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1. GeSnOI mid-infrared laser technology

Author

Jean-Michel Hartmann, Nicolas Pauc, Emilie Sakat, Frederic Boeuf, Jérémie Chrétien, Julien Chaste, Vincent Calvo, Alexei Chelnokov, Moustafa El Kurdi, Marvin Frauenrath, Vincent Reboud, Maksym Gromovyi, Andjelika Bjelajac, Binbin Wang, Gilles Patriarche, Etienne Herth, Philippe Boucaud, Centre de Nanosciences et de Nanotechnologies (C2N), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'hétéroepitaxie et ses applications (CRHEA), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), STMicroelectronics [Crolles] (ST-CROLLES), PHotonique, ELectronique et Ingénierie QuantiqueS (PHELIQS), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Laboratoire Charles Fabry / Nanophotonique, Laboratoire Charles Fabry (LCF), Institut d'Optique Graduate School (IOGS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut d'Optique Graduate School (IOGS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), STMicroelectronics, Département de Nanophysique (DEPHY), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), and ANR-17-CE24-0015,ELEGANTE,Laser GeSn sur silicium sous pompagae électrique(2017)

Subjects
Materials science, Silicon, Silicon photonics, photonics, chemistry.chemical_element, Laser, 02 engineering and technology, Substrate (electronics), 01 natural sciences, Article, law.invention, Semiconductor laser theory, 010309 optics, Resonator, [SPI]Engineering Sciences [physics], law, 0103 physical sciences, Applied optics. Photonics, [PHYS.COND]Physics [physics]/Condensed Matter [cond-mat], 1234567890(), Semiconductor lasers, [PHYS]Physics [physics], business.industry, Integrated optics, QC350-467, Optics. Light, 021001 nanoscience & nanotechnology, Atomic and Molecular Physics, and Optics, Electronic, Optical and Magnetic Materials, TA1501-1820, Microresonators, GeSn, Semiconductor, microdisks, chemistry, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, Optoelectronics, Whispering-gallery wave, Photonics, 0210 nano-technology, business
Abstract

GeSn alloys are promising materials for CMOS-compatible mid-infrared lasers manufacturing. Indeed, Sn alloying and tensile strain can transform them into direct bandgap semiconductors. This growing laser technology however suffers from a number of limitations, such as poor optical confinement, lack of strain, thermal, and defects management, all of which are poorly discussed in the literature. Herein, a specific GeSn-on-insulator (GeSnOI) stack using stressor layers as dielectric optical claddings is demonstrated to be suitable for a monolithically integration of planar Group-IV semiconductor lasers on a versatile photonic platform for the near- and mid-infrared spectral range. Microdisk-shape resonators on mesa structures were fabricated from GeSnOI, after bonding a Ge0.9Sn0.1 alloy layer grown on a Ge strain-relaxed-buffer, itself on a Si(001) substrate. The GeSnOI microdisk mesas exhibited significantly improved optical gain as compared to that of conventional suspended microdisk resonators formed from the as-grown layer. We further show enhanced vertical out-coupling of the disk whispering gallery mode in-plane radiation, with up to 30% vertical out-coupling efficiency. As a result, the GeSnOI approach can be a valuable asset in the development of silicon-based mid-infrared photonics that combine integrated sources in a photonic platform with complex lightwave engineering.

Published
2021
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2. Comprehensive Review of AL amyloidosis: some practical recommendations

Author

Florent Malard, Jean-Luc Harousseau, Ali Bazarbachi, Abdul Hamid Bazarbachi, Mohamad Mohty, Rama Al Hamed, Albert Einstein College of Medicine [New York], American University of Beirut [Beyrouth] (AUB), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, CRLCC René Gauducheau, Gestionnaire, Hal Sorbonne Université, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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
Oncology, medicine.medical_specialty, Amyloid, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Review Article, Plasma cell, Transplantation, Autologous, Bortezomib, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, Internal medicine, medicine, AL amyloidosis, Animals, Humans, Immunoglobulin Light-chain Amyloidosis, 1234567890(), RC254-282, business.industry, Amyloidosis, Daratumumab, Disease Management, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Hematology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Combination drug therapy, Disease Presentation, 030220 oncology & carcinogenesis, Immunotherapy, Neoplasm Recurrence, Local, business, Haematological diseases, 030215 immunology, medicine.drug, Stem Cell Transplantation
Abstract

