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985 results on '"Molecular Biotechnology Center"'

1. [Reveiw]Tumor specific cytotoxicity from subtropical plants in Okinawa

Author: IWASAKI, Hironori, OKU, Hirosuke, and Division of Molecular Biotechnology, Center of Molecular Bioscience, University of the Ryukyus
Subjects: 培養細胞, 抗腫瘍活性, 食品由来成分, スクリーニング
Abstract: 沖縄県は亜熱帯性の気候に属し、その強い環境ストレスから、植物の生体防御物質は温帯のものより豊富であることが知られている。これらの植物群を長く食材として利用してきた沖縄県民は、何らかの影響を受けていると考えられる。筆者らは沖縄における低発ガン率に注目し、食品性の抗腫瘍活性のスクリーニングを行った。特に、細胞増殖速度に依存しない抗腫瘍活性、「腫瘍選択的細胞抑制活性」についてスクリーニングを行った結果、沖縄県において特徴的に用いられている薬草茶であるサルカケミカン (Toddalia asiatica Lam.) に強い活性を見出した。単離された活性物質はジヒドロニチジン(Dihydronitidine : DHN) と同定された。DHNの抗腫瘍活性は既に示唆されていたが、今回の報告ではこれまでの活性だけでは説明できない抗腫瘍効果が示された。このDHNの選択的抑制活性は腫瘍細胞に特異的な物質輸送経路に依存していることが示唆された。今回示した腫瘍選択的細胞抑制活性は、特定の腫瘍細胞のみをターゲットとする新たな抗腫瘍剤の検索に貢献できると考えられた。
Published: 2007

2. Imaging of Dysfunctional Elastogenesis in Atherosclerosis Using an Improved Gadolinium-Based Tetrameric MRI Probe Targeted to Tropoelastin

Author: Alkystis Phinikaridou, Giuseppe Digilio, Federico Capuana, Silvio Aime, René M. Botnar, Sergio Padovan, Eyad Almouazen, Begoña Lavin, Laurence Heinrich-Balard, Sara Lacerda, Yves Chevalier, Rachele Stefania, Department of Life Sciences and Systems Biology [University of Turin], University of Turin, School of Biomedical Engineering and Imaging Sciences, King's college London, King‘s College London, Molecular Biotechnology Center, Università degli studi di Torino (UNITO), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Université d'Orléans (UO), Laboratoire d'automatique, de génie des procédés et de génie pharmaceutique (LAGEPP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Matériaux, ingénierie et science [Villeurbanne] (MATEIS), 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)-Centre National de la Recherche Scientifique (CNRS), Pontificia Universidad Católica de Chile: Santiago, Región Metropolitana, CL, IRCCS SDN Napoli, Università degli Studi del Piemonte Orientale, Dipartimento di Scienze e Innovazione Tecnologica, Alessandria, Italy, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Pontificia Universidad Católica de Chile (UC), Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Università degli studi di Torino = University of Turin (UNITO), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Centre National de la Recherche Scientifique (CNRS), Martins Vasco de Lacerda, Sara, and Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Contrast enhancement, MRI contrast agent, Gadolinium, chemistry.chemical_element, Contrast Media, Peptide, 030204 cardiovascular system & hematology, 01 natural sciences, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Time windows, Tropoelastin, [CHIM] Chemical Sciences, Drug Discovery, [CHIM]Chemical Sciences, Animals, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Mice, Knockout, biology, integumentary system, Molecular Structure, 010405 organic chemistry, Chemistry, [CHIM.MATE]Chemical Sciences/Material chemistry, Surface Plasmon Resonance, Atherosclerosis, Magnetic Resonance Imaging, 0104 chemical sciences, Elastin, Mice, Inbred C57BL, Disease Models, Animal, Biophysics, biology.protein, Molecular Medicine, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Molecular imaging
Abstract: International audience; Dysfunctional elastin turnover plays a major role in the progression of atherosclerotic plaques. Failure of tropoelastin cross-linking into mature elastin leads to the accumulation of tropoelastin within the growing plaque, increasing its instability. Here we present Gd4-TESMA, an MRI contrast agent specifically designed for molecular imaging of tropoelastin within plaques. Gd4-TESMA is a tetrameric probe composed of a tropoelastin-binding peptide (the VVGS-peptide) conjugated with four Gd(III)-DOTA-monoamide chelates. It shows a relaxivity per molecule of 34.0 ± 0.8 mM-1 s-1 (20 MHz, 298 K, pH 7.2), a good binding affinity to tropoelastin (KD = 41 ± 12 μM), and a serum half-life longer than 2 h. Gd4-TESMA accumulates specifically in atherosclerotic plaques in the ApoE-/- murine model of plaque progression, with 2 h persistence of contrast enhancement. As compared to the monomeric counterpart (Gd-TESMA), the tetrameric Gd4-TESMA probe shows a clear advantage regarding both sensitivity and imaging time window, allowing for a better characterization of atherosclerotic plaques.
Published: 2021

3. Noncatalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage

Author: Régis Blaise, Damien Ramel, Natalia F. Smirnova, Emilio Hirsch, Alessandra Ghigo, Muriel Laffargue, Nicole Malet, Pierre Vincent, Stéphanie Gayral, Adrien Lupieri, Isabelle Limon, Marie-Kerguelen Sarthou, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), 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), Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, Università degli studi di Torino (UNITO), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), and RAMEL, Damien
Subjects: Intimal hyperplasia, Vascular smooth muscle, [SDV]Life Sciences [q-bio], Myocytes, Smooth Muscle, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030204 cardiovascular system & hematology, Biology, PI3Kγ, 03 medical and health sciences, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, cAMP, medicine, Animals, Kinase activity, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Cell Proliferation, chemistry.chemical_classification, 0303 health sciences, Cell growth, Phosphodiesterase, Cell Biology, Arteries, medicine.disease, 3. Good health, Cell biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Enzyme, chemistry, Vascular smooth muscle cell, medicine.symptom, Phosphatidylinositol 3-Kinase, Intracellular
Abstract: International audience; Arterial remodeling in hypertension and intimal hyperplasia involves inflammation and disrupted flow, both of which contribute to smooth muscle cell dedifferentiation and proliferation. In this context, our previous results identified phosphoinositide 3-kinase gamma (PI3Kγ) as an essential factor in inflammatory processes of the arterial wall. Here, we identified for the first time a kinase-independent role of nonhematopoietic PI3Kγ in the vascular wall during intimal hyperplasia using PI3Kγ deleted mice and mice expressing a kinase-dead version of the enzyme. Moreover, we found that the absence of PI3Kγ in VSMCs leads to the modulation of cell proliferation associated with an increase in intracellular cAMP levels. Real-time analysis of cAMP dynamics revealed that PI3Kγ modulates the degradation of cAMP in primary vascular smooth muscle cells (VSMC) independent of its kinase activity through the regulation of the phosphodiesterase (PDE) 4 enzyme. Importantly, the use of an N-terminal competing peptide of PI3Kγ blocked primary VSMC proliferation. These data provide evidence for a kinase-independent role of PI3Kγ in arterial remodeling and reveal novel strategies targeting the docking function of PI3Kγ for the treatment of cardiovascular diseases.
Published: 2020

4. Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure

Author: Delphine Mika, V. Algalarrondo, Valérie Domergue, Aurelia Bourcier, Matthieu Dessillons, Pauline Robert, Kaouter Bouadjel, Jérôme Leroy, Philippe Mateo, Marta Lindner, Florence Lefebvre, Jean-Baptiste Michel, A. Varin, Flavien Charpentier, Rodolphe Fischmeister, Jean Piero Margaria, Jane-Lise Samuel, Ibrahim Bedioune, Sarah Karam, Patrick Lechêne, Susana Gomez, Emilio Hirsch, Françoise Gaudin, Grégoire Vandecasteele, Charlène Coquard, Alessandra Ghigo, Signalisation et physiopathologie cardiovasculaire (CARPAT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Department of Molecular Biotechnologies and Health Sciences [Torino, Italy] (Hematology Division), Università degli studi di Torino (UNITO), Ingénierie et Plateformes au Service de l'Innovation Thérapeutique (IPSIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, FISCHMEISTER, RODOLPHE, Università degli studi di Torino = University of Turin (UNITO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
Subjects: Genetic enhancement, Gene Expression, heart failure, 030204 cardiovascular system & hematology, phosphodiesterase 4, Negative regulator, chemistry.chemical_compound, Mice, 0302 clinical medicine, PDE4B, Transduction, Genetic, Myocytes, Cardiac, 0303 health sciences, Ventricular Remodeling, cardiac remodeling, cyclic AMP, genetic therapy, transgenic mice, Phosphodiesterase, Adrenergic beta-Agonists, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Phenotype, Heart Function Tests, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Disease Susceptibility, Cardiology and Cardiovascular Medicine, Genetically modified mouse, Adenosine monophosphate, medicine.medical_specialty, Genetic Vectors, Mice, Transgenic, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Physiology (medical), Internal medicine, Receptors, Adrenergic, beta, medicine, Animals, Humans, 030304 developmental biology, business.industry, Myocardium, Isoproterenol, β adrenergic, medicine.disease, Cyclic Nucleotide Phosphodiesterases, Type 4, Disease Models, Animal, Endocrinology, chemistry, Heart failure, business
Abstract: Background: The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca 2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. Methods: We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca 2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca 2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. Results: PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca 2+ current, Ca 2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (10 12 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. Conclusions: Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.
Published: 2020

5. Dissecting the Shared and Context-Dependent Pathways Mediated by the p140Cap Adaptor Protein in Cancer and in Neurons

Author: Jennifer Chapelle, Oksana Sorokina, Colin McLean, Vincenzo Salemme, Annalisa Alfieri, Costanza Angelini, Alessandro Morellato, Annie Adrait, Elisabetta Menna, Michela Matteoli, Yohann Couté, Ugo Ala, Emilia Turco, Paola Defilippi, J. Douglas Armstrong, School of Biological science, University of Edinburgh, Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Medical Pharmacology and Consiglio Nazionale delle Ricerche - Istitute of Neuroscience, University of Milano, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, Università degli studi di Torino = University of Turin (UNITO), Consiglio Nazionale delle Ricerche [Roma] (CNR), and Università degli studi di Torino (UNITO)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Synaptogenesis, Biology, Interactome, 03 medical and health sciences, Cell and Developmental Biology, 0302 clinical medicine, p140Cap, SRCIN1, mass spectrometry, protein interaction network, breast cancer, neuronal synapses, breast cancer, medicine, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Original Research, mass spectrometry, Cancer, Signal transducing adaptor protein, Cell Biology, Actin cytoskeleton, medicine.disease, SRCIN1, protein interaction network, 3. Good health, Cell biology, p140Cap, 030104 developmental biology, lcsh:Biology (General), 030220 oncology & carcinogenesis, Synaptic plasticity, Cancer cell, neuronal synapses, Postsynaptic density, Developmental Biology
Abstract: The p140Cap adaptor protein is a scaffold molecule physiologically expressed in few epithelial tissues, such as the mammary gland, and in differentiated neurons. While the role of p140Cap in mammary gland epithelia is not still understood, we already know that a significant subset of breast cancers express p140Cap. In the subgroup of ERBB2-amplified breast cancers, a high p140Cap status predicts a significantly lower probability of developing a distant event and a clear difference in survival. p140Cap is causal in dampening ERBB2-positive tumor cell progression, impairing tumor onset and growth, and counteracting epithelial mesenchymal transition, resulting in decreased metastasis formation. Since only a few p140Cap interacting proteins have been identified in breast cancer and the molecular complexes and pathways underlying the cancer function of p140Cap are largely unknown, we generated a p140Cap interactome from ERBB2-positive breast cancer cells, identifying cancer specific components and those shared with the synaptic interactome. We identified 373 interacting proteins in cancer cells, including those with functions relevant to cell adhesion, protein homeostasis, regulation of cell cycle and apoptosis, which are frequently deregulated in cancer. Within the interactome, we identified 15 communities (clusters) with topology-functional relationships. In neurons, where p140Cap is key in regulating synaptogenesis, synaptic transmission and synaptic plasticity, it establishes an extensive interactome with proteins that cluster to sub complexes located in the postsynaptic density. p140Cap interactors converge on key synaptic processes, including synaptic transmission, actin cytoskeleton remodeling and cell-cell junction organization. Comparing the breast cancer to the synaptic interactome, we found 39 overlapping proteins, a relatively small overlap. However, cell adhesion and remodeling of actin cytoskeleton clearly emerge as common terms in the shared subset. Thus, the functional signature of the two interactomes is primarily determined by organ/tissue and functional specificity, while the overlap provides a list of shared functional terms, which might be linked to both cancer and neurological functions.
Published: 2019

6. Transient Receptor Potential Channel Expression Signatures in Tumor-Derived Endothelial Cells: Functional Roles in Prostate Cancer Angiogenesis

Author: Bernardini, Michela, Brossa, Alessia, Chinigo, Giorgia, Grolez, Guillaume P., Trimaglio, Giulia, Allart, Laurent, Hulot, Audrey, Marot, Guillemette, Genova, Tullio, Joshi, Aditi, Mattot, Virginie, Fromont, Gaelle, Munaron, Luca, Bussolati, Benedetta, Prevarskaya, Natalia, Pla, Alessandra Fiorio, Gkika, Dimitra, Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 (PHYCELL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Molecular Biotechnology Center, Università degli studi di Torino = University of Turin (UNITO), Service de neurologie et pathologie du mouvement, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), BILILLE, MOdel for Data Analysis and Learning (MODAL), Laboratoire Paul Painlevé (LPP), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille), Dipartimento di Scienze della Vita e Biologia dei Sistemi, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Molecular Biotechnology and Health Sciences, Rôle des canaux ioniques membranaires et du calcium intracellulaire dans la physiopathologie de la prostate, Université de Lille, Sciences et Technologies-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et de Cytologie Pathologiques [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Università degli studi di Torino (UNITO), Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Paul Painlevé - UMR 8524 (LPP), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille)-Université de Lille, Sciences et Technologies, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Turin, CHU Lille, CNRS, Inserm, Université de Lille, METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Mécanismes de la Tumorigénèse et Thérapies Ciblées (M3T) - UMR 8161, Physiologie Cellulaire (PHYCEL) - U1003, Physiologie Cellulaire (PHYCELL) - U1003, Santé publique : épidémiologie et qualité des soins - EA 2694, Università degli studi di Torino = University of Turin [UNITO], Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 [PHYCELL], Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161 [M3T], Nutrition, croissance et cancer (U 1069) [N2C], Laboratoire Paul Painlevé - UMR 8524 (LPP), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-École polytechnique universitaire de Lille (Polytech Lille)
Subjects: [SDV]Life Sciences [q-bio], education, TRP, calcium channel, migration, prostate cancer, tumor angiogenesis, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Article
Abstract: Background: Transient receptor potential (TRP) channels control multiple processes involved in cancer progression by modulating cell proliferation, survival, invasion and intravasation, as well as, endothelial cell (EC) biology and tumor angiogenesis. Nonetheless, a complete TRP expression signature in tumor vessels, including in prostate cancer (PCa), is still lacking. Methods: In the present study, we profiled by qPCR the expression of all TRP channels in human prostate tumor-derived ECs (TECs) in comparison with TECs from breast and renal tumors. We further functionally characterized the role of the &lsquo, prostate-associated&rsquo, channels in proliferation, sprout formation and elongation, directed motility guiding, as well as in vitro and in vivo morphogenesis and angiogenesis. Results: We identified three &lsquo, genes whose expression is upregulated in prostate TECs: TRPV2 as a positive modulator of TEC proliferation, TRPC3 as an endothelial PCa cell attraction factor and TRPA1 as a critical TEC angiogenic factor in vitro and in vivo. Conclusions: We provide here the full TRP signature of PCa vascularization among which three play a profound effect on EC biology. These results contribute to explain the aggressive phenotype previously observed in PTEC and provide new putative therapeutic targets.
Published: 2019

7. Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Author: Théry, Clotilde, Witwer, Kenneth W, Aikawa, Elena, Alcaraz, Maria Jose, Anderson, Johnathon D, Andriantsitohaina, Ramaroson, Antoniou, Anna, Arab, Tanina, Archer, Fabienne, Atkin-Smith, Georgia K, Ayre, D Craig, Bach, Jean-Marie, Bachurski, Daniel, Baharvand, Hossein, Balaj, Leonora, Baldacchino, Shawn, Bauer, Natalie N, Baxter, Amy A, Bebawy, Mary, Beckham, Carla, Bedina Zavec, Apolonija, Benmoussa, Abderrahim, Berardi, Anna C, Bergese, Paolo, Bielska, Ewa, Blenkiron, Cherie, Bobis-Wozowicz, Sylwia, Boilard, Eric, Boireau, Wilfrid, Bongiovanni, Antonella, Borràs, Francesc E, Bosch, Steffi, Boulanger, Chantal M, Breakefield, Xandra, Breglio, Andrew M, Brennan, Meadhbh Á, Brigstock, David R, Brisson, Alain, Broekman, Marike Ld, Bromberg, Jacqueline F, Bryl-Górecka, Paulina, Buch, Shilpa, Buck, Amy H, Burger, Dylan, Busatto, Sara, Buschmann, Dominik, Bussolati, Benedetta, Buzás, Edit I, Byrd, James Bryan, Camussi, Giovanni, Carter, David Rf, Caruso, Sarah, Chamley, Lawrence W, Chang, Yu-Ting, Chen, Chihchen, Chen, Shuai, Cheng, Lesley, Chin, Andrew R, Clayton, Aled, Clerici, Stefano P, Cocks, Alex, Cocucci, Emanuele, Coffey, Robert J, Cordeiro-da-Silva, Anabela, Couch, Yvonne, Coumans, Frank Aw, Coyle, Beth, Crescitelli, Rossella, Criado, Miria Ferreira, D'Souza-Schorey, Crislyn, Das, Saumya, Datta Chaudhuri, Amrita, de Candia, Paola, De Santana, Eliezer F, De Wever, Olivier, Del Portillo, Hernando A, Demaret, Tanguy, Deville, Sarah, Devitt, Andrew, Dhondt, Bert, Di Vizio, Dolores, Dieterich, Lothar C, Dolo, Vincenza, Dominguez Rubio, Ana Paula, Dominici, Massimo, Dourado, Mauricio R, Driedonks, Tom Ap, Duarte, Filipe V, Duncan, Heather M, Eichenberger, Ramon M, Ekström, Karin, El Andaloussi, Samir, Elie-Caille, Celine, Erdbrügger, Uta, Falcón-Pérez, Juan M, Fatima, Farah, Fish, Jason E, Flores-Bellver, Miguel, Försönits, András, Frelet-Barrand, Annie, Fricke, Fabia, Fuhrmann, Gregor, Gabrielsson, Susanne, Gámez-Valero, Ana, Gardiner, Chris, Gärtner, Kathrin, Gaudin, Raphael, Gho, Yong Song, Giebel, Bernd, Gilbert, Caroline, Gimona, Mario, Giusti, Ilaria, Goberdhan, Deborah Ci, Görgens, André, Gorski, Sharon M, Greening, David W, Gross, Julia Christina, Gualerzi, Alice, Gupta, Gopal N, Gustafson, Dakota, Handberg, Aase, Haraszti, Reka A, Harrison, Paul, Hegyesi, Hargita, Hendrix, An, Hill, Andrew F, Hochberg, Fred H, Hoffmann, Karl F, Holder, Beth, Holthofer, Harry, Hosseinkhani, Baharak, Hu, Guoku, Huang, Yiyao, Huber, Veronica, Hunt, Stuart, Ibrahim, Ahmed Gamal-Eldin, Ikezu, Tsuneya, Inal, Jameel M, Isin, Mustafa, Ivanova, Alena, Jackson, Hannah K, Jacobsen, Soren, Jay, Steven M, Jayachandran, Muthuvel, Jenster, Guido, Jiang, Lanzhou, Johnson, Suzanne M, Jones, Jennifer C, Jong, Ambrose, Jovanovic-Talisman, Tijana, Jung, Stephanie, Kalluri, Raghu, Kano, Shin-Ichi, Kaur, Sukhbir, Kawamura, Yumi, Keller, Evan T, Khamari, Delaram, Khomyakova, Elena, Khvorova, Anastasia, Kierulf, Peter, Kim, Kwang Pyo, Kislinger, Thomas, Klingeborn, Mikael, Klinke, David J, Kornek, Miroslaw, Kosanović, Maja M, Kovács, Árpád Ferenc, Krämer-Albers, Eva-Maria, Krasemann, Susanne, Krause, Mirja, Kurochkin, Igor V, Kusuma, Gina D, Kuypers, Sören, Laitinen, Saara, Langevin, Scott M, Languino, Lucia R, Lannigan, Joanne, Lässer, Cecilia, Laurent, Louise C, Lavieu, Gregory, Lázaro-Ibáñez, Elisa, Le Lay, Soazig, Lee, Myung-Shin, Lee, Yi Xin Fiona, Lemos, Debora S, Lenassi, Metka, Leszczynska, Aleksandra, Li, Isaac Ts, Liao, Ke, Libregts, Sten F, Ligeti, Erzsebet, Lim, Rebecca, Lim, Sai Kiang, Linē, Aija, Linnemannstöns, Karen, Llorente, Alicia, Lombard, Catherine A, Lorenowicz, Magdalena J, Lörincz, Ákos M, Lötvall, Jan, Lovett, Jason, Lowry, Michelle C, Loyer, Xavier, Lu, Quan, Lukomska, Barbara, Lunavat, Taral R, Maas, Sybren Ln, Malhi, Harmeet, Marcilla, Antonio, Mariani, Jacopo, Mariscal, Javier, Martens-Uzunova, Elena S, Martin-Jaular, Lorena, Martinez, M Carmen, Martins, Vilma Regina, Mathieu, Mathilde, Mathivanan, Suresh, Maugeri, Marco, McGinnis, Lynda K, McVey, Mark J, Meckes, David G, Meehan, Katie L, Mertens, Inge, Minciacchi, Valentina R, Möller, Andreas, Møller Jørgensen, Malene, Morales-Kastresana, Aizea, Morhayim, Jess, Mullier, François, Muraca, Maurizio, Musante, Luca, Mussack, Veronika, Muth, Dillon C, Myburgh, Kathryn H, Najrana, Tanbir, Nawaz, Muhammad, Nazarenko, Irina, Nejsum, Peter, Neri, Christian, Neri, Tommaso, Nieuwland, Rienk, Nimrichter, Leonardo, Nolan, John P, Nolte-'t Hoen, Esther NM, Noren Hooten, Nicole, O'Driscoll, Lorraine, O'Grady, Tina, O'Loghlen, Ana, Ochiya, Takahiro, Olivier, Martin, Ortiz, Alberto, Ortiz, Luis A, Osteikoetxea, Xabier, Østergaard, Ole, Ostrowski, Matias, Park, Jaesung, Pegtel, D Michiel, Peinado, Hector, Perut, Francesca, Pfaffl, Michael W, Phinney, Donald G, Pieters, Bartijn Ch, Pink, Ryan C, Pisetsky, David S, Pogge von Strandmann, Elke, Polakovicova, Iva, Poon, Ivan Kh, Powell, Bonita H, Prada, Ilaria, Pulliam, Lynn, Quesenberry, Peter, Radeghieri, Annalisa, Raffai, Robert L, Raimondo, Stefania, Rak, Janusz, Ramirez, Marcel I, Raposo, Graça, Rayyan, Morsi S, Regev-Rudzki, Neta, Ricklefs, Franz L, Robbins, Paul D, Roberts, David D, Rodrigues, Silvia C, Rohde, Eva, Rome, Sophie, Rouschop, Kasper Ma, Rughetti, Aurelia, Russell, Ashley E, Saá, Paula, Sahoo, Susmita, Salas-Huenuleo, Edison, Sánchez, Catherine, Saugstad, Julie A, Saul, Meike J, Schiffelers, Raymond M, Schneider, Raphael, Schøyen, Tine Hiorth, Scott, Aaron, Shahaj, Eriomina, Sharma, Shivani, Shatnyeva, Olga, Shekari, Faezeh, Shelke, Ganesh Vilas, Shetty, Ashok K, Shiba, Kiyotaka, Siljander, Pia R-M, Silva, Andreia M, Skowronek, Agata, Snyder, Orman L, Soares, Rodrigo Pedro, Sódar, Barbara W, Soekmadji, Carolina, Sotillo, Javier, Stahl, Philip D, Stoorvogel, Willem, Stott, Shannon L, Strasser, Erwin F, Swift, Simon, Tahara, Hidetoshi, Tewari, Muneesh, Timms, Kate, Tiwari, Swasti, Tixeira, Rochelle, Tkach, Mercedes, Toh, Wei Seong, Tomasini, Richard, Torrecilhas, Ana Claudia, Tosar, Juan Pablo, Toxavidis, Vasilis, Urbanelli, Lorena, Vader, Pieter, van Balkom, Bas Wm, van der Grein, Susanne G, Van Deun, Jan, van Herwijnen, Martijn Jc, Van Keuren-Jensen, Kendall, van Niel, Guillaume, van Royen, Martin E, van Wijnen, Andre J, Vasconcelos, M Helena, Vechetti, Ivan J, Veit, Tiago D, Vella, Laura J, Velot, Émilie, Verweij, Frederik J, Vestad, Beate, Viñas, Jose L, Visnovitz, Tamás, Vukman, Krisztina V, Wahlgren, Jessica, Watson, Dionysios C, Wauben, Marca Hm, Weaver, Alissa, Webber, Jason P, Weber, Viktoria, Wehman, Ann M, Weiss, Daniel J, Welsh, Joshua A, Wendt, Sebastian, Wheelock, Asa M, Wiener, Zoltán, Witte, Leonie, Wolfram, Joy, Xagorari, Angeliki, Xander, Patricia, Xu, Jing, Yan, Xiaomei, Yáñez-Mó, María, Yin, Hang, Yuana, Yuana, Zappulli, Valentina, Zarubova, Jana, Žėkas, Vytautas, Zhang, Jian-Ye, Zhao, Zezhou, Zheng, Lei, Zheutlin, Alexander R, Zickler, Antje M, Zimmermann, Pascale, Zivkovic, Angela M, Zocco, Davide, Zuba-Surma, Ewa K, dB&C I&I, LS Celbiologie-Algemeen, Celbiologie, Afd Pharmaceutics, Sub General Pharmaceutics, Sub Biomol.Mass Spect. and Proteomics, Afd Pharmacology, Urology, Pathology, Medical Oncology, Immunité et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Johns Hopkins University School of Medicine [Baltimore], Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Immuno-Endocrinologie Cellulaire et Moléculaire [Nantes] (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Department for Molecular Biology and Nanobiotechnology, National Institute of chemitry, Slovenia, Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 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), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imagerie Moléculaire et Nanobiotechnologies - Institut Européen de Chimie et Biologie (IECB), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), Molecular Biotechnology Center, Università degli studi di Torino = University of Turin (UNITO), Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Centre for Sustainable Tropical Fisheries and Aquaculture, James Cook University (JCU), Department of Oncology - Pathology, Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm]-Karolinska Institutet [Stockholm], Departamento de Ciências Biológicas, Universidade do Porto = University of Porto, Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Cancer Research Institute Ghent (CRIG), Universiteit Gent = Ghent University [Belgium] (UGENT), Department of Medical and Surgical Sciences for Children and Adults [Modena, Italy] (Laboratory of Cellular Therapy), Università degli Studi di Modena e Reggio Emilia (UNIMORE), Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Center for Cooperative Research in Biosciences (CIC bioGUNE), Partner site Munich, German Centre for Infection Research (DZIF), Institute for Transfusion Medicine, University Hospital Essen, Universität Duisburg-Essen [Essen], Mécanismes Adaptatifs et Evolution (MECADEV), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Psychiatry, Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Department of Bacteriology and Immunology [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Rigshospitalet [Copenhagen], Copenhagen University Hospital, Dalhousie University [Halifax], Department of Biology, Molecular Cell Biology, University of Mainz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Glycobiologie et signalisation cellulaire, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, University of Gothenburg (GU), Universidad de Alicante, École supérieure du professorat et de l'éducation - Académie de Créteil (UPEC ESPE Créteil), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Antwerp (UA), Université Catholique de Louvain = Catholic University of Louvain (UCL), Research Institute, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Department of Veterinary Disease Biology [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Biologie et Pathologie du Neurone (Brain-C), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-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 Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-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), Department of Mathematics and Statistics, American University, University of Pretoria [South Africa], Ecole des Ingénieurs de la Ville de Paris (EIVP), Universitat Pompeu Fabra [Barcelona] (UPF), Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México (UNAM), Istituto Ortopedico Rizzoli, Department of Molecular Therapeutics, The Scripps Research Institute, Laboratoire d'Informatique de Grenoble (LIG ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC), Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), 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)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular Research Center, Massachusetts General Hospital [Boston], University Medical Center [Utrecht], University of Toronto, Fiocruz Minas - René Rachou Research Center / Instituto René Rachou [Belo Horizonte, Brésil], Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), 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), Federal University of Sao Paulo (Unifesp), Functional Genomics / Genómica Funcional [Montevideo], Institut Pasteur de Montevideo, Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Università degli Studi di Perugia (UNIPG), Hospital Santa Cristina Instituto de Investigación Sanitaria Princesa C, Unidad de Investigación, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Department of Physiology, University of California [San Francisco] (UCSF), University of California-University of California, University of Vermont [Burlington], Peking University [Beijing], Shandong Agricultural University (SDAU), State Key Laboratory of Quality Research in Chinese Medicine Taipa, Macau SAR, (Institute of Chinese Medical Sciences), Human Genetics, Universität Ulm - Ulm University [Ulm, Allemagne], INSERM, Institut Curie, INCa [INCA-11548], French National Research Agency [ANR-10-IDEX-0001-02 PSL*, ANR-11-LABX-0043], SIDACTION [17-1-AAE-1138], Fondation ARC [PGA1 RF20180206962, PJA 20171206453], NIDA [DA040385, DA047807], Ministry of Education, NIA [AG057430], NIMH [MH118164], Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Biotechnology and Biological Sciences Research Council (BBSRC)-Aberystwyth University, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), The Scripps Research Institute [La Jolla, San Diego], Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Università degli Studi di Perugia = University of Perugia (UNIPG), Instituto de Investigacion Sanitaria del Hospital de la Princesa, Hospital Universitario de La Princesa, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), ANR-17-CE09-0025,MADNESS,Une approche microfluidique générique pour la qualification des nanoparticules biologiques(2017), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Biomedical Engineering and Physics, ACS - Atherosclerosis & ischemic syndromes, ACS - Microcirculation, Laboratory Specialized Diagnostics & Research, Radiotherapie, RS: GROW - R2 - Basic and Translational Cancer Biology, Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université Nice Sophia Antipolis (... - 2019) (UNS), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Vétérinaire de Nantes-Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Università degli studi di Torino (UNITO), Universidade do Porto, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Johannes Gutenberg - Universität Mainz (JGU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Université de Toronto [Canada], Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192 (PRISM), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade do Porto [Porto], Ghent University [Belgium] (UGENT), FEMTO-ST Institute, Université de Technologie de Belfort-Montbeliard (UTBM)-Université de Franche-Comté (UFC)-CNRS : UMR6174, Mécanismes adaptatifs : des organismes aux communautés (MECADEV), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Johannes Gutenberg - University of Mainz (JGU), Université Catholique de Louvain (UCL), Universitat Pompeu Fabra [Barcelona], Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Laboratoire Réactions et Génie des Procédés (LRGP), Fiocruz Minas - René Rachou Research Center / Instituto René Rachou, 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), Functional Genomics Unit, Institut Curie-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Vermont College of Medicine [Burlington, VT, USA], Extracellular Vesicles, Molecular and Integrative Biosciences Research Programme, Thery, C., Witwer, K. W., Aikawa, E., Alcaraz, M. J., Anderson, J. D., Andriantsitohaina, R., Antoniou, A., Arab, T., Archer, F., Atkin-Smith, G. K., Ayre, D. C., Bach, J. -M., Bachurski, D., Baharvand, H., Balaj, L., Baldacchino, S., Bauer, N. N., Baxter, A. A., Bebawy, M., Beckham, C., Bedina Zavec, A., Benmoussa, A., Berardi, A. C., Bergese, P., Bielska, E., Blenkiron, C., Bobis-Wozowicz, S., Boilard, E., Boireau, W., Bongiovanni, A., Borras, F. E., Bosch, S., Boulanger, C. M., Breakefield, X., Breglio, A. M., Brennan, M. A., Brigstock, D. R., Brisson, A., Broekman, M. L. D., Bromberg, J. F., Bryl-Gorecka, P., Buch, S., Buck, A. H., Burger, D., Busatto, S., Buschmann, D., Bussolati, B., Buzas, E. I., Byrd, J. B., Camussi, G., Carter, D. R. F., Caruso, S., Chamley, L. W., Chang, Y. -T., Chaudhuri, A. D., Chen, C., Chen, S., Cheng, L., Chin, A. R., Clayton, A., Clerici, S. P., Cocks, A., Cocucci, E., Coffey, R. J., Cordeiro-da-Silva, A., Couch, Y., Coumans, F. A. W., Coyle, B., Crescitelli, R., Criado, M. F., D'Souza-Schorey, C., Das, S., de Candia, P., De Santana, E. F., De Wever, O., del Portillo, H. A., Demaret, T., Deville, S., Devitt, A., Dhondt, B., Di Vizio, D., Dieterich, L. C., Dolo, V., Dominguez Rubio, A. P., Dominici, M., Dourado, M. R., Driedonks, T. A. P., Duarte, F. V., Duncan, H. M., Eichenberger, R. M., Ekstrom, K., EL Andaloussi, S., Elie-Caille, C., Erdbrugger, U., Falcon-Perez, J. M., Fatima, F., Fish, J. E., Flores-Bellver, M., Forsonits, A., Frelet-Barrand, A., Fricke, F., Fuhrmann, G., Gabrielsson, S., Gamez-Valero, A., Gardiner, C., Gartner, K., Gaudin, R., Gho, Y. S., Giebel, B., Gilbert, C., Gimona, M., Giusti, I., Goberdhan, D. C. I., Gorgens, A., Gorski, S. M., Greening, D. W., Gross, J. C., Gualerzi, A., Gupta, G. N., Gustafson, D., Handberg, A., Haraszti, R. A., Harrison, P., Hegyesi, H., Hendrix, A., Hill, A. F., Hochberg, F. H., Hoffmann, K. F., Holder, B., Holthofer, H., Hosseinkhani, B., Hu, G., Huang, Y., Huber, V., Hunt, S., Ibrahim, A. G. -E., Ikezu, T., Inal, J. M., Isin, M., Ivanova, A., Jackson, H. K., Jacobsen, S., Jay, S. M., Jayachandran, M., Jenster, G., Jiang, L., Johnson, S. M., Jones, J. C., Jong, A., Jovanovic-Talisman, T., Jung, S., Kalluri, R., Kano, S. -I., Kaur, S., Kawamura, Y., Keller, E. T., Khamari, D., Khomyakova, E., Khvorova, A., Kierulf, P., Kim, K. P., Kislinger, T., Klingeborn, M., Klinke, D. J., Kornek, M., Kosanovic, M. M., Kovacs, A. F., Kramer-Albers, E. -M., Krasemann, S., Krause, M., Kurochkin, I. V., Kusuma, G. D., Kuypers, S., Laitinen, S., Langevin, S. M., Languino, L. R., Lannigan, J., Lasser, C., Laurent, L. C., Lavieu, G., Lazaro-Ibanez, E., Le Lay, S., Lee, M. -S., Lee, Y. X. F., Lemos, D. S., Lenassi, M., Leszczynska, A., Li, I. T. S., Liao, K., Libregts, S. F., Ligeti, E., Lim, R., Lim, S. K., Line, A., Linnemannstons, K., Llorente, A., Lombard, C. A., Lorenowicz, M. J., Lorincz, A. M., Lotvall, J., Lovett, J., Lowry, M. C., Loyer, X., Lu, Q., Lukomska, B., Lunavat, T. R., Maas, S. L. N., Malhi, H., Marcilla, A., Mariani, J., Mariscal, J., Martens-Uzunova, E. S., Martin-Jaular, L., Martinez, M. C., Martins, V. R., Mathieu, M., Mathivanan, S., Maugeri, M., Mcginnis, L. K., Mcvey, M. J., Meckes, D. G., Meehan, K. L., Mertens, I., Minciacchi, V. R., Moller, A., Moller Jorgensen, M., Morales-Kastresana, A., Morhayim, J., Mullier, F., Muraca, M., Musante, L., Mussack, V., Muth, D. C., Myburgh, K. H., Najrana, T., Nawaz, M., Nazarenko, I., Nejsum, P., Neri, C., Neri, T., Nieuwland, R., Nimrichter, L., Nolan, J. P., Nolte-'t Hoen, E. N. M., Noren Hooten, N., O'Driscoll, L., O'Grady, T., O'Loghlen, A., Ochiya, T., Olivier, M., Ortiz, A., Ortiz, L. A., Osteikoetxea, X., Ostegaard, O., Ostrowski, M., Park, J., Pegtel, D. M., Peinado, H., Perut, F., Pfaffl, M. W., Phinney, D. G., Pieters, B. C. H., Pink, R. C., Pisetsky, D. S., Pogge von Strandmann, E., Polakovicova, I., Poon, I. K. H., Powell, B. H., Prada, I., Pulliam, L., Quesenberry, P., Radeghieri, A., Raffai, R. L., Raimondo, S., Rak, J., Ramirez, M. I., Raposo, G., Rayyan, M. S., Regev-Rudzki, N., Ricklefs, F. L., Robbins, P. D., Roberts, D. D., Rodrigues, S. C., Rohde, E., Rome, S., Rouschop, K. M. A., Rughetti, A., Russell, A. E., Saa, P., Sahoo, S., Salas-Huenuleo, E., Sanchez, C., Saugstad, J. A., Saul, M. J., Schiffelers, R. M., Schneider, R., Schoyen, T. H., Scott, A., Shahaj, E., Sharma, S., Shatnyeva, O., Shekari, F., Shelke, G. V., Shetty, A. K., Shiba, K., Siljander, P. R. -M., Silva, A. M., Skowronek, A., Snyder, O. L., Soares, R. P., Sodar, B. W., Soekmadji, C., Sotillo, J., Stahl, P. D., Stoorvogel, W., Stott, S. L., Strasser, E. F., Swift, S., Tahara, H., Tewari, M., Timms, K., Tiwari, S., Tixeira, R., Tkach, M., Toh, W. S., Tomasini, R., Torrecilhas, A. C., Tosar, J. P., Toxavidis, V., Urbanelli, L., Vader, P., van Balkom, B. W. M., van der Grein, S. G., Van Deun, J., van Herwijnen, M. J. C., Van Keuren-Jensen, K., van Niel, G., van Royen, M. E., van Wijnen, A. J., Vasconcelos, M. H., Vechetti, I. J., Veit, T. D., Vella, L. J., Velot, E., Verweij, F. J., Vestad, B., Vinas, J. L., Visnovitz, T., Vukman, K. V., Wahlgren, J., Watson, D. C., Wauben, M. H. M., Weaver, A., Webber, J. P., Weber, V., Wehman, A. M., Weiss, D. J., Welsh, J. A., Wendt, S., Wheelock, A. M., Wiener, Z., Witte, L., Wolfram, J., Xagorari, A., Xander, P., Xu, J., Yan, X., Yanez-Mo, M., Yin, H., Yuana, Y., Zappulli, V., Zarubova, J., Zekas, V., Zhang, J. -Y., Zhao, Z., Zheng, L., Zheutlin, A. R., Zickler, A. M., Zimmermann, P., Zivkovic, A. M., Zocco, D., Zuba-Surma, E. K., dB&C I&I, LS Celbiologie-Algemeen, Celbiologie, Afd Pharmaceutics, Sub General Pharmaceutics, Sub Biomol.Mass Spect. and Proteomics, Afd Pharmacology, CCA - Imaging and biomarkers, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms
Subjects: ectosome, ectosomes, exosomes, extracellular vesicles, guidelines, microparticles, microvesicles, minimal information requirements, reproducibility, rigor, standardization, Histology, Cell Biology, [SDV]Life Sciences [q-bio], size-exclusion, Medicine and Health Sciences, CELL-DERIVED MICROPARTICLES, FIELD-FLOW FRACTIONATION, requirements, circulating, ComputingMilieux_MISCELLANEOUS, Manchester Cancer Research Centre, lcsh:Cytology, PROSTATE-CANCER, microparticle, Cell interaction, microvesicle, chromatography, Position Paper, guideline, Life Sciences & Biomedicine, ectosomes, exosomes, extracellular vesicles, guidelines, microparticles, microvesicles, minimal information requirements, reproducibility, rigor, standardization, MEMBRANE-VESICLES, FETAL BOVINE, Ectosomes, Exosomes, Extracellular Vesicles, Guidelines, Microparticles, Microvesicles, Minimal Information Requirements, Reproducibility, Rigor, Standardization, CIRCULATING MICROPARTICLES, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, ddc:570, exosome, SURFACE-PLASMON RESONANCE, ddc:610, lcsh:QH573-671, Biology, Interacció cel·lular, Science & Technology, ResearchInstitutes_Networks_Beacons/mcrc, Cell membranes, HUMAN URINARY EXOSOMES, PREANALYTICAL PARAMETERS, minimal information requirement, SIZE-EXCLUSION CHROMATOGRAPHY, 1182 Biochemistry, cell and molecular biology, extracellular vesicle, Human medicine, Membranes cel·lulars
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
Published: 2018

