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1. Glucose Starvation or Pyruvate Dehydrogenase Activation Induce a Broad, ERK5-Mediated, Metabolic Remodeling Leading to Fatty Acid Oxidation

Author

Abrar Ul Haq Khan, Hamideh Salehi, Catherine Alexia, Jose M. Valdivielso, Milica Bozic, Isabel C. Lopez-Mejia, Lluis Fajas, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Delphine Gitenay, Martin Villalba, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Bioingénierie et NanoSciences (LBN), Université de Montpellier (UM), Biomedical Research Institute of Lleida [Spain] (IRBLleida), Universitat de Lleida, Université de Lausanne = University of Lausanne (UNIL), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), This work was supported by INCA/DGOS PRT-K program 2021 (M.V., 2021-014). A.K.was the recipient of a fellowship from Higher Education Commission of Pakistan. This work wasalso supported by the 'Investissements d’avenir' Grant LabEx MAbImprove: ANR-10-LABX-53(M.V.). I.C.L.-M. is supported by a PRIMA grant from the Swiss National Science Foundation (SNSFPR00P3_193166)., and KARLI, Mélanie

Subjects
MESH: Oxidation-Reduction, [SDV]Life Sciences [q-bio], Fatty Acids, General Medicine, glycolysis, metabolic plasticity, MESH: Fatty Acids, MESH: Glucose, [SDV] Life Sciences [q-bio], metabolic flexibility, Glucose, ERK5, fatty acid oxidation, biochemistry, MESH: Mitogen-Activated Protein Kinase 7, MESH: Oxidoreductases, Oxidoreductases, Pyruvates, Oxidation-Reduction, Mitogen-Activated Protein Kinase 7, MESH: Pyruvates
Abstract

International audience; Cells have metabolic flexibility that allows them to adapt to changes in substrate availability. Two highly relevant metabolites are glucose and fatty acids (FA), and hence, glycolysis and fatty acid oxidation (FAO) are key metabolic pathways leading to energy production. Both pathways affect each other, and in the absence of one substrate, metabolic flexibility allows cells to maintain sufficient energy production. Here, we show that glucose starvation or sustained pyruvate dehydrogenase (PDH) activation by dichloroacetate (DCA) induce large genetic remodeling to propel FAO. The extracellular signal-regulated kinase 5 (ERK5) is a key effector of this multistep metabolic remodeling. First, there is an increase in the lipid transport by expression of low-density lipoprotein receptor-related proteins (LRP), e.g., CD36, LRP1 and others. Second, an increase in the expression of members of the acyl-CoA synthetase long-chain (ACSL) family activates FA. Finally, the expression of the enzymes that catalyze the initial step in each cycle of FAO, i.e., the acyl-CoA dehydrogenases (ACADs), is induced. All of these pathways lead to enhanced cellular FAO. In summary, we show here that different families of enzymes, which are essential to perform FAO, are regulated by the signaling pathway, i.e., MEK5/ERK5, which transduces changes from the environment to genetic adaptations.

Published
2022
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2. proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease

Author

Isidro Ferrer, Carme Espinet, Catherine Fleitas, Bahira Zammou, Joaquim Egea, Claire Rampon, Bolanle Fatimat Olabiyi, Biomedical Research Institute of Lleida [Spain] (IRBLleida), Universitat de Lleida, University of Bonn, Universitat de Barcelona (UB), L’Hospitalet de Llobregat [Barcelona, Spain], Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Toulouse Mind & Brain Institut (TMBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, and Rampon, Claire

Subjects
Male, [SDV]Life Sciences [q-bio], memory impairment, Morris water navigation task, Hippocampus, Hippocampal formation, Adult neurogenesis, Mice, 0302 clinical medicine, Nerve Growth Factor, dentate gyrus, Biology (General), Spectroscopy, Spatial Memory, Aged, 80 and over, Neurons, 0303 health sciences, biology, Neurogenesis, Brain, General Medicine, Memory impairment, Middle Aged, Alzheimer's disease, Computer Science Applications, [SDV] Life Sciences [q-bio], adult neurogenesis, Chemistry, Alzheimer’s disease, Neurotrophin, Adult, p75, Doublecortin Protein, QH301-705.5, Mice, Transgenic, Article, Catalysis, Inorganic Chemistry, Young Adult, 03 medical and health sciences, Alzheimer Disease, Animals, Humans, Dentate gyrus, Protein Precursors, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, Aged, 030304 developmental biology, Memory Disorders, pro-NGF, Organic Chemistry, Entorhinal cortex, Doublecortin, Mice, Inbred C57BL, Disease Models, Animal, nervous system, biology.protein, Neuroscience, 030217 neurology & neurosurgery
Abstract

