Author: "CCA - Target Discovery - Searchworks@Jio Institute Digital Library Search Results

285 results on '"CCA - Target Discovery '

1. Bortezomib before and after high-dose therapy in myeloma

Author: Marian Stevens-Kroef, M. van Marwijk Kooy, Henk M. Lokhorst, Hans-Walter Lindemann, Anna Potamianou, Gerard M. J. Bos, B. van der Holt, Igor Wolfgang Blau, Annemiek Broijl, Christoph Scheid, Peter Brossart, Pieter Sonneveld, Sonja Zweegman, R. Schaafsma, Sandra Croockewit, Reinier Raymakers, Le Jarari, Ulrich Duehrsen, H Salwender, Jens Hillengass, Dirk Hose, Elias K. Mai, Anna Jauch, Marc-Steffen Raab, Michael Pfreundschuh, Thomas Hielscher, Paula F. Ypma, Marie-Jose Kersten, Katja Weisel, Edo Vellenga, H. Goldschmidt, Uta Bertsch, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Hematologie (9), Hematology, CCA - Cancer immunology, CCA - Imaging, CCA - Biomarkers, CCA - Clinical Therapy Development, CCA - Evaluation of Cancer Care, CCA - Target Discovery & Preclinial Therapy Development, Anatomy and neurosciences, CCA - Cancer Treatment and Quality of Life, Clinical Haematology, AII - Amsterdam institute for Infection and Immunity, and AII - Inflammatory diseases
Subjects: Male, Melphalan, 2ND PRIMARY MALIGNANCIES, Cancer Research, DIAGNOSED MULTIPLE-MYELOMA, Medizin, PLUS DEXAMETHASONE, Bortezomib, 0302 clinical medicine, Autologous stem-cell transplantation, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Multiple myeloma, INTERGROUPE FRANCOPHONE, Hazard ratio, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Prognosis, Progression-Free Survival, Thalidomide, Oncology, 030220 oncology & carcinogenesis, DEXAMETHASONE COMBINATION, DELETION 17P, Female, Multiple Myeloma, medicine.drug, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, Adolescent, Urology, MAINTENANCE TREATMENT, Transplantation, Autologous, Young Adult, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, medicine, Humans, Progression-free survival, Aged, Chromosome Aberrations, business.industry, STEM-CELL TRANSPLANTATION, STAGING SYSTEM, medicine.disease, RANDOMIZED-TRIAL, Surgery, Transplantation, business, Follow-Up Studies, 030215 immunology
Abstract: The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR) = 0.76, 95% confidence interval (95% CI) of 0.65-0.89, P = 0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR = 0.89, 95% CI: 0.74-1.08, P = 0.24). The incidence of SPM were similar between the two arms (7% each, P = 0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size >= 10%) and renal impairment at baseline (serum creatinine > 2 mg dl(-1)) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR = 1.02, P = 0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.
Published: 2018

2. A chemical screen for medulloblastoma identifies quercetin as a putative radiosensitizer

Author: Dennis Biesmans, Thomas Wurdinger, Bakhos A. Tannous, Gertjan J.L. Kaspers, Jacqueline Cloos, Xiao-Nan Li, W. Peter Vandertop, David P. Noske, Matheus H.W. Crommentuijn, Esther Hulleman, Mari Kogiso, Lotte Hiddingh, Tonny Lagerweij, Neurosurgery, CCA - Target Discovery & Preclinial Therapy Development, Hematology laboratory, and Pediatric surgery
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Radiosensitizer, Radiation-Sensitizing Agents, Cell Survival, medicine.medical_treatment, small molecule, Mice, Nude, screen, Kaplan-Meier Estimate, medulloblastoma, Cell Line, quercetin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Cell Line, Tumor, medicine, Animals, Humans, University medical, heterocyclic compounds, General hospital, Cerebellar Neoplasms, Cells, Cultured, Medulloblastoma, Hematology, radiosensitizer, Molecular Structure, business.industry, Cancer, medicine.disease, Xenograft Model Antitumor Assays, Surgery, Radiation therapy, Gene Expression Regulation, Neoplastic, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Female, Drug Screening Assays, Antitumor, business, Quercetin, Research Paper
Abstract: // Tonny Lagerweij 1, 2, 3, * , Lotte Hiddingh 1, 2, 3, * , Dennis Biesmans 1, 3 , Matheus H.W. Crommentuijn 3 , Jacqueline Cloos 1 , Xiao-Nan Li 4 , Mari Kogiso 4 , Bakhos A. Tannous 5 , W. Peter Vandertop 2 , David P. Noske 2, 3 , Gertjan J.L. Kaspers 1 , Tom Wurdinger 2, 3, 5 , Esther Hulleman 1, 2, 3 1 Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands 3 Department of Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands 4 Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA 5 Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Esther Hulleman, email: e.hulleman@vumc.nl Keywords: medulloblastoma, quercetin, radiosensitizer, small molecule, screen Received: October 04, 2015 Accepted: February 20, 2016 Published: March 8, 2016 ABSTRACT Treatment of medulloblastoma in children fails in approximately 30% of patients, and is often accompanied by severe late sequelae. Therefore, more effective drugs are needed that spare normal tissue and diminish long-term side effects. Since radiotherapy plays a pivotal role in the treatment of medulloblastoma, we set out to identify novel drugs that could potentiate the effect of ionizing radiation. Thereto, a small molecule library, consisting of 960 chemical compounds, was screened for its ability to sensitize towards irradiation. This small molecule screen identified the flavonoid quercetin as a novel radiosensitizer for the medulloblastoma cell lines DAOY, D283-med, and, to a lesser extent, D458-med at low micromolar concentrations and irradiation doses used in fractionated radiation schemes. Quercetin did not affect the proliferation of neural precursor cells or normal human fibroblasts. Importantly, in vivo experiments confirmed the radiosensitizing properties of quercetin. Administration of this flavonoid at the time of irradiation significantly prolonged survival in orthotopically xenografted mice. Together, these findings indicate that quercetin is a potent radiosensitizer for medulloblastoma cells that may be a promising lead for the treatment of medulloblastoma in patients.
Published: 2016

3. Feasibility of cell-free circulating tumor DNA testing for lung cancer

Author: Maria Gonzalez-Cao, Elisa Giovannetti, Niki Karachaliou, Mariacarmela Santarpia, Giuseppe Altavilla, Rafael Rosell, Medical oncology laboratory, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Lung Neoplasms, Clinical Biochemistry, Cell free, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Drug Discovery, Biopsy, Biomarkers, Tumor, medicine, Humans, Anaplastic Lymphoma Kinase, Liquid biopsy, Lung cancer, Protein Kinase Inhibitors, Genotyping, Mutation, medicine.diagnostic_test, business.industry, Biochemistry (medical), Receptor Protein-Tyrosine Kinases, DNA, Neoplasm, medicine.disease, ErbB Receptors, circulating cell-free DNA (cfDNA), EGFR mutations, non-small-cell lung cancer, 030104 developmental biology, Drug Resistance, Neoplasm, Egfr mutation, Circulating tumor DNA, 030220 oncology & carcinogenesis, Cancer research, business
Abstract: Tumor tissue genotyping is used routinely for lung cancer to identify specific targetable oncogenic alterations, including EGFR mutations and ALK rearrangements. However, tumor tissue from a single biopsy is often insufficient for molecular testing, may offer a limited evaluation because of tumor heterogeneity and can be difficult to obtain. Cell-free circulating tumor DNA has been widely investigated as a potential surrogate for tissue biopsy for noninvasive assessment of tumor-related genomic alterations. New techniques have improved EGFR mutations detection in ctDNA, thus supporting the use of this liquid biopsy for predicting response to EGFR tyrosine kinase inhibitors (TKIs) and monitoring the emergence of resistance. The serial evaluation of ctDNA during treatment is feasible and can be used to track tumor changes in real time and for a wide range of clinically useful applications.
Published: 2016

4. Role of the tumor stroma in resistance to anti-angiogenic therapy

Author: Elisabeth J. M. Huijbers, Judy R. van Beijnum, Patrycja Nowak-Sliwinska, Siamack Sabrkhany, Victor L. Thijssen, Arjan W. Griffioen, Medical oncology laboratory, CCA - Target Discovery & Preclinial Therapy Development, Radiation Oncology, Fysiologie, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, and Promovendi CD
Subjects: 0301 basic medicine, Cancer Research, Stromal cell, Survival, Angiogenesis, Circulating endothelial cell, Resistance, Angiogenesis Inhibitors, Antineoplastic Agents, Stroma, Biology, Endothelial progenitor cell, Angiopoietin, 03 medical and health sciences, Neoplasms, medicine, Animals, Humans, Pharmacology (medical), Pharmacology, Tumor, Neovascularization, Pathologic, Anti-angiogenic therapy, Endothelial stem cell, 030104 developmental biology, Infectious Diseases, Oncology, Drug Resistance, Neoplasm, Immunology, Cancer research, Myeloid-derived Suppressor Cell, Hepatocyte growth factor, Stromal Cells, medicine.drug
Abstract: Several angiogenesis inhibitors are currently used in the clinic for treatment of cancer. While anti-angiogenesis treatment can improve treatment outcome, the overall benefit on patient survival is still rather limited. This is partially explained by intrinsic or acquired resistance of tumor cells to angiostatic drugs. In addition, it has become evident that extrinsic mechanisms are also involved in resistance to angiostatic therapy. Most of these extrinsic mechanisms reside in the tumor stroma, which is composed of different cell types, including endothelial (progenitor) cells, smooth muscle cells, pericytes, (myo)fibroblasts, immune cells and platelets. In the current review, we describe the role of these stromal cells in the resistance to anti-angiogenic drugs and discuss possible strategies to overcome resistance and enhance the efficacy of angiostatic therapy.
Published: 2016

5. Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression

Author: Federico Caligaris-Cappio, Maurilio Ponzoni, Cristina Scielzo, Dejan Lazarevic, Michela Riba, Federica Barbaglio, Nico van Rooijen, Achille Anselmo, Pamela Ranghetti, Tania Veliz Rodriguez, Davide Cittaro, Carola Ries, Giorgia Simonetti, Christian Klein, Paolo Ghia, Martina Rocchi, Giovanni Galletti, Angelo Corti, Michele De Palma, Lydia Scarfò, Maria Teresa Sabrina Bertilaccio, Galletti, G, Scielzo, C, Barbaglio, F, Véliz Rodriguez, T, Riba, M, Lazarevic, D, Cittaro, D, Simonetti, G, Ranghetti, P, Scarfò, L, Ponzoni, M, Rocchi, M, Corti, Angelo, Anselmo, A, van Rooijen, N, Klein, C, Hermine Ries, C, Ghia, PAOLO PROSPERO, De Palma, M, Caligaris Cappio, F, Bertilaccio, Mts, Molecular cell biology and Immunology, CCA - Target Discovery & Preclinial Therapy Development, Galletti, Giovanni, Scielzo, Cristina, Barbaglio, Federica, Rodriguez, Tania Véliz, Riba, Michela, Lazarevic, Dejan, Cittaro, Davide, Simonetti, Giorgia, Ranghetti, Pamela, Scarfò, Lydia, Ponzoni, Maurilio, Rocchi, Martina, Anselmo, Achille, van Rooijen, Nico, Klein, Christian, Ries, Carola H, Ghia, Paolo, De Palma, Michele, Caligaris Cappio, Federico, and Bertilaccio, Maria Teresa Sabrina
Subjects: 0301 basic medicine, Macrophage, Chronic lymphocytic leukemia, Apoptosis, Cell Communication, Mice, hemic and lymphatic diseases, Transplantation, Heterologou, Tumor Microenvironment, CD20, B-Lymphocytes, Leukemia, biology, Gene Expression Regulation, Leukemic, B-Lymphocyte, Antibodies, Monoclonal, Liposome, Cell killing, medicine.anatomical_structure, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Disease Progression, Tumor necrosis factor alpha, Survival Analysi, Human, Signal Transduction, Primary Cell Culture, Transplantation, Heterologous, Mice, Transgenic, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Tumor microenvironment, Animal, Macrophages, Apoptosi, CSF1R, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Survival Analysis, 030104 developmental biology, Immunology, Liposomes, biology.protein, Bone marrow, Clodronic Acid, Neoplasm Transplantation
Abstract: The role of monocytes/macrophages in the development and progression of chronic lymphocytic leukemia (CLL) is poorly understood. Transcriptomic analyses show that monocytes/macrophages and leukemic cells cross talk during CLL progression. Macrophage depletion impairs CLL engraftment, drastically reduces leukemic growth, and favorably impacts mouse survival. Targeting of macrophages by either CSF1R signaling blockade or clodrolip-mediated cell killing has marked inhibitory effects on established leukemia also. Macrophage killing induces leukemic cell death mainly via the TNF pathway and reprograms the tumor microenvironment toward an antitumoral phenotype. CSF1R inhibition reduces leukemic cell load, especially in the bone marrow, and increases circulating CD20(+) leukemic cells. Accordingly, co-targeting TAMs and CD20-expressing leukemic cells provides a survivalbenefit in the mice. These results establish the important role of macrophages in CLL and suggest therapeutic strategies based on interfering with leukemia-macrophage interactions.
Published: 2016

6. Targetable genetic features of primary testicular and primary central nervous system lymphomas

Author: Ekaterina S. Jordanova, Bjoern Chapuy, Chip Stewart, Azra H. Ligon, Liye Zhang, Andrew Dunford, Heather Homer, Gerald Illerhaus, Aaron R. Thorner, Ryan Abo, Miyuki Aono, Scott J. Rodig, Todd R. Golub, Keith L. Ligon, Yuxiang Tan, David Meredith, Margaret A. Shipp, Gad Getz, Stefano Monti, Heather Sun, Daphne de Jong, Gang Liu, Margaretha G.M. Roemer, Erica Linden, Judith A. Ferry, Geraldine S. Pinkus, Friedrich Feuerhake, Matthew D. Ducar, Paul Van Hummelen, Gordon J. Freeman, Daniel Gusenleitner, Pathology, Obstetrics and gynaecology, CCA - Target Discovery & Preclinial Therapy Development, and Other departments
Subjects: Male, 0301 basic medicine, medicine.medical_treatment, Immunology, Biology, medicine.disease_cause, Mediastinal Neoplasms, Biochemistry, Translocation, Genetic, Targeted therapy, Central Nervous System Neoplasms, 03 medical and health sciences, 0302 clinical medicine, Testicular Neoplasms, medicine, Humans, B-cell lymphoma, Genetics, Mutation, Lymphoid Neoplasia, Primary central nervous system lymphoma, Cell Biology, Hematology, medicine.disease, BCL6, Neoplasm Proteins, Lymphoma, 030104 developmental biology, Testicular Lymphoma, Genetic Loci, 030220 oncology & carcinogenesis, Female, Lymphoma, Large B-Cell, Diffuse, Diffuse large B-cell lymphoma
Abstract: Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL.
Published: 2016

7. Applications of molecular diagnostics for personalized treatment of head and neck cancer: state of the art

Author: Ruud H. Brakenhoff, C. René Leemans, Steven W. Mes, Otolaryngology / Head & Neck Surgery, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Bioinformatics, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Biomarkers, Tumor, Genetics, Genetic predisposition, Humans, Medicine, Precision Medicine, Stage (cooking), Radiation treatment planning, Molecular Biology, business.industry, Head and neck cancer, Precision medicine, medicine.disease, Molecular diagnostics, Head and neck squamous-cell carcinoma, 3. Good health, 030104 developmental biology, Molecular Diagnostic Techniques, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Molecular Medicine, Field cancerization, business
Abstract: Squamous cell carcinomas of the head and neck are the sixth most frequent tumors worldwide. Risk factors are carcinogenic exposure, infection with the human papillomavirus (HPV) and genetic predisposition. Lymph node metastasis in the neck and HPV status are major prognostic factors. There are several important clinical challenges that determine the research agenda in head and neck cancer. The first is more accurate staging, particularly of occult metastatic lymph nodes in the neck. A second challenge is the lack of biomarkers for personalized therapy. There are a number of treatment modalities that can be employed both single and in combination, but at present only site and stage of the tumor are used for treatment planning. Provided here is an overview of the successes and failures of molecular diagnostic approaches that have been and are being evaluated to address these clinical challenges.
Published: 2016

8. Molecular imaging of aurora kinase A (AURKA) expression: Synthesis and preclinical evaluation of radiolabeled alisertib (MLN8237)

Author: Joost Verbeek, Mark A. van de Wiel, Annemieke C. Hiemstra, Kevin Adamzek, Pien M. Delis-van Diemen, Albert A. Geldof, Otto S. Hoekstra, Remond J.A. Fijneman, Daniel Bradley, Stephen G. Stroud, Albert D. Windhorst, Jeroen A.C.M. Goos, Gerrit A. Meijer, Pathology, Radiology and nuclear medicine, Urology, CCA - Target Discovery & Preclinial Therapy Development, Epidemiology and Data Science, Medical oncology, ICaR - Heartfailure and pulmonary arterial hypertension, and ICaR - Ischemia and repair
Subjects: Cancer Research, Pathology, medicine.medical_specialty, Biodistribution, Chemistry Techniques, Synthetic, 030218 nuclear medicine & medical imaging, Metastasis, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Tissue Distribution, Radiology, Nuclear Medicine and imaging, Aurora Kinase A, Liver Neoplasms, Biological Transport, Azepines, medicine.disease, digestive system diseases, In vitro, Gene Expression Regulation, Neoplastic, Pyrimidines, chemistry, Isotope Labeling, Positron-Emission Tomography, 030220 oncology & carcinogenesis, Alisertib, Cancer cell, Cancer research, Molecular Medicine, Colorectal Neoplasms, A431 cells
Abstract: Survival of patients after resection of colorectal cancer liver metastasis (CRCLM) is 36%-58%. Positron emission tomography (PET) tracers, imaging the expression of prognostic biomarkers, may contribute to assign appropriate management to individual patients. Aurora kinase A (AURKA) expression is associated with survival of patients after CRCLM resection.We synthesized [(3)H]alisertib and [(11)C]alisertib, starting from [(3)H]methyl nosylate and [(11)C]methyl iodide, respectively. We measured in vitro uptake of [(3)H]alisertib in cancer cells with high (Caco2), moderate (A431, HCT116, SW480) and low (MKN45) AURKA expression, before and after siRNA-mediated AURKA downmodulation, as well as after inhibition of P-glycoprotein (P-gp) activity. We measured in vivo uptake and biodistribution of [(11)C]alisertib in nude mice, xenografted with A431, HCT116 or MKN45 cells, or P-gp knockout mice.[(3)H]Alisertib was synthesized with an overall yield of 42% and [(11)C]alisertib with an overall yield of 23%±9% (radiochemical purity ≥99%). Uptake of [(3)H]alisertib in Caco2 cells was higher than in A431 cells (P=.02) and higher than in SW480, HCT116 and MKN45 cells (P.01). Uptake in A431 cells was higher than in SW480, HCT116 and MKN45 cells (P.01). Downmodulation of AURKA expression reduced [(3)H]alisertib uptake in Caco2 cells (P.01). P-gp inhibition increased [(3)H]alisertib uptake in Caco2 (P.01) and MKN45 (P.01) cells. In vivo stability of [(11)C]alisertib 90min post-injection was 94.7%±1.3% and tumor-to-background ratios were 2.3±0.8 (A431), 1.6±0.5 (HCT116) and 1.9±0.5 (MKN45). In brains of P-gp knockout mice [(11)C]alisertib uptake was increased compared to uptake in wild-type mice (P.01) CONCLUSIONS: Radiolabeled alisertib can be synthesized and may have potential for the imaging of AURKA, particularly when AURKA expression is high. However, the exact mechanisms underlying alisertib accumulation need further investigation.Radiolabeled alisertib may be used for non-invasively measuring AURKA protein expression and to stratify patients for treatment accordingly.
Published: 2016

