Institute National Of La Sante

Angers, France

Institute National Of La Sante

Angers, France
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Doumazane E.,French National Center for Scientific Research | Doumazane E.,Institute National Of La Sante | Doumazane E.,Universites Of Montpellier 1 And 2 | Scholler P.,French National Center for Scientific Research | And 13 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

In multimeric cell-surface receptors, the conformational changes of the extracellular ligand-binding domains (ECDs) associated with receptor activation remain largely unknown. This is the case for the dimeric metabotropic glutamate receptors even though a number of ECD structures have been solved. Here, using an innovative approach based on cell-surface labeling and FRET, we demonstrate that a reorientation of the ECDs is associated with receptor and G-protein activation. Our approach helps identify partial agonists and highlights allosteric interactions between the effector and binding domains. Any approach expected to stabilize the active conformation ofthe effector domain increased the agonist potency in stabilizing the active ECDs conformation. These data provide key information on the structural dynamics and drug action at metabotropic glutamate receptors and validate an approach for tackling such analysis on other receptors.

De Villiers T.,University of Cape Town | Odio A.,Heritage Medical Research Institute | Palacios S.,Instituto Palacios | Chapurlat R.,Institute National Of La Sante | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Odanacatib (ODN) is a selective cathepsin K inhibitor being developed to treat osteoporosis. Objective: The effects ofODNwere evaluatedonbonemineral density (BMD), biochemical markers of bone turnover, and safety in patients previously treated with alendronate. Design: This was a randomized, double-blind, placebo-controlled, 24-month study. Setting: The study was conducted at private or institutional practices. Participants: Postmenopausal women (n = 243) ≥60 years of age with low BMD at the total hip, femoral neck, or trochanter (T-score≤-2.5 but>-3.5 without prior fracture or≤-1.5 but>-3.5 with prior fracture) on alendronate for ≥3 years. Intervention: The intervention included ODN 50 mg or placebo weekly. Main Outcome Measures: The primary end point was percentage change from baseline of femoralneck BMD at month 24. BMD was assessed by dual-energy x-ray absorptiometry at baseline and 6, 12, and 24 months. Biochemical markers of bone turnover (serum C-telopeptides of type 1 collagen,urinary N-telopeptides of type 1 collagen, serum bone specific alkaline phosphatase, and serum N-terminal propeptide of type 1 collagen) were measured at baseline and 3, 6, 12, 18, and 24 months. Results: In the ODN group, BMD changes from baseline at the femoral neck, trochanter, total hip, and lumbar spine at 24 months (1.7%, 1.8%, 0.8%, and 2.3%, respectively) were significantly different from the placebo group. ODN significantly decreased urinary N-telopeptides of type 1collagen to creatinine ratio and significantly increased serum N-terminal propeptide of type 1 collagen compared with placebo. Serum C-telopeptides of type 1 collagen was unexpectedly increasedwith ODN treatment. The safety profile appeared similar between groups.Conclusions: ODN provided incremental BMD gains in osteoporotic women after alendronate treatment. © 2013 by The Endocrine Society.

Morillon B.,Ecole Normale Superieure de Paris | Lehongre K.,Ecole Normale Superieure de Paris | Frackowiak R.S.J.,University of Lausanne | Frackowiak R.S.J.,Instituto Of Ricovero E Cura A Carattere Scientifico Santa Lucia | And 3 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

The physiological basis of human cerebral asymmetry for language remains mysterious. We have used simultaneous physiological and anatomical measurements to investigate the issue. Concentrating on neural oscillatory activity in speech-specific frequency bands and exploring interactions between gestural (motor) and auditory-evoked activity, we find, in the absence of language-related processing, that left auditory, somatosensory, articulatory motor, and inferior parietal cortices show specific, lateralized, speech-related physiological properties. With the addition of ecologically valid audiovisual stimulation, activity in auditory cortex synchronizes with left-dominant input from the motor cortex at frequencies corresponding to syllabic, but not phonemic, speech rhythms. Our results support theories of language lateralization that posit a major role for intrinsic, hardwired perceptuomotor processing in syllabic parsing and are compatible both with the evolutionary view that speech arose from a combination of syllable-sized vocalizations and meaningful hand gestures and with developmental observations suggesting phonemic analysis is a developmentally acquired process.