8. Synaptic Interactome Mining Reveals p140Cap as a New Hub for PSD Proteins Involved in Psychiatric and Neurological Disorders

Author: Annalisa Alfieri, Oksana Sorokina, Annie Adrait, Costanza Angelini, Isabella Russo, Alessandro Morellato, Michela Matteoli, Elisabetta Menna, Elisabetta Boeri Erba, Colin McLean, J. Douglas Armstrong, Ugo Ala, Joseph D. Buxbaum, Alfredo Brusco, Yohann Couté, Silvia De Rubeis, Emilia Turco, Paola Defilippi, School of Biological science, University of Edinburgh, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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), Department of Medical Pharmacology and Consiglio Nazionale delle Ricerche - Istitute of Neuroscience, University of Milano, Consiglio Nazionale delle Ricerche [Roma] (CNR), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, Università degli studi di Torino (UNITO), Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Medical Sciences, Exploring the Dynamics of Proteomes (www.edyp.fr), Laboratoire Biologie à Grande Echelle, U1038 INSERM/CEA/UGA, Biosciences and Biotechnology Institute of Grenoble (BIG), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), European Project: 720270,H2020 Pilier Excellent Science,H2020-Adhoc-2014-20,HBP SGA1(2016), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Università degli studi di Torino = University of Turin (UNITO)
Subjects: 0301 basic medicine, medicine.medical_specialty, Dendritic spine, autism, Neurotransmission, Biology, Interactome, lcsh:RC321-571, Synapse, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Postsynaptic potential, medicine, synaptic transmission, Psychiatry, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Molecular Biology, Original Research, synaptic plasticity, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Autism, Epilepsy, Intellectual disability, P140Cap, Postsynaptic density, Schizophrenia, Synaptic plasticity, Synaptic transmission, Long-term potentiation, schizophrenia, p140Cap, 030104 developmental biology, postsynaptic density, intellectual disability, epilepsy, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Altered synaptic function has been associated with neurological and psychiatric conditions including intellectual disability, schizophrenia and autism spectrum disorder (ASD). Amongst the recently discovered synaptic proteins is p140Cap, an adaptor that localizes at dendritic spines and regulates their maturation and physiology. We recently showed that p140Cap knockout mice have cognitive deficits, impaired long-term potentiation (LTP) and long-term depression (LTD), and immature, filopodia-like dendritic spines. Only a few p140Cap interacting proteins have been identified in the brain and the molecular complexes and pathways underlying p140Cap synaptic function are largely unknown. Here, we isolated and characterized the p140Cap synaptic interactome by co-immunoprecipitation from crude mouse synaptosomes, followed by mass spectrometry-based proteomics. We identified 351 p140Cap interactors and found that they cluster to sub complexes mostly located in the postsynaptic density (PSD). p140Cap interactors converge on key synaptic processes, including transmission across chemical synapses, actin cytoskeleton remodeling and cell-cell junction organization. Gene co-expression data further support convergent functions: the p140Cap interactors are tightly co-expressed with each other and with p140Cap. Importantly, the p140Cap interactome and its co-expression network show strong enrichment in genes associated with schizophrenia, autism, bipolar disorder, intellectual disability and epilepsy, supporting synaptic dysfunction as a shared biological feature in brain diseases. Overall, our data provide novel insights into the molecular organization of the synapse and indicate that p140Cap acts as a hub for postsynaptic complexes relevant to psychiatric and neurological disorders.
Published: 2017

9. Inter-Protein Sequence Co-Evolution Predicts Known Physical Interactions in Bacterial Ribosomes and the Trp Operon

Author: Andrea Pagnani, Martin Weigt, Christoph Feinauer, Hendrik Szurmant, Politecnico di Torino = Polytechnic of Turin (Polito), The SCRIPPS Research Institute (SCRIPPS), University of California [Los Angeles] (UCLA), University of California-University of California, Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology (LCQB), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Molecular Biotechnology Center, Università degli studi di Torino (UNITO), The Scripps Research Institute [La Jolla, San Diego], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-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), and Università degli studi di Torino = University of Turin (UNITO)
Subjects: Proteomics, Protein Structure Comparison, PROTEIN INTERACTION NETWORKS, 0301 basic medicine, Molecular Networks (q-bio.MN), lcsh:Medicine, Biochemistry, Quantitative Biology - Quantitative Methods, Ribosome, trp operon, protein-protein interaction, PROTEIN-PROTEIN INTERACTIONS, Aromatic Amino Acids, Protein sequencing, Inference, Nucleic Acids, Large ribosomal subunit, Protein Interaction Mapping, Macromolecular Structure Analysis, Quantitative Biology - Molecular Networks, Amino Acids, lcsh:Science, Quantitative Methods (q-bio.QM), SEQUENCE ALIGNMENT, Genetics, Multidisciplinary, Organic Compounds, Tryptophan, Ribosome Subunits, Small, Chemistry, Physical Sciences, TRP OPERON, PROTEIN STRUCTURE COMPARISON TRYPTOPHAN, Coevolution, Sequence Analysis, Algorithms, Network Analysis, Research Article, Computer and Information Sciences, Protein Structure, Sequence alignment, Computational biology, Biology, Research and Analysis Methods, Protein–protein interaction, Evolution, Molecular, 03 medical and health sciences, Operon, Computational Techniques, Escherichia coli, Animals, Computer Simulation, MULTIPLE ALIGNMENT CALCULATION, SEQUENCE ALIGNMENT, PROTEIN INTERACTION NETWORKS, PROTEIN INTERACTIONS, PROTEIN-PROTEIN INTERACTIONS, PROTEIN STRUCTURE COMPARISON TRYPTOPHAN, TRP OPERON, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Molecular Biology Techniques, Sequencing Techniques, Operons, Molecular Biology, Sequence (medicine), Organic Chemistry, lcsh:R, Chemical Compounds, Biology and Life Sciences, Proteins, DNA, Ribosomal RNA, Split-Decomposition Method, Biosynthetic Pathways, PROTEIN INTERACTIONS, 030104 developmental biology, FOS: Biological sciences, MULTIPLE ALIGNMENT CALCULATION, Cattle, lcsh:Q, Ribosome Subunits, Large, Ribosomes
Abstract: International audience; Interaction between proteins is a fundamental mechanism that underlies virtually all biological processes. Many important interactions are conserved across a large variety of species. The need to maintain interaction leads to a high degree of co-evolution between residues in the interface between partner proteins. The inference of protein-protein interaction networks from the rapidly growing sequence databases is one of the most formidable tasks in systems biology today. We propose here a novel approach based on the Direct-Coupling Analysis of the co-evolution between inter-protein residue pairs. We use ribosomal and trp operon proteins as test cases: For the small resp. large ribosomal subunit our approach predicts protein interaction partners at a true-positive rate of 70% resp. 90% within the first 10 predictions, with areas of 0.69 resp. 0.81 under the ROC curves for all predictions. In the trp operon, it assigns the two largest interaction scores to the only two interactions experimentally known. On the level of residue interactions we show that for both the small and the large ribosomal subunit our approach predicts interacting residues in the system with a true positive rate of 60% and 85% in the first 20 predictions. We use artificial data to show that the performance of our approach depends crucially on the size of the joint multiple sequence alignments and analyze how many sequences would be necessary for a perfect prediction if the sequences were sampled from the same model that we use for prediction. Given the performance of our approach on the test data we speculate that it can be used to detect new interactions, especially in the light of the rapid growth of available sequence data.
Published: 2016

10. Intramammary Application of Non-Methylated-CpG Oligodeoxynucleotides (CpG) Inhibits both Local and Systemic Mammary Carcinogenesis in Female BALB/c Her-2/neu Transgenic Mice

