Démarche utilisée par Creusot Forge pour l'amélioration des gammes de fabrication de ses pièces

Creusot Forge s'est tourné vers la simulation numérique afin d'améliorer et de développer ses gammes de forgeage. Les récentes évolutions du logiciel FORGE ont permis à Creusot Forge de développer une approche originale de simulation de ses opérations de forgeage et de traitement thermique visant à garantir la qualité de ses produits. Face au renouveau des programmes nucléaires civils et au développement de centrales de nouvelle génération, cette démarche a été largement utilisée en s'appuyant sur 40 années de savoir faire ainsi que sur une parfaite connaissance métallurgique de ses lingots

Prognostic and predictive value of Immunoscore in stage III colorectal cancer: pooled analysis of 2,608 cases from the SCOT and IDEA-HORG studies

Purpose Immunoscore (IS) is prognostic in stage III colorectal cancer (CRC) and may predict benefit of duration (6 v 3 months) of adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. We sought to determine IS prognostic and predictive value in stage-III CRC treated with adjuvant FOLFOX or oral capecitabine and infusional oxaliplatin (CAPOX) in the SCOT and IDEA-HORG trials. Methods Three thousand sixty-one cases had tumor samples, of which 2,643 (1,792 CAPOX) were eligible for IS testing. Predefined cutoffs (IS-Low and IS-High) were used to classify cases into two groups for analysis of disease-free survival (3-year DFS) and multivariable-adjusted hazard ratios (mvHRs) by Cox regression. Results IS was determined in 2,608 (99.5%) eligible cases, with 877 (33.7%) samples classified as IS-Low. IS-Low tumors were more commonly high-risk (T4 and/or N2; 52.9% IS-Low v 42.2% IS-High; P < .001) and in younger patients (P = .024). Patients with IS-Low tumors had significantly shorter DFS in the CAPOX, FOLFOX, and combined cohorts (mvHR, 1.52 [95% CI, 1.28 to 1.82]; mvHR, 1.58 [95% CI, 1.22 to 2.04]; and mvHR, 1.55 [95% CI, 1.34 to 1.79], respectively; P < .001 all comparisons), regardless of sex, BMI, clinical risk group, tumor location, treatment duration, or chemotherapy regimen. IS prognostic value was greater in younger (≤65 years) than older (>65 years) patients in the CAPOX cohort (mvHR, 1.92 [95% CI, 1.50 to 2.46] v 1.28 [95% CI, 1.01 to 1.63], PINTERACTION = .026), and in DNA mismatch repair proficient than deficient mismatch repair disease (mvHR, 1.68 [95% CI, 1.41 to 2.00] v 0.67 [95% CI, 0.30 to 1.49], PINTERACTION = .03), although these exploratory analyses were uncorrected for multiple testing. Adding IS to a model containing all clinical variables significantly improved prediction of DFS (likelihood ratio test, P < .001) regardless of MMR status. Conclusion IS is prognostic in stage III CRC treated with FOLFOX or CAPOX, including within clinically relevant tumor subgroups. Possible variation in IS prognostic value by age and MMR status, and prediction of benefit from extended adjuvant therapy merit validation

RECHERCHE DE GENES IMPLIQUES DANS LA METAMORPHOSE DU CERVEAU CHEZ DROSOPHILA MELANOGASTER (CIBOULOT REGULE LA DYNAMIQUE DES FILAMENTS D'ACTINE AU COURS DE LA CROISSANCE NEURONALE)