9. Anti-angiogenic properties of chlorambucil derivatives with fluorous and hydrocarbon appendages

Author: Arjan W. Griffioen, Andrea Weiss, Patrycja Nowak-Sliwinska, Catherine M. Clavel, Emilia Păunescu, Paul J. Dyson, CCA - Target Discovery & Preclinial Therapy Development, and Medical oncology laboratory
Subjects: 0301 basic medicine, Angiogenesis, Pharmaceutical Science, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, In vivo, Ovarian carcinoma, Drug Discovery, medicine, Pharmacology, chemistry.chemical_classification, Chlorambucil, Organic Chemistry, In vitro, Chorioallantoic membrane, 030104 developmental biology, Hydrocarbon, chemistry, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, medicine.drug
Abstract: Chlorambucil (CLB) derivatives with long fluorous (referred to as 1 and 2) or hydrocarbon (3) chains have been evaluated in a series of in vitro and in vivo assays. In cell viability inhibition assays, both derivatives 2 and 3 show selective cytotoxicity towards human immortalized endothelial cells (ECRF24), while lacking activity against human ovarian carcinoma cell lines, contrary to the activity of CLB. Compound 3 also significantly inhibits sprout formation in an in vivo model of induced angiogenesis following photodynamic vascular occlusion in the chorioallantoic membrane (CAM) model. Moreover, intravenous administration of CLB and its derivatives in the non-perturbed CAM vasculature resulted in important changes in the vascular morphology. Notably, the growth of human ovarian carcinoma tumors implanted on the CAM was significantly inhibited by 2 and 3, i.e. by 70 and 53%, respectively, compared to vehicle treated tumors. Taken together, these results show that anchoring long fluorous or hydrocarbon chains to the carboxylic group of CLB leads to compounds showing increased anti-angiogenic activity which also effectively inhibit tumor growth in vivo.
Published: 2016

10. Moving towards personalised therapy in head and neck squamous cell carcinoma through analysis of next generation sequencing data

Author: Alfio Ferlito, Alessandra Rinaldo, Juan P. Rodrigo, Jens Ahm Sørensen, Carol R. Bradford, Maciej Giefing, Krzysztof Szyfter, Robert P. Takes, Ruud H. Brakenhoff, J.C. Brenner, Małgorzata Wierzbicka, Boudewijn J.M. Braakhuis, Otolaryngology / Head & Neck Surgery, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Cancer Research, Disease, Bioinformatics, HNSCC, 0302 clinical medicine, Carcinoma, Squamous Cell/drug therapy, Precision Medicine, Comparative Genomic Hybridization, medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, NGS technology, Phenotype, Treatment Outcome, Oncology, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Genetic complexity, Carcinoma, Squamous Cell, Biomarkers, Tumor/genetics, Genetic Testing/methods, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Tumour heterogeneity, Antineoplastic Agents, Article, DNA sequencing, 03 medical and health sciences, Predictive Value of Tests, Biomarkers, Tumor, medicine, Animals, Humans, Genetic Predisposition to Disease, Genetic Testing, Genetic testing, Squamous Cell Carcinoma of Head and Neck, business.industry, Patient Selection, Head and neck cancer, Antineoplastic Agents/therapeutic use, Head and Neck Neoplasms/drug therapy, Precision medicine, medicine.disease, Head and neck squamous-cell carcinoma, 030104 developmental biology, Personalised medicine, Target genes, business, Comparative genomic hybridization
Abstract: Item does not contain fulltext Personalised medicine tumour boards, which leverage genomic data to improve clinical management, are becoming standard for the treatment of many cancers. This paper is designed as a primer to assist clinicians treating head and neck squamous cell carcinoma (HNSCC) patients with an understanding of the discovery and functional impact of recurrent genetic lesions that are likely to influence the management of this disease in the near future. This manuscript integrates genetic data from publicly available array comparative genome hybridization (aCGH) and next-generation sequencing genetics databases to identify the most common molecular alterations in HNSCC. The importance of these genetic discoveries is reviewed and how they may be incorporated into clinical care decisions is discussed. Considerations for the role of genetic stratification in the clinical management of head and neck cancer are maturing rapidly and can be improved by integrating data sets. This article is meant to summarise the discoveries made using multiple genomic platforms so that the head and neck cancer care provider can apply these discoveries to improve clinical care.
Published: 2016

11. An immediate, single intravesical instillation of mitomycin C is of benefit in patients with non-muscle-invasive bladder cancer irrespective of prognostic risk groups

Author: André N. Vis, Jakko A. Nieuwenhuijzen, Goedele M.A. Beckers, R. Jeroen A. van Moorselaar, Birgit I. Lissenberg-Witte, Tessa van Ginkel, Judith Bosschieter, Urology, CCA - Imaging and biomarkers, CCA - Cancer Treatment and quality of life, Other Research, CCA - Evaluation of Cancer Care, CCA - Imaging, CCA - Cancer biology and immunology, CCA - Biomarkers, CCA - Cancer immunology, CCA - Clinical Therapy Development, Epidemiology and Data Science, CCA - Quality of Life, CCA - Target Discovery & Preclinial Therapy Development, and APH - Methodology
Subjects: medicine.medical_specialty, Urology, medicine.medical_treatment, Mitomycin, 030232 urology & nephrology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Risk groups, Randomized controlled trial, law, Risk Factors, medicine, Humans, In patient, Aged, Chemotherapy, Bladder cancer, Antibiotics, Antineoplastic, Proportional hazards model, business.industry, Mitomycin C, Middle Aged, medicine.disease, Prognosis, Editorial, Oncology, Urinary Bladder Neoplasms, 030220 oncology & carcinogenesis, Female, business, Non muscle invasive
Abstract: Background: In a recent meta-analysis, subgroups of patients were defined that may not benefit from a single, immediate instillation with chemotherapy. This led to a change in the European Association of Urology bladder cancer guidelines. In a previous paper, our group confirmed the efficacy of an immediate instillation of mitomycin C (MMC). However, prognostic groups in that study differ from those in the meta-analysis. Therefore, we performed a reanalysis using contemporary risk groups. Objectives: To validate whether specific subgroups of patients with non–muscle-invasive bladder cancer (NMIBC) benefit from an immediate instillation with MMC. Patients and methods: All 2,243 NMIBC patients enrolled in our randomized controlled trial between 1998 and 2003 were analyzed. Treatment effect was investigated for all subgroups, including subgroups that did not benefit from an immediate instillation according to the meta-analysis. Time to recurrence was assessed using Kaplan-Meier curves and multivariable Cox regression. Differences in treatment effect between subgroups was tested using the variable treatment by covariate interactions in a Cox regression model. Results: The difference in time to recurrence was statistically significant in favor of an immediate instillation with MMC (P < 0.001) which corresponds to a 25% risk reduction (hazard ratio: 0.75, 95% confidence interval, 0.64–0.88, P < 0.001). Treatment effect of an immediate instillation with MMC did not differ significantly between any of the subgroups. Conclusions: In contrast to the recommendations in the European Association of Urology guidelines, we could not identify any subgroup of patients with NMIBC who do not benefit from an immediate instillation with MMC after transurethral resection.
Published: 2018

12. High-Throughput Firefly Luciferase Reporter Assays

Author: Siebring-van Olst, Ellen, van Beusechem, Victor W, Medical oncology laboratory, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, CCA - Biomarkers, and CCA - Target Discovery & Preclinial Therapy Development
Abstract: Firefly luciferase reporter gene assays find wide application in high-throughput screens to identify molecular components of biological networks or to identify chemical compounds capable of interfering with cellular signaling. Here, we present methods to prepare affordable firefly luciferase assay reagents and procedures to use these reagents in reporter gene high-throughput screening with large batches of 96-well cell culture plates.
Published: 2018

13. Position statement on radiopharmaceutical production for clinical trials

Author: M. S. Cooper, M. Desruet, R. Schiavo, Arturo Chiti, Vijay Kumar, Sally W. Schwarz, Albert D. Windhorst, Y. Liu, Iván Peñuelas, A. Buck, J. Croasdale, Guy Bormans, C. Rossetti, Medical psychology, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, CCA - Treatment and quality of life, CCA - Evaluation of Cancer Care, CCA - Imaging, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: Position statement, lcsh:Medical physics. Medical radiology. Nuclear medicine, medicine.medical_specialty, lcsh:R895-920, Eu countries, 030218 nuclear medicine & medical imaging, Analytical Chemistry, 03 medical and health sciences, 0302 clinical medicine, Clinical trials, Medicine, Production (economics), Pharmacology (medical), Radiology, Nuclear Medicine and imaging, Medical physics, Pharmacology, business.industry, lcsh:RM1-950, THERAPEUTIC RADIOPHARMACEUTICALS, Regulatory, Clinical trial, lcsh:Therapeutics. Pharmacology, Work (electrical), Risk analysis (engineering), 030220 oncology & carcinogenesis, Position Paper, Radiopharmaceuticals, business, Diagnostic radiopharmaceuticals
Abstract: The EU regulation 536/2014 aims to facilitate the experimental use of diagnostic radiopharmaceuticals in particular for GMP requirements and needs to be applied in EU countries. As definitely clarified by this survey, the application is still far from being completed due to national restrictions that are conflicting with the content of the above EU regulation. Although the nuclear medicine centers are obliged to be compliant with national regulatory, national authorities have to be required to work towards full application of the regulation. On the other hand, an update of 536/2014 that includes therapeutic radiopharmaceuticals would also be beneficial to a rational and safe advance of nuclear medicine.
Published: 2017

