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10 results on '"Interactions cellulaires neuroendocriniennes (ICN)"'

1. Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Chinot, Marc Sanson, Hadrien Peyrière, Emeline Tabouret, Thomas Graillon, Ahmed Idbaih, Stéphane Honoré, Anita Cohen, Matthieu Peyre, Dominique Figarella-Branger, Pierre-Hugues Roche, Noémie Basset, Mohamed Boucekine, Maryline Barrie, Henry Dufour, Michel Kalamarides, Chantal Campello, Didier Autran, Anne Barlier, Catherine Roche, Karine Baumstarck, Stéphane Fuentes, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service de Neurochirurgie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Département de neurochirurgie, Hôpital Nord [CHU - APHM], Département de Neurochirurgie [CHU Timone], SERVICE DE NEUROONCOLOGIE MARSEILLE, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Assistance Publique-Hôpitaux de Marseille (AP-HM), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix-Marseille Université - Faculté de médecine (AMU MED), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Hôpital Beaujon [AP-HP]-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU)

Subjects
Male, Cancer Research, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Octreotide, Gastroenterology, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Meningeal Neoplasms, Prospective Studies, Receptors, Somatostatin, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, TOR Serine-Threonine Kinases, Middle Aged, 3. Good health, Tumor Burden, Survival Rate, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Patient Safety, Meningioma, medicine.drug, Recurrent Meningioma, Adult, medicine.medical_specialty, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, otorhinolaryngologic diseases, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Everolimus, neoplasms, Survival rate, Aged, business.industry, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, nervous system diseases, Clinical trial, Radiation therapy, Neoplasm Recurrence, Local, business, 030217 neurology & neurosurgery
Abstract

Purpose: Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas. Patients and Methods: Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety. Results: A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003). Conclusions: The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.

Published
2019

2. Metabolomics signatures of a subset of RET variants according to their oncogenic risk level

Author

Nathalie Bouzamondo, Pascal Reynier, Delphine Prunier-Mirebeau, Anne Barlier, Xavier Dieu, Delphine Drui, Gilles Simard, Charlotte Veyrat-Durebex, Juan Manuel Chao de la Barca, Morgane Le Mao, Françoise Borson-Chazot, Céline Bris, Cédric Gadras, Lydie Tessier, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département d'Endocrinologie [CHU Nantes] (Institut du Thorax), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut du Thorax [Nantes], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Mitochondrie : Régulations et Pathologie, Service Biochimie et Génétique, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Risk, Cancer Research, Ret gene, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Cell, Endogeny, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Proto-Oncogene Mas, Germline, Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Metabolomics, medicine, Animals, Humans, Thyroid Neoplasms, Phosphorylation, Allele, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, Genetics, 0303 health sciences, Models, Statistical, [SDV.BA]Life Sciences [q-bio]/Animal biology, Proto-Oncogene Proteins c-ret, Genetic Variation, Medullary thyroid cancer, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, Carcinoma, Neuroendocrine, 3. Good health, medicine.anatomical_structure, Oncology, Cell culture, 030220 oncology & carcinogenesis, Mutation, Metabolome, NIH 3T3 Cells, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Signal Transduction
Abstract

Thirty percent of medullary thyroid carcinomas (MTCs) are related to dominant germline pathogenic variants in the RET proto-oncogene. According to their aggressiveness, these pathogenic variants are classified in three risk levels: ‘moderate’, ‘high’ and ‘highest’. The present study compares the metabolomics profiles of five pathogenic variants, whether already classified or not. We have generated six stable murine fibroblast cell lines (NIH3T3) expressing the WT allele or variants of the human RET gene, with different levels of pathogenicity, including the M918V variant that is yet to be accurately classified. We carried out a targeted metabolomics study of the cell extracts with a QTRAP mass spectrometer, using the Biocrates Absolute IDQ p180 kit, which allows the quantification of 188 endogenous molecules. The data were then subjected to multivariate statistical analysis. One hundred seventy three metabolites were accurately measured. The metabolic profiles of the cells expressing the RET variants were found to be correlated with their oncogenic risk. In addition, the statistical model we constructed for predicting the oncogenic risk attributed a moderate risk to the M918V variant. Our results indicate that metabolomics may be useful for characterizing the pathogenicity of the RET gene variants and their levels of aggressiveness.

