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Le Touquet – Paris-Plage, France

Corvol J.-C.,French Institute of Health and Medical Research | Bonnet C.,French Institute of Health and Medical Research | Charbonnier-Beaupel F.,French Institute of Health and Medical Research | Bonnet A.-M.,APHP Assistance Publique Hopitaux de Paris | And 16 more authors.
Annals of Neurology | Year: 2011

Objective: In Parkinson disease (PD), the selective C-O-methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMTHH), intermediate (Val/Met, COMTHL), or low (Met/Met, COMTLL). The objective of this study was to determine the response to entacapone in COMTHH and COMTLL PD patients. Methods Thirty-three PD patients, homozygous for the COMT alleles COMTHH (n = 17) and COMTLL (n = 16), were randomized in a double-blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells. Results The gain in the best ON time was higher in COMTHH than in COMTLL patients (39 ± 10 vs 9 ± 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMTHH than in COMTLL patients (+62 ± 6% vs +34 ± 8%, p = 0.01). COMT inhibition by entacapone was higher in COMTHH than in COMTLL patients (-0.54 ± 0.07 vs -0.31 ± 0.06 pmol/min/mg protein, p = 0.02). Interpretation The COMTHH genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined. © 2011 American Neurological Association.

Broet P.,Genome Institute of Singapore | Broet P.,University Paris - Sud | Dalmasso C.,Genome Institute of Singapore | Tan E.H.,National University of Singapore | And 15 more authors.
Clinical Cancer Research | Year: 2011

Purpose: East-Asian (EA) patients with non-small-cell lung cancer (NSCLC) are associated with a high proportion of nonsmoking women, epidermal growth factor receptor (EGFR)-activating somatic mutations, and clinical responses to tyrosine kinase inhibitors. We sought to identify novel molecular differences between NSCLCs from EA and Western European (WE) patients. Experimental Design: A total of 226 lung adenocarcinoma samples from EA (n = 90) and WE (n = 136) patients were analyzed for copy number aberrations (CNA) by using a common high-resolution SNP (single nucleotide polymorphism) microarray platform. Univariate and multivariate analyses were carried out to identify CNAs specifically related to smoking history, EGFR mutation status, and ethnicity. Results: The overall genomic profiles of adenocarcinomas from EA and WE patients were highly similar. Univariate analyses revealed several CNAs significantly associated with ethnicity, EGFR mutation, and smoking, but not to gender, and KRAS or p53 mutations. A multivariate model identified four ethnic-specific recurrent CNAs - significantly higher rates of copy number gain were observed on 16p13.13 and 16p13.11 in EA tumors, whereas higher rates of genomic loss on 19p13.3 and 19p13.11 were observed in tumors from WE patients. We identified several potential driver genes in these regions, showing a positive correlation between cis-localized copy number changes and transcriptomic changes. Conclusion: 16p copy number gains (EA) and 19p losses (WE) are ethnic-specific chromosomal aberrations in lung adenocarcinoma. Patient ethnicity should be considered when evaluating future NSCLC therapies targeting genes located on these areas. ©2011 AACR.

Gerardin P.,University of Rouen | Wendland J.,University of Paris Descartes | Bodeau N.,APHP Assistance Publique Hopitaux de Paris | Galin A.,APHP Assistance Publique Hopitaux de Paris | And 9 more authors.
Journal of Clinical Psychiatry | Year: 2011

Objective: Animal studies have shown sex differences in the impact of prenatal maternal stress on the offspring. The aim of this prospective case-control study was to assess the effect of prenatal depression on newborn and 1-year-old infant characteristics as related to gender, controlling for confounding variables. Method: We screened 205 pregnant women from April 2004 to November 2006 for depressive symptoms. Inclusion in the prenatal depression group (n = 34) was based on meeting DSM-IV criteria for major depressive episode. We excluded postnatal depression from the control group (n = 79) by routine screening at 2 and 6 months. Newborn and 1-year-old infant characteristics were evaluated with the Neonatal Behavioral Assessment Scale (NBAS) and the Infant-Toddler Social and Emotional Assessment, respectively. Results: Despite our use of numerous exclusion criteria (eg, at-risk pregnancy, preterm delivery), prenatal depression highly correlated with anxiety and stress scores. Male newborns of mothers with prenatal depression had lower scores than controls on the motor skills and regulation of states NBAS clusters (P = .03 and P = .026, respectively). At 1 year, infants of prenatally depressed mothers presented higher scores on generalized anxiety (P = .002), particularly in males (P = .009); activity/impulsivity (P = .042); and sleep problems (P = .023) than controls. Conclusions: As in animal studies, depression during pregnancy may affect infant development in a way that is related to gender. Early gender differences observed to be associated with depression, stress, and anxiety during pregnancy may be a key to under standing the higher prevalence in males of child psychiatric disorders. © Copyright 2010 Physicians Postgraduate Press, Inc.

Frampas E.,Hotel Dieu | Lassau N.,University Paris - Sud | Zappa M.,APHP Assistance Publique Hopitaux de Paris | Vullierme M.-P.,APHP Assistance Publique Hopitaux de Paris | And 3 more authors.
European Journal of Radiology | Year: 2013

Purpose: To investigate whether there is any correlation between standard endpoints and tumor perfusion measurements with Perfusion CT and Dynamic Contrast-Enhanced Ultrasonography (DCE-US) in patients with advanced Hepatocellular Carcinoma (HCC) treated with targeted therapy. Materials and methods: Nineteen patients were evaluated during targeted therapy (sorafenib n = 16, sunitinib n = 3). Changes in tumor perfusion measurements between baseline and month 1 were assessed and compared using RECIST progression criteria at month 2. Results: Median time to progression according to RECIST was 117 days and median time to death was 208 days. Perfusion CT values before treatment were significantly increased in HCC compared to the surrounding liver (n = 17, P <.02). Eleven patients received complete examinations with both techniques at baseline and month 1. A non-significant decrease was found in all Perfusion CT values between RECIST nonprogressors (n = 7) and progressors (n = 4): mean Blood Volume: -27.9 vs. -11.1% and mean Blood Flow: -25.0 vs. -11.7% respectively. With DCE-US, opposite changes were found (mean Area Under the Curve AUC: -38.3 vs. 436.3%). RECIST progression at month 2 was significantly correlated with a threshold 40% decrease in AUC (P =.015). None of the patients with a decrease in AUC ≥ 40% was a progressor at month 2. Conclusion: Despite perfusion changes with both Perfusion CT and DCE-US in patients receiving treatment, only DCE-US at month 1 (with a decrease in the AUC of more than 40%) predicted non-progression at month 2 and may be a potential surrogate marker of tumor response during targeted therapy. © 2012 Elsevier Ireland Ltd.

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