Young J.,University Paris - Sud | Young J.,Hopitaux Universitaires Paris Sud | Young J.,Institute National Of La Sante
Journal of Clinical Endocrinology and Metabolism | Year: 2012

The term "congenital hypogonadotropic hypogonadism" (CHH) refers to a group of disorders featuring complete or partial pubertal failure due to insufficient secretion of the pituitary gonadotropins LH and FSH. Many boys (or their parents) will seek medical consultation because of partial or absent virilization after 14 yr of age. Small testes are very frequent, but height is generally normal. Laboratory diagnosis of hypogonadotropic hypogonadismis relatively simple, with very low circulating total testosterone and low to low-normal gonadotropin and inhibin B levels. This hormone profile rules out a primary testicular disorder. Before diagnosing CHH, however, it is necessary to rule out a pituitary tumor or pituitary infiltration by imaging studies, juvenile hemochromatosis, and a systemic disorder that, by undermining nutritional status, could affect gonadotropin secretion and pubertal development. Anterior pituitary function must be thoroughly investigated to rule out a more complex endocrine disorder with multiple hormone deficiencies and thus to conclude that the hypogonadotropic hypogonadism is isolated. The most likely differential diagnosis before age 18 yr is constitutional delay of puberty. A part from non-Kallmann syndromic forms, which are often diagnosed during childhood, the two main forms of CHH seen by endocrinologists are Kallmann syndrome, in which CHH is associated with impaired sense of smell, and isolated CHH with normal olfaction. Anosmia can be easily diagnosed by questioning the patient, whereas olfactometry is necessary to determine reliably whether olfaction is normal or partially defective. This step is important be fore embarking on a search for genetic mutations, which will also be useful for genetic counseling. The choice of a particular hormone replacement therapy protocolaimed at virilizing the patient will depend on age at diagnosis and local practices. Copyright © 2012 by The Endocrine Society.

Selimovic D.,Institute National Of La Sante | Selimovic D.,University of Strasbourg | Porzig B.B.O.W.,Cell Therapeutics | El-Khattouti A.,University of Mississippi Medical Center | And 8 more authors.
Cellular Signalling | Year: 2013

Generally, both endoplasmic reticulum (ER) stress and mitochondrial dysregulation are a potential therapeutic target of anticancer agents including bortezomib.The treatment of melanoma cells with bortezomib was found to induce apoptosis together with the upregulation of Noxa, Mcl-1, and HSP70 proteins, and the cleavage of LC3 and autophagic formation. Also, bortezomib induced ER-stress as evidenced by the increase of intracellular Ca2+ release. In addition, bortezomib enhanced the phosphorylation of inositol-requiring transmembrane kinase and endonuclease 1α (IRE1α), apoptosis signal-regulating kinase 1 (ASK1), c-jun-N-terminal kinase (JNK) and p38, and the activation of the transcription factors AP-1, ATF-2, Ets-1, and HSF1. Bortezomib-induced mitochondrial dysregulation was associated with the accumulation of reactive oxygen species (ROS), the release of both apoptosis inducing factor (AIF) and cytochrome c, the activation of caspase-9 and caspase-3, and cleavage of Poly (ADP-ribose) polymerase (PARP). The pretreatment of melanoma cells with the inhibitor of caspase-3 (Ac-DEVD-CHO) was found to block bortezomib-induced apoptosis that subsequently led to the increase of autophagic formation. In contrast, the inhibition of ASK1 abrogated bortezomib-induced autophagic formation and increased apoptosis induction. Furthermore, the inhibition of JNK, of HSP70 also increased apoptosis induction without influence of bortezomib-induced autophagic formation. Based on the inhibitory experiments, the treatment with bortezomib triggers the activation of both ER-stress-associated pathways, namely IRE1α-ASK1-p38-ATF-2/ets-1-Mcl-1, and IRE1α-ASK1-JNK-AP-1/HSF1-HSP70 as well as mitochondrial dysregulation-associated pathways, namely ROS-ASK1-JNK-AP-1/HSF1-HS70, and AIF-caspase-3-PARP and Cyt.c, and caspase-9-caspase-3-PARP. Taken together, our data demonstrates for the first time the molecular mechanisms, whereby bortezomib triggers both apoptosis and autophagic formation in melanoma cells. © 2012 Elsevier Inc.

Puy H.,Center Francais des Porphyries | Puy H.,Institute National Of La Sante | Gouya L.,Center Francais des Porphyries | Gouya L.,Institute National Of La Sante | And 3 more authors.
The Lancet | Year: 2010

Hereditary porphyrias are a group of eight metabolic disorders of the haem biosynthesis pathway that are characterised by acute neurovisceral symptoms, skin lesions, or both. Every porphyria is caused by abnormal function of a separate enzymatic step, resulting in a specific accumulation of haem precursors. Seven porphyrias are the result of a partial enzyme deficiency, and a gain of function mechanism has been characterised in a new porphyria. Acute porphyrias present with acute attacks, typically consisting of severe abdominal pain, nausea, constipation, confusion, and seizure, and can be life-threatening. Cutaneous porphyrias present with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe cutaneous photosensitivity and chronic haemolysis or chronic neurological symptoms with or without photosensitivity. Porphyrias are still underdiagnosed, but when they are suspected, and dependent on clinical presentation, simple first-line tests can be used to establish the diagnosis in all symptomatic patients. Diagnosis is essential to enable specific treatments to be started as soon as possible. Screening of families to identify presymptomatic carriers is crucial to decrease risk of overt disease of acute porphyrias through counselling about avoidance of potential precipitants. © 2010 Elsevier Ltd. All rights reserved.