AU COURS DE LA METAMORPHOSE DE DROSOPHILE, LE CERVEAU SE COMPLEXIFIE EN MEME TEMPS QUE L'ANIMAL. CERTAINES CELLULES LARVAIRES DEGENERENT, D'AUTRES RETRACTENT LEURS PROJECTIONS PUIS EN EMETTENT DE NOUVELLES PROPRES A L'ADULTE. DES NEURONES IMMATURES SE DIFFERENCIENT DE NOVO. QUELS SONT LES MECANISMES MOLECULAIRES ET CELLULAIRES IMPLIQUES DANS CES REMANIEMENTS ? LE GENE LINOTTE (LIO) CODE POUR UN RECEPTEUR A DOMAINE TYROSINE KINASE HOMOLOGUE A LA PROTEINE HUMAINE RYK. LIO EST IMPLIQUEE DANS LA DIFFERENCIATION DES NEURONES DE LA REGION CENTRALE DU CERVEAU ADULTE. DE NOUVEAUX GENES IMPLIQUES DANS LA METAMORPHOSE DE LA REGION CENTRALE DU CERVEAU, ONT ETE ISOLES A PARTIR DE 821 LIGNEES ENHANCER-TRAP PGAL4 : 104 LIGNEES ONT ETE SELECTIONNEES SUR UN PROFIL D'EXPRESSION AU 3 E M E STADE LARVAIRE DANS LA REGION CENTRALE DU CERVEAU. PARMI CES LIGNEES 5 MUTANTS DE STRUCTURE DU CERVEAU ONT ETE ISOLES SUR UN CRIBLE DE COUPES PARAFFINES DE CERVEAUX ADULTES HOMOZYGOTES POUR L'INSERT. 1 MUTANT SEULEMENT A ETE ISOLE PARMI 89 LIGNEES CONTROLE DONT LE PROFIL D'EXPRESSION EST EXTERIEUR A LA REGION CENTRALE, DEMONTRANT LA VALIDITE DES CRIBLES. UN DE CES MUTANTS, CIBOULOT (CIB), PRESENTE UNE ANOMALIE DU COMPLEXE CENTRAL QUE L'ON SUGGERE ETRE UN ARRET DE LA CROISSANCE AXONALE. CIB CODE POUR UNE PROTEINE POSSEDANT 3 DOMAINES REPETES, CHACUN HAUTEMENT SIMILAIRE A LA SEQUENCE DE LA THYMOSINE . CETTE PROTEINE EST EXPRIMEE CHEZ LES VERTEBRES DANS LE CERVEAU EMBRYONNAIRE AU COURS DE LA CROISSANCE NEURONALE. SA FONCTION EST DE FAVORISER LA FORMATION D'UN STOCK D'ACTINE DANS LA CELLULE EN FORMANT UN COMPLEXE REVERSIBLE AVEC CELLE-CI, AFIN DE PROMOUVOIR LA MOTILITE CELLULAIRE. L'ETUDE BIOCHIMIQUE DE CIB A REVELE QU'ELLE NE SE COMPORTE PAS COMME UNE THYMOSINE MAIS COMME UNE PROFILINE. EN EFFET LE COMPLEXE CIB-ACTINE A UNE FONCTION DUALISTE SUR LA POLYMERISATION DE L'ACTINE : LORSQUE L'EXTREMITE LA PLUS DYNAMIQUE DES FILAMENTS EST BLOQUEE LE COMPLEXE NE PARTICIPE PAS A LA POLYMERISATION (CELLULE AU REPOS) ; LORSQUE CES EXTREMITES SONT LIBRES (CELLULES EN MOUVEMENT) LE COMPLEXE PARTICIPE ACTIVEMENT A LA POLYMERISATION, ACCELERANT LA MOTILITE. IN VIVO NOUS AVONS MONTRE QUE CIB COOPERE AVEC LA PROFILINE DE DROSOPHILE CHICKADEE AU COURS DE LA METAMORPHOSE DU CERVEAU. NOUS SUGGERERONS UN MODELE DE LA FONCTION DE CIB ET CHIC DANS LA DYNAMIQUE DU CYTOSQUELETTE D'ACTINE AU COURS DE LA CROISSANCE NEURONALE.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

La Gentrification, c'est quoi ?

info:eu-repo/semantics/publishe

Comparison of Immune Response Assessment in Colon Cancer by Immunoscore (Automated Digital Pathology) and Pathologist Visual Scoring

Adjunction of immune response into the TNM classification system improves the prediction of colon cancer (CC) prognosis. However, immune response measurements have not been used as robust biomarkers of pathology in clinical practice until the introduction of Immunoscore (IS), a standardized assay based on automated artificial intelligence assisted digital pathology. The strong prognostic impact of the immune response, as assessed by IS, has been widely validated and IS can help to refine treatment decision making in early CC. In this study, we compared pathologist visual scoring to IS. Four pathologists evaluated tumor specimens from 50 early-stage CC patients and classified the CD3+ and CD8+ T-cell densities at the tumor site (T-score) into 2 (High/Low) categories. Individual and overall pathologist scoring of immune response (before and after training for immune response assessment) were compared to the reference IS (High/Low). Pathologists’ disagreement with the reference IS was observed in almost half of the cases (48%) and training only slightly improved the accuracy of pathologists’ classification. Agreement among pathologists was minimal with a Kappa of 0.34 and 0.57 before and after training, respectively. The standardized IS assay outperformed expert pathologist assessment in the clinical setting

Riluzole for treating spasticity in patients with chronic traumatic spinal cord injury: Study protocol in the phase ib/iib adaptive multicenter randomized controlled RILUSCI trial.

BackgroundSatisfactory treatment is often lacking for spasticity, a highly prevalent motor disorder in patients with spinal cord injury (SCI). Low concentrations of riluzole potently reduce the persistent sodium current, the post-SCI increase in which contributes to spasticity. The repurposing of this drug may therefore constitute a useful potential therapeutic option for relieving SCI patients suffering from chronic traumatic spasticity.ObjectiveRILUSCI is a phase 1b-2b trial designed to assess whether riluzole is a safe and biologically effective means of managing spasticity in adult patients with traumatic chronic SCI.MethodsIn this multicenter double-blind trial, adults (aged 18-65 years) suffering from spasticity after SCI (target enrollment: 90 participants) will be randomly assigned to be given either a placebo or a recommended daily oral dose of riluzole for two weeks. The latter dose will be previously determined in phase 1b of the study by performing double-blind dose-finding tests using a Bayesian continuous reassessment method. The primary endpoint of the trial will be an improvement in the Modified Ashworth Score (MAS) or the Numerical Rating Score (NRS) quantifying spasticity. The secondary outcomes will be based on the safety and pharmacokinetics of riluzole as well as its impact on muscle spasms, pain, bladder dysfunction and quality of life. Analyses will be performed before, during and after the treatment and the placebo-controlled period.ConclusionTo the best of our knowledge, this clinical trial will be the first to document the safety and efficacy of riluzole as a means of reducing spasticity in patients with chronic SCI.Trial registrationThe clinical trial, which is already in progress, was registered on the ClinicalTrials.gov website on August 9, 2016 under the registration number NCT02859792.Trial sponsorAssistance Publique-Hôpitaux de Marseille