14. Objective smartphone measurements of physical activity and fitness in patients with cancer

Author: Joeri A J Douma, Henk M.W. Verheul, Laurien M. Buffart, Medical oncology, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, CCA - Treatment and quality of life, CCA - Biomarkers, CCA - Cancer biology, CCA - Cancer immunology, CCA - Clinical Therapy Development, CCA - Imaging, CCA - Quality of Life, CCA - Target Discovery & Preclinial Therapy Development, Epidemiology and Data Science, APH - Health Behaviors & Chronic Diseases, and CCA - Evaluation of Cancer Care
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Performance status, business.industry, Physical activity, Cancer, medicine.disease, Advanced cancer, Systemic therapy, Objective assessment, Internal medicine, Medicine, In patient, business
Abstract: 132 Background: Optimal (study) treatment for patients with advanced cancer is influenced by their performance status (PS) before initiation of systemic therapy. An objective assessment of a patient’s physical function is difficult to make and is currently heavily depending on the estimation of their PS by the treating physician. Objectively measured physical activity (PA) and physical fitness (FIT) may be more predictive for survival and treatment tolerability than their PS. We hypothesize that an objective measurement may provide more accurate estimates of a patient’s physical function and thereby a better outcome of (study) treatment. Unfortunately, routine objective measurements are time consuming and costly. Therefore, we aimed to investigate the validity and reliability of smartphone measurements of PA and FIT in patients with cancer. Methods: At present, 56 ambulant patients with various types of cancer participated. Patients wore an accelerometer for 7, and an IPhone for 14 consecutive days to measure the mean number of steps per day. Patients performed a 6MWT twice with the use of an smartphone application in their home environment and once in a test environment in the hospital. To assess the validity, we calculated the intraclass correlation coefficient (ICC) between the accelerometer and the first week of the IPhone for PA, and between the 6MWT in the hospital and the home environment for FIT. To assess reliability, we calculated the ICC between the IPhone week 1 and 2 for PA, and between the first and second 6MWT in the home environment for FIT. Results: Validity was excellent for PA (ICC = 0.96,p < 0.05) and low for FIT (ICC = 0.33,p < 0.05). We found excellent reliability for PA (ICC 0.94,p < 0.05) and FIT (ICC = 0.93,p < 0.05). Conclusions: In this study we found that objective smartphone measurements of PA are valid and reliable. FIT assessments were reliable, but in its present form its validity was low. A prospective study has been initiated to investigate whether objectively measured PA and/or FIT, better predicts early trial discontinuation and survival than PS or patient-reported physical function.
Published: 2017

15. Effect of magnesium treatment and glucose levels on delayed cerebral ischemia in patients with subarachnoid hemorrhage

Author: Sanne M. Dorhout Mees, Gabriel J.E. Rinkel, Walter M. van den Bergh, Ale Algra, Jolien F. Leijenaar, Neurology, Amsterdam Neuroscience - Neurodegeneration, NCA - neurodegeneration, Neurosurgery, CCA - Cancer biology and immunology, CCA - Target Discovery & Preclinial Therapy Development, Intensive Care Medicine, ANS - Neurovascular Disorders, ANS - Amsterdam Neuroscience, ANS - Systems & Network Neuroscience, and Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE)
Subjects: Male, Neurology, Clinical Trial, Phase III, magnesium, law.invention, Brain Ischemia, Brain ischemia, Randomized controlled trial, law, Magnesium, glucose, Non-U.S. Gov't, Research Support, Non-U.S. Gov't, DCI, MILD HYPOTHERMIA 35-DEGREES-C, Hazard ratio, Fasting, Middle Aged, RANDOMIZED CONTROLLED-TRIAL, Clinical Trial, Treatment Outcome, Anesthesia, SAH, Randomized Controlled Trial, delayed cerebral ischemia, Female, Adult, medicine.medical_specialty, Subarachnoid hemorrhage, Tomography Scanners, X-Ray Computed, subarachnoid hemorrhage, Ischemia, chemistry.chemical_element, Research Support, Placebo, Clinical Trial, Phase I, Phase I, Phase III, Double-Blind Method, STROKE TRIAL, Journal Article, medicine, Humans, cardiovascular diseases, Delayed cerebral ischemia, Aged, business.industry, medicine.disease, EFFICACY, Glucose, chemistry, RAT, business
Abstract: Background Magnesium treatment did not improve outcome in patients with aneurysmal subarachnoid haemorrhage in the Magnesium in Aneurysmal Subarachnoid Haemorrhage II trial. We hypothesized that high glucose levels may have offset a potential beneficial effect to prevent delayed cerebral ischemia. We investigated if magnesium treatment led to less delayed cerebral ischemia and if glucose levels interacted with magnesium treatment in the Magnesium in Aneurysmal Suba-rachnoid Haemorrhage II trial. Aim To investigate the effect of magnesium treatment on occurrence of delayed cerebral ischemia and the interaction between glucose levels and magnesium treatment in subarachnoid hemorrhage patients. Methods The Magnesium in Aneurysmal Subarachnoid Haemorrhage was a phase III randomized placebo-controlled trial assessing the effect of magnesium sulphate on clinical outcome in aneurysmal subarachnoid hemorrhage patients. For the current study, we included only the patients admitted to the University Medical Centre-Utrecht. We calculated hazard ratios for occurrence of delayed cerebral ischemia in patients treated with magnesium vs. placebo for the entire study population, and separately in the subgroups of patients with high and low mean fasting and mean daily glucose levels until onset of delayed cerebral ischemia. We used the cross-product of magnesium and glucose in the regression analysis to evaluate whether an interaction between magnesium and glucose existed. Results We included 616 patients: 307 received magnesium and 309 placebo; 156 patients had delayed cerebral ischemia. Hazard ratio for magnesium on occurrence of delayed cerebral ischemia was 1.0 (95% confidence interval: 0.7-1.4). Results were similar in patients with low or high fasting or daily glucose levels. We found no interactions between magnesium treatment and high fasting ( P = 0.54) and daily glucose ( P = 0.60). Conclusions Magnesium treatment did not reduce the risk of delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage, nor was there an interaction with glucose levels. It is therefore unlikely that glucose levels explain the failure of magnesium to prevent delayed cerebral ischemia and poor outcome after aneurysmal subarachnoid hemorrhage.
Published: 2015

16. Spinal cord stimulation as adjuvant during chemotherapy and reirradiation treatment of recurrent high-grade gliomas

Author: Eugenio Ruiz-Egea, Bernardino Clavo, Peter Sminia, Miguel Á. Caramés, Francisco Robaina, Emilio Otermin, Adam Szolna, Ignacio J. Jorge, Raquel Cabrera, Norberto Santana-Rodríguez, Pedro Llontop, Radiation Oncology, CCA - Cancer biology and immunology, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: Adult, Male, Oncology, medicine.medical_specialty, medicine.medical_treatment, Antineoplastic Agents, Young Adult, Internal medicine, medicine, Humans, Survival rate, Spinal Cord Stimulation, Chemotherapy, Temozolomide, Tumor hypoxia, Performance status, Brain Neoplasms, business.industry, Standard treatment, Glioma, Middle Aged, medicine.disease, Combined Modality Therapy, Surgery, Survival Rate, Radiation therapy, Complementary and alternative medicine, Retreatment, Female, Neoplasm Recurrence, Local, Glioblastoma, business, Anaplastic astrocytoma, medicine.drug
Abstract: AIMS: Relapsed high-grade gliomas (HGGs) have poor prognoses and there is no standard treatment. HGGs have ischemia/hypoxia associated and, as such, drugs and oxygen have low access, with increased resistance to chemotherapy and radiotherapy. Tumor hypoxia modification can improve outcomes and overall survival in some patients with these tumors. In previous works, we have described that cervical spinal cord stimulation can modify tumor microenvironment in HGG by increasing tumor blood flow, oxygenation, and metabolism. The aim of this current, preliminary, nonrandomized, study was to assess the clinical effect of spinal cord stimulation during brain reirradiation and chemotherapy deployed for the treatment of recurrent HGG; the hypothesis being that an improvement in oxygenated blood supply would facilitate enhanced delivery of the scheduled therapy.MATERIALS AND METHODS: Seven patients had spinal cord stimulation applied during the scheduled reirradiation and chemotherapy for the treatment of recurrent HGG (6 anaplastic gliomas and 1 glioblastoma). Median dose of previous irradiation was 60 Gy (range = 56-72 Gy) and median dose of reirradiation was 46 Gy (range = 40-46 Gy). Primary end point of the study was overall survival (OS) following confirmation of HGG relapse.RESULTS: From the time of diagnosis of last tumor relapse before reirradiation, median OS was 39 months (95% CI = 0-93) for the overall study group: 39 months (95% CI = 9-69) for those with anaplastic gliomas and 16 months for the patient with glioblastoma. Posttreatment, doses of corticosteroids was significantly decreased (P = .026) and performance status significantly improved (P = .046).CONCLUSIONS: Spinal cord stimulation during reirradiation and chemotherapy is feasible and well tolerated. In our study, spinal cord stimulation was associated with clinical improvement and longer survival than previously reported in recurrent anaplastic gliomas. Spinal cord stimulation as adjuvant during chemotherapy and reirradiation in relapsed HGGs merits further research.
Published: 2014