Author: Guido Forni, Piero Musiani, Carlos A. Guzmán, Cristina Mastini, Manuela Iezzi, Claudia Curcio, Federica Cavallo, Pablo D. Becker, and Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Torino, 10126 Torino, Italy.
Subjects: Cancer Research, Pathology, medicine.medical_specialty, Time Factors, Receptor, ErbB-2, CpG Oligodeoxynucleotide, Antineoplastic Agents, Mice, Transgenic, medicine.disease_cause, Lymphocyte Depletion, Injections, BALB/c, Interferon-gamma, Mice, Mammary Glands, Animal, Adjuvants, Immunologic, Cell Line, Tumor, Drug Discovery, medicine, Animals, Neoplasm Invasiveness, Glycoproteins, Interferon Type II, Pharmacology, Mice, Inbred BALB C, Innate immune system, biology, Oncogene, Mammary Neoplasms, Experimental, DNA, biology.organism_classification, Immunity, Innate, Rats, Killer Cells, Natural, Cell Transformation, Neoplastic, Immunity, Natural, Oligodeoxyribonucleotides, Oncology, CpG site, Disease Progression, Female, Lymph Nodes, Lymph, Carcinogenesis, CD8
Abstract: CpG are powerful drugs activating the innate immune system. In this study, the ability of their intramammary administration in impeding the devastating progression of carcinogenesis in all the mammary glands of female BALB/c mice transgenic for the rat neu transforming oncogene was assessed. Starting when in situ carcinomas were scattered over all their mammary glands (week 10), mice received CpG injections in the stroma of the fourth left gland. Local neoplastic progression was inhibited by six monthly administrations. CpG not only delayed the onset of carcinomas in the injected gland, but also hampered their progression. Extended latency was observed for tumors in glands both close to and far from the injection site. When the experiment ended (week 45), no tumors were palpable in 67% of the injected glands and a markedly impaired tumor growth was evident in the others. An impressive local infiltrate of CD11b(+) cells with the morphologic features of macrophages, plasma cells, B220(+) B cells, and CD4(+) and CD8(+) T cells was quickly recruited to the CpG-treated glands. High quantities of IFN-gamma producing cells were only present in the ipsilateral axillary draining lymph nodes of the treated glands. Enhanced natural killer (NK) lytic activity was also detected in the spleens. Inhibition of progression was weaker when only four injections were given, and abolished by in vivo depletion of NK cells. CpG monotherapy is thus effective in an aggressive model of autochthonous cancer. The results strongly support the administration of CpG as a local monotherapy of multiple invasive microscopic lesions.
Published: 2008

11. Classification of current anticancer immunotherapies

Author: Chiara Castelli, Axel Hoos, Anna Karolina Palucka, Aitziber Buqué, Kenneth J. Pienta, Aled Clayton, Daniel E. Speiser, Jean-Pierre Mach, Klas Kärre, Richard G. Vile, Maha Ayyoub, Norma Bloy, Theresa L. Whiteside, Eli Gilboa, Naiyer A. Rizvi, Cornelis J. M. Melief, Alexander Knuth, Bruno Silva-Santos, Lisa M. Coussens, James E. Talmadge, Jean-Yves Blay, Rolf Kiessling, Lorenzo Moretta, Alexander M.M. Eggermont, Estaban Celis, Anne Caignard, Mario P. Colombo, Abhishek D. Garg, José Manuel Bravo-San Pedro, Pramod K. Srivastava, Dmitry I. Gabrilovich, Wolf H. Fridman, Catherine Sautès-Fridman, Eric Tartour, Fabrizio Mattei, Patrizia Agostinis, Philipp Beckhove, Laura Bracci, Vincenzo Cerundolo, Giuseppe Giaccone, Fernando Aranda, Angel Porgador, Elisa E. Baracco, Radek Spisek, Jean Pierre Abastado, Michael T. Lotze, Ron N. Apte, Federica Cavallo, Benoît Van den Eynde, Weiping Zou, François Ghiringhelli, Hans Schreiber, Jitka Fucikova, Lorenzo Galluzzi, Adekunke Odunsi, Erika Vacchelli, Roland S. Liblau, Hideho Okada, Hiroshi Shiku, Laurence Zitvogel, Pawel Kalinski, Guido Kroemer, Oliver Kepp, George C. Prendergast, Eva Klein, Francesca Castoldi, Enrico Lugli, Jedd D. Wolchok, Anne Hosmalin, Sjoerd H. van der Burg, Hermann Wagner, Mark J. Smyth, Nicholas P. Restifo, Dirk Jäger, John M. Kirkwood, Gabriel A. Rabinovich, Sacha Gnjatic, Madhav V. Dhodapkar, E. A. Mittendorf, Douglas T. Fearon, Ignacio Melero, Marcus E. Peter, Jérôme Galon, Domenico Mavilio, Laura Senovilla, Claire E. Lewis, Barbara Seliger, Jeffrey S. Weber, UCL - SSS/DDUV - Institut de Duve, Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Paris-Sud - Paris 11 (UP11), Sotio a.c., Pole d’innovation thérapeutique en oncologie, Institut de Recherches Internationales Servier, Cell Death Research and Therapy (CDRT) Laboratory, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Group of Immune receptors of the Innate and Adaptive System, Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Cancer Vaccines and Immune Regulation, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Translational Immunology Division, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Immunotherapy of Human Tumors, Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Molecular Biotechnology Center, Dept. of Molecular Biotechnology and Health Sciences, Università degli studi di Torino = University of Turin (UNITO), Cancer Immunology, Inflammation and Tolerance Program, Augusta University, University System of Georgia (USG)-University System of Georgia (USG), MRC Human Immunology Unit, The Weatherall Institute of Molecular Medicine, University of Oxford-University of Oxford, Department of Oncology - Pathology, Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm]-Karolinska Institutet [Stockholm], Institute of Cancer & Genetics, Cardiff University, Velindre Cancer Centre, Knight Cancer Institute, Oregon Health and Science University [Portland] (OHSU), Sect. of Hematology and Immunobiology,Yale Cancer Center, Yale University [New Haven], Institut Gustave Roussy (IGR), Cold Spring Harbor Laboratory, NY, Cold Spring Harbor, Centre de Recherche des Cordeliers (CRC), Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University [Prague] (CU), Dept. of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Lombardi Comprehensive Cancer Center, Georgetown University [Washington] (GU), Dept. of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami [Coral Gables], Glaxo Smith Kline, Cancer Immunotherapy Consortium, 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), National Center for Tumor Diseases, University Medical Center Heidelberg, Hillman Cancer Center, University of Pittsburg, Department of Surgery, Cancer Institute-University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Dept. of Immunology and Infectious Diseases and Microbiology, University of Pittsburgh (PITT), Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institutet [Stockholm], Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Dept. of Oncology, Karolinska Institute Hospital, Cancer Institute Laboratory, Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Institut de Biochimie, Université de Lausanne = University of Lausanne (UNIL), Dept. of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano = University of Milan (UNIMI), Dept. of Immunology, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Clínica Universidad de Navarra [Pamplona], ISA Therapeutics, Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Research Dept. of Surgical Oncology, The University of Texas, Istituto Giannina Gaslini, Center for Immunotherapy [Buffalo], Roswell Park Cancer Institute [Buffalo] (RPCI), Dept. of Neurological Surgery, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), The Jackson Laboratory [Bar Harbor] (JAX), Div. of Hematology/Oncology, Northwestern University, The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev (BGU)-Faculty of Health Sciences and Cancer Research Center, Cell Biology and Signaling Program, Thomas Jefferson University-Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University)-Jefferson (Philadelphia University + Thomas Jefferson University), Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental [Buenos Aires] (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Memorial Sloane Kettering Cancer Center [New York], Dept. of Pathology, The Cancer Research Center, University of Chicago, Institute of Medical Immunology, Martin-Luther-Universität Halle Wittenberg (MLU), Department of Immuno-gene Therapy, Mie University, Instituto de Medicina Molecular, Universidade de Lisboa = University of Lisbon (ULISBOA), Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, School of Medicine, University of Queensland [Brisbane], Ludwig Cancer Research Center, Dept. of Immunology, University of Connecticut (UCONN), Carole and Ray Neag Comprehensive Cancer Center, Laboratory of Transplantation Immunology, Dept. of Pathology and Microbiology, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immunologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Dept. of Clinical Oncology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Ludwig Institute for Cancer Research, de Duve Institute, Dept. of Molecular Medicine and Immunology, Mayo Clinic College of Medicine, Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center & Research Institute, University of Pittsburgh School of Medicine, Dept. of Medicine and Ludwig Center, Weill Medical College of Cornell University [New York], Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Pôle de biologie, GK is supported by the Ligue contre le Cancer(équipe labelisée), Agence Nationale de la Recherche(ANR), Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, Institut National du Cancer(INCa), Fondation Bettencourt-Schueller, Fondation deFrance, Fondation pour la Recherche Médicale (FRM), theEuropean Commission (ArtForce), the European ResearchCouncil (ERC), the LabEx Immuno-Oncology, the SIRICStratified Oncology Cell DNA Repair and Tumor ImmuneElimination (SOCRATE), the SIRIC Cancer Researchand Personalized Medicine (CARPEM), and the ParisAlliance of Cancer Research Institutes (PACRI). MPC issupported by Association for Cancer Research (AIRC). SGis supported by Cancer Vaccine Collaborative and CancerResearch Institute. MJS is supported by the NationalHealth and Medical Research Council of Australia, the QIMR Berghofer Medical Research Institute, andthe Susan G Komen Breast Cancer Foundation. FM issupported by a grant from the Italian Ministry of Health., Repositório da Universidade de Lisboa, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto Superiore di Sanità, Università degli studi di Torino (UNITO), University of Oxford [Oxford]-University of Oxford [Oxford], University of Pennsylvania [Philadelphia], Georgetown University, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne (UNIL), University of Milan, Roswell Park Cancer Institute [Buffalo], University of California [San Francisco] (UCSF), University of California-University of California, Universidade de Lisboa (ULISBOA), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Bos, Mireille, Apoptose, cancer et immunité ( Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 ), Institut Gustave Roussy ( IGR ) -Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ), Catholic University of Leuven ( KU Leuven ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), German Cancer Research Center, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Università degli studi di Torino ( UNITO ), Georgia Regents University Cancer Center, Cancer Center Karolinska [Karolinska Institutet] ( CCK ), Oregon Health & Science University [Portland] ( OHSU ), Institut Gustave Roussy ( IGR ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Charles University, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), University of Miami, Institut Cochin ( 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 ), Cancer Institute-University of Pittsburgh, University of Pittsburgh, Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lausanne ( UNIL ), Center for Immunotherapy, University of California [San Francisco] ( UCSF ), The Jackson Laboratory for Genomics Medicine, Ben-Gurion University of the Negev ( BGU ) -Faculty of Health Sciences and Cancer Research Center, Instituto de Biología y Medicina Experimental (IBYME), National Cancer Institute (NCI), Memorial Sloan Kettering Cancer Center ( MSKCC ), Martin Luther University Halle-Wittenberg, Mie University Graduate School of Medicine, Universidade de Lisboa ( ULISBOA ), University of Lausanne, University of Connecticut School of Medicine, Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Catholique de Louvain ( UCL ), Technical University of Munich ( TUM ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), and Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: immunostimulatory cytokines, medicine.medical_treatment, Review, Bioinformatics, DNA-based vaccines, Efficacy, 0302 clinical medicine, Cancer immunotherapy, Neoplasms, peptide-based vaccines, 0303 health sciences, Patología, purl.org/becyt/ford/3.1 [https], CANCER, 3. Good health, Medicina Básica, Oncology, checkpoint blockers, 030220 oncology & carcinogenesis, QR180, purl.org/becyt/ford/3 [https], Immunotherapy, CIENCIAS MÉDICAS Y DE LA SALUD, medicine.drug_class, Inmunología, adoptive cell transfer, dendritic cell-based interventions, oncolytic viruses, Toll-like receptor agonists, Monoclonal antibody, RC0254, 03 medical and health sciences, Immune system, Antigen, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, IMMUNOTHERAPIES, business.industry, Cancer, medicine.disease, R1, Oncolytic virus, Immunology, business
Abstract: © 2014. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited., During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
Published: 2014

12. Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib

Author: Fiorio Pla, Alessandra, Brossa, Alessia, Bernardini, Michela, Genova, Tullio, Grolez, Guillaume, Villers, Arnaud, Leroy, Xavier, Prevarskaya, Natalia, Gkika, Dimitra, Bussolati, Benedetta, Rôle des canaux ioniques membranaires et du calcium intracellulaire dans la physiopathologie de la prostate, Université de Lille, Sciences et Technologies-Institut National de la Santé et de la Recherche Médicale (INSERM), Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università degli studi di Torino (UNITO), Molecular Biotechnology Center, Service Urologie, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille, Service d'anatomopathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), This study was supported by Italian Ministry of University and Research(MIUR) Prin08 to BB and by grants from Ministère de l’Education Nationale,Inserm, France to DG. MB is supported by the Vinci program 2012-UniversitéFranco Italienne., Taibi, Nadia, Università degli studi di Torino = University of Turin (UNITO), Département de neurologie [Lille], Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 (PHYCELL), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille
Subjects: Male, Niacinamide, Cancer Research, Indoles, Cell Survival, [SDV]Life Sciences [q-bio], Angiogenesis Inhibitors, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, urologic and male genital diseases, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Cell Line, Tumor, Sunitinib, Genetics, Humans, Pyrroles, Phosphorylation, Protein Kinase Inhibitors, Cell Proliferation, Neoplasm Staging, Prostate cancer, Phenylurea Compounds, VEGF receptor, Anti-angiogenic therapy, Endothelial Cells, Prostatic Neoplasms, Middle Aged, Sorafenib, Vascular Endothelial Growth Factor Receptor-2, female genital diseases and pregnancy complications, Androgen receptor, Oncology, Drug Resistance, Neoplasm, Drug resistance, Neoplasm Grading, Biomarkers, Research Article
Abstract: Background Prostate cancer is the second leading cause of male cancer death in developed countries. Although the role of angiogenesis in its progression is well established, the efficacy of anti-angiogenic therapy is not clearly proved. Whether this could depend on differential responses between tumor and normal endothelial cells has not been tested. Methods We isolated and characterized three lines of endothelial cells from prostate cancer and we tested the effect of Sunitinib and Sorafenib, and the combined treatment with the anti-androgen Casodex, on their angiogenic functions. Results Endothelial cells isolated from prostate tumors showed angiogenic properties and expression of androgen and vascular endothelial cell growth factor receptors. Sunitinib affected their proliferation, survival and motility while Sorafenib only showed a minor effect. At variance, Sunitinib and Sorafenib showed similar cytotoxic and anti-angiogenic effects on normal endothelial cells. Sorafenib and Sunitinib inhibited vascular endothelial cell growth factor receptor2 phosphorylation of prostate cancer endothelial cells, while they differentially modulated Akt phosphorylation as no inhibitory effect of Sorafenib was observed on Akt activation. The combined treatment of Casodex reverted the observed resistance to Sorafenib both on cell viability and on Akt activation, whereas it did not modify the response to Sunitinib. Conclusions Our study demonstrates a resistant behavior of endothelial cells isolated from prostate cancer to Sorafenib, but not Sunitinib. Moreover, it shows the benefit of a multi-target therapy combining anti-angiogenic and anti-hormonal drugs to overcome resistance. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-939) contains supplementary material, which is available to authorized users.
Published: 2013

13. Visual Search of Neuropil-Enriched RNAs from Brain In Situ Hybridization Data through the Image Analysis Pipeline Hippo-ATESC

Author: Mario Giacobini, Barbara Bardoni, Gaia Berto, Samantha Zongaro, F. Bianchi, Roberto Ugolotti, Pablo Mesejo, Ivan Molineris, Stefano Cagnoni, Ferdinando Di Cunto, Intelligent Bio-Inspired Systems lab (IBISlab), Department of Information Engineering, University of Parma, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Molecular Biotechnology Center, Università degli studi di Torino (UNITO), Department of Veterinary Sciences, European Project: 238819,EC:FP7:PEOPLE,FP7-PEOPLE-ITN-2008,MIBISOC(2009), Università degli studi di Parma = University of Parma (UNIPR), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Università degli studi di Torino = University of Turin (UNITO)
Subjects: Dendritic spine, Deformable Models, Neuropil, lcsh:Medicine, Hippocampus, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Mice, 0302 clinical medicine, Image Processing, Computer-Assisted, Feature Selection, lcsh:Science, In Situ Hybridization, Genetics, 0303 health sciences, Multidisciplinary, Differential Evolution, Non-coding RNA, medicine.anatomical_structure, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Algorithms, Research Article, Image Registration, Computational biology, In situ hybridization, Biology, Image Segmentation, 03 medical and health sciences, Atlases as Topic, Hippocampus Localization, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Animals, Humans, RNA, Messenger, 030304 developmental biology, Visual search, Internet, Genetic Algorithms, Gene Expression Profiling, lcsh:R, Brain atlas, RNA, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Gene expression profiling, lcsh:Q, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery, Soft Computing, Software
Abstract: International audience; Motivation: RNA molecules specifically enriched in the neuropil of neuronal cells and in particular in dendritic spines are of great interest for neurobiology in virtue of their involvement in synaptic structure and plasticity. The systematic recognition of such molecules is therefore a very important task. High resolution images of RNA in situ hybridization experiments contained in the Allen Brain Atlas (ABA) represent a very rich resource to identify them and have been so far exploited for this task through human-expert analysis. However, software tools that may automatically address the same objective are not very well developed. Results: In this study we describe an automatic method for exploring in situ hybridization data and discover neuropil-enriched RNAs in the mouse hippocampus. We called it Hippo-ATESC (Automatic Texture Extraction from the Hippocampal region using Soft Computing). Bioinformatic validation showed that the Hippo-ATESC is very efficient in the recognition of RNAs which are manually identified by expert curators as neuropil-enriched on the same image series. Moreover, we show that our method can also highlight genes revealed by microdissection-based methods but missed by human visual inspection. We experimentally validated our approach by identifying a non-coding transcript enriched in mouse synaptosomes. The code is freely available on the web at http://ibislab.ce.unipr.it/software/hippo/.
Published: 2013