Immunoscore immune checkpoint using spatial quantitative analysis of CD8 and PD-L1 markers is predictive of the efficacy of anti- PD1/PD-L1 immunotherapy in non-small cell lung cancer

International audienceBackground Anti-PD-1 and PD-L1 antibodies (mAbs) are approved immunotherapy agents to treat metastatic non-small cell lung cancer (NSCLC) patients. Only a minority of patients responds to these treatments and biomarkers predicting response are currently lacking. Methods Immunoscore-Immune-Checkpoint (Immunoscore-IC), an in vitro diagnostic test, was used on 471 routinesingle FFPE-slides, and the duplex-immunohistochemistry CD8 and PD-L1 staining was quantified using digital-pathology. Analytical validation was performed on two independent cohorts of 206 NSCLC patients. Quantitative parameters related to cell location, number, proximity and clustering were analysed. The Immunoscore-IC was applied on a first cohort of metastatic NSCLC patients (n = 133), treated with anti-PD1 or anti-PD-L1 mAbs. Another independent cohort (n = 132) served as validation. Findings Anti-PDL1 clone (HDX3) has similar characteristics as anti-PD-L1 clones (22C3, SP263). Densities of PD-L1+ cells, CD8+ cells and distances between CD8+ and PD-L1+ cells were quantified and the Immunoscore-IC classification was computed. Using univariate Cox model, 5 histological dichotomised variables (CD8 free of PD-L1+ cells, CD8 clusters, CD8 cells in proximity of PD-L1 cells, CD8 density and PD-L1 cells in proximity of CD8 cells) were significantly associated with Progression-Free Survival (PFS) (all P < 0.0001). Immunoscore-IC classification improved the discriminating power of prognostic model, which included clinical variables andpathologist PD-L1 assessment. In two categories, the Immunoscore-IC risk-score was significantly associated with patients’ PFS (HR = 0.39, 95% CI (0.26–0.59), P < 0.0001) and Overall Survival (OS) (HR = 0.42, 95% CI (0.27–0.65), P < 0.0001) in the training-set. Further increased hazard ratios (HR) were found when stratifying patients into three-category Immunoscore-IC (IS-IC). All patients with Low-IS-IC progressed in less than 18 months, whereas PFS at 36 months were 34% and 33% of High-IS-IC patients in the training and validation sets, respectively.Interpretation Immunoscore-IC is a powerful tool to predict the efficacy of immune-checkpoint inhibitors (ICIs) inpatients with NSCLC

The Immunoscore in Localized Urothelial Carcinoma Treated with Neoadjuvant Chemotherapy: Clinical Significance for Pathologic Responses and Overall Survival

International audience(1) Background-The five-year overall survival (OS) of muscle-invasive bladder cancer (MIBC) with neoadjuvant chemotherapy and cystectomy is around 50%. There is no validated biomarker to guide the treatment decision. We investigated whether the Immunoscore (IS) could predict the pathologic response to neoadjuvant chemotherapy and survival outcomes. (2) Methods-This retrospective study evaluated the IS in 117 patients treated using neoadjuvant chemotherapy for localized MIBC from six centers (France and Greece). Pre-treatment tumor samples were immunostained for CD3+ and CD8+ T cells and quantified to determine the IS. The results were associated with the response to neoadjuvant chemotherapy, time to recurrence (TTR), and OS. (3) Results-Low (IS-0), intermediate (IS-1-2), and high (IS-3-4) ISs were observed in 36.5, 43.7, and 19.8% of the cohort, respectively. IS was positively associated with a pathologic complete response (pCR; p-value = 0.0096). A high IS was found in 35.7% of patients with a pCR, whereas it was found in 11.3% of patients without a pCR. A low IS was observed in 48.4% of patients with no pCR and in 21.4% of patients with a pCR. Low-, intermediate-, and high-IS patients had five-year recurrence-free rates of 37.2%, 36.5%, and 72.6%, respectively. In the multivariable analysis, a high IS was associated with a prolonged TTR (high vs. low: p = 0.0134) and OS (high vs. low: p = 0.011). (4) Conclusions-This study showed the significant prognostic and predictive roles of IS regarding localized MIBC