17. Influence of health insurance status on paediatric non-Hodgkin's lymphoma treatment in Kenya

Author: Terry A. Vik, Gertjan J.L. Kaspers, Jodi L. Skiles, Stephen C. Martin, Festus Njuguna, Gilbert Olbara, Hugo A. Martijn, Saskia Mostert, Peter M. van de Ven, Sandra Langat, Pediatric surgery, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, APH - Methodology, ACS - Heart failure & arrhythmias, Epidemiology and Data Science, CCA - Imaging and biomarkers, CCA - Clinical Therapy Development, CCA - Evaluation of Cancer Care, CCA - Imaging, CCA - Biomarkers, CCA - Cancer biology, CCA - Cancer immunology, CCA - Quality of Life, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: non-Hodgkin's lymphoma, Pediatrics, medicine.medical_specialty, health insurance status, business.industry, Medical record, Confounding, Childhood malignancy, Disease, medicine.disease, Lymphoma, Non-Hodgkin's lymphoma, 03 medical and health sciences, low-income country, 0302 clinical medicine, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, medicine, Health insurance, childhood cancer, Original Article, 030212 general & internal medicine, Stage (cooking), business
Abstract: Objective: Non-Hodgkin's lymphoma (NHL) is the most common childhood malignancy in sub-Saharan Africa. Survival rates for NHL are higher than 80% in high-income countries.This study explores treatment outcomes of children with NHL in Kenya, a sub-Saharan low-income country, and the association between health insurance status at diagnosis and treatment outcomes.Design: This was a retrospective medical records study. All children diagnosed with NHL in 2010, 2011 and 2012 were included. Data on treatment outcomes and health insurance status at diagnosis were collected.Results: Of all 63 patients with NHL, 35% abandoned treatment, 22% had progressive or relapsed disease, 14% died and 29% had event-free survival. Most patients (73%) had no health insurance at diagnosis. Treatment outcomes in children with or without health insurance at diagnosis differed significantly (p=0.005). The most likely treatment outcome in children with health insurance at diagnosis was event-free survival (53%), whereas in children without health insurance at diagnosis it was abandonment of treatment (44%). Crude HR for treatment failure was 3.1 (95% CI 1.41 to 6.60, p=0.005) for uninsured versus insured children. The event-free survival estimate was significantly higher in children with health insurance at diagnosis than in patients without health insurance at diagnosis (p=0.003). Stage of disease at diagnosis was identified as a confounder of this association (adjusted HR=2.4, 95% CI 0.95 to 6.12, p=0.063).Conclusions: Survival of children with NHL in Kenya is much lower compared with high-income countries. Abandonment of treatment is the most common cause of treatment failure. Health insurance at diagnosis was associated with better treatment outcomes and survival.
Published: 2017

18. Time intervals from aneurysmal subarachnoid hemorrhage to treatment and factors contributing to delay

Author: Menno, Robbert, Menno R, Germans, Jantien, Hoogmoed, H A Stéphanie, van Straaten, Bert A, Coert, W, Peter Vandertop, Dagmar, Verbaan, Neurosurgery, Amsterdam Neuroscience, Graduate School, Amsterdam Cardiovascular Sciences, CCA - Cancer biology and immunology, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: Adult, Male, medicine.medical_specialty, Time Factors, Neurology, Subarachnoid hemorrhage, Time to treatment, Emergency treatment, Severity of Illness Index, Patient Admission, Aneurysm treatment, Outcome Assessment, Health Care, medicine, Humans, Referral and Consultation, Retrospective Studies, Neuroradiology, business.industry, Intracranial Aneurysm, Middle Aged, Subarachnoid Hemorrhage, Prognosis, medicine.disease, Surgery, Treatment center, Ischemic stroke, Female, Neurology (clinical), Emergency Service, Hospital, business
Abstract: In the management of aneurysmal subarachnoid hemorrhage (aSAH), aneurysm treatment as early as feasible is mandatory to minimize the risk of a rebleed and may thus improve outcome. We assessed the different time intervals from the first symptoms of aSAH to start of aneurysm treatment in an effort to identify which factors contribute mostly to a delay in time to treatment. In 278 aSAH patients, time intervals between the different steps from initial hemorrhage to aneurysm treatment were retrospectively reviewed, and delaying factors were determined. Half of the patients presented to a hospital within 115 min (IQR 60-431). The median (IQR) interval from hemorrhage to diagnosis was 169 min (96-513), and from diagnosis to treatment 1,057 min (416-1,428), or 17.6 h. Aneurysm treatment started within 24 h in 76 % of treated patients. Independent factors predicting delay to treatment were primary presentation at a referring hospital and admission to the treatment center later in the day. Delay in treatment was not independently related to poor outcome. The interval to aneurysm treatment might be improved upon by immediate and direct transport to the treatment center combined with optimization of in-hospital logistics, following the 'time-is-brain' concept so successfully adopted in the treatment of ischemic stroke.
Published: 2014

19. Better to be alone than in bad company:The antagonistic effect of cisplatin and crizotinib combination therapy in non-small cell lung cancer

Author: Patrick Pauwels, Filip Lardon, Nele Van Der Steen, Godefridus J Peters, Christian Rolfo, Christophe Deben, Vanessa Deschoolmeester, Paul Germonpré, Elisa Giovannetti, An Wouters, Medical oncology laboratory, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, cMET, Combination therapy, 03 medical and health sciences, 0302 clinical medicine, Non-small cell lung cancer, Crizotinib, Internal medicine, medicine, Lung cancer, Cisplatin, business.industry, respiratory system, Basic Study, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Non small cell, business, medicine.drug
Abstract: AIM: To investigate the potential benefit of combining the cMET inhibitor crizotinib and cisplatin we performed in vitro combination studies.METHODS: We tested three different treatment schemes in four non-small cell lung cancer (NSCLC) cell lines with a different cMET/epidermal growth factor receptor genetic background by means of the sulforhodamine B assay and performed analysis with Calcusyn.RESULTS: All treatment schemes showed an antagonistic effect in all cell lines, independent of the cMET status. Despite their different genetic backgrounds, all cell lines (EBC-1, HCC827, H1975 and LUDLU-1) showed antagonistic combination indexes ranging from 1.3-2.7. These results were independent of the treatment schedule.CONCLUSION: These results discourage further efforts to combine cMET inhibition with cisplatin chemotherapy in NSCLC.
Published: 2016

20. A specific inhibitor of lactate dehydrogenase overcame the resistance toward gemcitabine in hypoxic mesothelioma cells, and modulated the expression of the human equilibrative transporter-1

Author: Godefridus J. Peters, Filippo Minutolo, Valentina E. Gomez, Leticia G. Leon, Elisa Giovannetti, Paolo Andrea Zucali, Medical oncology laboratory, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Mesothelioma, Programmed cell death, Antimetabolites, Antineoplastic, Indoles, LDH, Gene Expression, human equilibrative transporter-1, Biochemistry, Deoxycytidine, Flow cytometry, Equilibrative Nucleoside Transporter 1, 03 medical and health sciences, chemistry.chemical_compound, Inhibitory Concentration 50, 0302 clinical medicine, Lactate dehydrogenase, Cell Line, Tumor, Genetics, medicine, Humans, mechanisms of action studies, medicine.diagnostic_test, L-Lactate Dehydrogenase, Cell growth, Anticancer nucleosides, Drug Synergism, General Medicine, Hypoxia (medical), Gemcitabine, Cell Hypoxia, Isoenzymes, 030104 developmental biology, chemistry, Anaerobic glycolysis, Cell culture, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, gemcitabine, mesothelioma, Molecular Medicine, Cancer research, medicine.symptom, Drug Screening Assays, Antitumor, Lactate Dehydrogenase 5, medicine.drug
Abstract: Malignant pleural mesothelioma (MPM) is a very hypoxic malignancy, and hypoxia has been associated with resistance towards gemcitabine. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis. Therefore we investigated the combination of a new LDH-A inhibitor (NHI-1) with gemcitabine in MPM cell lines. Under hypoxia (O2 tension of 1%) the cell growth inhibitory effects of gemcitabine, were reduced, as demonstrated by a 5- to 10-fold increase in IC50s. However, the simultaneous addition of NHI-1 was synergistic (combination index < 1). Flow cytometry demonstrated that hypoxia caused a G1 arrest, whereas the combination of NHI-1 significantly increased gemcitabine-induced cell death. Finally, the mRNA expression levels of the human equilibrative transporter-1 (hENT1) were significantly down-regulated under hypoxia, but treatment with NHI-1 was associated with a recovery of hENT1 expression. In conclusion, our data show that hypoxia increased MPM resistance to gemcitabine. However, cell death induction and modulation of the key transporter in gemcitabine uptake may contribute to the synergistic interaction of gemcitabine with the LDH-A inhibitor NHI-1 and support further studies for the rational development of this combination.
Published: 2016

21. Sensitive liquid chromatography mass spectrometry (LC-MS) assay reveals novel insights on DNA methylation and incorporation of gemcitabine, its metabolite difluorodeoxyuridine, deoxyuridine, and RX-3117 into DNA