Amyloid light chain (AL) amyloidosis is among the more common and more severe of the amyloidoses usually involving the slow proliferation of a bone-marrow-residing plasma cell (PC) clone and the secretion of unstable immunoglobulin-free light chains (FLC) that infiltrate peripheral tissues and result in detrimental end-organ damage. Disease presentation is rather vague, and the hallmark of treatment is early diagnosis before irreversible end-organ damage. Once diagnosed, treatment decision is transplant-driven whereby ~20% of patients are eligible for autologous stem cell transplantation (ASCT) with or without bortezomib-based induction. In the setting of ASCT-ineligibility, bortezomib plays a central role in upfront treatment with the recent addition of daratumumab to the current emerging standard of care. In general, management of AL amyloidosis is aimed at achieving deep, durable responses with very close monitoring for early detection of relapse/refractory disease. This article provides a comprehensive review of the management of patients with AL amyloidosis including goals of therapy, current treatment guidelines in the setting of both ASCT-eligibility and ineligibility, treatment response monitoring recommendations, toxicity management, and treatment of relapse/refractory disease.

Published
2021
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3. Mesopelagic microbial carbon production correlates with diversity across different marine particle fractions

Author

Christian Tamburini, Fabrice Armougom, Hans-Peter Grossart, Sophie Guasco, Frédéric A. C. Le Moigne, Virginie Riou, Marc Garel, Chloé M. J. Baumas, Nagib Bhairy, Institut méditerranéen d'océanologie (MIO), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Toulon (UTLN), and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Geologic Sediments, Mesopelagic zone, Heterotroph, chemistry.chemical_element, Biology, Microbiology, Article, Microbial ecology, 03 medical and health sciences, 1234567890(), Seawater, Ecosystem, 14. Life underwater, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Marine snow, [SDU.OCEAN]Sciences of the Universe [physics]/Ocean, Atmosphere, Total organic carbon, 0303 health sciences, Carbon dioxide in Earth's atmosphere, 030306 microbiology, Ecology, Heterotrophic Processes, Biogeochemistry, 15. Life on land, Prokaryotic Cells, chemistry, 13. Climate action, Species richness, Carbon
Abstract

The vertical flux of marine snow particles significantly reduces atmospheric carbon dioxide concentration. In the mesopelagic zone, a large proportion of the organic carbon carried by sinking particles dissipates thereby escaping long term sequestration. Particle associated prokaryotes are largely responsible for such organic carbon loss. However, links between this important ecosystem flux and ecological processes such as community development of prokaryotes on different particle fractions (sinking vs. non-sinking) are yet virtually unknown. This prevents accurate predictions of mesopelagic organic carbon loss in response to changing ocean dynamics. Using combined measurements of prokaryotic heterotrophic production rates and species richness in the North Atlantic, we reveal that carbon loss rates and associated microbial richness are drastically different with particle fractions. Our results demonstrate a strong negative correlation between prokaryotic carbon losses and species richness. Such a trend may be related to prokaryotes detaching from fast-sinking particles constantly enriching non-sinking associated communities in the mesopelagic zone. Existing global scale data suggest this negative correlation is a widespread feature of mesopelagic microbes.

Published
2021
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4. Preclinical pharmacology of a lipophenol in a mouse model of light-induced retinopathy

Author

Nicolas Pinquier, Philippe Brabet, Joseph Vercauteren, Céline Crauste, Nicolas Taveau, David Cia, Thierry Durand, Vasiliki Kalatzis, Espérance Moine, Laurent Guillou, Aurélie Cubizolle, Crauste, Céline, APPEL À PROJETS GÉNÉRIQUE 2018 - Les lipohenols de nouveaux anti-oxydants et stresseurs carbonylés pour combattre la dégénérescence maculaire - - LipoPheRet2018 - ANR-18-CE18-0017 - AAPG2018 - VALID, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), SATT AxLR, ANR-18-CE18-0017,LipoPheRet,Les lipohenols de nouveaux anti-oxydants et stresseurs carbonylés pour combattre la dégénérescence maculaire(2018), and Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM)