14. Automatic segmentation of hippocampus in histological images of mouse brains using deformable models and random forest

Author: Roberto Ugolotti, Pablo Mesejo, Stefano Cagnoni, Mario Giacobini, Ferdinando Di Cunto, Intelligent Bio-Inspired Systems lab (IBISlab), Università degli studi di Parma = University of Parma (UNIPR), Molecular Biotechnology Center, Università degli studi di Torino = University of Turin (UNITO), Department of Veterinary Sciences, and European Project: 238819,EC:FP7:PEOPLE,FP7-PEOPLE-ITN-2008,MIBISOC(2009)
Subjects: Deformable Models, Computer science, Scale-space segmentation, 02 engineering and technology, Image Segmentation, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 030218 nuclear medicine & medical imaging, Otsu's method, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, image analysis, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, 0202 electrical engineering, electronic engineering, information engineering, Computer vision, Segmentation, Parametric statistics, Random Forest, Landmark, business.industry, Neurosciences, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Pattern recognition, Image segmentation, Thresholding, Random forest, evolutionary computation, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], symbols, 020201 artificial intelligence & image processing, Artificial intelligence, business, Histological Images
Abstract: International audience; We perform a two-step segmentation of the hippocam-pus in histological images. First, we maximize the overlap of an empirically-derived parametric Deformable Model with two crucial landmark sub-structures in the brain image using Differential Evolution. Then, the points located in the previous step determine the region where a thresh-olding technique based on Otsu's method is to be applied. Finally, the segmentation is expanded employing Random Forest in the regions not covered by the model. Our approach showed an average segmentation accuracy of the 92.25% and 92.11% on test sets comprising 15 real and 15 synthetic images, respectively.
Published: 2012

15. Automatic Hippocampus Localization in Histological Images using Differential Evolution-Based Deformable

Author: Mesejo, Pablo, Ugolotti, Roberto, Di Cunto, Ferdinando, Giacobini, Mario, Cagnoni, Stefano, Intelligent Bio-Inspired Systems lab (IBISlab), Università degli studi di Parma = University of Parma (UNIPR), Molecular Biotechnology Center, Università degli studi di Torino = University of Turin (UNITO), Department of Veterinary Sciences, and European Project: 238819,EC:FP7:PEOPLE,FP7-PEOPLE-ITN-2008,MIBISOC(2009)
Subjects: Deformable Models, Particle Swarm Optimization, Genetic Algorithms, Levenberg–Marquardt, Hippocampus Localization, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Differential Evolution, Scatter Search, Simulated Annealing, Global Continuous Optimization, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract: International audience; In this paper, the localization of structures in biomedical images is considered as a multimodal global continuous optimization problem and solved by means of soft computing techniques. We have developed an automatic method aimed at localizing the hippocampus in histological images, after discoveries indicating the relevance of structural changes of this region as early biomarkers for Alzheimer’s disease and epilepsy. The localization is achieved by searching the parameters of an empirically-derived deformable model of the hippocampus which maximize its overlap with the corresponding anatomical structure in histological brain images. The comparison between six real-parameter optimization techniques (Levenberg–Marquardt, Differential Evolution, Simulated Annealing, Genetic Algorithms, Particle Swarm Optimization and Scatter Search) shows that Differential Evolution significantly outperforms the other techniques in this task, providing successful localizations in 90.9% and 93.0% of two test sets of real and synthetic images, respectively.
Published: 2012

16. Automatic hippocampus localization in histological images using PSO-based deformable models

Author: Pablo Mesejo, Stefano Cagnoni, Roberto Ugolotti, Ferdinando Di Cunto, Mario Giacobini, Intelligent Bio-Inspired Systems lab (IBISlab), Università degli studi di Parma = University of Parma (UNIPR), Molecular Biotechnology Center, Università degli studi di Torino = University of Turin (UNITO), Department of Veterinary Sciences, and European Project: 238819,EC:FP7:PEOPLE,FP7-PEOPLE-ITN-2008,MIBISOC(2009)
Subjects: Deformable Models, Computer science, Hippocampus, 02 engineering and technology, Affine Registration, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 03 medical and health sciences, 0302 clinical medicine, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, image analysis, Atlas (anatomy), [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, 0202 electrical engineering, electronic engineering, information engineering, medicine, Scatter Search, Computer vision, Simulated Annealing, business.industry, Genetic Algorithms, evolutionary computation, particle swarm optimization, Brain atlas, Active Shape Models, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Allen Brain Atlas, medicine.anatomical_structure, Automatic Localization, Particle Swarm Optimization, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Brain section, 020201 artificial intelligence & image processing, Artificial intelligence, Affine transformation, business, 030217 neurology & neurosurgery
Abstract: International audience; The Allen Brain Atlas (ABA) is a cellular-resolution, genome-wide map of gene expression in the mouse brain which allows users to compare gene expression patterns in neuroanatomical structures. The correct localization of the structures is the first step to carry on this comparison in an automatic way. In this paper we present a completely automatic tool for the localization of the hippocampus that can be easily adapted also to other subcortical structures. This goal is achieved in two distinct phases. The first phase, called "best reference slice selection", is performed by comparing the image of the brain with a reference Atlas provided by ABA using a two-step affine registration. By doing so the system is able to automatically find to which brain section the image corresponds and wherein the image the hippocampus is roughly located. The second phase, the proper "hippocampus localization", is based on a method that combines Particle Swarm Optimization (PSO) and a novel technique inspired by Active Shape Models (ASMs). The hippocampus is found by adapting a deformable model derived statistically, in order to make it overlap with the hippocampus image. Experiments on a test set of 120 images yielded a perfect or good localization in 89.2% of cases.
Published: 2011

17. Increasing membrane polyunsaturated fatty acids sensitizes non-small cell lung cancer to anti-PD-1/PD-L1 immunotherapy.

Author: La Vecchia S, Fontana S, Salaroglio IC, Anobile DP, Digiovanni S, Akman M, Jafari N, Godel M, Costamagna C, Corbet C, Kopecka J, and Riganti C
Subjects: Humans, Animals, Programmed Cell Death 1 Receptor metabolism, Programmed Cell Death 1 Receptor antagonists & inhibitors, Letrozole pharmacology, Letrozole therapeutic use, Mice, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Cell Line, Tumor, Immunotherapy methods, Sterol Regulatory Element Binding Protein 1 metabolism, Sterol Regulatory Element Binding Protein 1 genetics, Stearoyl-CoA Desaturase metabolism, Stearoyl-CoA Desaturase genetics, Xenograft Model Antitumor Assays, Female, Docosahexaenoic Acids pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms immunology, Lung Neoplasms genetics, Lung Neoplasms pathology, B7-H1 Antigen metabolism, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Fatty Acids, Unsaturated pharmacology
Abstract: Immune checkpoints inhibitors (ICIs) as anti-PD-1/anti-PD-L1 have been approved as first-line treatment in patients with non-small cell lung cancer (NSCLC), but only 25 % of patients achieve durable response. We previously unveiled that estrogen receptor α transcriptionally up-regulates PD-L1 and aromatase inhibitors such as letrozole increase the efficacy of pembrolizumab. Here we investigated if letrozole may have additional immune-sensitizing mechanisms. We found that higher the level of PD-L1 in NSCLC, higher the activation of SREBP1c that transcriptionally increases fatty acid synthase and stearoyl-CoA desaturase enzymes, increasing the amount of polyunsaturated fatty acids (PUFAs). Letrozole further up-regulated SREBP1c-mediated transcription of lipogenic genes, and increased the amount of PUFAs, thereby leading to greater membrane fluidity and reduced binding between PD-L1 and PD-1. The same effects were observed upon supplementation with ω3-PUFA docosahexaenoic acid (DHA) that enhanced the efficacy of pembrolizumab in humanized NSCLC immune-xenografts. We suggest that PUFA enrichment in membrane phospholipids improves the efficacy of ICIs. We propose to repurpose letrozole or DHA as new immune-sensitizing agents in NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Published: 2024
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18. Molecular Basis and Diagnostic Approach to Isolated and Syndromic Lateralized Overgrowth in Childhood.

Author: Bellucca S, Carli D, Gazzin A, Massuras S, Cardaropoli S, Luca M, Coppo P, Caprioglio M, La Selva R, Piglionica M, Bontempo P, D'Elia G, Bagnulo R, Ferrero GB, Resta N, and Mussa A
Subjects: Humans, Retrospective Studies, Female, Male, Child, Child, Preschool, Infant, Growth Disorders diagnosis, Growth Disorders genetics, Adolescent, Class I Phosphatidylinositol 3-Kinases genetics, Beckwith-Wiedemann Syndrome genetics, Beckwith-Wiedemann Syndrome diagnosis
Abstract: Objective: To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics., Study Design: We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum, PIK3CA-related overgrowth spectrum (PROS), vascular overgrowth, or isolated LO, based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield., Results: This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions, and 11% reclassified. Beckwith-Wiedemann spectrum was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PIK3CA-related overgrowth spectrum had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. Vascular overgrowth demonstrated significant clinical overlap with other syndromes. A molecular diagnosis of isolated LO proved challenging, with only 21% of cases classifiable into a specific condition., Conclusions: LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which is crucial for addressing potential cancer predisposition, enabling precision medicine treatments, and guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of a tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield., Competing Interests: Declaration of Competing Interest No funding was required for this work. The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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19. Antibodies get under the skin.

Author: Levra Levron C, Piacenti G, and Donati G
Subjects: Humans, Antibodies metabolism, Antibodies immunology, Sebaceous Glands metabolism, Sebaceous Glands immunology, Animals, Skin Diseases immunology, Skin immunology, Skin metabolism
Abstract: By inhibiting receptor-ligand interactions in sebaceous glands, antibodies may be able to treat certain skin conditions., Competing Interests: CL, GP, GD No competing interests declared, (© 2024, Levra Levron, Piacenti et al.)
Published: 2024
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20. Systematic identification of interchromosomal interaction networks supports the existence of specialized RNA factories.

Author: Hristov BH, Noble WS, and Bertero A
Subjects: Animals, Mice, Humans, RNA metabolism, RNA genetics, Receptors, Odorant genetics, Receptors, Odorant metabolism, Chromosomes genetics, Binding Sites, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, Chromatin metabolism, Chromatin genetics, Gene Regulatory Networks, Computational Biology methods, RNA Splicing, Plasmodium falciparum genetics, Plasmodium falciparum metabolism
Abstract: Most studies of genome organization have focused on intrachromosomal ( cis ) contacts because they harbor key features such as DNA loops and topologically associating domains. Interchromosomal ( trans ) contacts have received much less attention, and tools for interrogating potential biologically relevant trans structures are lacking. Here, we develop a computational framework that uses Hi-C data to identify sets of loci that jointly interact in trans This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets of trans -contacting loci. We validate trans-C in three increasingly complex models of established trans contacts: the Plasmodium falciparum var genes, the mouse olfactory receptor "Greek islands," and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes coregulated by the same trans -acting element (i.e., a transcription or splicing factor) colocalize in three dimensions to form "RNA factories" that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same DNA-binding proteins interact with one another in trans , especially those bound by factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA-binding proteins correlates with trans interaction of the encoding loci. We observe that these trans -interacting loci are close to nuclear speckles. These findings support the existence of trans - interacting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types of trans interactions, empowering studies of a poorly understood aspect of genome architecture., (© 2024 Hristov et al.; Published by Cold Spring Harbor Laboratory Press.)
Published: 2024
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21. Inference and design of antibody specificity: From experiments to models and back.

Author: Fernandez-de-Cossio-Diaz J, Uguzzoni G, Ricard K, Anselmi F, Nizak C, Pagnani A, and Rivoire O
Subjects: Peptide Library, Ligands, Epitopes immunology, Epitopes chemistry, Antibodies chemistry, Antibodies immunology, Protein Engineering methods, Humans, Protein Binding, Antibody Specificity, Computational Biology methods
Abstract: Exquisite binding specificity is essential for many protein functions but is difficult to engineer. Many biotechnological or biomedical applications require the discrimination of very similar ligands, which poses the challenge of designing protein sequences with highly specific binding profiles. Experimental methods for generating specific binders rely on in vitro selection, which is limited in terms of library size and control over specificity profiles. Additional control was recently demonstrated through high-throughput sequencing and downstream computational analysis. Here we follow such an approach to demonstrate the design of specific antibodies beyond those probed experimentally. We do so in a context where very similar epitopes need to be discriminated, and where these epitopes cannot be experimentally dissociated from other epitopes present in the selection. Our approach involves the identification of different binding modes, each associated with a particular ligand against which the antibodies are either selected or not. Using data from phage display experiments, we show that the model successfully disentangles these modes, even when they are associated with chemically very similar ligands. Additionally, we demonstrate and validate experimentally the computational design of antibodies with customized specificity profiles, either with specific high affinity for a particular target ligand, or with cross-specificity for multiple target ligands. Overall, our results showcase the potential of leveraging a biophysical model learned from selections against multiple ligands to design proteins with tailored specificity, with applications to protein engineering extending beyond the design of antibodies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fernandez-de-Cossio-Diaz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Published: 2024
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22. miR-210 is essential to retinal homeostasis in fruit flies and mice.

Author: Colaianni D, Virga F, Tisi A, Stefanelli C, Zaccagnini G, Cusumano P, Sales G, Preda MB, Martelli F, Taverna D, Mazzone M, Bertolucci C, Maccarone R, and De Pittà C
Subjects: Animals, Mice, Mice, Knockout, Lipid Metabolism genetics, Retinal Degeneration genetics, Retinal Degeneration metabolism, Retinal Degeneration physiopathology, MicroRNAs genetics, MicroRNAs metabolism, Retina metabolism, Homeostasis, Drosophila melanogaster genetics
Abstract: Background: miR-210 is one of the most evolutionarily conserved microRNAs. It is known to be involved in several physiological and pathological processes, including response to hypoxia, angiogenesis, cardiovascular diseases and cancer. Recently, new roles of this microRNA are emerging in the context of eye and visual system homeostasis. Recent studies in Drosophila melanogaster unveiled that the absence of miR-210 leads to a progressive retinal degeneration characterized by the accumulation of lipid droplets and disruptions in lipid metabolism. However, the possible conservation of miR-210 knock-out effect in the mammalian retina has yet to be explored., Results: We further investigated lipid anabolism and catabolism in miR-210 knock-out (KO) flies, uncovering significant alterations in gene expression within these pathways. Additionally, we characterized the retinal morphology of flies overexpressing (OE) miR-210, which was not affected by the increased levels of the microRNA. For the first time, we also characterized the retinal morphology of miR-210 KO and OE mice. Similar to flies, miR-210 OE did not affect retinal homeostasis, whereas miR-210 KO mice exhibited photoreceptor degeneration. To explore other potential parallels between miR-210 KO models in flies and mice, we examined lipid metabolism, circadian behaviour, and retinal transcriptome in mice, but found no similarities. Specifically, RNA-seq confirmed the lack of involvement of lipid metabolism in the mice's pathological phenotype, revealing that the differentially expressed genes were predominantly associated with chloride channel activity and extracellular matrix homeostasis. Simultaneously, transcriptome analysis of miR-210 KO fly brains indicated that the observed alterations extend beyond the eye and may be linked to neuronal deficiencies in signal detection and transduction., Conclusions: We provide the first morphological characterization of the retina of miR-210 KO and OE mice, investigating the role of this microRNA in mammalian retinal physiology and exploring potential parallels with phenotypes observed in fly models. Although the lack of similarities in lipid metabolism, circadian behaviour, and retinal transcriptome in mice suggests divergent mechanisms of retinal degeneration between the two species, transcriptome analysis of miR-210 KO fly brains indicates the potential existence of a shared upstream mechanism contributing to retinal degeneration in both flies and mammals., (© 2024. The Author(s).)
Published: 2024
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23. From Cancer to Immune Organoids: Innovative Preclinical Models to Dissect the Crosstalk between Cancer Cells and the Tumor Microenvironment.