In recent decades, neurogenesis in the adult brain has been well demonstrated in anumber of animal species, including humans. Interestingly, work with rodents has shown that adultneurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, asincreasing neurogenesis improves memory, while its disruption triggers the opposite effect. Adultneurogenesis declines with age and has been suggested to play a role in impaired progressive learningand memory loss seen in Alzheimer’s disease (AD). Therefore, therapeutic strategies designed toboost adult hippocampal neurogenesis may be beneficial for the treatment of AD. The precursor formsof neurotrophins, such as pro-NGF, display remarkable increase during AD in the hippocampusand entorhinal cortex. In contrast to mature NGF, pro-NGF exerts adverse functions in survival,proliferation, and differentiation. Hence, we hypothesized that pro-NGF and its p75 neurotrophinreceptor (p75NTR) contribute to disrupting adult hippocampal neurogenesis during AD. To test thishypothesis, in this study, we took advantage of the availability of mouse models of AD (APP/PS1),which display memory impairment, and AD human samples to address the role of pro-NGF/p75NTRsignaling in different aspects of adult neurogenesis. First, we observed that DG doublecortin (DCX) +progenitors express p75NTR both, in healthy humans and control animals, although the percentageof DCX+ cells are significantly reduced in AD. Interestingly, the expression of p75NTR in theseprogenitors is significantly decreased in AD conditions compared to controls. In order to assessthe contribution of the pro-NGF/p75NTR pathway to the memory deficits of APP/PS1 mice, weinjected pro-NGF neutralizing antibodies (anti-proNGF) into the DG of control and APP/PS1 miceand animals are subjected to a Morris water maze test. Intriguingly, we observed that anti-pro-NGF significantly restored memory performance of APP/PS1 animals and significantly increasethe percentage of DCX+ progenitors in the DG region of these animals. In summary, our resultssuggest that pro-NGF is involved in disrupting spatial memory in AD, at least in part by blockingadult neurogenesis. Moreover, we propose that adult neurogenesis alteration should be taken intoconsideration for better understanding of AD pathology. Additionally, we provide a new molecularentry point (pro-NGF/p75NTR signaling) as a promising therapeutic target in AD. This work was supported by “Fundació La Marató 2015” (C.E.). We thank, IRB Lleida Biobank (B.0000682), PLATAFORMA BIOBANCOS PT13/0010/0014, HUB-ICO-IDIBELL Biobankfor providing human tissue, and UAI IRBLleida for management support

Published
2021
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3. Hyperkalemia in Chronic Kidney Disease in the New Era of Kidney Protection Therapies

Author

Pantelis Sarafidis, Alberto Ortiz, Charles J. Ferro, Francesca Mallamaci, Olga Balafa, Jose M. Valdivielso, Patrick Rossignol, Robert Ekart, Patrick B. Mark, Lucia Del Vecchio, Biomedical Research Institute of Lleida [Spain] (IRBLleida), Universitat de Lleida, University of Ioannina, University medical centre Maribor (UKC Maribor), University Hospitals Birmingham [Birmingham, Royaume-Uni], Ospedali Riuniti, Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Aristotle University of Thessaloniki, Sant'Anna Hospital, Universidad Autónoma de Madrid (UAM), Española de Nefrología, FRIAT, and Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. PR is supported by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' program (reference: ANR-15-RHUS-0004), by the French PIA project 'Lorraine Université d’Excellence' (reference: ANR-15-IDEX-04-LUE), the ANR FOCUS-MR (reference: ANR-15-CE14-0032-01), ERA-CVD EXPERT (reference: ANR-16-ECVD-0002-02), Contrat de Plan Etat Lorraine IT2MP and FEDER Lorraine., ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-CE14-0032,MR-focus,Régulation, Diagnostique et Thérapeutique ciblée du récepteur minéralocorticoïde dans le remodelage cardiaque(2015), ANR-16-ECVD-0002,EXPERT,Exploring new pathways in age-related heart diseases(2016), DE CARVALHO, Philippe, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Régulation, Diagnostique et Thérapeutique ciblée du récepteur minéralocorticoïde dans le remodelage cardiaque - - MR-focus2015 - ANR-15-CE14-0032 - AAPG2015 - VALID, and Exploring new pathways in age-related heart diseases - - EXPERT2016 - ANR-16-ECVD-0002 - ERA-CVD - VALID