Subjects
0301 basic medicine, Retinal degeneration, Light, genetic structures, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Pharmacology, medicine.disease_cause, Biochemistry, 0302 clinical medicine, 1234567890(), Mice, Knockout, Retinal Degeneration, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Medicine, Molecular Medicine, Disease Susceptibility, Tomography, Optical Coherence, Visual phototransduction, Retinopathy, cis-trans-Isomerases, Docosahexaenoic Acids, QD415-436, Phloroglucinol, Biologics, Retina, Article, Retinoids, 03 medical and health sciences, Phenols, Retinal Diseases, In vivo, Electroretinography, medicine, Animals, Molecular Biology, business.industry, Macular degeneration, medicine.disease, eye diseases, Mice, Inbred C57BL, Disease Models, Animal, Kinetics, 030104 developmental biology, RPE65, 030221 ophthalmology & optometry, sense organs, business, Oxidative stress
Abstract

Environmental light has deleterious effects on the outer retina in human retinopathies, such as ABCA4-related Stargardt’s disease and dry age-related macular degeneration. These effects involve carbonyl and oxidative stress, which contribute to retinal cell death and vision loss. Here, we used an albino Abca4−/− mouse model, the outer retina of which shows susceptibility to acute photodamage, to test the protective efficacy of a new polyunsaturated fatty acid lipophenol derivative. Anatomical and functional analyses demonstrated that a single intravenous injection of isopropyl-phloroglucinol-DHA, termed IP-DHA, dose-dependently decreased light-induced photoreceptor degeneration and preserved visual sensitivity. This protective effect persisted for 3 months. IP-DHA did not affect the kinetics of the visual cycle in vivo or the activity of the RPE65 isomerase in vitro. Moreover, IP-DHA administered by oral gavage showed significant protection of photoreceptors against acute light damage. In conclusion, short-term tests in Abca4-deficient mice, following single-dose administration and light exposure, identify IP-DHA as a therapeutic agent for the prevention of retinal degeneration., Experimental & Molecular Medicine: Vision loss: Shedding light on how to prevent retinal damage Treating retinal damage in both aging and young patients might now be easier, thanks to treatment with a lipophenol, an omega-3 fatty acid linked to an antioxidant. The retina is the part of the eye that senses light, aided by light-sensitive pigments. However, these light-sensitive pigments can be converted by light to toxic byproducts, and in some individuals, these toxic byproducts can accumulate, damaging the retina and leading to vision loss. Philippe Brabet at the Montpellier Institute of Neuroscience in France and co-workers found that lipophenol treatment protected retinal cells from damage in a mouse model of retinal disease, and that a single dose has been effective in preserving vision. These results may help in finding new treatments for retinal diseases such as Stargardt disease and age-related macular degeneration.

Published
2020
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5. The domestication of Cucurbita argyrosperma as revealed by the genome of its wild relative

Author

Gabriela Castellanos-Morales, Erika Aguirre-Planter, Yocelyn T. Gutiérrez-Guerrero, Rafael Lira-Saade, Guillermo Sánchez-de la Vega, Josué Barrera-Redondo, Luis E. Eguiarte, Jonás A. Aguirre-Liguori, Xitlali Aguirre-Dugua, Maud I. Tenaillon, Instituto de Ecologia, Universidad Nacional Autónoma de México (UNAM), Génétique Quantitative et Evolution - Le Moulon (Génétique Végétale) (GQE-Le Moulon), and AgroParisTech-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0106 biological sciences, 0301 basic medicine, Cucurbita argyrosperma, Plant domestication, Population genetics, Introgression, Plant Science, Horticulture, Subspecies, 01 natural sciences, Biochemistry, Article, Gene flow, 03 medical and health sciences, Genetics, Cucurbita, Domestication, 1234567890(), 2. Zero hunger, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], biology, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], food and beverages, Genomics, biology.organism_classification, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], humanities, 030104 developmental biology, Evolutionary biology, Cucurbita moschata, Gourd, 010606 plant biology & botany, Biotechnology
Abstract