Author: Picca F, Giannotta C, Tao J, Giordanengo L, Munir HMW, Botta V, Merlini A, Mogavero A, Garbo E, Poletto S, Bironzo P, Doronzo G, Novello S, Taulli R, and Bersani F
Subjects: Humans, Animals, Immunotherapy methods, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Cancer-Associated Fibroblasts immunology, Tumor Microenvironment immunology, Organoids pathology, Neoplasms immunology, Neoplasms pathology, Neoplasms therapy
Abstract: Genomic-oriented oncology has improved tumor classification, treatment options, and patient outcomes. However, genetic heterogeneity, tumor cell plasticity, and the ability of cancer cells to hijack the tumor microenvironment (TME) represent a major roadblock for cancer eradication. Recent biotechnological advances in organotypic cell cultures have revolutionized biomedical research, opening new avenues to explore the use of cancer organoids in functional precision oncology, especially when genomics alone is not a determinant. Here, we outline the potential and the limitations of tumor organoids in preclinical and translational studies with a particular focus on lung cancer pathogenesis, highlighting their relevance in predicting therapy response, evaluating treatment toxicity, and designing novel anticancer strategies. Furthermore, we describe innovative organotypic coculture systems to dissect the crosstalk with the TME and to test the efficacy of different immunotherapy approaches, including adoptive cell therapy. Finally, we discuss the potential clinical relevance of microfluidic mini-organ technology, capable of reproducing tumor vasculature and the dynamics of tumor initiation and progression, as well as immunomodulatory interactions among tumor organoids, cancer-associated fibroblasts (CAFs) and immune cells, paving the way for next-generation immune precision oncology.
Published: 2024
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24. A Non-natural Peptide Targeting the A-kinase Anchoring Function of PI3Kγ for Therapeutic cAMP Modulation in Pulmonary Cells.

Author: Della Sala A, Tasca L, Butnarasu C, Sala V, Prono G, Murabito A, Garbero OV, Millo E, Terranova L, Blasi F, Gramegna A, Aliberti S, Massarotti A, Visentin S, Hirsch E, and Ghigo A
Abstract: A-kinase anchoring proteins (AKAPs) are key orchestrators of cyclic AMP (cAMP) signaling that act by recruiting protein kinase A (PKA) in proximity of its substrates and regulators to specific subcellular compartments. Modulation of AKAPs function offers the opportunity to achieve compartment-restricted modulation of the cAMP/PKA axis, paving the way to new targeted treatments. For instance, blocking the AKAP activity of PI3Kγ improves lung function by inducing cAMP-mediated bronchorelaxation, ion transport and anti-inflammatory responses. Here, we report the generation of a non-natural peptide, DRI-Pep #20, optimized to disrupt the AKAP function of PI3Kγ. DRI-Pep #20 mimicked the native interaction between the N-terminal domain of PI3Kγ and PKA, demonstrating nanomolar affinity for PKA, high resistance to protease degradation and high permeability to the pulmonary mucus barrier. DRI-Pep #20 triggered cAMP elevation both in vivo in the airway tract of mice upon intratracheal administration, and in vitro in bronchial epithelial cells of cystic fibrosis (CF) patients. In CF cells, DRI-Pep #20 rescued the defective function of the cAMP-operated channel cystic fibrosis conductance regulator (CFTR), by boosting the efficacy of approved CFTR modulators. Overall, this study unveils DRI-Pep #20 as a potent PI3Kγ/PKA disruptor for achieving therapeutic cAMP elevation in chronic respiratory disorders., Competing Interests: Competing Interests Alessandra Ghigo and Emilio Hisch are cofounders and shareholders of Kither Biotech Srl. Valentina Sala and Laura Tasca are employees of Kither Biotech Srl. All other authors report no conflict., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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25. Experimental variables determine the outcome of RAS-RAS interactions.

Author: Zhou Z, Nguyen TL, Li X, Poujol C, Berlinska E, Michelina SV, Kapp JN, Plückthun A, Winslow MM, Ambrogio C, Shan Y, Santamaría D, and Westover KD
Abstract: RAS clustering at the cell membrane is critical to activate signaling in cells, but whether this clustering is mediated exclusively by its c-terminal hypervariable region, receives contributions from the G-domain of RAS, and/or is influenced by secondary effectors has been intensely debated. Reports that G-domain mutations do not modulate RAS-RAS interactions, have led some to question the validity of previous experiments that indicate the G-domain plays a role in RAS clustering/interactions. Here we reconcile these findings by clarifying the impact of experimental variables, such as protein expression levels, cellular context, RAS zygosity, and secondary effector interactions on RAS clustering. Lack of control over these variables impact the results using G-domain mutations across various assay systems and can lead to unsound conclusions., Competing Interests: Declaration of interests K.D.W is a member of the SAB and equity holder in Velorum Therapeutics. Additionally, K.D.W has served on advisory boards or provided professional services for Sanofi, Amgen, Reactive Biosciences, AstraZeneca and Vibliome Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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26. An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress.

Author: Sorge M, Savoré G, Gallo A, Acquarone D, Sbroggiò M, Velasco S, Zamporlini F, Femminò S, Moiso E, Morciano G, Balmas E, Raimondi A, Nattenberg G, Stefania R, Tacchetti C, Rizzo AM, Corsetto P, Ghigo A, Turco E, Altruda F, Silengo L, Pinton P, Raffaelli N, Sniadecki NJ, Penna C, Pagliaro P, Hirsch E, Riganti C, Tarone G, Bertero A, and Brancaccio M
Subjects: Animals, Humans, Mice, Lipid Metabolism, Stress, Physiological, Oxidation-Reduction, Myocardium metabolism, Trimetazidine pharmacology, Mitochondria metabolism, Myocytes, Cardiac metabolism, Reactive Oxygen Species metabolism
Abstract: Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress., (© 2024. The Author(s).)
Published: 2024
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27. Cancer drug-tolerant persister cells: from biological questions to clinical opportunities.

Author: Russo M, Chen M, Mariella E, Peng H, Rehman SK, Sancho E, Sogari A, Toh TS, Balaban NQ, Batlle E, Bernards R, Garnett MJ, Hangauer M, Leucci E, Marine JC, O'Brien CA, Oren Y, Patton EE, Robert C, Rosenberg SM, Shen S, and Bardelli A
Subjects: Tumor Microenvironment, Drug Tolerance, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Neoplasms drug therapy
Abstract: The emergence of drug resistance is the most substantial challenge to the effectiveness of anticancer therapies. Orthogonal approaches have revealed that a subset of cells, known as drug-tolerant 'persister' (DTP) cells, have a prominent role in drug resistance. Although long recognized in bacterial populations which have acquired resistance to antibiotics, the presence of DTPs in various cancer types has come to light only in the past two decades, yet several aspects of their biology remain enigmatic. Here, we delve into the biological characteristics of DTPs and explore potential strategies for tracking and targeting them. Recent findings suggest that DTPs exhibit remarkable plasticity, being capable of transitioning between different cellular states, resulting in distinct DTP phenotypes within a single tumour. However, defining the biological features of DTPs has been challenging, partly due to the complex interplay between clonal dynamics and tissue-specific factors influencing their phenotype. Moreover, the interactions between DTPs and the tumour microenvironment, including their potential to evade immune surveillance, remain to be discovered. Finally, the mechanisms underlying DTP-derived drug resistance and their correlation with clinical outcomes remain poorly understood. This Roadmap aims to provide a comprehensive overview of the field of DTPs, encompassing past achievements and current endeavours in elucidating their biology. We also discuss the prospect of future advancements in technologies in helping to unveil the features of DTPs and propose novel therapeutic strategies that could lead to their eradication., (© 2024. Springer Nature Limited.)
Published: 2024
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28. A novel combinatory treatment against a CDDP-resistant non-small cell lung cancer based on a Ruthenium(II)-cyclopentadienyl compound.

Author: Salaroglio IC, Stefanova D, Teixeira RG, Oliveira NFB, Ahmed A, Fusi F, Tzankova V, Yordanov Y, Machuqueiro M, Saponara S, Valente A, and Riganti C
Subjects: Humans, Animals, Cell Line, Tumor, Mice, Nude, Apoptosis drug effects, Xenograft Model Antitumor Assays, Ruthenium chemistry, Ruthenium pharmacology, Mice, DNA Damage drug effects, Organometallic Compounds pharmacology, Organometallic Compounds therapeutic use, Female, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Cisplatin pharmacology, Cisplatin therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Drug Resistance, Neoplasm drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use
Abstract: The therapeutic approach to many solid tumors, including non-small cell lung cancer (NSCLC), is mainly based on the use of platinum-containing anticancer agents and is often characterized by acquired or intrinsic resistance to the drug. Therefore, the search for safer and more effective drugs is still an open challenge. Two organometallic ruthenium(II)-cyclopentadienyl compounds [Ru(η 5 -C 5 H 4 CHO)(Me 2 bipy)(PPh 3 )] + (RT150) and [Ru(η 5 -C 5 H 4 CH 2 OH)(Me 2 bipy)(PPh 3 )][CF 3 SO 3 ] (RT151) were tested against a panel of cisplatin-resistant NSCLC cell lines and xenografts. They were more effective than cisplatin in inducing oxidative stress and DNA damage, affecting the cell cycle and causing apoptosis. Importantly, they were found to be inhibitors of drug efflux transporters. Due to this property, the compounds significantly increased the retention and cytotoxicity of cisplatin within NSCLC cells. Notably, they did not display high toxicity in vitro against non-transformed cells (red blood cells, fibroblasts, bronchial epithelial cells, cardiomyocytes, and endothelial cells). Both compounds induced vasorelaxation and reduced endothelial cell migration, suggesting potential anti-angiogenic properties. RT151 confirmed its efficacy against NSCLC xenografts resistant to cisplatin. Either alone or combined with low doses of cisplatin, RT151 showed a good biodistribution profile in the liver, kidney, spleen, lung, and tumor. Hematochemical analysis and post-mortem organ pathology confirmed the safety of the compound in vivo, also when combined with cisplatin. To sum up, we have confirmed the effectiveness of a novel class of drugs against cisplatin-resistant NSCLC. Additionally, the compounds have a good biocompatibility and safety profile., Competing Interests: Declaration of Competing Interest The Authors declare that they have not conflicts of interest. The Authors declare that they do not have used any artificial intelligence-based tools during the writing process., (Copyright © 2024. Published by Elsevier Ltd.)
Published: 2024
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29. Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy.

Author: van der Sluijs PJ, Moutton S, Dingemans AJM, Weis D, Levy MA, Boycott KM, Arberas C, Baldassarri M, Beneteau C, Brusco A, Coutton C, Dabir T, Dentici ML, Devriendt K, Faivre L, van Haelst MM, Jizi K, Kempers MJ, Kerkhof J, Kharbanda M, Lachlan K, Marle N, McConkey H, Mencarelli MA, Mowat D, Niceta M, Nicolas C, Novelli A, Orlando V, Pichon O, Rankin J, Relator R, Ropers FG, Rosenfeld JA, Sachdev R, Sandaradura SA, Shukarova-Angelovska E, Steenbeek D, Tartaglia M, Tedder MA, Trajkova S, Winer N, Woods J, de Vries BBA, Sadikovic B, Alders M, and Santen GWE
Abstract: Background: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype., Methods: We collected patients with duplications encompassing ARID1A and ARID1B duplications., Results: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1-1.2 Mb(1-44 genes) for ARID1A and 0.9-10.3 Mb(2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation re-analysis, resulting in the reclassification of two ARID1A and two ARID1B duplications as pathogenic., Conclusion: Our findings reveal that ARID1B duplications manifest a clinical phenotype and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole gene duplication rather than haploinsufficiency., (Copyright © 2024. Published by Elsevier Inc.)
Published: 2024
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30. Prediction and functional interpretation of inter-chromosomal genome architecture from DNA sequence with TwinC.

Author: Jha A, Hristov B, Wang X, Wang S, Greenleaf WJ, Kundaje A, Aiden EL, Bertero A, and Noble WS
Abstract: Three-dimensional nuclear DNA architecture comprises well-studied intra-chromosomal ( cis ) folding and less characterized inter-chromosomal ( trans ) interfaces. Current predictive models of 3D genome folding can effectively infer pairwise cis -chromatin interactions from the primary DNA sequence but generally ignore trans contacts. There is an unmet need for robust models of trans -genome organization that provide insights into their underlying principles and functional relevance. We present TwinC, an interpretable convolutional neural network model that reliably predicts trans contacts measurable through genome-wide chromatin conformation capture (Hi-C). TwinC uses a paired sequence design from replicate Hi-C experiments to learn single base pair relevance in trans interactions across two stretches of DNA. The method achieves high predictive accuracy (AUROC=0.80) on a cross-chromosomal test set from Hi-C experiments in heart tissue. Mechanistically, the neural network learns the importance of compartments, chromatin accessibility, clustered transcription factor binding and G-quadruplexes in forming trans contacts. In summary, TwinC models and interprets trans genome architecture, shedding light on this poorly understood aspect of gene regulation., Competing Interests: Competing interests A. K. is on the scientific advisory board of SerImmune, TensorBio, and AINovo, a consultant with Arcardia Science and Inari, a consultant with Illumina and PatchBio and has a financial stake in DeepGenomics, Immunai, SerImmune and Freenome.
Published: 2024
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31. Cancer cell stiffening via CoQ 10 and UBIAD1 regulates ECM signaling and ferroptosis in breast cancer.

Author: Tosi G, Paoli A, Zuccolotto G, Turco E, Simonato M, Tosoni D, Tucci F, Lugato P, Giomo M, Elvassore N, Rosato A, Cogo P, Pece S, and Santoro MM
Subjects: Humans, Animals, Female, Mice, Cell Line, Tumor, Cell Membrane metabolism, Lung Neoplasms metabolism, Lung Neoplasms pathology, Lung Neoplasms genetics, Gene Expression Regulation, Neoplastic, Ubiquinone analogs & derivatives, Ubiquinone metabolism, Ferroptosis genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, Breast Neoplasms genetics, Breast Neoplasms drug therapy, Extracellular Matrix metabolism, Signal Transduction
Abstract: CoQ 10 (Coenzyme Q 10 ) is an essential fat-soluble metabolite that plays a key role in cellular metabolism. A less-known function of CoQ 10 is whether it may act as a plasma membrane-stabilizing agent and whether this property can affect cancer development and progression. Here, we show that CoQ 10 and its biosynthetic enzyme UBIAD1 play a critical role in plasmamembrane mechanical properties that are of interest for breast cancer (BC) progression and treatment. CoQ 10 and UBIAD1 increase membrane fluidity leading to increased cell stiffness in BC. Furthermore, CoQ 10 and UBIAD1 states impair ECM (extracellular matrix)-mediated oncogenic signaling and reduce ferroptosis resistance in BC settings. Analyses on human patients and mouse models reveal that UBIAD1 loss is associated with BC development and progression and UBIAD1 expression in BC limits CTCs (circulating tumor cells) survival and lung metastasis formation. Overall, this study reveals that CoQ 10 and UBIAD1 can be further investigated to develop therapeutic interventions to treat BC patients with poor prognosis., (© 2024. The Author(s).)
Published: 2024
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32. Early-onset cancers: Biological bases and clinical implications.

Author: Mauri G, Patelli G, Sartore-Bianchi A, Abrignani S, Bodega B, Marsoni S, Costanzo V, Bachi A, Siena S, and Bardelli A
Subjects: Humans, Environmental Exposure adverse effects, Risk Factors, Exposome, Neoplasms pathology, Age of Onset
Abstract: Since the nineties, the incidence of sporadic early-onset (EO) cancers has been rising worldwide. The underlying reasons are still unknown. However, identifying them is vital for advancing both prevention and intervention. Here, we exploit available knowledge derived from clinical observations to formulate testable hypotheses aimed at defining the causal factors of this epidemic and discuss how to experimentally test them. We explore the potential impact of exposome changes from the millennials to contemporary young generations, considering both environmental exposures and enhanced susceptibilities to EO-cancer development. We emphasize how establishing the time required for an EO cancer to develop is relevant to defining future screening strategies. Finally, we discuss the importance of integrating multi-dimensional data from international collaborations to generate comprehensive knowledge and translate these findings back into clinical practice., Competing Interests: Declaration of interests A. Bardelli reports personal fees from Guardant Health and Inivata during the conduct of the study as well as grants from AstraZeneca, Boehringer Ingelheim, and NeoPhore outside the submitted work; in addition, A. Bardelli is a shareholder of NeoPhore and Kither. G.M. and G.P. received honoraria from COR2ED. S.S. is an advisory board member for Agenus, AstraZeneca, Bayer, BMS, CheckmAb, Daiichi Sankyo, Guardant Health, Merck, Novartis, Roche-Genentech, and Seagen. A.S.-B. reports personal fees from Amgen, Bayer, Pierre Fabre, Servier, Guardant Health, and Novartis during the conduct of the study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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33. DNA repair-dependent immunogenic liabilities in colorectal cancer: opportunities from errors.