Subjects
Hyperkalemia, Polymers, [SDV]Life Sciences [q-bio], Disease, urologic and male genital diseases, Bioinformatics, Renin-Angiotensin System, chemistry.chemical_compound, Mineralocorticoid receptor, Pharmacotherapy, medicine, Humans, Pharmacology (medical), Renal Insufficiency, Chronic, Sodium-Glucose Transporter 2 Inhibitors, Mineralocorticoid Receptor Antagonists, Kidney, business.industry, Silicates, Patient Acuity, Metabolic acidosis, Patiromer, medicine.disease, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, chemistry, medicine.symptom, business, Kidney disease
Abstract

International audience; Despite recent therapeutic advances, chronic kidney disease (CKD) is one of the fastest growing global causes of death. This illustrates limitations of current therapeutic approaches and, potentially, unidentified knowledge gaps. For decades, renin-angiotensin-aldosterone system (RAAS) blockers have been the mainstay of therapy for CKD. However, they favor the development of hyperkalemia, which is already common in CKD patients due to the CKD-associated decrease in urinary potassium (K+) excretion and metabolic acidosis. Hyperkalemia may itself be life-threatening as it may trigger potentially lethal arrhythmia, and additionally may limit the prescription of RAAS blockers and lead to low-K+ diets associated to low dietary fiber intake. Indeed, hyperkalemia is associated with adverse kidney, cardiovascular, and survival outcomes. Recently, novel kidney protective therapies, ranging from sodium/glucose cotransporter 2 (SGLT2) inhibitors to new mineralocorticoid receptor antagonists have shown efficacy in clinical trials. Herein, we review K+ pathophysiology and the clinical impact and management of hyperkalemia considering these developments and the availability of the novel K+ binders patiromer and sodium zirconium cyclosilicate, recent results from clinical trials targeting metabolic acidosis (sodium bicarbonate, veverimer), and an increasing understanding of the role of the gut microbiota in health and disease.

Published
2021
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4. Continuous professional development: Elevating sleep and breathing disorder education in europe

Author

MariaR. Bonsignore, Pierantonio Laveneziana, Sophia E. Schiza, Winfried Randerath, Manuel Sánchez-de-la-Torre, Anita K. Simonds, Andrea Aliverti, Schiza S.E., Randerath W., Sanchez-De-la-torre M., Aliverti A., Bonsignore M.R., Simonds A.K., Laveneziana P., Laveneziana, Pierantonio, University of Crete [Heraklion] (UOC), University of Cologne, Biomedical Research Institute of Lleida [Spain] (IRBLleida), Universitat de Lleida, Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Politecnico di Milano [Milan] (POLIMI), Università degli studi di Palermo - University of Palermo, Istituto per la Ricerca e l’Innovazione Biomedica (IRIB), Consiglio Nazionale delle Ricerche (CNR), Royal Brompton and Harefield NHS Foundation Trust, Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département Médico-Universitaire APPROCHES, CHU Tenon [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], education, sleep, professional development, Settore MED/10 - Malattie Dell'Apparato Respiratorio, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Sleep and breathing, Medicine, 030212 general & internal medicine, Continuous Professional Development, lcsh:RC705-779, business.industry, Editorials, lcsh:Diseases of the respiratory system, humanities, 3. Good health, nervous system diseases, respiratory tract diseases, [SDV] Life Sciences [q-bio], 030228 respiratory system, Continuing professional development, business, Bit (key)
Abstract

Sleep and breathing disorders are highly prevalent, representing a growing subspecialty of respiratory medicine. The term sleep disordered breathing (SDB) encompasses a range of conditions characterised by abnormal breathing during sleep, from chronic or habitual snoring, to frank obstructive sleep apnoea (OSA) or, in some cases, central sleep apnoea (CSA) and hypoventilation syndromes. OSA is the commonest form of SDB, leading to many potential consequences and adverse clinical outcomes, including excessive daytime sleepiness, impaired daytime function, metabolic dysfunction, and an increased risk of cardiovascular disease and mortality [1]. The estimated reported prevalence of moderate-to-severe SDB (≥15 events·h−1) was 23.4% in women and 49.7% in men, and the prevalence of symptomatic OSA was 9% and 13%, respectively [2]. However, in some populations, the prevalence of OSA is substantially higher, such as in patients been evaluated for bariatric surgery (estimated range 70–80%), in patients who have had a transient ischaemic attack or stroke (estimated range 60–70%) and in patients with cardiometabolic disease [3–6]. Limited data have been reported on CSA and non-obstructive sleep-related hypoventilation, which have received considerable interest in the sleep field within the past 10 years. Even if their prevalence was noted to be quite low relative to the prevalence of OSA [7], they are quite common in specific subpopulations [8–10]., The @EuroRespSoc launches a new sleep and breathing disorders continuous professional development programme http://bit.ly/30PU01P