Despite their economic importance and well-characterized domestication syndrome, the genomic impact of domestication and the identification of variants underlying the domestication traits in Cucurbita species (pumpkins and squashes) is currently lacking. Cucurbita argyrosperma, also known as cushaw pumpkin or silver-seed gourd, is a Mexican crop consumed primarily for its seeds rather than fruit flesh. This makes it a good model to study Cucurbita domestication, as seeds were an essential component of early Mesoamerican diet and likely the first targets of human-guided selection in pumpkins and squashes. We obtained population-level data using tunable Genotype by Sequencing libraries for 192 individuals of the wild and domesticated subspecies of C. argyrosperma across Mexico. We also assembled the first high-quality wild Cucurbita genome. Comparative genomic analyses revealed several structural variants and presence/absence of genes related to domestication. Our results indicate a monophyletic origin of this domesticated crop in the lowlands of Jalisco. We found evidence of gene flow between the domesticated and wild subspecies, which likely alleviated the effects of the domestication bottleneck. We uncovered candidate domestication genes that are involved in the regulation of growth hormones, plant defense mechanisms, seed development, and germination. The presence of shared selected alleles with the closely related species Cucurbita moschata suggests domestication-related introgression between both taxa.

Published
2021
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6. Morphological studies of rose prickles provide new insights

Author

Laurence Hibrand-Saint Oyant, Tatiana Thouroude, Fabienne Simonneau, Fabrice Foucher, Ningning Zhou, Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), SFR UA 4207 QUAlité et SAnté du Végétal (QUASAV), Université d'Angers (UA)-Université de Nantes (UN)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Ecole supérieure d'Agricultures d'Angers (ESA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), National Natural Science Foundation of China (NSFC), China Scholarship Council, 2017-3109., National Natural Science Foundation of China (NSFC) : 31760585, and China Scholarship Council : [2017]3109.

Subjects
0106 biological sciences, Population, Gland cell, Plant Science, Horticulture, Biology, 01 natural sciences, Biochemistry, Article, 03 medical and health sciences, Botany, Genetics, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, 1234567890(), education, 030304 developmental biology, 0303 health sciences, Developmental stage, education.field_of_study, Plant morphogenesis, Non-model organisms, Meristem, Trichome, [SDV.BV.AP]Life Sciences [q-bio]/Vegetal Biology/Plant breeding, 010606 plant biology & botany, Biotechnology
Abstract

Prickles are common structures in plants that play a key role in defense against herbivores. In theRosagenus, prickles are widely present with great diversity in terms of form and density. For cut rose production, prickles represent an important issue, as they can damage the flower and injure workers. Our objectives were to precisely describe the types of prickles that exist in roses, their tissues of origin and their development. We performed a detailed histological analysis of prickle initiation and development in a rose F1 population. Based on the prickle investigation of 110 roses, we proposed the first categorization of prickles in theRosagenus. They are mainly divided into two categories, nonglandular prickles (NGPs) and glandular prickles (GPs), and subcategories were defined based on the presence/absence of hairs and branches. We demonstrated that NGPs and GPs both originate from multiple cells of the ground meristem beneath the protoderm. For GPs, the gland cells originate from the protoderm of the GP at the early developmental stage. Our findings clearly demonstrate that prickles are not modified trichomes (which originate from the protoderm). These conclusions are different from the current mainstream hypothesis. These results provide a foundation for further studies on prickle initiation and development in plants.