Mateescu B.,University Pierre and Marie Curie | Mateescu B.,Institute National Of La Sante | Batista L.,University Pierre and Marie Curie | Batista L.,Institute National Of La Sante | And 13 more authors.
Nature Medicine | Year: 2011

Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.

Kavvadas P.,Institute National Of La Sante | Weis L.,Institute National Of La Sante | Abed A.B.,Institute National Of La Sante | Feldman D.L.,Novartis | And 2 more authors.
Hypertension | Year: 2013

Aliskiren, a direct renin inhibitor, is a novel antihypertensive drug. To study whether aliskiren can reverse chronic kidney disease, we administered it to renin transgenic mice, a strain characterized by elevated blood pressure and a slow decline of renal function, mimicking well the progression of hypertensive chronic kidney disease. Ten-month-old transgenic mice were treated either with aliskiren or placebo for 28 days. Age-matched wild-type mice treated or not with aliskiren were considered as normotensive controls. Aliskiren reduced blood pressure to wild-type levels from as early as day 14. Proteinuria and cardiac hypertrophy and fibrosis were also normalized. Renal interstitial fibrosis and inflammation were significantly ameliorated in aliskiren-treated mice (shown by the decrease of proinflammatory and profibrotic markers), and the phenotypes of tubular epithelial cells and podocytes were restored as evidenced by the reappearance of cellular proteins characteristic of normal phenotype of these cells. Profibrotic p38 and Erk mitogen-activated protein kinases were highly activated in placebo-treated transgenic animals. Aliskiren treatment cancelled this activation. This nephroprotection was not attributed to the antihypertensive activity of aliskiren, because blood pressure normalization after treatment with hydralazine failed to induce the regression of renal fibrosis. Direct inhibition of renin can restore renal function and structure in aged hypertensive animals with existing proteinuria. This finding suggests that, in addition to antihypertensive action, aliskiren can be also used to treat chronic kidney disease. © 2013 American Heart Association, Inc.

Antonucci L.,Ecole Polytechnique - Palaiseau | Antonucci L.,Institute National Of La Sante | Solinas X.,Ecole Polytechnique - Palaiseau | Solinas X.,Institute National Of La Sante | And 4 more authors.
Optics Express | Year: 2012

A method of asynchronous optical sampling based on freerunning lasers with no requirement on the repetition rates is presented. The method is based on the a posteriori determination of the delay between each pair of pulses. A resolution better than 400 fs over 13 ns total delay scan is demonstrated. In addition to the advantages of conventional asynchronous sampling techniques, this method allows a straightforward implementation on already-existing laser systems using a fiber-based setup and an appropriate acquisition procedure. © 2012 Optical Society of America.

Bousquet C.,Institute National Of La Sante | Lasfargues C.,Institute National Of La Sante | Chalabi M.,Institute National Of La Sante | Billah S.M.,Institute National Of La Sante | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Among the innovative molecules used to manage neuroendocrine tumors, there is growing interest in combining the somatostatin analogs octreotide or pasireotide (SOM230) and everolimus (RAD001), an inhibitor that targets the protein kinase mammalian target of rapamycin (mTOR). Evidence Acquisition: The aims of this review were to describe the signaling pathways targeted independently by somatostatin analogs and everolimus and to summarize the scientific rationale for the potential additive or synergistic antitumor effects of combined therapy. Evidence Synthesis: The somatostatin analogs (octreotide and lanreotide) have potent inhibitory effects on hypersecretion, thereby alleviating the symptoms associated with neuroendocrine tumors. Furthermore, the antitumor potential of octreotide is now well documented. Pasireotide, a somatostatin analog, has the advantage of targeting a wider range of somatostatin receptors (subtypes 1, 2, 3, and 5) than the analogs previously used in clinical practice (which preferentially target subtype 2) and thus has a broader spectrum of activity. Everolimus is a rapamycin analog that inhibits mTOR, but it is more soluble than rapamycin and can be administered orally. mTOR is a protein kinase involved in many signaling pathways, primarily those initiated by tyrosine kinase receptors. Sustained mTOR activity leads to the induction of cell growth, proliferation, and cell survival. Everolimus therefore has obvious potential in cancer therapy. Conclusions: The combination of somatostatin analogs and everolimus in therapeutic trials offers a promising treatment option for neuroendocrine tumors. Copyright © 2012 by The Endocrine Society.

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