Published
2020
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5. SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. A consensus statement by the EURECA-m and the DIABESITY working groups of the ERA-EDTA

Author

Pantelis Sarafidis, Ziad A. Massy, Radovan Hojs, Esteban Porrini, Alberto Ortiz, Khaled Khazim, Denis Fouque, Charles J. Ferro, Jose M. Valdivielso, Carmine Zoccali, Petro Ruggenenti, Andrzej Wiecek, Enrique Morales, Robert Ekart, Jolanta Malyszko, Mads Hornum, Gérard M. London, Francesca Mallamaci, Jaicoa Observatory, Universidad Politécnica de Valencia, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Aristotle University of Thessaloniki, University Hospitals Birmingham [Birmingham, Royaume-Uni], Hospital Universitario 12 de Octubre [Madrid], Universidad Autonoma de Madrid (UAM), Medical University of Warsaw - Poland, University of Maribor, Galilee Medical Center [Nahariya, Israel], Biomedical Research Institute of Lleida [Spain] (IRBLleida), Universitat de Lleida, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Université de Lyon, Centre Hospitalier Manhès [Fleury-Mérogis], Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy], Universidad de La Laguna [Tenerife - SP] (ULL), Hospital Universitario De Canarias, University of Silesia in Katowice, Ospedali riuniti di Reggio Calabria [Reggio Calabria, Italy], Universitat Politècnica de València (UPV), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), CarMeN, laboratoire, Universidad Autónoma de Madrid (UAM), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Blood Glucose, Heart Diseases, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, 030209 endocrinology & metabolism, Disease, 030204 cardiovascular system & hematology, Bioinformatics, Kidney, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, 0302 clinical medicine, Weight loss, Glucagon-Like Peptide 1, Diabetes mellitus, Weight Loss, Medicine, Humans, Hypoglycemic Agents, Renal Insufficiency, Chronic, Sodium-Glucose Transporter 2 Inhibitors, Glucagon-like peptide 1 receptor, ComputingMilieux_MISCELLANEOUS, Societies, Medical, Randomized Controlled Trials as Topic, Cardioprotection, Transplantation, business.industry, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Blood pressure, Diabetes Mellitus, Type 2, Nephrology, Practice Guidelines as Topic, Disease Progression, medicine.symptom, business, Kidney disease
Abstract

Chronic kidney disease (CKD) in patients with diabetes mellitus (DM) is a major problem of public health. Currently, many of these patients experience progression of cardiovascular and renal disease, even when receiving optimal treatment. In previous years, several new drug classes for the treatment of type 2 DM have emerged, including inhibitors of renal sodium–glucose co-transporter-2 (SGLT-2) and glucagon-like peptide-1 (GLP-1) receptor agonists. Apart from reducing glycaemia, these classes were reported to have other beneficial effects for the cardiovascular and renal systems, such as weight loss and blood pressure reduction. Most importantly, in contrast to all previous studies with anti-diabetic agents, a series of recent randomized, placebo-controlled outcome trials showed that SGLT-2 inhibitors and GLP-1 receptor agonists are able to reduce cardiovascular events and all-cause mortality, as well as progression of renal disease, in patients with type 2 DM. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of SGLT-2 inhibitors and GLP-1 analogues, analyses the potential mechanisms involved in these actions and discusses their place in the treatment of patients with CKD and DM.

Published
2018
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6. Activated leukocyte cell adhesion molecule (ALCAM) is a marker of recurrence and promotes cell migration, invasion, and metastasis in early-stage endometrioid endometrial cancer