Author: Amodio V, Vitiello PP, Bardelli A, and Germano G
Abstract: Colorectal cancer (CRC) remains one of the major causes of cancer death worldwide. Chemotherapy continues to serve as the primary treatment modality, while immunotherapy is largely ineffective for the majority of CRC patients. Seminal discoveries have emphasized that modifying DNA damage response (DDR) mechanisms confers both cell-autonomous and immune-related vulnerabilities across various cancers. In CRC, approximately 15% of tumours exhibit alterations in the mismatch repair (MMR) machinery, resulting in a high number of neoantigens and the activation of the type I interferon response. These factors, in conjunction with immune checkpoint blockades, collectively stimulate anticancer immunity. Furthermore, although less frequently, somatic alterations in the homologous recombination (HR) pathway are observed in CRC; these defects lead to genome instability and telomere alterations, supporting the use of poly (ADP-ribose) polymerase (PARP) inhibitors in HR-deficient CRC patients. Additionally, other DDR inhibitors, such as Ataxia Telangiectasia and Rad3-related protein (ATR) inhibitors, have shown some efficacy both in preclinical models and in the clinical setting, irrespective of MMR proficiency. The aim of this review is to elucidate how preexisting or induced vulnerabilities in DNA repair pathways represent an opportunity to increase tumour sensitivity to immune-based therapies in CRC., (© 2024. The Author(s).)
Published: 2024
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34. MicroRNAs in metabolism for precision treatment of lung cancer.

Author: Carrà G, Petiti J, Tolino F, Vacca R, and Orso F
Subjects: Humans, Precision Medicine methods, Tumor Microenvironment genetics, Gene Expression Regulation, Neoplastic, Animals, Energy Metabolism genetics, Autophagy genetics, MicroRNAs genetics, MicroRNAs metabolism, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms therapy
Abstract: The dysregulation of miRNAs in lung cancer has been extensively documented, with specific miRNAs acting as both tumor suppressors and oncogenes, depending on their target genes. Recent research has unveiled the regulatory roles of miRNAs in key metabolic pathways, such as glycolysis, the tricarboxylic acid cycle, fatty acid metabolism, and autophagy, which collectively contribute to the aberrant energy metabolism characteristic of cancer cells. Furthermore, miRNAs are increasingly recognized as critical modulators of the tumor microenvironment, impacting immune response and angiogenesis. This review embarks on a comprehensive journey into the world of miRNAs, unraveling their multifaceted roles, and more notably, their emerging significance in the context of cancer, with a particular focus on lung cancer. As we navigate this extensive terrain, we will explore the fascinating realm of miRNA-mediated metabolic rewiring, a phenomenon that plays a pivotal role in the progression of lung cancer and holds promise in the development of novel therapeutic strategies., (© 2024. The Author(s).)
Published: 2024
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35. Targeting stress induction of GRP78 by cardiac glycoside oleandrin dually suppresses cancer and COVID-19.

Author: Ha DP, Shin WJ, Liu Z, Doche ME, Lau R, Leli NM, Conn CS, Russo M, Lorenzato A, Koumenis C, Yu M, Mumenthaler SM, and Lee AS
Abstract: Background: Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19., Results: Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na + /K + -ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release., Conclusion: Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19., (© 2024. The Author(s).)
Published: 2024
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36. A Multicenter Real-life Prospective Study of Axicabtagene Ciloleucel versus Tisagenlecleucel Toxicity and Outcomes in Large B-cell Lymphomas.

Author: Stella F, Chiappella A, Casadei B, Bramanti S, Ljevar S, Chiusolo P, Di Rocco A, Tisi MC, Carrabba MG, Cutini I, Martino M, Dodero A, Bonifazi F, Santoro A, Sorà F, Botto B, Barbui AM, Russo D, Musso M, Grillo G, Krampera M, Olivieri J, Ladetto M, Cavallo F, Massaia M, Arcaini L, Pennisi M, Zinzani PL, Miceli R, and Corradini P
Subjects: Humans, Male, Female, Middle Aged, Prospective Studies, Aged, Adult, Antigens, CD19 immunology, Antigens, CD19 therapeutic use, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Treatment Outcome, Receptors, Antigen, T-Cell therapeutic use, Receptors, Antigen, T-Cell immunology, Aged, 80 and over, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse immunology, Lymphoma, Large B-Cell, Diffuse mortality, Biological Products adverse effects, Biological Products therapeutic use, Biological Products administration & dosage
Abstract: This real-world prospective observational study across 21 Italian centers (CART-SIE) compares axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) outcomes in 485 patients with relapsed/refractory large B-cell lymphoma with baseline characteristics matched by stabilized inverse propensity score weighting. Axi-cel versus tisa-cel had higher all-grade cytokine release syndrome (78.6% vs. 89.3%, P = 0.0017) and neurotoxicity (9.9% vs. 32.2%, P < 0.0001) but also superior progression-free survival (PFS) at 1 year (46.5% vs. 34.1%, P = 0.0009). Even among patients who failed bridging therapy, axi-cel PFS was superior to tisa-cel (37.5% vs. 22.7%, P = 0.0059). Differences in overall survival and high-grade immune toxicities were not significant. The CAR-HEMATOTOX score not only predicted hematologic toxicity but also 1-year survival outcomes (51.5% in CAR-HEMATOTOX high vs. 77.2% in CAR-HEMATOTOX low, P < 0.0001). Twenty patients developed second primary malignancies, including two cases of T-cell neoplasms. These findings enable more informed selection of anti-CD19 CAR T-cell therapy, balancing bridging, safety, and efficacy considerations for individual patients. Significance: The findings of this study on 485 patients with relapsed/refractory large B-cell lymphoma treated with commercial axi-cel and tisa-cel indicate axi-cel's superior PFS after propensity score weighting. The predictive utility of CAR-HEMATOTOX in assessing not only toxicity but also outcomes across both CAR T-cell products may guide future risk-stratified management strategies., (©2024 The Authors; Published by the American Association for Cancer Research.)
Published: 2024
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37. Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors.

Author: Fernández-García F, Fernández-Rodríguez A, Fustero-Torre C, Piñeiro-Yáñez E, Wang H, Lechuga CG, Callejas S, Álvarez R, López-García A, Esteban-Burgos L, Salmón M, San Román M, Guerra C, Ambrogio C, Drosten M, Santamaría D, Al-Shahrour F, Dopazo A, Barbacid M, and Musteanu M
Subjects: Animals, Mice, Humans, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, AMP-Activated Protein Kinase Kinases, Cell Line, Tumor, Tumor Microenvironment immunology, Tumor Microenvironment genetics, AMP-Activated Protein Kinases, Lung Neoplasms genetics, Lung Neoplasms immunology, Lung Neoplasms pathology, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Interferon Type I metabolism, Interferon Type I genetics, Signal Transduction, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors pharmacology, Mutation
Abstract: Lung cancer is the leading cause of cancer mortality worldwide. KRAS oncogenes are responsible for at least a quarter of lung adenocarcinomas, the main subtype of lung cancer. After four decades of intense research, selective inhibitors of KRAS oncoproteins are finally reaching the clinic. Yet, their effect on overall survival is limited due to the rapid appearance of drug resistance, a likely consequence of the high intratumoral heterogeneity characteristic of these tumors. In this study, we have attempted to identify those functional alterations that result from KRAS oncoprotein expression during the earliest stages of tumor development. Such functional changes are likely to be maintained during the entire process of tumor progression regardless of additional co-occurring mutations. Single-cell RNA sequencing analysis of murine alveolar type 2 cells expressing a resident Kras oncogene revealed impairment of the type I interferon pathway, a feature maintained throughout tumor progression. This alteration was also present in advanced murine and human tumors harboring additional mutations in the p53 or LKB1 tumor suppressors. Restoration of type I interferon (IFN) signaling by IFN-β or constitutive active stimulator of interferon genes (STING) expression had a profound influence on the tumor microenvironment, switching them from immunologically "cold" to immunologically "hot" tumors. Therefore, enhancement of the type I IFN pathway predisposes KRAS mutant lung tumors to immunotherapy treatments, regardless of co-occurring mutations in p53 or LKB1., Competing Interests: Competing interests statement:The authors declare no competing interest.
Published: 2024
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38. Coding, or non-coding, that is the question.

Author: Poliseno L, Lanza M, and Pandolfi PP
Subjects: Humans, Animals, Protein Biosynthesis, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Untranslated genetics, RNA, Untranslated metabolism, Open Reading Frames genetics
Abstract: The advent of high-throughput sequencing uncovered that our genome is pervasively transcribed into RNAs that are seemingly not translated into proteins. It was also found that non-coding RNA transcripts outnumber canonical protein-coding genes. This mindboggling discovery prompted a surge in non-coding RNA research that started unraveling the functional relevance of these new genetic units, shaking the classic definition of "gene". While the non-coding RNA revolution was still taking place, polysome/ribosome profiling and mass spectrometry analyses revealed that peptides can be translated from non-canonical open reading frames. Therefore, it is becoming evident that the coding vs non-coding dichotomy is way blurrier than anticipated. In this review, we focus on several examples in which the binary classification of coding vs non-coding genes is outdated, since the same bifunctional gene expresses both coding and non-coding products. We discuss the implications of this intricate usage of transcripts in terms of molecular mechanisms of gene expression and biological outputs, which are often concordant, but can also surprisingly be discordant. Finally, we discuss the methodological caveats that are associated with the study of bifunctional genes, and we highlight the opportunities and challenges of therapeutic exploitation of this intricacy towards the development of anticancer therapies., (© 2024. The Author(s).)
Published: 2024
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39. Association between intestinal microflora and obesity.

Author: Savytska M, Kozyk M, Strubchevska K, Yosypenko K, Falalyeyeva T, Kobyliak N, Boccuto L, Pellicano R, Fagoonee S, Scarpellini E, and Abenavoli L
Subjects: Humans, Prebiotics, Anti-Bacterial Agents therapeutic use, Obesity microbiology, Gastrointestinal Microbiome, Dysbiosis complications, Probiotics therapeutic use
Abstract: Obesity has become one of modern society's most serious health problems. Studies from the last 30 years revealed a direct relationship between imbalanced energy intake and increased healthcare costs related to the treatment or management of obesity. Recent research has highlighted significant effects of gut microbial composition on obesity. We aimed to report the current knowledge on the definition, composition, and functions of intestinal microbiota. We have performed an extensive review of the literature searching for the following key words: metabolism, gut microbiota, dysbiosis, and obesity. There is evidence that an association between intestinal microbiota and obesity exists at any age. There are complex genetic, metabolic, and inflammatory mechanisms involved in the pathogenesis of obesity. Revision of indications for use of probiotics, prebiotics, and antibiotics in obese patients should be considered. Microbial composition of the gut may be an important factor involved in the development of obesity. Changes in the gut microbiota may result in changes in human metabolism and weight loss.
Published: 2024
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40. Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family.

Author: Trinchillo A, Valente V, Esposito M, Migliaccio M, Iovino A, Picciocchi M, Cuomo N, Caccavale C, Nocerino C, De Rosa L, Salvatore E, Pierantoni GM, Menchise V, Paladino S, and Criscuolo C
Subjects: Humans, Female, Male, Adult, Middle Aged, Phenotype, Young Adult, Adolescent, Genes, Dominant, Child, Aged, Spastic Paraplegia, Hereditary genetics, Pedigree, Membrane Proteins genetics, Mutation
Abstract: Background: SPG18 is caused by mutations in the endoplasmic reticulum lipid raft associated 2 (ERLIN2) gene. Autosomal recessive (AR) mutations are usually associated with complicated hereditary spastic paraplegia (HSP), while autosomal dominant (AD) mutations use to cause pure SPG18., Aim: To define the variegate clinical spectrum of the SPG18 and to evaluate a dominant negative effect of erlin2 (encoded by ERLIN2) on oligomerization as causing differences between AR and AD phenotypes., Methods: In a four-generation pedigree with an AD pattern, a spastic paraplegia multigene panel test was performed. Oligomerization of erlin2 was analyzed with velocity gradient assay in fibroblasts of the proband and healthy subjects., Results: Despite the common p.V168M mutation identified in ERLIN2, a phenoconversion to amyotrophic lateral sclerosis (ALS) was observed in the second generation, pure HSP in the third generation, and a complicated form with psychomotor delay and epilepsy in the fourth generation. Erlin2 oligomerization was found to be normal., Discussion: We report the first AD SPG18 family with a complicated phenotype, and we ruled out a dominant negative effect of V168M on erlin2 oligomerization. Therefore, our data do not support the hypothesis of a relationship between the mode of inheritance and the phenotype, but confirm the multifaceted nature of SPG18 on both genetic and clinical point of view. Clinicians should be aware of the importance of conducting an in-depth clinical evaluation to unmask all the possible manifestations associated to an only apparently pure SPG18 phenotype. We confirm the genotype-phenotype correlation between V168M and ALS emphasizing the value of close follow-up., (© 2024. The Author(s).)
Published: 2024
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41. RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade.

Author: Nokin MJ, Mira A, Patrucco E, Ricciuti B, Cousin S, Soubeyran I, San José S, Peirone S, Caizzi L, Vietti Michelina S, Bourdon A, Wang X, Alvarez-Villanueva D, Martínez-Iniesta M, Vidal A, Rodrigues T, García-Macías C, Awad MM, Nadal E, Villanueva A, Italiano A, Cereda M, Santamaría D, and Ambrogio C
Subjects: Humans, Animals, Mice, Cell Line, Tumor, Mutation, Female, Xenograft Model Antitumor Assays, Guanosine Triphosphate metabolism, Acetonitriles, Piperazines, Pyridines, Pyrimidines, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors, Proto-Oncogene Proteins p21(ras) metabolism, Drug Resistance, Neoplasm genetics, Drug Resistance, Neoplasm drug effects, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms pathology
Abstract: Selective KRAS G12C inhibitors have been developed to covalently lock the oncogene in the inactive GDP-bound state. Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRAS G12C -mutated previously treated advanced non-small cell lung cancer. Drug treatment imposes selective pressures leading to the outgrowth of drug-resistant variants. Mass sequencing from patients' biopsies identified a number of acquired KRAS mutations -both in cis and in trans- in resistant tumors. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS-GTP loading. Using the preclinical tool tri-complex KRAS G12C -selective covalent inhibitor, RMC-4998 (also known as RM-029), that targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRAS G12C (ON) inhibitor RMC-6291 alone or in combination with KRAS G12C (OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading., (© 2024. The Author(s).)
Published: 2024
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42. Correction: TFEB controls sensitivity to chemotherapy and immuno-killing in non-small cell lung cancer.

Author: Akman M, Monteleone C, Doronzo G, Godel M, Napoli F, Merlini A, Campani V, Nele V, Balmas E, Chontorotzea T, Fontana S, Digiovanni S, Alice Barbu F, Astanina E, Jafari N, Chiara Salaroglio I, Kopecka J, De Rosa G, Mohr T, Bertero A, Righi L, Novello S, Vittorio Scagliotti G, Bussolino F, and Riganti C
Published: 2024
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43. MCT1-dependent lactate recycling is a metabolic vulnerability in colorectal cancer cells upon acquired resistance to anti-EGFR targeted therapy.

Author: Richiardone E, Al Roumi R, Lardinois F, Giolito MV, Ambroise J, Boidot R, Drotleff B, Ghesquière B, Bellahcène A, Bardelli A, Arena S, and Corbet C
Subjects: Humans, Cell Line, Tumor, Animals, Mice, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Glycolysis drug effects, Xenograft Model Antitumor Assays, Cell Proliferation drug effects, Monocarboxylic Acid Transporters metabolism, Monocarboxylic Acid Transporters genetics, Monocarboxylic Acid Transporters antagonists & inhibitors, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Colorectal Neoplasms metabolism, Colorectal Neoplasms genetics, Drug Resistance, Neoplasm, Symporters metabolism, Symporters genetics, Lactic Acid metabolism, ErbB Receptors metabolism, ErbB Receptors antagonists & inhibitors, Cetuximab pharmacology
Abstract: Despite the implementation of personalized medicine, patients with metastatic CRC (mCRC) still have a dismal overall survival due to the frequent occurrence of acquired resistance mechanisms thereby leading to clinical relapse. Understanding molecular mechanisms that support acquired resistance to anti-EGFR targeted therapy in mCRC is therefore clinically relevant and key to improving patient outcomes. Here, we observe distinct metabolic changes between cetuximab-resistant CRC cell populations, with in particular an increased glycolytic activity in KRAS-mutant cetuximab-resistant CRC cells (LIM1215 and OXCO2) but not in KRAS-amplified resistant DiFi cells. We show that cetuximab-resistant LIM1215 and OXCO2 cells have the capacity to recycle glycolysis-derived lactate to sustain their growth capacity. This is associated with an upregulation of the lactate importer MCT1 at both transcript and protein levels. Pharmacological inhibition of MCT1, with AR-C155858, reduces the uptake and oxidation of lactate and impairs growth capacity in cetuximab-resistant LIM1215 cells both in vitro and in vivo. This study identifies MCT1-dependent lactate utilization as a clinically actionable, metabolic vulnerability to overcome KRAS-mutant-mediated acquired resistance to anti-EGFR therapy in CRC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.A. reports personal fees from MSD Italia and a patent (international PCT patent application No. WO 2023/199255 and Italian patent application No. 102022000007535) outside the submitted work. A.Ba. reports receipt of grants/research support from Neophore, AstraZeneca and Boehringer Ingelheim and honoraria/consultation fees from Guardant Health and Inivata. A.Ba. is a stock shareholder of Neophore and Kither Biotech. A.Ba. is an advisory board member for Inivata, Neophore, Roche/Genentech. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Published: 2024
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44. Mechanisms of damage and therapies for cardiac amyloidosis: a role for inflammation?