Published
2021
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7. Exercise-induced sudden cardiac death is caused by mitochondrio-nuclear translocation of AIF

Author

Abdellatif, Mahmoud, Kroemer, Guido, Medical University Graz, Institut Gustave Roussy (IGR), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska Institutet [Stockholm], Gestionnaire, Hal Sorbonne Université, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)

Subjects
Cell Death, Calpain, lcsh:Cytology, [SDV]Life Sciences [q-bio], Comment, Apoptosis Inducing Factor, Apoptosis, Arrhythmias, Mitochondria, [SDV] Life Sciences [q-bio], Mice, Physical Conditioning, Animal, Necroptosis, Animals, Myocytes, Cardiac, lcsh:QH573-671, Cardiomyopathies, 1234567890(), ComputingMilieux_MISCELLANEOUS
Abstract

Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (

Published
2021
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8. Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis

Author

Piu Chan, Ronald Melki, Yong Tang, Jia-Yi Li, Jian Jun Guo, Feng Yue, Chuang Guo, Dong-Yan Song, Lin Yuan, Xin Liang, Luc Bousset, Wen Li, Jing Tang, Northeastern University [Shenyang], Peking University [Beijing], Centre National de la Recherche Scientifique (CNRS), Chongqing Medical University, Shenzhen Univerisity [Shenzhen], Molecular Imaging Research Center [Fontenay-aux-Roses] (MIRCen), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and ANR-17-JPCD-0002-02 - TransPathND- ANR-17-JPCD-0005-01 - Protest-70

Subjects
0301 basic medicine, Male, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Parkinson's disease, Immunology, Substantia nigra, Article, Midbrain, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, medicine, Animals, Humans, lcsh:QH573-671, 1234567890(), Neuroinflammation, Administration, Intranasal, chemistry.chemical_classification, Tyrosine hydroxylase, lcsh:Cytology, Putamen, Dopaminergic, Parkinson Disease, Cell Biology, Substantia Nigra, Macaca fascicularis, 030104 developmental biology, Endocrinology, Globus pallidus, chemistry, nervous system, Transferrin, alpha-Synuclein, Microglia, 030217 neurology & neurosurgery
Abstract

Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.

Published
2020
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9. Phosphorylation of eukaryotic initiation factor-2α (eIF2α) in autophagy

Author

Friedemann Loos, Marion Leduc, Juliette Humeau, Guido Kroemer, Giulia Cerrato, Oliver Kepp, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Gustave Roussy (IGR), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska Institutet [Stockholm], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and Gestionnaire, Hal Sorbonne Université

Subjects
Cancer Research, [SDV]Life Sciences [q-bio], Immunology, Phosphatase, Mutant, Eukaryotic Initiation Factor-2, Article, Serine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, eIF-2 Kinase, 0302 clinical medicine, Eukaryotic initiation factor, Cell Line, Tumor, Macroautophagy, Autophagy, Integrated stress response, Animals, Humans, lcsh:QH573-671, Phosphorylation, 1234567890(), 030304 developmental biology, 0303 health sciences, lcsh:Cytology, Kinase, Chemistry, Cell Biology, Phosphoric Monoester Hydrolases, Cell biology, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Cell signalling
Abstract

The integrated stress response is characterized by the phosphorylation of eukaryotic initiation factor-2α (eIF2α) on serine 51 by one out of four specific kinases (EIF2AK1 to 4). Here we provide three series of evidence suggesting that macroautophagy (to which we refer to as autophagy) induced by a variety of distinct pharmacological agents generally requires this phosphorylation event. First, the induction of autophagic puncta by various distinct compounds was accompanied by eIF2α phosphorylation on serine 51. Second, the modulation of autophagy by >30 chemically unrelated agents was partially inhibited in cells expressing a non-phosphorylable (S51A) mutant of eIF2α or lacking all four eIF2α kinases, although distinct kinases were involved in the response to different autophagy inducers. Third, inhibition of eIF2α phosphatases was sufficient to stimulate autophagy. In synthesis, it appears that eIF2α phosphorylation is a central event for the stimulation of autophagy.