Author

Devis, Laura, Moiola, Cristian, Masia, Nuria, Martinez-Garcia, Elena, Santacana, Maria, Stirbat, Tomita Vasilica, Brochard-Wyart, Françoise, García, Ángel, Alameda, Francesc, Cabrera, Silvia, Palacios, Jose, Moreno-Bueno, Gema, Abal, Miguel, Thomas, William, Dufour, Sylvie, Matias-Guiu, Xavier, Santamaria, Anna, Reventos, Jaume, Gil-Moreno, Antonio, Colas, Eva, Biomedical Research Group in Gynecology [Barcelona, Spain] (Vall Hebron Research Institute), Universitat Autònoma de Barcelona (UAB)-Vall Hebron Research Institute [Barcelona, Spain], Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Pathology Department [Barcelona, Spain], Vall d'Hebron University Hospital [Barcelona], Department of Pathology [Barcelona, Spain], Hospital del Mar [Barcelona, Spain], Department of Chemistry [Aarhus], Aarhus University [Aarhus], Polytechnical University Madrid, parent, Spanish National Cancer Research Center (CNIO), Translational Laboratory [Santiago de Compostela, Spain] (Medical Oncology Department), Complexo Hospitalario Universitario de Santiago-Servizo Galego de Saude (SERGAS)-Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Department of Natural Sciences [New London, NH, USA] (Colby-Sawyer College), Colby-Sawyer College [New London, NH, USA], Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Eq. 6 - Morphogenèse et génétique moléculaire (Inserm U955 - IMRB), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Arnau de Vilanova University Hospital [Lleida, Spain], Biomedical Research Institute of Lleida [Spain] (IRBLleida), Universitat de Lleida, Cell Cycle and Ovarian Cancer Group, Spain, Vall d’Hebron Research Institute (VHIR)-Biomedical Research Unit in Gynecology, Spain, Basic Sciences Department [Barcelona, Spain], Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)-International University of Catalonia [Barcelona, Spain], and Gynecological Oncology Department [Barcelona, Spain]

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

Endometrial cancer is the most common gynaecological cancer in western countries, being the most common subtype of endometrioid tumours. Most patients are diagnosed at an early stage and present an excellent prognosis. However, a number of those continue to suffer recurrence, without means of identification by risk classification systems. Thus, finding a reliable marker to predict recurrence becomes an important unmet clinical issue. ALCAM is a cell–cell adhesion molecule and member of the immunoglobulin superfamily that has been associated with the genesis of many cancers. Here, we first determined the value of ALCAM as a marker of recurrence in endometrioid endometrial cancer by conducting a retrospective multicentre study of 174 primary tumours. In early-stage patients (N = 134), recurrence-free survival was poorer in patients with ALCAM-positive compared to ALCAM-negative tumours (HR 4.237; 95% CI 1.01–17.76). This difference was more significant in patients with early-stage moderately–poorly differentiated tumours (HR 9.259; 95% CI 2.12–53.47). In multivariate analysis, ALCAM positivity was an independent prognostic factor in early-stage disease (HR 6.027; 95% CI 1.41–25.74). Then we demonstrated in vitro a role for ALCAM in cell migration and invasion by using a loss-of-function model in two endometrial cancer cell lines. ALCAM depletion resulted in a reduced primary tumour size and reduced metastatic local spread in an orthotopic murine model. Gene expression analysis of ALCAM-depleted cell lines pointed to motility, invasiveness, cellular assembly, and organization as the most deregulated functions. Finally, we assessed some of the downstream effector genes that are involved in ALCAM-mediated cell migration; specifically FLNB, TXNRD1, and LAMC2 were validated at the mRNA and protein level. In conclusion, our results highlight the potential of ALCAM as a recurrent biomarker in early-stage endometrioid endometrial cancer and point to ALCAM as an important molecule in endometrial cancer dissemination by regulating cell migration, invasion, and metastasis.

Published
2017
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7. A Unified Nomenclature and Amino Acid Numbering for Human PTEN

