliome pleural malin (21,2%) et le cancer de l'ovaire (11,7 %). Le site primitif du cancer est inconnu chez 17,6 % des patients. Chez seulement 2 patientes sur 36, la pleurésie maligne a révélé un cancer du sein, alors qu'il est la première cause retrouvée parmi l'ensemble des pleurésies malignes, représentant 30.6% des étiologies. Aucune pleurésie n'a révélé un cancer de la prostate et dans un seul cas, un cancer du colon. Dans l'exploration de la pleurésie, la majorité des patients a bénéficié d'un scanner thoracique (84.7%), fréquemment d'une échographie ou d'un scanner abdominal (51.7%) et d'une fibroscopie bronchique (32.9%). D'autres examens ont été engagés chez un tiers des patients, notamment une mammographie chez 23.5% des patientes. La médiane de survie des patients est courte de 6,6 mois. Un traitement spécifique par chimio ou hormonothérapie est engagé chez 37.6% des patients. Un talcage pleural est effectué chez plus de la moitié des patients (52.9%). Conclusion : Les pleurésies malignes révélatrices d'un cancer sont fréquentes. L'étude de leur étiologie par rapport à l'ensemble des pleurésies malignes montre une prépondérance des cancers bronchiques et en plus chez la femme du cancer de l'ovaire. La fréquence du mésothéliome pleural malin est importante dans notre région à forte incidence. Les pleurésies révèlent rarement un cancer du sein ou de la prostate. Ces résultats motivent la réalisation, pour ces pleurésies malignes révélatrices d'un cancer, d'un bilan paraclinique limité. Les examens à envisager sont un scanner thoracique, une fibroscopie bronchique, et chez la femme, une imagerie de l'abdomen.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Rescuing SLAMF3 Expression Restores Sorafenib Response in Hepatocellular Carcinoma Cells through the Induction of Mesenchymal-to-Epithelial Transition

International audienceSimple Summary Sorafenib is a treatment for advanced HCC which demonstrated a poor objective response rate due to important induction of resistance. We demonstrated that induction of acquired-resistance to sorafenib in Huh-7 cell line leads to the loss of SLAMF3 expression, a tumor suppressor receptor in HCC. In these cells, the sorafenib-resistant phenotype is characterized by the increase of aggressiveness and induction of the epithelial-to-mesenchymal transition. Acquired-resistance to sorafenib induce a multipotent mesenchymal stem cells characteristic. Interestingly, SLAMF3 overexpression reversed the epithelial-to-mesenchymal transition and decreased metastatic potential in sorafenib-resistant cells through the control of ERK1/2 and mTOR signaling pathways. SLAMF3 seems to be a theranostics tools to the management of sorafenib treatment. Background: Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) patients results in poor prognosis. Epithelial-to-mesenchymal transition (EMT) is the major mechanism implicated in the resistance to sorafenib. We have reported the tumor suppressor role of SLAMF3 (signaling lymphocytic activation molecules family 3) in HCC progression and highlighted its implication in controlling the MRP-1 transporter activity. These data suggest the implication of SLAMF3 in sorafenib resistance mechanisms. Methods: We evaluated the resistance to sorafenib in Huh-7 cells treated with progressive doses (Res cells). We investigated the link between acquired resistance to sorafenib and SLAMF3 expression by flow cytometry and Western blot methods. Furthermore, we analyzed the EMT and the stem cell potential of cells resistant to sorafenib. Results: Sorafenib resistance was confirmed in Res cells by analyzing the cell viability in the presence of sorafenib. The mesenchymal transition, in Res cells, was confirmed by high migratory index and the expression of EMT antigens. Interestingly, we found that loss of SLAMF3 expression corresponded to sorafenib-resistant phenotypes. The overexpression of SLAMF3 reversed EMT, decreased metastatic potential and inhibited mTOR/ERK1/2 in Res cells. Conclusions: We propose that rescuing SLAMF3 expression in resistant cells could represent a potential therapeutic strategy to enhance sorafenib efficacy in HCC patients

Efficacy of Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer with Leptomeningeal Metastases Pretreated with EGFR-Tyrosine Kinase Inhibitors

International audienceThe prognosis of patients with non-small cell lung cancer (NSCLC) who develop leptomeningeal metastasis (LM) is poor

Genotoxicity of Escherichia coli Nissle 1917 strain cannot be dissociated from its probiotic activity

International audienceOral administration of the probiotic bacterium Escherichia coli Nissle 1917 improves chronic inflammatory bowel diseases, but the molecular basis for this therapeutic efficacy is unknown. E. coli Nissle 1917 harbors a cluster of genes coding for the biosynthesis of hybrid nonribosomal peptide-polyketide(s). This biosynthetic pathway confers the ability for bacteria to induce DNA double strand breaks in eukaryotic cells. Here we reveal that inactivation of the clbA gene within this genomic island abrogated the ability for the strain to induce DNA damage and chromosomal abnormalities in non-transformed cultured rat intestinal epithelial cells but is required for the probiotic activity of E. coli Nissle 1917. Thus, evaluation of colitis severity induced in rodent fed with E. coli Nissle 1917 or an isogenic non-genotoxic mutant demonstrated the need for a functional biosynthetic pathway both in the amelioration of the disease and in the modulation of cytokine expression. Feeding rodents with a complemented strain for which genotoxicity was restored confirmed that this biosynthetic pathway contributes to the health benefits of the probiotic by modulating its immunomodulatory properties. Our data provide additional evidence for the benefit of this currently used probiotic in colitis but remind us that an efficient probiotic may also have side effects as any other medication

Mammary SLAMF3 Regulates Store-Operated Ca2+ Entry and Migration Through STIM1 in Breast Cancer Cells and Cell Lines