Published
2020
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10. Stratification and prediction of remission in first-episode psychosis patients: the OPTiMiSE cohort study

Author

Martinuzzi, E, Barbosa, S, Daoudlarian, D, Bel Haj Ali, W, Gilet, C, Fillatre, L, Khalfallah, O, Troudet, R, Jamain, S, Fond, G, Sommer, I, Leucht, S, Dazzan, P, McGuire, P, Arango, C, Diaz-Caneja, CM, Fleischhacker, W, Rujescu, D, Glenthøj, B, Winter, I, Kahn, RS, Yolken, R, Lewis, S, Drake, R, Davidovic, L, Leboyer, M, Glaichenhaus, N, OPTiMiSE Study Group, De Hert, Marc, Diabète de Type 1 : mécanismes et traitements immunologiques, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia-Antipolis (I3S) / Equipe IMAGES-CREATIVE, Signal, Images et Systèmes (Laboratoire I3S - SIS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia-Antipolis (I3S) / Projet MEDIACODING, 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), INSERM U955, équipe 15, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Réseau de coopération scientifique en santé mentale, Fondation FondaMental [Créteil]-Fondation FondaMental [Créteil]-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), Brain Centre Rudolf Magnus [Utrecht], University Medical Center [Utrecht], Psychological Medicine, Psychiatry Department, Adolescent Unit, Hospital General Universitario Gregorio Marañón, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Stanley Laboratory of Developmental Neurovirology, Johns Hopkins University Medical Center, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Immunologie des muqueuses et inflammation, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Réseau de coopération scientifique en santé mentale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
0301 basic medicine, Male, Pediatrics, SYMPTOMS, Internationality, ComputerSystemsOrganization_COMPUTERSYSTEMIMPLEMENTATION, Physiology, [SDV]Life Sciences [q-bio], law.invention, Cohort Studies, 0302 clinical medicine, Randomized controlled trial, law, 1234567890(), ComputingMilieux_MISCELLANEOUS, Inflammation/metabolism, NONSTEROIDAL ANTIINFLAMMATORY DRUGS, ASSOCIATION, ddc, 3. Good health, Psychiatry and Mental health, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Cytokines, Female, Biological psychiatry, Antipsychotic Agents, Cohort study, Adult, medicine.medical_specialty, Treatment response, TheoryofComputation_COMPUTATIONBYABSTRACTDEVICES, Adolescent, MEDLINE, 1ST EPISODE, SCHIZOPHRENIA-PATIENTS, Cytokines/blood, Article, lcsh:RC321-571, CYTOKINE ALTERATIONS, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, First episode psychosis, MENTAL-DISORDERS, medicine, Humans, AGENTS, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Nicolas Glaichenhaus 1234567890(), Biological Psychiatry, TREATMENT RESPONSE, Inflammation, Psychiatric Status Rating Scales, INTERLEUKIN-15, business.industry, Correction, Psychotic Disorders/blood, 030104 developmental biology, Logistic Models, Psychotic Disorders, Multicenter study, Marion Leboyer, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Psychiatric status rating scales, business, Biomarkers, 030217 neurology & neurosurgery, Antipsychotic Agents/therapeutic use, Biomarkers/blood
Abstract

Early response to first-line antipsychotic treatments is strongly associated with positive long-term symptomatic and functional outcome in psychosis. Unfortunately, attempts to identify reliable predictors of treatment response in first-episode psychosis (FEP) patients have not yet been successful. One reason for this could be that FEP patients are highly heterogeneous in terms of symptom expression and underlying disease biological mechanisms, thereby impeding the identification of one-size-fits-all predictors of treatment response. We have used a clustering approach to stratify 325 FEP patients into four clinical subtypes, termed C1A, C1B, C2A and C2B, based on their symptoms assessed using the Positive and Negative Syndrome Scale (PANSS) scale. Compared to C1B, C2A and C2B patients, those from the C1A subtype exhibited the most severe symptoms and were the most at risk of being non-remitters when treated with the second-generation antipsychotic drug amisulpride. Before treatment, C1A patients exhibited higher serum levels of several pro-inflammatory cytokines and inflammation-associated biomarkers therefore validating our stratification approach on external biological measures. Most importantly, in the C1A subtype, but not others, lower serum levels of interleukin (IL)-15, higher serum levels of C-X-C motif chemokine 12 (CXCL12), previous exposure to cytomegalovirus (CMV), use of recreational drugs and being younger were all associated with higher odds of being non-remitters 4 weeks after treatment. The predictive value of this model was good (mean area under the curve (AUC) = 0.73 ± 0.10), and its specificity and sensitivity were 45 ± 0.09% and 83 ± 0.03%, respectively. Further validation and replication of these results in clinical trials would pave the way for the development of a blood-based assisted clinical decision support system in psychosis. ispartof: Translational Psychiatry vol:9 issue:1 pages:1-20 ispartof: location:United States status: published