Author: Godefridus J. Peters, Michael H. Kristensen, Richard J. Honeywell, Dzjemma Sarkisjan, Ietje Kathmann, Medical oncology laboratory, CCA - Target Discovery & Preclinial Therapy Development, and Medical oncology
Subjects: 0301 basic medicine, Metabolite, Cytidine, Biochemistry, Deoxycytidine, Mass Spectrometry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Liquid chromatography–mass spectrometry, Limit of Detection, Cell Line, Tumor, Genetics, medicine, Humans, Chemistry, General Medicine, Methylation, DNA, DNA Methylation, Molecular biology, Gemcitabine, Deoxyuridine, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, DNA methylation, Molecular Medicine, RNA, Floxuridine, medicine.drug, Chromatography, Liquid
Abstract: Antimetabolites are incorporated into DNA and RNA, affecting their function. Liquid-chromatography-mass-spectrometry (LC-MS-MS) permits the sensitive, selective analysis of normal nucleosides. The method was adapted to measure the incorporation of deoxyuridine, gemcitabine (difluorodeoxycytidine), its metabolite difluorodeoxyuridine (dFdU), and the novel compound fluorocyclopentenylcytosine (RX3117). DNA was degraded to its deoxynucleotides for quantification by LC-MS-MS, gradient chromatography on a Phenomenex prodigy-3-ODS with positive ionization. The range of deoxyuridine DNA-mis-incorporation varied nine-fold in 27 cell lines (leukemia, colon, ovarian, lung cancer). At low-folate conditions a 2.1-fold increase in deoxyuridine was observed. Global methylation (given as % 5-methyl-deoxycytidine) was comparable between the cell lines (4.6-6.5%). Exposure of A2780 cells to 1 μM gemcitabine (4 hours) resulted in 3.6 pmol gemcitabine/μg DNA, but in AG6000 cells (deoxycytidine-kinase-deficient) no incorporation was found. However, when A2780, AG6000, or CCRF-CEM cells were exposed to 100 μM dFdU we found it as gemcitabine, 20.5, 19.6, and 0.51 pmol gemcitabine/μg DNA, respectively. Preincubation of CCRF-CEM cells with cyclopentenyl-cytosine (a CTP-synthetase inhibitor) increased dFdU incorporation four-fold. Apparently dFdU is activated independently of deoxycytidine-kinase and possibly converted in-situ to dFdCMP. RX3117 was incorporated into both DNA and RNA (0.0037 and 0.00515 pmol/μg, respectively). In summary, a sensitive method to quantify the incorporation of gemcitabine, deoxyuridine, and RX-3117 was developed, which revealed that dFdU was incorporated into DNA as the parent compound gemcitabine.
Published: 2016

22. hENT-1 Expression and Localization Predict Outcome After Adjuvant Gemcitabine in Resected Cholangiocarcinoma Patients

Author: Elisa Giovannetti, Laura L. Meijer, Jisce R. Puik, Geert Kazemier, Godefridus J. Peters, Surgery, Medical oncology laboratory, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Antimetabolites, Antineoplastic, medicine.medical_treatment, Treatment outcome, Equilibrative nucleoside transporter 1, Deoxycytidine, Disease-Free Survival, Cholangiocarcinoma, Equilibrative Nucleoside Transporter 1, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, In patient, Letters to the Editor, Aged, Chemotherapy, biology, business.industry, Middle Aged, Gemcitabine, 030104 developmental biology, Bile Duct Neoplasms, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, biology.protein, Biomarker (medicine), Female, business, Adjuvant, medicine.drug
Abstract: The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine.Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazard ratios (HRs) of relapse and associated 95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score.Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24-0.99, p = .046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI 0.34-2.68; three to four cycles: HR 0.99, 95% CI 0.34-2.90; five to six cycles: HR 0.27, 95% CI 0.10-0.77).hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting.Gemcitabine is becoming an increasingly used adjuvant modality in cholangiocarcinoma (CC), but limited data are available on predictive biomarkers of response. In this study, patients receiving more than four cycles of adjuvant gemcitabine and harboring Human equilibrative nucleoside transporter 1 (hENT-1, the major transporter involved in gemcitabine intracellular uptake) on tumor cell membrane had a longer disease-free survival compared with patients negative or positive for hENT-1 only in the cytoplasm of tumor cells. Overall these results may lay the basis for further prospective randomized trials based on a larger population of patients and may prove useful for tailoring appropriate gemcitabine-based chemotherapy for CC patients in the adjuvant setting.
Published: 2016

23. The role of pharmacogenetics in capecitabine efficacy and toxicity

Author: Henk-Jan Guchelaar, Siu W. Lam, Epie Boven, Medical oncology, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Antimetabolites, Antineoplastic, Drug-Related Side Effects and Adverse Reactions, Efficacy, Single-nucleotide polymorphism, Pharmacology, Genetic polymorphisms, Polymorphism, Single Nucleotide, Carboxylesterase, Capecitabine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Cytidine Deaminase, Neoplasms, medicine, Clinical endpoint, Humans, Radiology, Nuclear Medicine and imaging, Adverse effect, Dihydrouracil Dehydrogenase (NADP), Methylenetetrahydrofolate Reductase (NADPH2), Thymidine Phosphorylase, biology, Toxicity, business.industry, General Medicine, 030104 developmental biology, Pharmacogenetics, 030220 oncology & carcinogenesis, Pharmacodynamics, Methylenetetrahydrofolate reductase, biology.protein, DPYD, Fluorouracil, business, medicine.drug, Genome-Wide Association Study
Abstract: Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) and approved for treatment of various malignancies. Hereditary genetic variants may affect a drug's pharmacokinetics or pharmacodynamics and account for differences in treatment response and adverse events among patients. In this review we present the current knowledge on genetic variants, commonly single-nucleotide polymorphisms (SNPs), tested in cohorts of cancer patients and possibly useful for prediction of capecitabine efficacy or toxicity. Capecitabine is activated to 5-FU by CES, CDA and TYMP , of which SNPs in CDA and CES2 were found to be associated with efficacy and toxicity. In addition, variants in genes of the 5-FU metabolic pathway, including TYMS , MTHFR and DPYD also influenced capecitabine efficacy and toxicity. In particular, well-known SNPs in TYMS and DPYD as well as putative DPYD SNPs had an association with clinical outcome as well as adverse events. Inconsistent findings may be attributable to factors related to ethnic differences, sample size, study design, study endpoints, dosing schedule and the use of multiple agents. Of the SNPs described in this review, dose reduction of fluoropyrimidines based on the presence of DPYD variants * 2A (rs3918290), * 13 (rs55886062), −2846A>T (rs67376798) and −1236G>A/HapB3 (rs56038477) has already been recommended. Other variants merit further validation to establish their definite role in explanation of interindividual differences in the outcome of capecitabine-based therapy.
Published: 2016

24. Investigating miRNA-mRNA regulatory networks using crosslinking immunoprecipitation methods for biomarker and target discovery in cancer

Author: Justin Stebbing, Jonathan Krell, Adam E Frampton, Leandro Castellano, Mireia Mato Prado, Elisa Giovannetti, Medical oncology laboratory, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Immunoprecipitation, Gene regulatory network, Computational biology, PAR-CLIP, Biology, Bioinformatics, pancreatic Cancer, Pathology and Forensic Medicine, 03 medical and health sciences, RNA interference, Neoplasms, microRNA, Genetics, Biomarkers, Tumor, cancer, Animals, Humans, Gene Regulatory Networks, RNA, Messenger, Molecular Biology, Gene, therapy, Sequence Analysis, RNA, CLASH, RNA, Computational Biology, High-Throughput Nucleotide Sequencing, RNA sequencing, Biomarker (cell), MicroRNAs, 030104 developmental biology, Molecular Medicine, biomarker, RNA Interference, targetome
Abstract: Introduction: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. Recently, different experimental approaches, such as RNA Sequencing, crosslinking immunoprecipitation (CLIP) methods and its variations, together with computational approaches have been developed to elucidate the miRNA-mRNA targetome. Areas covered: This report focuses on comparing the different experimental and computational approaches, describing their advantages and disadvantages and providing several examples of preclinical (in vitro and in vivo) and clinical studies that have identified miRNA target genes in various tumour types, including breast, ovary, colorectal and pancreas. Expert commentary: The combination of CLIP methods with bioinformatic analyses is essential to better predict miRNA-mRNA interactions and associate their specific pathways within the extensive regulatory network. Nevertheless, further studies are needed to overcome the difficulties these methods have, in order to find a gold standard method that identifies, without any bias, the regulatory association between miRNAs and their target mRNAs.
Published: 2016

25. Integrated in vivo genetic and pharmacologic screening identifies co-inhibition of EGRF and ROCK as a potential treatment regimen for triple-negative breast cancer

Author: Sedef Iskit, Daniel S. Peeper, Aida Shahrabi, Pasi Halonen, Patricia A. Possik, Cor Lieftink, Roderick L. Beijersbergen, Pathology, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, in vivo screen, medicine.medical_treatment, EGFR, Triple Negative Breast Neoplasms, Disease, Mice, SCID, Pharmacology, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, In vivo, Mice, Inbred NOD, Cell Line, Tumor, ROCK, medicine, Animals, Humans, Protein Kinase Inhibitors, Triple-negative breast cancer, Cell Proliferation, Mice, Knockout, rho-Associated Kinases, business.industry, Cell growth, Drug Synergism, medicine.disease, targeted therapy, Xenograft Model Antitumor Assays, ErbB Receptors, 030104 developmental biology, HEK293 Cells, Oncology, 030220 oncology & carcinogenesis, Cancer research, Female, RNA Interference, business, TNBC, Genetic screen, Priority Research Paper
Abstract: Breast cancer is the second most common cause of cancer-related deaths worldwide among women. Despite several therapeutic options, 15% of breast cancer patients succumb to the disease owing to tumor relapse and acquired therapy resistance. Particularly in triple-negative breast cancer (TNBC), developing effective treatments remains challenging owing to the lack of a common vulnerability that can be exploited by targeted approaches. We have previously shown that tumor cells have different requirements for growth in vivo than in vitro. Therefore, to discover novel drug targets for TNBC, we performed parallel in vivo and in vitro genetic shRNA dropout screens. We identified several potential drug targets that were required for tumor growth in vivo to a greater extent than in vitro. By combining pharmacologic inhibitors acting on a subset of these candidates, we identified a synergistic interaction between EGFR and ROCK inhibitors. This combination effectively reduced TNBC cell growth by inducing cell cycle arrest. These results illustrate the power of in vivo genetic screens and warrant further validation of EGFR and ROCK as combined pharmacologic targets for breast cancer.
Published: 2016

