Interrelations entre les protéines Rho et le récepteur des oestrogènes alpha dans des modèles de cancers mammaires

L'hormonothérapie est recommandée dans environ deux tiers des cancers du sein exprimant le récepteur des œstrogènes (RE) et/ ou le récepteur de la progestérone (RP). Cependant, il y a apparition systématique de résistances qui imposent la recherche de nouvelles cibles thérapeutiques. Les œstrogènes agissent via le REa mais il a été démontré des interrelations majeures entre le REa et la voie de facteurs de croissance en particulier avec les protéines Rho. L'objectif de ce travail de thèse était de déterminer s'il existe un dialogue entre le REa et les protéines Rho A, B et C, les éventuels mécanismes mis en jeu et l'implication dans la tumorigenèse mammaire. Dans un premier temps, nos résultats ont permis de mettre en évidence que RhoB est un élément clé de la régulation de l'expression du REa et du RP. Pour cela, nous avons utilisé des modèles cellulaires, animaux et des tumeurs de patientes. Dans un second volet de ce travail, nous nous sommes concentrés sur les effets de RhoA et RhoC sur les activités du REa. RhoA et RhoC modifient également le recrutement de REa sur les promoteurs de différents gènes cibles du REa mais sans corrélation avec les modulations d'activités transcriptionnelles observées. A l'inverse de RhoB, RhoA diminue l'expression du REa alors que RhoC n'a pas d'effet. L'ensemble de ces résultats nous a donc permis de montrer que malgré leur très forte homologie, RhoA,B et C ont toutes 3 des rôles, mais différents, sur l'expression et les effets transcriptionnels du REa dans les cellules de cancers du sein. De plus, l'importance de RhoB comme agent pro-prolifératif dans des cellules mammaires hormonodépendantes est un axe majeur à développer.Hormone therapy is recommended in approximately two thirds of breast cancers which express the Estrogen Receptor alpha (ERa) and/or Progesterone Receptor (PR). Nevertheless, there are many cases of systemic resistance to the treatment that impose to find new therapeutic targets. Estrogens act via ERa but cross-talks between ERa and growth factor pathways have been demonstrated, especially with Rho proteins. The aim of this study was to determine the cross-talks existing between ERa and the RhoA, B and C proteins, the mechanisms of these cross-talks and their involvement in mammary tumorigenesis. First of all, our results showed that RhoB controls ERa and PR expressions. For this, we used mammary cell lines, RhoB deficient mice and tumors from patients. A positive regulation loop has been demonstrated between RhoB and ERa. RhoB appears then to be pro-oncogenic in hormone-dependant mammary tumors cells, inversely to its usual role of tumor suppressor gene for other cancer locations. Moreover our results clearly show that RhoB controls ERa transcriptional activities and the recruitment of its cofactors (including ERa itself) on PR promotor. In a second part, we analyzed the effects of RhoA and RhoC on ERa activities. RhoA and RhoC modify too ERa recruitment on 4 of its target genes, but without any correlation with the observed modulations of transcription. Opposite to RhoB, RhoA decreases ERa expression whereas RhoC has no effect. In a third part, we identified another reciprocal positive regulation between RhoB and HDAC1. The first results obtained in vitro have been confirmed in RhoB deficient mice. Taken together, these results suggest that in spite of their sequence homology, RhoA, B and C all act, but in different manners, on ERa expression and transcriptional activities in mammary cancer cells. Furthermore, the importance of RhoB as proliferative agent in mammary hormone dependant cancer cells is a major research area to consider

Performance and Diagnostic Value of Genome-Wide Noninvasive Prenatal Testing in Multiple Gestations.