Published
2019
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11. Iron chelation by curcumin suppresses both curcumin-induced autophagy and cell death together with iron overload neoplastic transformation

Author

Patrice X. Petit, Gaël Nicolas, Franck Sureau, Aoula Moustapha, Ana Šarić, Nathan E. Rainey, Saints-Pères Paris Institute for Neurosciences (SPINN - UMR 8003), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Molecular Medicine [Zagreb, Croatia], Rudjer Boskovic Institute [Zagreb], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Jean PERRIN, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Sureau, Franck, Saints-Pères Paris Institute for Neurosciences (SPPIN - UMR 8003), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Laboratoire Jean Perrin (LJP), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cell death, Cancer Research, Programmed cell death, Cell biology, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], lcsh:RC254-282, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Mitophagy, medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Neoplastic transformation, lcsh:QH573-671, 1234567890(), biology, lcsh:Cytology, Autophagy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Deferoxamine, Ferritin, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Hereditary hemochromatosis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Curcumin, biology.protein, medicine.drug
Abstract

Abstract Iron overload, notably caused by hereditary hemochromatosis, is an excess storage of iron in various organs that causes tissue damage and may promote tumorigenesis. To manage that disorder, free iron depletion can be induced by iron chelators like deferoxamine that are of increasing interest also in the cancer field since iron stock could be a potent target for managing tumorigenesis. Curcumin, a well-known active substance extracted from the turmeric rhizome, destabilizes endoplasmic reticulum, and secondarily lysosomes, thereby increasing mitophagy/autophagy and subsequent apoptosis. Recent findings show that cells treated with curcumin also exhibit a decrease in ferritin, which is consistent with its chemical structure and iron chelating activity. Here we investigated how curcumin influences the intracellular effects of iron overload via Fe-nitriloacetic acid or ferric ammonium citrate loading in Huh-7 cells and explored the consequences in terms of antioxidant activity, autophagy, and apoptotic signal transduction. In experiments with T51B and RL-34 epithelial cells, we have found evidence that curcumin-iron complexation abolishes both curcumin-induced autophagy and apoptosis, together with the tumorigenic action of iron overload.

Published
2019
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12. Thymine DNA glycosylase as a novel target for melanoma

Author

Dorjbal Dorjsuren, Guillaume Davidson, Karthik Devarajan, Jaroslav Jelinek, Irwin Davidson, Rossella Tricarico, Timothy J. Yen, Anton Simeonov, Margret B. Einarson, Neil Beeharry, Joseph R. Testa, Vikram Bhattacharjee, Antonio Giordano, Laura Cosentino, Robert W. Sobol, Richard A. Katz, Yuwaraj Kadariya, Pietro Mancuso, Lionel Larue, Hongmao Sun, Emmanuelle Nicolas, Alfonso Bellacosa, Jadavpur University, MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Fox Chase Cancer Center, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, and Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Cancer Research, DNA repair, Melanoma, Experimental, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, SCID, Biology, Article, 03 medical and health sciences, Cytosine, 0302 clinical medicine, 1234567890(), Cell Line, Tumor, Genetics, medicine, Animals, Humans, Molecular Targeted Therapy, Enzyme Inhibitors, Molecular Biology, Melanoma, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Mice, Knockout, Cell Cycle, Base excision repair, Cell cycle, DNA Methylation, medicine.disease, Xenograft Model Antitumor Assays, Thymine DNA Glycosylase, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, DNA demethylation, 030220 oncology & carcinogenesis, Cancer cell, DNA methylation, Cancer research, Female, Thymine-DNA glycosylase
Abstract