International audienceStore Operated Calcium Entry (SOCE) is the main route for calcium entry in breast cells. After it’s activation by STromal Interaction Molecule (STIM) during endoplasmic reticulum store depletion, membrane channels ORAI are the main actors of this cell calcium entry. STIM, ORAI and SOCE alterations might contribute to Breast Cancer (BC) carcinogenesis. Recently, we reported the tumor suppressor role of Signaling Lymphocytic Activation Molecule Family member 3 (SLAMF3) on HepatoCellular Carcinoma (HCC) progression. SLAMF3 has been shown to regulate the activity of immune cells by modulating the calcium influx. In this report, we aimed at exploring the role of SLAMF3 in regulating SOCE and migration of BC cells. We quantified and compared the expression of SLAMF3 and STIM1 by quantitative RT-PCR in tumor and healthy resections of 14 patients followed at the University Hospital of Amiens. The expressions of SLAMF3 and STIM1 were also quantified and compared in non-invasive T47D and invasive MDA-MB-231 cell lines by quantitative RT-PCR, Western blot and flow cytometry. We determined the Ca2+ basal entry as well as SOCE by Mn2+ quenching and calcium imaging, respectively, in T47D and MDA-MB-231 cells overexpressing SLAMF3 ectopically. The cell proliferation and migration/invasion were investigated by MTT, wound healing assay and Boyden chambers tests, respectively. First, we report the expression of SLAMF3 in mammary epithelial cells. We highlight the complete loss of SLAMF3 expression in invasive BC cell lines compared to non-invasive cells. In addition, we show that the forced expression of SLAMF3 in invasive cells down-regulate specifically the STIM1 expression in invasive compared to non-invasive mammary cell lines. Interestingly, an inverse correlation is observed between the low expression of SLAMF3 and the high expression of STIM1 in primary human BC tissues. Our results indicate that SLAMF3 reduces SOCE and therefore restricts BC cell migration by decreasing STIM1 expression. Therefore, SLAMF3 might be used as a predictive marker of BC evolution and aggressiveness

Interplay between Siderophores and Colibactin Genotoxin Biosynthetic Pathways in Escherichia coli

International audienceIn Escherichia coli, the biosynthetic pathways of several small iron-scavenging molecules known as siderophores (enterobactin, salmochelins and yersiniabactin) and of a genotoxin (colibactin) are known to require a 4'-phosphopantetheinyl transferase (PPTase). Only two PPTases have been clearly identified: EntD and ClbA. The gene coding for EntD is part of the core genome of E. coli, whereas ClbA is encoded on the pks pathogenicity island which codes for colibactin. Interestingly, the pks island is physically associated with the high pathogenicity island (HPI) in a subset of highly virulent E. coli strains. The HPI carries the gene cluster required for yersiniabactin synthesis except for a gene coding its cognate PPTase. Here we investigated a potential interplay between the synthesis pathways leading to the production of siderophores and colibactin, through a functional interchangeability between EntD and ClbA. We demonstrated that ClbA could contribute to siderophores synthesis. Inactivation of both entD and clbA abolished the virulence of extra-intestinal pathogenic E. coli (ExPEC) in a mouse sepsis model, and the presence of either functional EntD or ClbA was required for the survival of ExPEC in vivo. This is the first report demonstrating a connection between multiple phosphopantetheinyl-requiring pathways leading to the biosynthesis of functionally distinct secondary metabolites in a given microorganism. Therefore, we hypothesize that the strict association of the pks island with HPI has been selected in highly virulent E. coli because ClbA is a promiscuous PPTase that can contribute to the synthesis of both the genotoxin and siderophores. The data highlight the complex regulatory interaction of various virulence features with different functions. The identification of key points of these networks is not only essential to the understanding of ExPEC virulence but also an attractive and promising target for the development of anti-virulence therapy strategies

Three-Year Overall Survival of Patients With Advanced Non–Small-Cell Lung Cancers With ≥50% PD-L1 Expression Treated With First-Line Pembrolizumab Monotherapy in a Real-World Setting (ESCKEYP GFPC Study)

International audienceOutside clinical trials, few data are available on the effect of long-term first-line pembrolizumab in patients with advanced non–small-cell lung cancers with ≥50% of tumor cells expressing programmed cell death ligand 1 (PD-L1). This French, multicenter study included consecutive advanced patients with non–small-cell lung cancer given first-line pembrolizumab alone between May 2017 (authorization date for this indication) and November 2019 (authorization date for pembrolizumab–chemotherapy combination). Information was collected from patients’ medical files, with a local evaluation of the response and progression-free survival (PFS). Overall survival (OS) was calculated from pembrolizumab onset using the Kaplan-Meier method. The analysis concerned 845 patients, managed in 33 centers: median age: 65 (range: 59–72) years, 67.8% men, 78.1% Eastern Cooperative Oncology Group performance status 0/1, 38.9%/51.5%/6.6% active, ex or never-smokers, respectively, 10.9%/16.8% taking or recently took corticosteroids/antibiotics, 69.6% nonsquamous histology, 48.9% ≥75% PD-L1–positive, and 20.8% had brain metastases at diagnosis. After a median (95% CI) follow-up of 45 (44.1–45.9) months, respective median (95% CI) PFS and OS lasted 8.2 (6.9–9.2) and 22 (8.5–25.9) months; 3-year PFS and OS rates were 25.4% and 39.4%, respectively. Multivariate analysis retained never-smoker status, adenocarcinoma histology, Eastern Cooperative Oncology Group performance status ≥2, and neutrophil/lymphocyte ratio >4 as being significantly associated with shorter survival, but not brain metastases at diagnosis or <75% PD-L1 tumor-cell expression. These long-term results of pembrolizumab efficacy based on a nationwide “real-world” cohort reproduced those obtained in clinical trials