Published
2019

3. Octreotide therapy in meningiomas: in vitro study, clinical correlation, and literature review

Author

Anne Barlier, Pierre-Hugues Roche, Céline Defilles, Amira Mohamed, Alexandru Saveanu, Olivier Chinot, Thomas Graillon, David Romano, Dominique Figarella-Branger, Henry Dufour, Stéphane Fuentes, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de neurochirurgie, Hôpital de la Timone [CHU - APHM] (TIMONE), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'endocrinologie moléculaire, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Nord [CHU - APHM], Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut des Sciences du Mouvement Etienne Jules Marey (ISM), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Département de neurooncologie, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and figarella-branger, dominique

Subjects
medicine.medical_specialty, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Antineoplastic Agents, Hormonal, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Somatostatin Analog Therapy, Octreotide, [SDV.CAN]Life Sciences [q-bio]/Cancer, In Vitro Techniques, Neuroendocrine tumors, somatostatin, meningioma, Meningioma, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Internal medicine, Tumor Cells, Cultured, Humans, Medicine, Correlation of Data, merlin, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, therapy, business.industry, Somatostatin receptor, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Medicine, medicine.disease, 3. Good health, Somatostatin, Endocrinology, 030220 oncology & carcinogenesis, Cancer research, business, 030217 neurology & neurosurgery, octreotide, medicine.drug, SST2
Abstract

OBJECTIVEMeningiomas express somatostatin receptor subtype 2 (SST2), which is targeted by the somatostatin analog octreotide. However, to date, using somatostatin analog therapy for the treatment of these tumors in clinical practice has been debated. This study aims to clarify the in vitro effects of octreotide on meningiomas for precise clinical applications.METHODSThe effects of octreotide were analyzed in a large series of 80 meningiomas, including 31 World Health Organization (WHO) Grade II and 4 WHO Grade III tumors, using fresh primary cell cultures to study the impact on cell viability, apoptosis, and signal transduction pathways.RESULTSSST2 mRNA was detected in 100% of the tested meningiomas at levels similar to those observed in other SST2-expressing tumors, neuroendocrine tumors, or pituitary adenomas. Octreotide significantly decreased cell proliferation in 88% of meningiomas but did not induce cell death. On average, cell proliferation was more inhibited in the meningioma group expressing a high level of SST2 than in the low-SST2 group. Moreover, octreotide response was positively correlated to the level of merlin protein and inversely correlated to the level of phosphorylated p70-S6 kinase, a downstream effector of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway. Octreotide inhibited Akt phosphorylation and activated tyrosine phosphatase without impacting the extracellular regulated kinase (ERK) pathway.CONCLUSIONSOctreotide acts exclusively as an antiproliferative agent and does not promote apoptosis in meningioma in vitro. Therefore, in vivo, octreotide is likely to limit tumor growth rather than induce tumor shrinkage. A meta-analysis of the literature reveals an interest in octreotide for the treatment of WHO Grade I tumors, particularly those in the skull base for which the 6-month progression-free survival level reached 92%. Moreover, somatostatin analogs, which are well-tolerated drugs, could be of interest for use as co-targeting therapies for aggressive meningiomas.