26. Blood-brain barrier crossing and breakthroughs in glioblastoma therapy

Author: Sminia, P, Westerman, B A, Radiation Oncology, CCA - Cancer biology and immunology, CCA - Target Discovery & Preclinial Therapy Development, Neurosurgery, and CCA - Innovative therapy
Published: 2016

27. TOXICITY AND EFFICACY OF CONVECTION-ENHANCED DELIVERY WITH LIPOSOMAL DOXORUBICIN IN DIPG AND THALAMIC PEDIATRIC HIGH GRADE GLIOMA MODELS

Author: Sewing, A. Charlotte P., Lagerweij, Tonny, Vuurden, Dannis G., Veringa, Susanna J. E., Vandertop, W. Pieter, Noske, David P., Wesseling, Pieter, Gertjan Kaspers, Hulleman, Esther, Pediatric surgery, Neurosurgery, CCA - Target Discovery & Preclinial Therapy Development, and Pathology
Published: 2016

28. Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma

Author: Christian U. Blank, Alessia Gasparini, Paula Kroon, Jannie Borst, Hideo Yagita, Inge Verbrugge, Marian Peeters, Marcel Verheij, Marcel A. Deken, Jules Gadiot, Radiation Oncology, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Mice, 0302 clinical medicine, PD-1, CD137, Cytotoxic T cell, Immunology and Allergy, Melanoma, Immunogenicity, Antibodies, Monoclonal, Combined Modality Therapy, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Original Article, Proto-Oncogene Proteins B-raf, T cell, Immunology, Antineoplastic Agents, Mice, Transgenic, Immunomodulation, 03 medical and health sciences, Tumor Necrosis Factor Receptor Superfamily, Member 9, Lymphocytes, Tumor-Infiltrating, medicine, Animals, Humans, Codon, Radiotherapy, business.industry, medicine.disease, Lymphocyte Subsets, Blockade, Radiation therapy, Disease Models, Animal, 030104 developmental biology, BRAFV600, Mutation, Cancer research, Stereotactic, Human medicine, business, Biomarkers
Abstract: T cell checkpoint blockade with antibodies targeting programmed cell death (ligand)-1 (PD-1/PD-L1) and/or cytotoxic T lymphocyte-antigen 4 (CTLA-4) has improved therapy outcome in melanoma patients. However, a considerable proportion of patients does not benefit even from combined α-CTLA-4 and α-PD-1 therapy. We therefore examined to which extent T cell (co)stimulation and/or stereotactic body radiation therapy (SBRT) could further enhance the therapeutic efficacy of T cell checkpoint blockade in a genetically engineered mouse melanoma model that is driven by PTEN-deficiency, and BRAFV600 mutation, as in human, but lacks the sporadic UV-induced mutations. Tumor-bearing mice were treated with different combinations of immunomodulatory antibodies (α-CTLA-4, α-PD-1, α-CD137) or interleukin-2 (IL-2) alone or in combination with SBRT. None of our immunotherapeutic approaches (alone or in combination) had any anti-tumor efficacy, while SBRT alone delayed melanoma outgrowth. However, α-CD137 combined with α-PD-1 antibodies significantly enhanced the anti-tumor effect of SBRT, while the anti-tumor effect of SBRT was not enhanced by interleukin-2, or the combination of α-CTLA-4 and α-PD-1. We conclude that α-CD137 and α-PD-1 antibodies were most effective in enhancing SBRT-induced tumor growth delay in this mouse melanoma model, outperforming the ability of IL-2, or the combination of α-CTLA-4 and α-PD-1 to synergize with SBRT. Given the high mutational load and increased immunogenicity of human melanoma with the same genotype, our findings encourage testing α-CD137 and α-PD-1 alone or in combination with SBRT clinically, particularly in patients refractory to α-CTLA-4 and/or α-PD-1 therapy. Electronic supplementary material The online version of this article (doi:10.1007/s00262-016-1843-4) contains supplementary material, which is available to authorized users.
Published: 2016

29. The MEK1/2 Inhibitor Pimasertib Enhances Gemcitabine Efficacy-Letter

Author: Elisa Giovannetti, Ugo Boggi, Amir Avan, Leticia G. Leon, Fabio Vistoli, Niccola Funel, Godefridus J. Peters, Medical oncology laboratory, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: Oncology, medicine.medical_specialty, Cancer Research, Pancreatic ductal adenocarcinoma, Ribonucleotide, business.industry, digestive system diseases, Gemcitabine, Downregulation and upregulation, Internal medicine, medicine, Pimasertib, business, medicine.drug
Abstract: We have read with interest the article by Vena and colleagues ([1][1]), on the combination of the MEK1/2 inhibitor pimasertib with gemcitabine in pancreatic ductal adenocarcinoma (PDAC). MEK emerged as a promising target to sensitize gemcitabine therapy through downregulation of the ribonucleotide
Published: 2016

30. No Significant Cytotoxic Effect of the EZH2 Inhibitor Tazemetostat (EPZ-6438) on Pediatric Glioma Cells with Wildtype Histone 3 or Mutated Histone 3.3

Author: CM Kramm, Stefan M. Pfister, Fabian Schill, Esther Hulleman, Maria Wiese, Steven A. Johnsen, Dominik Sturm, Pediatric surgery, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Male, Adolescent, Cell Survival, Pyridones, Morpholines, DNA Mutational Analysis, Statistics as Topic, macromolecular substances, Epigenesis, Genetic, Histones, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Glioma, Cell Line, Tumor, medicine, Tumor Cells, Cultured, Cytotoxic T cell, Humans, Enhancer of Zeste Homolog 2 Protein, Cancer epigenetics, Epigenetics, Child, Regulation of gene expression, biology, Brain Neoplasms, EZH2, Biphenyl Compounds, medicine.disease, 3. Good health, 030104 developmental biology, Histone, Gene Expression Regulation, 030220 oncology & carcinogenesis, Child, Preschool, Pediatrics, Perinatology and Child Health, Benzamides, biology.protein, Cancer research, Female, PRC2, Glioblastoma
Abstract: Background: Glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) belong to the most aggressive cancers in children with poor prognosis and limited therapeutic options. Therapeutic targeting of epigenetic proteins may offer new treatment options. Preclinical studies identified Enhancer of Zeste Homolog 2 (EZH2) within polycomb repressor complex 2 (PRC2) as a potential epigenetic anti-tumor target in adult GBM cells but similar inhibition studies in pediatric GBM/DIPG were still missing. Moreover, approximately 30% of pediatric high grade gliomas (pedHGG) including GBM and DIPG harbor a lysine 27 mutation (K27M) in histone 3.3 (H3.3) which is correlated with poor outcome and was shown to influence EZH2 function. Patients, materials and methods: The present study investigated the correlation of expression of EZH2 and other PRC2 genes (EZH1, SUZ12, EED) with overall survival of pediatric GBM patients and the cytotoxic impact of EZH2 inhibition by the novel agent Tazemetostat in pediatric GBM/DIPG cells harboring either a H3.3 mutation or a H3 wildtype. Results: EZH2 gene expression does not correlate with survival of pedHGG patients, and EZH2 inhibition does not induce significant cytotoxicity in pedHGG cells independently of H3.3 mutations. Discussion and conclusion: We suggest that EZH2 inhibition might not offer an effective single agent treatment option for paedHGG patients. However, the therapeutic efficacy in combination with cytotoxic and/or other epigenetically active agents still has to be elucidated.
Published: 2016

31. On the pharmacogenetics of non-small cell lung cancer treatment

Author: Mariacarmela Santarpia, Christian Rolfo, Leticia G. Leon, G.J. Peters, Elisa Giovannetti, Medical oncology laboratory, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Lung Neoplasms, Antineoplastic Agents, Pemetrexed, Toxicology, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Internal medicine, Animals, Humans, Medicine, Medical prescription, Lung cancer, Biology, Survival rate, EGFR inhibitors, lung cancer, methodological challenges, pemetrexed, pharmacogenetic studies, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Drug Resistance, Neoplasm, Humans, Lung Neoplasms, Neoplasm Recurrence, Local, Patient Selection, Pemetrexed, Pharmacogenetics, Receptor, Epidermal Growth Factor, Survival Rate, Toxicology, Pharmacology, EGFR inhibitors, Pharmacology, business.industry, Pharmacology. Therapy, General Medicine, medicine.disease, ErbB Receptors, Survival Rate, Chemistry, 030104 developmental biology, Pharmacogenetics, 030220 oncology & carcinogenesis, DECIPHER, Non small cell, Neoplasm Recurrence, Local, business, medicine.drug
Abstract: Introduction. Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches.
Published: 2016

32. Multifactorial resistance to aminopeptidase inhibitor prodrug CHR2863 in myeloid leukemia cells: down-regulation of carboxylesterase 1, drug sequestration in lipid droplets and pro-survival activation ERK/Akt/mTOR