OBJECTIVE: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies. METHODS: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic-diamniotic twin cohort. RESULTS: Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic-monoamniotic and 25 triplet cases. Two monochorionic-diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic-diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12-100%) and a specificity of 100% (95% CI 99.86-100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06-95.44%) sensitivity and 100% (95% CI 99.86-100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65-100%) sensitivity and 99.96% (95% CI 99.79-99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies. CONCLUSION: Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic-diamniotic twin gestations

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Decomposability and mental representation of French verbs

In French, regardless of stem regularity, inflectional verbal suffixes are extremely regular and paradigmatic. Considering the complexity of the French verbal system, we argue that all French verbs are polymorphemic forms that are decomposed during visual recognition independently of their stem regularity. We conducted a behavioural experiment in which we manipulated the surface and cumulative frequencies of verbal inflected forms and asked participants to perform a visual lexical decision task. We tested four types of verbs with respect to their stem variants: a. fully regular (parler ‘to speak’, [parl-]); b. phonological change e/E verbs with orthographic markers (répéter ‘to repeat’, [répét-] and [répèt-]); c. phonological change o/O verbs without orthographic markers (adorer ‘to adore’, [ador-] and [adOr-]); and d. idiosyncratic (boire ‘to drink’, [boi-] and [buv-]). For each type of verb, we contrasted four conditions, forms with high and low surface frequencies and forms with high and low cumulative frequencies. Our results showed a significant cumulative frequency effect for the fully regular and idiosyncratic verbs, indicating that different stems within idiosyncratic verbs (such as [boi-] and [buv-]) have distinct representations in the mental lexicon as different fully regular verbs. For the phonological change verbs, we found a significant cumulative frequency effect only when considering the two forms of the stem together ([répét-] and [répèt-]), suggesting that they share a single abstract and underspecified phonological representation. Our results also revealed a significant surface frequency effect for all types of verbs, which may reflect the recombination of the stem lexical representation with the functional information of the suffixes. Overall, these results indicate that all inflected verbal forms in French are decomposed during visual recognition and that this process could be due to the regularities of the French inflectional verbal suffixes

Interrelations entre les protéines Rho et le récepteur des oestrogènes alpha dans des modèles de cancers mammaires

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Extrahepatic portal vein aneurysm.

International audiencePortal vein aneurysms (PVAs) are usually incidental on imaging and asymptomatic. If it is symptomatic or associated with a pathologic finding, a treatment is recommended. We report a case of a 75-year-old Caucasian man presenting with symptomatic and size-increasing portosplenomesenteric aneurysms. Interventional radiology was not indicated because of the large size. A surgical approach was chosen for the patient. Surgical technique consists of an aneurysmorrhaphy in the first time and in the second time, a Goretex prosthesis placement involving the vein. Early complication was treated with a radiologic approach. Six months after surgery, patient had no more symptoms. PVA management remains a surgical challenge for surgeon, for timing and type of treatment

La Réserve intégrale de Bagaud : un laboratoire naturel de restauration écologique

absen

High Fructose Diet inducing diabetes rapidly impacts olfactory epithelium and behavior in mice

indexation en coursInternational audienceType 2 Diabetes (T2D), a major public health issue reaching worldwide epidemic, has been correlated with lower olfactory abilities in humans. As olfaction represents a major component of feeding behavior, its alteration may have drastic consequences on feeding behaviors that may in turn aggravates T2D. In order to decipher the impact of T2D on the olfactory epithelium, we fed mice with a high fructose diet (HFruD) inducing early diabetic state in 4 to 8 weeks. After only 4 weeks of this diet, mice exhibited a dramatic decrease in olfactory behavioral capacities. Consistently, this decline in olfactory behavior was correlated to decreased electrophysiological responses of olfactory neurons recorded as a population and individually. Our results demonstrate that, in rodents, olfaction is modified by HFruD-induced diabetes. Functional, anatomical and behavioral changes occurred in the olfactory system at a very early stage of the disease

Eradication du rat noir et des griffes de sorcières sur l'île de Bagaud (Parc National de Port-Cros): conséquences sur les communautés d'invertébrés

Abstrac