Published
2017

4. Pasireotide is more effective than octreotide, alone or combined with everolimus on human meningioma in vitro

Author

Céline Defilles, Pierre-Hugues Roche, Alexandru Saveanu, Henry Dufour, Olivier Chinot, Christophe Lisbonis, Anne Barlier, Stéphane Fuentes, David Romano, Thomas Graillon, Dominique Figarella-Branger, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Service de pathologie et neuropathologie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Mouvement Etienne Jules Marey (ISM), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and Barlier, Anne

Subjects
medicine.medical_specialty, [SDV]Life Sciences [q-bio], Octreotide, Neuroendocrine tumors, Pharmacology, somatostatin, meningioma, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Acromegaly, medicine, merlin, PI3K/AKT/mTOR pathway, pasireotide, Everolimus, Somatostatin receptor, business.industry, medicine.disease, Pasireotide, 3. Good health, [SDV] Life Sciences [q-bio], Somatostatin, Endocrinology, Oncology, chemistry, 030220 oncology & carcinogenesis, mTOR, business, 030217 neurology & neurosurgery, Research Paper, medicine.drug
Abstract

International audience; Pasireotide is a somatostatin analog (SSA) that targets somatostatin receptor subtype 1 (SST1), SST2, SST3, and SST5 with a high affinity. Pasireotide has a better antisecretory effect in acromegaly, Cushing's disease, and neuroendocrine tumors than octreotide. In this study, we compared the effects of pasireotide to those of octreotide in vitro on meningioma primary cell cultures, both alone and in combination with the mTOR inhibitor everolimus. Significant mRNA expression levels of SST1, SST2, and SST5 were observed in 40.5%, 100%, and 35% of meningioma samples, respectively. Pasireotide had a significantly stronger inhibitory effect on cell proliferation than octreotide. The effect of pasireotide, but not of octreotide, was significantly stronger in the group expressing the highest level of SST1 mRNA. Combined treatment with pasireotide and everolimus induced a higher reduction in cell viability than that with octreotide plus everolimus. Moreover, pasireotide decreased Akt phosphorylation and reversed everolimus-induced Akt hyperphosphorylation to a higher degree than octreotide. Using 4E-BP1 siRNA (si4E-BP), we demonstrated that 4E-BP1 protein silencing significantly reversed the response to everolimus, both alone and in combination with SSAs. Moreover, si4E-BP completely reversed the inhibition of cyclin D1 expression level and the increase in p27kip1 induced by SSAs, both alone and in combination with everolimus. Our results strongly support the need for further studies on the combination of pasireotide and everolimus in medical therapy for meningiomas.

Published
2017

5. Lessons from monogenic causes of growth hormone deficiency

Author

Alexandru Saveanu, Thierry Brue, Nicolas Jullien, Anne Barlier, Rachel Reynaud, Frederic Castinetti, Teddy Fauquier, Alain Enjalbert, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Département Logique des Usages, Sciences sociales et Sciences de l'Information (IMT Atlantique - LUSSI), IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut de Génomique Fonctionnelle (IGF), and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adult, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Hypopituitarism, 030105 genetics & heredity, Biology, Bioinformatics, Growth hormone deficiency, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Endocrine system, Humans, Allele, Child, Gene, Transcription factor, ComputingMilieux_MISCELLANEOUS, Genetics, Homeodomain Proteins, Human Growth Hormone, General Medicine, medicine.disease, Phenotype, Pituitary Gland, Transcription Factor Gene, Transcription Factor Pit-1
Abstract

Through the multicentric international GENHYPOPIT network, 10 transcription factor genes involved in pituitary development have been screened in more than 1200 patients with constitutional hypopituitarism over the past two decades. The present report summarizes the main lessons learned from this phenotype-based genetic screening: (1) genetically determined hypopituitarism does not necessarily present during childhood; (2) constitutional hypopituitarism may be characterized by a pure endocrine phenotype or by various combinations of endocrine deficits and visceral malformations; (3) syndromic hypopituitarism may also be observed in patients with POU1F1 or PROP1 mutations; (4) in cases of idiopathic hypopituitarism, extensive genetic screening identifies gene alterations in a minority of patients; (5) functional studies are imperfect in determining the involvement of an allelic variant in a specific pituitary phenotype.