Author

Seong-Seng Tan, Ramon Parsons, Nicholas K. Tonks, Paolo Pinton, Nicolas Wolff, Vrushank Davé, Rafael Malagoli Rocha, Britta J. Eickholt, Seung-Rock Lee, Rudiger Woscholski, Suzanne J. Baker, Arne Gericke, Hong Wu, Frank B. Furnari, Rafael Pulido, Maria Magdalena Georgescu, Jeroen den Hertog, Mathias Lösche, Benjamin D. Hopkins, Bangyan L. Stiles, María Molina, Manuel S. Rodriguez, João T. Barata, Manuel Serrano, Xeujun Jiang, Arkaitz Carracedo, Prerna Malaney, Xavier Matias-Guiu, Peter N. Devreotes, Vuk Stambolic, Akira Suzuki, Ian D. Chin-Sang, Víctor J. Cid, Lloyd C. Trotman, Charis Eng, Alonzo H. Ross, Nick R. Leslie, Pier Paolo Pandolfi, Carmen Rivas, BioCruces Research Institute, University of the Basque Country [Bizkaia] (UPV/EHU)-Hospital Universitario Cruces = Cruces University Hospital, Ikerbasque - Basque Foundation for Science, St Jude Children's Research Hospital, Instituto de Medicina Molecular (iMM), Faculdade de Medicina [Lisboa], Universidade de Lisboa (ULISBOA)-Universidade de Lisboa (ULISBOA), CIC BioGUNE, CIC Spain, University of the Basque Country [Bizkaia] (UPV/EHU), Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain] (IRYCIS), Universidad de Alcalá - University of Alcalá (UAH), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Queen's University [Kingston, Canada], H. Lee Moffitt Cancer Center and Research Institute, Morsani College of Medicine [Tampa, USA], University of South Florida [Tampa] (USF), Hubrecht Institute [Utrecht, Netherlands], University Medical Center [Utrecht]-Royal Netherlands Academy of Arts and Sciences (KNAW), Institute Biology Leiden (IBL), Universiteit Leiden [Leiden], Johns Hopkins University School of Medicine [Baltimore], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genomic Medicine Institute [Cleveland], Cleveland Clinic, School of medicine [Cleveland, USA], Case Western Reserve University [Cleveland], Ludwig Institute for Cancer Research, University of Texas Southwestern Medical Center [Dallas], Worcester Polytechnic Institute, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Memorial Sloane Kettering Cancer Center [New York], Chonnam National University Medical School [Gwangju, South Korea], Chonnam National University [Gwangju], Carnegie Mellon University [Pittsburgh] (CMU), National Institute of Standards and Technology [Gaithersburg] (NIST), Arnau de Vilanova University Hospital [Lleida, Spain], Biomedical Research Institute of Lleida [Spain] (IRBLleida), Universitat de Lleida, Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Università degli Studi di Ferrara (UniFE), Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Biocomputing Unit [Madrid], Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas [Barcelona, Spain] (CiMUS-US), Universidade de Santiago de Compostela [Spain] (USC ), Instituto de Investigaciones Sanitarias, A. C. Camargo Hospital [São Paulo], Inbiomed [Spain], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Spanish National Cancer Research Center (CNIO), University of Toronto, Princess Margaret Hospital, University Health Network, School of Pharmacy [USC, Los Angeles], University of Southern California (USC), Graduate School of Medicine [Akita, Japan], Akita University, University of Melbourne, Cold Spring Harbor Laboratory (CSHL), Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry [Imperial College London], Imperial College London, University of California [Los Angeles] (UCLA), University of California, Peking University [Beijing], Heriot-Watt University [Edinburgh] (HWU), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU)-Hospital Universitario Cruces = Cruces University Hospital, Universidade de Lisboa = University of Lisbon (ULISBOA)-Universidade de Lisboa = University of Lisbon (ULISBOA), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Universiteit Leiden, Università degli Studi di Ferrara = University of Ferrara (UniFE), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of California (UC), Hubrecht Institute for Developmental Biology and Stem Cell Research, and Repositório da Universidade de Lisboa

Subjects
MESH: Databases, Protein, MESH: Terminology as Topic, MESH: Amino Acids, MESH: Codon, Initiator, [SDV]Life Sciences [q-bio], Phosphatase, Codon, Initiator, ComputingMilieux_LEGALASPECTSOFCOMPUTING, MESH: Amino Acid Sequence, Oncogenicity, Biochemistry, MESH: PTEN Phosphohydrolase, Germline, Article, Terminology as Topic, PTEN, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Amino Acids, Databases, Protein, Molecular Biology, Gene, Peptide sequence, PI3K/AKT/mTOR pathway, Genetics, chemistry.chemical_classification, MESH: Humans, biology, PTEN Phosphohydrolase, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, 3. Good health, Amino acid, ComputingMilieux_GENERAL, chemistry, Cancer research, biology.protein
Abstract

© Copyright 2015 by the American Association for the Advancement of Science; all rights reserved., The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line of patients with tumor predisposition or with neurological or cognitive disorders, which makes the PTEN gene and protein a major focus of interest in current biomedical research. After almost two decades of intense investigation on the 403-residue-long PTEN protein, a previously uncharacterized form of PTEN has been discovered that contains 173 amino-terminal extra amino acids, as a result of an alternate translation initiation site. To facilitate research in the field and to avoid ambiguities in the naming and identification of PTEN amino acids from publications and databases, we propose here a unifying nomenclature and amino acid numbering for this longer form of PTEN.

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