Author: Bellofatto IA, Nikolaou PE, Andreadou I, Canepa M, Carbone F, Ghigo A, Heusch G, Kleinbongard P, Maack C, Podesser BK, Stamatelopoulos K, Stellos K, Vilahur G, Montecucco F, and Liberale L
Abstract: The term cardiac amyloidosis (CA) refers to the accumulation of extracellular amyloid deposits in the heart because of different conditions often affecting multiple organs including brain, kidney and liver. Notably, cardiac involvement significantly impacts prognosis of amyloidosis, with cardiac biomarkers playing a pivotal role in prognostic stratification. Therapeutic management poses a challenge due to limited response to conventional heart failure therapies, necessitating targeted approaches aimed at preventing, halting or reversing amyloid deposition. Mechanisms underlying organ damage in CA are multifactorial, involving proteotoxicity, oxidative stress, and mechanical interference. While the role of inflammation in CA remains incompletely understood, emerging evidence suggests its potential contribution to disease progression as well as its utility as a therapeutic target. This review reports on the cardiac involvement in systemic amyloidosis, its prognostic role and how to assess it. Current and emerging therapies will be critically discussed underscoring the need for further efforts aiming at elucidating CA pathophysiology. The emerging evidence suggesting the contribution of inflammation to disease progression and its prognostic role will also be reviewed possibly offering insights into novel therapeutic avenues for CA., (© 2024. The Author(s).)
Published: 2024
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45. Active thymus in adult with lung cancer: preliminary results from the Adult Thymic Project.

Author: Sobrero S, Patrucco E, Napoli F, Ragazzini R, Milazzo R, Vaisitti F, Ambrogio C, Bonfanti P, Rena O, Ruffini E, Righi L, and Leo F
Abstract: Thymus is considered a non-functional remnant in adults, but some evidence suggest that it may harbor residual activity. Lung cancer patients represent the ideal model to study thymic residual activity, as their thymus can be easily harvested during surgery. This study was designed to confirm the presence of residual thymic activity both in adult mice (step 1) and in humans (step 2). In step 1, lung cancer was induced by activating k-ras mutation in a cohort of 20 young and adult mice. After killing, thymus and lungs were analyzed. Thymus was considered active when medullary was evident, cortico-medullary ratio was 50:50 or higher and adipose involution was present. In step 2, a cohort of 20 patients, undergoing surgery for lung cancer, had biopsy of pericardial fat pad, site of ectopic thymus. Thymus was considered present if Hassall's bodies were detected. In mice, active thymus was detected in a high proportion of cases, without significant difference between adult and young (70% vs 44.4% respectively). Two cases without evidence of lung tumor had a fully functional thymus. In humans, ectopic thymus was detected in the pericardial fat pad in 2 cases (10.5%), confirmed by immunohistochemistry. Signs of previous thymic activity were detected in 8 additional patients. Results confirmed thymus activity in animal models and humans with lung cancer, providing the rationale for future systematic mediastinal thymic biopsy. The comprehension of interactions between thymus, lymphocytes and tumor may open a new potentially targetable perspective in lung cancer., (© 2024. The Author(s).)
Published: 2024
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46. In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAF V600E lung adenocarcinoma.

Author: Nokin MJ, Darbo E, Richard E, San José S, de Hita S, Prouzet-Mauleon V, Turcq B, Gerardelli L, Crake R, Velasco V, Koopmansch B, Lambert F, Xue JY, Sang B, Horne J, Ziemons E, Villanueva A, Blomme A, Herfs M, Cataldo D, Calvayrac O, Porporato P, Nadal E, Lito P, Jänne PA, Ricciuti B, Awad MM, Ambrogio C, and Santamaría D
Subjects: Humans, Cell Line, Tumor, Animals, Ferroptosis drug effects, Ferroptosis genetics, Mice, Oxidative Stress drug effects, Oximes pharmacology, Imidazoles pharmacology, Pyridones pharmacology, Pyrimidinones pharmacology, Lipid Peroxidation drug effects, Mutation genetics, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung pathology, Adenocarcinoma of Lung metabolism, Phospholipid Hydroperoxide Glutathione Peroxidase metabolism, Phospholipid Hydroperoxide Glutathione Peroxidase genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Lung Neoplasms metabolism, Histone Deacetylase Inhibitors pharmacology
Abstract: The current targeted therapy for BRAF V600E -mutant lung cancer consists of a dual blockade of RAF/MEK kinases often combining dabrafenib/trametinib (D/T). This regimen extends survival when compared to single-agent treatments, but disease progression is unavoidable. By using whole-genome CRISPR screening and RNA sequencing, we characterize the vulnerabilities of both persister and D/T-resistant cellular models. Oxidative stress together with concomitant induction of antioxidant responses is boosted by D/T treatment. However, the nature of the oxidative damage, the choice of redox detoxification systems, and the resulting therapeutic vulnerabilities display stage-specific differences. Persister cells suffer from lipid peroxidation and are sensitive to ferroptosis upon GPX4 inhibition in vivo. Biomarkers of lipid peroxidation are detected in clinical samples following D/T treatment. Acquired alterations leading to mitogen-activated protein kinase (MAPK) reactivation enhance cystine transport to boost GPX4-independent antioxidant responses. Similarly to BRAF V600E -mutant melanoma, histone deacetylase (HDAC) inhibitors decrease D/T-resistant cell viability and extend therapeutic response in vivo., Competing Interests: Declaration of interests D.S. received research fees from Aelin Therapeutics. C.A. received research fees from Revolution Medicines, Aelin Therapeutics, Verastem, Roche, and Boehringer Ingelheim. E.N. reports research funding from Pfizer and Roche. P.L. is listed as an inventor on patent applications filed by MSKCC that describe approaches to treat KRAS or BRAF-mutant tumors. P.A.J. has received consulting fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Takeda Oncology, ACEA Biosciences, Eli Lilly and Company, Araxes Pharma, Ignyta, Mirati Therapeutics, Novartis, Loxo Oncology, Daiichi Sankyo, Sanofi Oncology, Voronoi, SFJ Pharmaceuticals, Takeda Oncology, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Biocartis, Allorion Therapeutics, Accutar Biotech, Monte Rosa, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality, and AbbVie; post-marketing royalties from DFCI-owned intellectual property on EGFR mutations licensed to Lab Corp; sponsored research agreements with AstraZeneca, Daiichi Sankyo, Puma, Boehringer Ingelheim, Eli Lilly and Company, Revolution Medicines, and Astellas Pharmaceuticals; and stock ownership in Gatekeeper Pharmaceuticals. M.M.A. reports grants and personal fees from Genentech, grants and personal fees from Bristol Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, grants from Lilly, and personal fees from Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDX, Mirati, NextCure, Novartis, EMD Serono, and Panvaxal/NovaRx, outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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47. In pancreatic cancer patients, chemotherapy reshapes the gene expression profile and antigen receptor repertoire of T lymphocytes and enhances their effector response to tumor-associated antigens.

Author: Brugiapaglia S, Bulfamante S, Curcio C, Arigoni M, Calogero R, Bonello L, Genuardi E, Spadi R, Satolli MA, Campra D, Giordano D, Cappello P, Cordero F, and Novelli F
Subjects: Humans, Male, Female, Transcriptome, Aged, Middle Aged, T-Lymphocytes immunology, T-Lymphocytes metabolism, Gene Expression Regulation, Neoplastic, Gene Expression Profiling, Phosphopyruvate Hydratase genetics, Phosphopyruvate Hydratase immunology, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Receptors, Antigen, T-Cell immunology, Pancreatic Neoplasms immunology, Pancreatic Neoplasms therapy, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Antigens, Neoplasm immunology, Antigens, Neoplasm genetics, Carcinoma, Pancreatic Ductal therapy, Carcinoma, Pancreatic Ductal immunology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal drug therapy
Abstract: Introduction: Pancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 13%. Less than 20% of patients have a resectable tumor at diagnosis due to the lack of distinctive symptoms and reliable biomarkers. PDA is resistant to chemotherapy (CT) and understanding how to gain an anti-tumor effector response following stimulation is, therefore, critical for setting up an effective immunotherapy., Methods: Proliferation, and cytokine release and TCRB repertoire of from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumor-associated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. Transcriptional state of PDA patient PBMC was investigated using RNA-Seq before and after CT., Results: CT increased the number of TAA recognized by T lymphocytes, which positively correlated with patient survival, and high IFN-γ production TAA-induced responses were significantly increased after CT. We found that some ENO1-stimulated T cell clonotypes from CT-treated patients were expanded or de-novo induced, and that some clonotypes were reduced or even disappeared after CT. Patients that showed a higher number of effector responses to TAA (high IFN-γ/IL-10 ratio) after CT expressed increased fatty acid-related transcriptional signature. Conversely, patients that showed a higher number of regulatory responses to TAA (low IFN-γ/IL-10 ratio) after CT significantly expressed an increased IRAK1/IL1R axis-related transcriptional signature., Conclusion: These data suggest that the expression of fatty acid or IRAK1/IL1Rrelated genes predicts T lymphocyte effector or regulatory responses to TAA in patients that undergo CT. These findings are a springboard to set up precision immunotherapies in PDA based on the TAA vaccination in combination with CT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Brugiapaglia, Bulfamante, Curcio, Arigoni, Calogero, Bonello, Genuardi, Spadi, Satolli, Campra, Giordano, Cappello, Cordero and Novelli.)
Published: 2024
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48. TFEB controls sensitivity to chemotherapy and immuno-killing in non-small cell lung cancer.

Author: Akman M, Monteleone C, Doronzo G, Godel M, Napoli F, Merlini A, Campani V, Nele V, Balmas E, Chontorotzea T, Fontana S, Digiovanni S, Barbu FA, Astanina E, Jafari N, Salaroglio IC, Kopecka J, De Rosa G, Mohr T, Bertero A, Righi L, Novello S, Scagliotti GV, Bussolino F, and Riganti C
Subjects: Humans, Mice, Animals, Female, Immunotherapy methods, Cell Line, Tumor, Male, Retrospective Studies, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Lung Neoplasms drug therapy, Lung Neoplasms immunology, Lung Neoplasms pathology, Lung Neoplasms genetics, Lung Neoplasms metabolism
Abstract: Background: In non-small cell lung cancer (NSCLC) the efficacy of chemo-immunotherapy is affected by the high expression of drug efflux transporters as ABCC1 and by the low expression of ABCA1, mediating the isopentenyl pyrophosphate (IPP)-dependent anti-tumor activation of Vγ9Vδ2 T-lymphocytes. In endothelial cells ABCA1 is a predicted target of the transcription factor EB (TFEB), but no data exists on the correlation between TFEB and ABC transporters involved in the chemo-immuno-resistance in NSCLC., Methods: The impact of TFEB/ABCC1/ABCA1 expression on NSCLC patients' survival was analyzed in the TCGA-LUAD cohort and in a retrospective cohort of our institution. Human NSCLC cells silenced for TFEB (shTFEB) were analyzed for ABC transporter expression, chemosensitivity and immuno-killing. The chemo-immuno-sensitizing effects of nanoparticles encapsulating zoledronic acid (NZ) on shTFEB tumors and on tumor immune-microenvironment were evaluated in Hu-CD34 + mice by single-cell RNA-sequencing., Results: TFEB low ABCA1 low ABCC1 high and TFEB high ABCA1 high ABCC1 low NSCLC patients had the worst and the best prognosis, respectively, in the TCGA-LUAD cohort and in a retrospective cohort of patients receiving platinum-based chemotherapy or immunotherapy as first-line treatment. By silencing shTFEB in NSCLC cells, we demonstrated that TFEB was a transcriptional inducer of ABCA1 and a repressor of ABCC1. shTFEB cells had also a decreased activity of ERK1/2/SREBP2 axis, implying reduced synthesis and efflux via ABCA1 of cholesterol and its intermediate IPP. Moreover, TFEB silencing reduced cholesterol incorporation in mitochondria: this event increased the efficiency of OXPHOS and the fueling of ABCC1 by mitochondrial ATP. Accordingly, shTFEB cells were less immuno-killed by the Vγ9Vδ2 T-lymphocytes activated by IPP and more resistant to cisplatin. NZ, which increased IPP efflux but not OXPHOS and ATP production, sensitized shTFEB immuno-xenografts, by reducing intratumor proliferation and increasing apoptosis in response to cisplatin, and by increasing the variety of anti-tumor infiltrating cells (Vγ9Vδ2 T-lymphocytes, CD8 + T-lymphocytes, NK cells)., Conclusions: This work suggests that TFEB is a gatekeeper of the sensitivity to chemotherapy and immuno-killing in NSCLC, and that the TFEB low ABCA1 low ABCC1 high phenotype can be predictive of poor response to chemotherapy and immunotherapy. By reshaping both cancer metabolism and tumor immune-microenvironment, zoledronic acid can re-sensitize TFEB low NSCLCs, highly resistant to chemo- and immunotherapy., (© 2024. The Author(s).)
Published: 2024
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49. Dickkopf-1 (DKK1) drives growth and metastases in castration-resistant prostate cancer.

Author: Rinella L, Fiorentino G, Compagno M, Grange C, Cedrino M, Marano F, Bosco O, Vissio E, Delsedime L, D'Amelio P, Bussolati B, Arvat E, and Catalano MG
Subjects: Male, Humans, Animals, Mice, Neoplasm Metastasis, Cell Line, Tumor, Cell Movement, Xenograft Model Antitumor Assays, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Intercellular Signaling Peptides and Proteins metabolism, Intercellular Signaling Peptides and Proteins genetics, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant genetics, Cell Proliferation
Abstract: Metastatic castration-resistant prostate cancer (mCRPC) is associated with a poor prognosis and remains an incurable fatal disease. Therefore, the identification of molecular markers involved in cancer progression is urgently needed to develop more-effective therapies. The present study investigated the role of the Wnt signaling modulator Dickkopf-1 (DKK1) in the growth and metastatic progression of mCRPC. DKK1 silencing through siRNA and deletion via CRISPR/Cas9 editing were performed in two different metastatic castration-resistant prostate cancer cell lines (PC3 and DU145). A xenograft tumor model was used to assess tumor growth and metastases. In in vitro experiments, both DKK1 silencing and deletion reduced cell growth and migration of both cell lines. DKK1 knockout clones (DKK1-KO) exhibited cell cycle arrest, tubulin reorganization, and modulation of tumor metastasis-associated genes. Furthermore, in DKK1-KO cells, E-cadherin re-expression and its membrane co-localization with β-catenin were observed, contributing to reduced migration; Cadherin-11, known to increase during epithelial-mesenchymal transition, was down-regulated in DKK1-KO cells. In the xenograft mouse model, DKK1 deletion not only reduced tumor growth but also inhibited the formation of lung metastases. In conclusion, our findings support the key role of DKK1 in the growth and metastatic dissemination of mCRPC, both in vitro and in vivo., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2024
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50. Cardiovascular toxicities of immune therapies for cancer - a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology.

Author: Tocchetti CG, Farmakis D, Koop Y, Andres MS, Couch LS, Formisano L, Ciardiello F, Pane F, Au L, Emmerich M, Plummer C, Gulati G, Ramalingam S, Cardinale D, Brezden-Masley C, Iakobishvili Z, Thavendiranathan P, Santoro C, Bergler-Klein J, Keramida K, de Boer RA, Maack C, Lutgens E, Rassaf T, Fradley MG, Moslehi J, Yang EH, De Keulenaer G, Ameri P, Bax J, Neilan TG, Herrmann J, Mbakwem AC, Mirabel M, Skouri H, Hirsch E, Cohen-Solal A, Sverdlov AL, van der Meer P, Asteggiano R, Barac A, Ky B, Lenihan D, Dent S, Seferovic P, Coats AJS, Metra M, Rosano G, Suter T, Lopez-Fernandez T, and Lyon AR
Abstract: The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus., (© 2024 European Society of Cardiology.)
Published: 2024
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