Published
2017

6. Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs?

Author

Flora Poizat, David Romano, Catherine Roche, Tullio Florio, Anne Barlier, Vincent Moutardier, Manuela Albertelli, Thierry Brue, Diego Ferone, Stéphane Garcia, Federica Barbieri, Jean Robert Delpero, Patricia Niccoli, Corinne Gerard, Alexandru Saveanu, Amira Mohamed, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Genova = University of Genoa (UniGe), Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Surgical Oncology, Université de la Méditerranée - Aix-Marseille 2, Hôpital Nord [CHU - APHM], Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), and Universita degli studi di Genova

Subjects
0301 basic medicine, Oncology, Octreotide, Apoptosis, Neuroendocrine tumors, chemistry.chemical_compound, 0302 clinical medicine, Tumor Cells, Cultured, Medicine, primary culture, co-treatment, everolimus, human pancreatic neuroendocrine tumors, somatostatin analogs, biology, TOR Serine-Threonine Kinases, Chromogranin A, Drug Synergism, 3. Good health, Neuroendocrine Tumors, Somatostatin, 030220 oncology & carcinogenesis, medicine.drug, Signal Transduction, Research Paper, medicine.medical_specialty, Cell Survival, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Stomach Neoplasms, Internal medicine, Intestinal Neoplasms, Humans, PI3K/AKT/mTOR pathway, Everolimus, business.industry, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Pasireotide, Pancreatic Neoplasms, 030104 developmental biology, chemistry, Immunology, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, Proto-Oncogene Proteins c-akt
Abstract

// Amira Mohamed 1, 2 , David Romano 1 , Alexandru Saveanu 1, 2 , Catherine Roche 2 , Manuela Albertelli 3 , Federica Barbieri 3 , Thierry Brue 1, 4 , Patricia Niccoli 5 , Jean-Robert Delpero 6 , Stephane Garcia 8 , Diego Ferone 3 , Tullio Florio 3 , Vincent Moutardier 9 , Flora Poizat 7, * , Anne Barlier 1, 2, * and Corinne Gerard 1 1 Aix Marseille Univ, CNRS, CRN2M, Marseille, France 2 APHM, Conception Hospital, Molecular Biology Laboratory, Marseille, France 3 Department of Internal Medicine and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy 4 APHM, Conception Hospital, Endocrinology Department, Marseille, France 5 Paoli Calmettes Cancer Institute, Oncology Department, IPC CoE-ENETS, Marseille, France 6 Paoli Calmettes Cancer Institute, Surgery Department, IPC CoE-ENETS, Marseille, France 7 Paoli Calmettes Cancer Institute, Biopathology Department, IPC CoE-ENETS, Marseille, France 8 APHM, North Hospital, Pathology Laboratory, Marseille, France 9 APHM, North Hospital, Surgery Department, Marseille, France * These authors have contributed equally to this work Correspondence to: Corinne Gerard, email: corinne.gerard@univ-amu.fr Keywords: everolimus, somatostatin analogs, human pancreatic neuroendocrine tumors, primary culture, co-treatment Received: July 26, 2016 Accepted: March 22, 2017 Published: April 10, 2017 ABSTRACT Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA.

Published
2017

7. RAPID DIFFERENTIAL DIAGNOSIS OF POLYURIA-POLYDIPSIA SYNDROME IN CHILDREN: THE COPEPTIN APPROACH. A CASE REPORT

Author

VERGIER, JULIA, Jr, Fromonot, Julien, MACEDO, Alix Alvares De Azevedo, GODEFROY, ALICE, MARQUANT, EMELINE, Guieu, Régis, Tsimaratos, Michel, Reynaud, Rachel, Dysoxie, suractivité : aspects cellulaires et intégratifs thérapeutiques (DS-ACI / UMR MD2), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Guieu, régis, and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2017