Melanoma is an aggressive neoplasm with increasing incidence that is classified by the NCI as a recalcitrant cancer, i.e., a cancer with poor prognosis, lacking progress in diagnosis and treatment. In addition to conventional therapy, melanoma treatment is currently based on targeting the BRAF/MEK/ERK signaling pathway and immune checkpoints. As drug resistance remains a major obstacle to treatment success, advanced therapeutic approaches based on novel targets are still urgently needed. We reasoned that the base excision repair enzyme thymine DNA glycosylase (TDG) could be such a target for its dual role in safeguarding the genome and the epigenome, by performing the last of the multiple steps in DNA demethylation. Here we show that TDG knockdown in melanoma cell lines causes cell cycle arrest, senescence, and death by mitotic alterations; alters the transcriptome and methylome; and impairs xenograft tumor formation. Importantly, untransformed melanocytes are minimally affected by TDG knockdown, and adult mice with conditional knockout of Tdg are viable. Candidate TDG inhibitors, identified through a high-throughput fluorescence-based screen, reduced viability and clonogenic capacity of melanoma cell lines and increased cellular levels of 5-carboxylcytosine, the last intermediate in DNA demethylation, indicating successful on-target activity. These findings suggest that TDG may provide critical functions specific to cancer cells that make it a highly suitable anti-melanoma drug target. By potentially disrupting both DNA repair and the epigenetic state, targeting TDG may represent a completely new approach to melanoma therapy.

Published
2019
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13. Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation

Author

Marchal, Claire, de Dieuleveult, Maud, Saint-Ruf, Claude, Guinot, Nadège, Ferry, Laure, Olalla Saad, Sara T., Lazarini, Mariana, Defossez, Pierre-Antoine, Miotto, Benoit, Miotto, Benoit, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Hematology and Blood Transfusion Center [Campinas, Brazil], University of Campinas/Hemocentro-Unicamp [Campinas, Brazil] -Instituto Nacional de Ciência e Tecnologia do Sangue [Campinas, Brazil], Department of Biological Sciences [Diadema, Brazil], Federal University of Sao Paulo (Unifesp), This work was supported by grants from Electricité de France (#123518) and Ligue Contre le Cancer - Comité de Paris (RS11/75-81, RS12/75/95-21, RS13/75-59). Work of B.M. is supported by FP7 Marie Curie action (PIRG07-GA-2010-268448), Fondation pour la Recherche Médicale (AJE20151234749), Institut National du Cancer-Plan Cancer (ASC15018KSA) and Institut Cochin (POC2016). PAD was supported by grants from Fondation ARC (Projet 2014), Ligue contre le cancer – Comité de Paris, and Institut National du Cancer (PLBIO 2015_1-PLBIO-01-DRA-1). ML and STOS are supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), and Instituto Nacional de Ciência e Tecnologia do Sangue [Campinas, Brazil]-University of Campinas/Hemocentro-Unicamp [Campinas, Brazil]

Subjects
[SDV] Life Sciences [q-bio], [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV]Life Sciences [q-bio], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 1234567890(), lcsh:RC254-282, Article
Abstract

International audience; DNA methyltransferase inhibitor (DNMTi) treatments have been used for patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and have shown promising beneficial effects in some other types of cancers. Here, we demonstrate that the transcriptional repressor ZBTB38 is a critical regulator of the cellular response to DNMTi. Treatments with 5-azacytidine, or its derivatives decitabine and zebularine, lead to down-regulation of ZBTB38 protein expression in cancer cells, in parallel with cellular damage. The depletion of ZBTB38 by RNA interference enhances the toxicity of DNMTi in cell lines from leukemia and from various solid tumor types. Further we observed that inactivation of ZBTB38 causes the up-regulation of CDKN1C mRNA, a previously described indirect target of DNMTi. We show that CDKN1C is a key actor of DNMTi toxicity in cells lacking ZBTB38. Finally, in patients with MDS a high level of CDKN1C mRNA expression before treatment correlates with a better clinical response to a drug regimen combining 5-azacytidine and histone deacetylase inhibitors. Collectively, our results suggest that the ZBTB38 protein is a target of DNMTi and that its depletion potentiates the toxicity of DNMT inhibitors in cancer cells, providing new opportunities to enhance the response to DNMT inhibitor therapies in patients with MDS and other cancers.

Published
2018
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