8. Assessment of glycemic control in nursing home residents with diabetes

Author

Charles Oliver, L. Mari, Michel Grino, Frédérique Retornaz, Hôpital Européen [Fondation Ambroise Paré - Marseille], Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Blood Glucose, Male, medicine.medical_specialty, HbA1c, endocrine system diseases, Medicine (miscellaneous), Blood sugar, 030209 endocrinology & metabolism, Hypoglycemia, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Medicine, Humans, Hypoglycemic Agents, Insulin, 030212 general & internal medicine, Intensive care medicine, Glycemic, Aged, Blood glucose monitoring, Aged, 80 and over, Glycated Hemoglobin, Nutrition and Dietetics, medicine.diagnostic_test, business.industry, Chronic hyperglycemia, Blood glucose in long term care home residents, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, nutritional and metabolic diseases, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Nursing Homes, Blood chemistry, Relative risk, Hyperglycemia, Female, France, Geriatrics and Gerontology, Nursing homes, business
Abstract

International audience; Objective: To describe glycemic control in nursing home residents with diabetes and to evaluate the relevance of HbA1c in the detection of hypoglycemia risk.Design and methods: Diabetes treatment, geriatric assessment, blood capillary glucose (n= 24,682), and HbA1c were collected from medical charts of 236 southern France nursing home residents during a 4-month period. Glycemic control was divided into four categories: tight, fair, and moderate or severe chronic hyperglycemia using the High Blood Glucose Index or the analysis of blood glucose frequency distribution. Hypoglycemia episodes were identified by medical or biological records.Results: Glucose control was tight in 59.3 % and fair in 19.1 % of the residents. Chronic exposure to hyperglycemia was observed in 21.6 % of the residents (severe in 9.7 % and moderate in 11.9 %). Hypoglycemia was noticed in 42/236 (17.8%), in all categories of glycemic control. Relative hypoglycemia risk was significantly (P = 0.0095) higher in residents with moderate chronic hyperglycemia compared with those with tight control. The majority of residents with hypoglycemia (39/42) or chronic hyperglycemia (45/51) were insulin-treated. The relative risk of hypoglycemia was not significantly associated with HbA1c values.Conclusion: Hypoglycemia risk in nursing home residents is observed in all categories of glycemic control. In tight control, the potency of antidiabetic treatment should be reduced. In chronic hyperglycemia, diet and treatment should be reevaluated in order to reduce glucose variability. HbA1c is not sufficient for hypoglycemia risk detection; capillary blood glucose monitoring is warranted for nursing homes residents with diabetes.

Published
2017

9. Development of a high-yielding bioprocess for 11-α hydroxylation of canrenone under conditions of oxygen-enriched air supply

Author

Valerio De Vitis, Immacolata Serra, Francesco Molinari, Ricardo Pinheiro de Souza Oliveira, Benedetta Guidi, Andrea Pinto, Martina Letizia Contente, Roberto Lenna, Diego Romano, Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Studi Aziendali e Sociali, Contente, M, Guidi, B, Serra, I, De Vitis, V, Romano, D, Pinto, A, Lenna, R, de Souza Oliveira, R, and Molinari, F

Subjects
0301 basic medicine, Aspergillus ochraceu, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Clinical Biochemistry, Steroid hydroxylation, Hydroxylation, 01 natural sciences, Biochemistry, Mixed Function Oxygenases, 03 medical and health sciences, chemistry.chemical_compound, Endocrinology, Biotransformation, Canrenone, medicine, Organic chemistry, BIOTRANSFORMAÇÃO, Solubility, Bioprocess, Monooxygenase, Molecular Biology, Pharmacology, Aspergillus ochraceus, biology, 010405 organic chemistry, Organic Chemistry, Substrate (chemistry), Biocatalysi, biology.organism_classification, 0104 chemical sciences, Oxygen, 030104 developmental biology, chemistry, Biocatalysis, Fermentation, medicine.drug
Abstract

International audience; A high yielding bioprocess for 11-α hydroxylation of canrenone (1a) using Aspergillus ochraceus ATCC 18500 was developed. The optimization of the biotransformation involved both fermentation (for achieving highly active mycelium of A. ochraceus) and biotransformation with the aim to obtain 11-α hydroxylation with high selectivity and yield. A medium based on sucrose as C-source resulted particularly suitable for conversion of canrenone into the corresponding 11-hydroxy derivative, whereas the use of O2-enriched air and dimethyl sulfoxide (DMSO) as a co-solvent for increasing substrate solubility played a crucial role for obtaining high yields (\textgreater95%) of the desired product in high chemical purity starting from 30mM (10.2g/L) of substrate. The structure of the hydroxylated product was confirmed by a combination of two-dimensional NMR proton-proton correlation techniques.

Published
2016

10. Autophosphorylation on S614 inhibits the activity and the transforming potential of BRAF

Author

Karsten Boldt, David Romano, Mohamed Ali Jarboui, Walter Kolch, Yves Texier, Nicola Horn, Alex von Kriegsheim, Armin Zebisch, Christian Johannes Gloeckner, Marius Ueffing, Nora Rauch, Layal Dernayka, Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Protein Science, Helmholtz Zentrum München = German Research Center for Environmental Health, Division of Experimental Ophthalmology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen-Center of Ophthalmology-Medical Proteome Center, Conway Institute of Biomolecular and Biomedical Research [Dublin, Irlande], University College Dublin [Dublin] (UCD), Systems Biology Ireland, School of Medicine and Medical Science [Dublin, Irlande], and German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM)

Subjects
0301 basic medicine, MAPK/ERK pathway, Proto-Oncogene Proteins B-raf, endocrine system diseases, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, genetics [Mutation], medicine.disease_cause, Proto-Oncogene Mas, Cell Line, BRAF, 03 medical and health sciences, Mice, Phosphoserine, Inhibition of kinase activity and transformation, metabolism [Proto-Oncogene Proteins B-raf], medicine, metabolism [Phosphoserine], Animals, Humans, ddc:610, Amino Acid Sequence, Kinase activity, Phosphorylation, Protein kinase A, skin and connective tissue diseases, neoplasms, Mitogen-Activated Protein Kinase Kinases, Mutation, S614 autophosphorylation, biology, Chemistry, metabolism [Cell Transformation, Neoplastic], Autophosphorylation, Cell Biology, digestive system diseases, Rats, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Cell Transformation, Neoplastic, Mitogen-activated protein kinase, chemistry [Proto-Oncogene Proteins B-raf], Cancer research, biology.protein, metabolism [Mitogen-Activated Protein Kinase Kinases], pathology [Cell Transformation, Neoplastic], V600E, Protein Binding
Abstract

The BRAF proto-oncogene serine/threonine-protein kinase, known as BRAF, belongs to the RAF kinase family. It regulates the MAPK/ERK signalling pathway affecting several cellular processes such as growth, survival, differentiation, and cellular transformation. BRAF is mutated in ~8% of all human cancers with the V600E mutation constituting ~90% of mutations. Here, we have used quantitative mass spectrometry to map and compare phosphorylation site patterns between BRAF and BRAF V600E. We identified sites that are shared as well as several quantitative differences in phosphorylation abundance. The highest difference is phosphorylation of S614 in the activation loop which is ~5fold enhanced in BRAF V600E. Mutation of S614 increases the kinase activity of both BRAF and BRAF V600E and the transforming ability of BRAF V600E. The phosphorylation of S614 is mitogen inducible and the result of autophosphorylation. These data suggest that phosphorylation at this site is inhibitory, and part of the physiological shut-down mechanism of BRAF signalling. European Commission - Seventh Framework Programme (FP7) Science Foundation Ireland

Published
2016

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