Author: Marjon Al, Durga M.S.H. Chandrupatla, Elisa Giovannetti, Willem F. Lems, David Krige, Richard J. Honeywell, George L. Scheffer, Rene P.J. Musters, Sarah Kammerer, Pieternella A. Kramer, Hans W.M. Niessen, Yehuda G. Assaraf, Jacqueline Cloos, Sue Ellen Verbrugge, Rik J. Scheper, Tanja D. de Gruijl, Gert J. Ossenkoppele, Godefridus J. Peters, Tom O'Toole, Gerrit Jansen, Rheumatology, CCA - Target Discovery & Preclinial Therapy Development, Medical oncology laboratory, Physiology, ICaR - Ischemia and repair, Molecular cell biology and Immunology, Pathology, Cardio-thoracic surgery, Hematology laboratory, and Hematology
Subjects: 0301 basic medicine, MAPK/ERK pathway, Carboxylesterase 1, lipid droplets, Down-Regulation, Apoptosis, Drug resistance, Biology, Aminopeptidases, 03 medical and health sciences, Lipid droplet, Humans, Prodrugs, Phosphorylation, Protein kinase B, PI3K/AKT/mTOR pathway, aminopeptidase, rapamycin, TOR Serine-Threonine Kinases, Myeloid leukemia, Prodrug, carboxylesterase, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, Immunology, Cancer research, mTOR, Carboxylic Ester Hydrolases, Proto-Oncogene Proteins c-akt, Research Paper
Abstract: Aminopeptidase inhibitors are receiving attention as combination chemotherapeutic agents for the treatment of refractory acute myeloid leukemia. However, the factors determining therapeutic efficacy remain elusive. Here we identified the molecular basis of acquired resistance to CHR2863, an orally available hydrophobic aminopeptidase inhibitor prodrug with an esterase-sensitive motif, in myeloid leukemia cells. CHR2863 enters cells by diffusion and is retained therein upon esterase activity-mediated conversion to its hydrophilic active metabolite drug CHR6768, thereby exerting amino acid depletion. Carboxylesterases (CES) serve as candidate prodrug activating enzymes given CES1 expression in acute myeloid leukemia specimens. We established two novel myeloid leukemia sublines U937/CHR2863(200) and U937/CHR2863(5uM), with low (14-fold) and high level (270-fold) CHR2863 resistance. The latter drug resistant cells displayed: (i) complete loss of CES1-mediated drug activation associated with down-regulation of CES1 mRNA and protein, (ii) marked retention/sequestration of the prodrug, (iii) a substantial increase in intracellular lipid droplets, and (iv) a dominant activation of the pro-survival Akt/mTOR pathway. Remarkably, the latter feature coincided with a gain of sensitivity to the mTOR inhibitor rapamycin. These finding delineate the molecular basis of CHR2863 resistance and offer a novel modality to overcome this drug resistance in myeloid leukemia cells.
Published: 2016

33. Optimization of drug combinations using Feedback System Control

Author: Arjan W. Griffioen, Xianting Ding, Patrycja Nowak-Sliwinska, Andrea Weiss, Chih-Ming Ho, Hubert van den Bergh, Paul J. Dyson, CCA - Target Discovery & Preclinial Therapy Development, and Medical oncology laboratory
Subjects: 0301 basic medicine, Drug, Bioinformatics, High-throughput screening, media_common.quotation_subject, Drug Evaluation, Preclinical, Computational biology, Drug resistance, Pharmacology, Biology, Medical and Health Sciences, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Substance Misuse, 0302 clinical medicine, Drug Therapy, Humans, Selection (genetic algorithm), media_common, Protocol (science), Mechanism (biology), Drug Synergism, Biological Sciences, Preclinical, Drug Combinations, 030104 developmental biology, 030220 oncology & carcinogenesis, Control system, Differential evolution, Combination, Chemical Sciences, Drug Evaluation, Drug Therapy, Combination, Biological Assay, Drug Abuse (NIDA only)
Abstract: We describe a protocol for the discovery of synergistic drug combinations for the treatment of disease. Synergistic drug combinations lead to the use of drugs at lower doses, which reduces side effects and can potentially lead to reduced drug resistance, while being clinically more effective than the individual drugs. To cope with the extremely large search space for these combinations, we developed an efficient combinatorial drug screening method called the Feedback System Control (FSC) technique. Starting with a broad selection of drugs, the method follows an iterative approach of experimental testing in a relevant bioassay and analysis of the results by FSC. First, the protocol uses a cell viability assay to generate broad dose-response curves to assess the efficacy of individual compounds. These curves are then used to guide the dosage input of each drug to be tested in combination. Data from applied drug combinations are input into the differential evolution (DE) algorithm, which predicts new combinations to be tested in vitro. This process identifies optimal drug-dose combinations, while saving orders of magnitude in experimental effort. The complete optimization process is estimated to take similar to 4 weeks. FSC does not require insight into the disease mechanism, and it has therefore been applied to find combination therapies for many different pathologies, including cancer and infectious diseases, and it has also been used in organ transplantation.
Published: 2016

34. Protein degradation as a target for anticancer therapy: molecular mechanisms of efficacy and acquired resistance to proteasome and aminopeptidase inhibitors

Author: Peters, G. J., Ossenkoppele, G. J., Cloos, J., Jansen, G., Medical oncology laboratory, CCA - Target Discovery & Preclinial Therapy Development, Hematology, Hematology laboratory, and Rheumatology
Published: 2016

35. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Author: Daniel J. Klionsky, Kotb Abdelmohsen, Akihisa Abe, Md Joynal Abedin, Hagai Abeliovich, Abraham Acevedo Arozena, Hiroaki Adachi, Christopher M. Adams, Peter D. Adams, Khosrow Adeli, Peter J. Adhihetty, Sharon G. Adler, Galila Agam, Rajesh Agarwal, Manish K. Aghi, Maria Agnello, Patrizia Agostinis, Patricia V. Aguilar, Julio Aguirre Ghiso, Edoardo M. Airoldi, Slimane Ait Si Ali, Takahiko Akematsu, Emmanuel T. Akporiaye, Mohamed Al Rubeai, Guillermo M. Albaiceta, Chris Albanese, Diego Albani, Matthew L. Albert, Jesus Aldudo, Hana Algül, Mehrdad Alirezaei, Iraide Alloza, Alexandru Almasan, Maylin Almonte Beceril, Emad S. Alnemri, Covadonga Alonso, Nihal Altan Bonnet, Dario C. Altieri, Silvia Alvarez, Lydia Alvarez Erviti, Sandro Alves, Giuseppina Amadoro, Atsuo Amano, Consuelo Amantini, Santiago Ambrosio, Ivano Amelio, Amal O. Amer, Mohamed Amessou, Angelika Amon, Zhenyi An, Frank A. Anania, Stig U. Andersen, Usha P. Andley, Catherine K. Andreadi, Nathalie Andrieu Abadie, Alberto Anel, David K. Ann, Shailendra Anoopkumar Dukie, Manuela Antonioli, Hiroshi Aoki, Nadezda Apostolova, Saveria Aquila, Katia Aquilano, Koichi Araki, Eli Arama, Agustin Aranda, Jun Araya, Alexandre Arcaro, Esperanza Arias, Hirokazu Arimoto, Aileen R. Ariosa, Jane L. Armstrong, Thierry Arnould, Ivica Arsov, Katsuhiko Asanuma, Valerie Askanas, Eric Asselin, Ryuichiro Atarashi, Sally S. Atherton, Julie D. Atkin, Laura D. Attardi, Patrick Auberger, Georg Auburger, Laure Aurelian, Riccardo Autelli, Laura Avagliano, Maria Laura Avantaggiati, Limor Avrahami, Suresh Awale, Neelam Azad, Tiziana Bachetti, Jonathan M. Backer, Dong Hun Bae, Jae sung Bae, Ok Nam Bae, Soo Han Bae, Eric H. Baehrecke, Seung Hoon Baek, Stephen Baghdiguian, Agnieszka Bagniewska Zadworna, Hua Bai, Jie Bai, Xue Yuan Bai, Yannick Bailly, Kithiganahalli Narayanaswamy Balaji, Walter Balduini, Andrea Ballabio, Rena Balzan, Rajkumar Banerjee, Gábor Bánhegyi, Haijun Bao, Benoit Barbeau, Maria D. Barrachina, Esther Barreiro, Bonnie Bartel, Alberto Bartolomé, Diane C. Bassham, Maria Teresa Bassi, Robert C. Bast Jr, Alakananda Basu, Maria Teresa Batista, Henri Batoko, Maurizio Battino, Kyle Bauckman, Bradley L. Baumgarner, K. Ulrich Bayer, Rupert Beale, Jean François Beaulieu, George R. Beck Jr, Christoph Becker, J. David Beckham, Pierre André Bédard, Patrick J. Bednarski, Thomas J. Begley, Christian Behl, Christian Behrends, Georg MN Behrens, Kevin E. Behrns, Eloy Bejarano, Amine Belaid, Francesca Belleudi, Giovanni Bénard, Guy Berchem, Daniele Bergamaschi, Matteo Bergami, Ben Berkhout, Laura Berliocchi, Amélie Bernard, Monique Bernard, Francesca Bernassola, Anne Bertolotti, Amanda S. Bess, Sébastien Besteiro, Saverio Bettuzzi, Savita Bhalla, Shalmoli Bhattacharyya, Sujit K. Bhutia, Caroline Biagosch, Michele Wolfe Bianchi, Martine Biard Piechaczyk, Viktor Billes, Claudia Bincoletto, Baris Bingol, Sara W. Bird, Marc Bitoun, Ivana Bjedov, Craig Blackstone, Lionel Blanc, Guillermo A. Blanco, Heidi Kiil Blomhoff, Emilio Boada Romero, Stefan Böckler, Marianne Boes, Kathleen Boesze Battaglia, Lawrence H. Boise, Alessandra Bolino, Andrea Boman, Paolo Bonaldo, Matteo Bordi, Jürgen Bosch, Luis M. Botana, Joelle Botti, German Bou, Marina Bouché, Marion Bouchecareilh, Marie Josée Boucher, Michael E. Boulton, Sebastien G. Bouret, Patricia Boya, Michaël Boyer Guittaut, Peter V. Bozhkov, Nathan Brady, Vania MM Braga, Claudio Brancolini, Gerhard H. Braus, José M. Bravo San Pedro, Lisa A. Brennan, Emery H. Bresnick, Patrick Brest, Dave Bridges, MarieAgnès Bringer, Marisa Brini, Glauber C. Brito, Bertha Brodin, Paul S. Brookes, Eric J. Brown, Karen Brown, Hal E. Broxmeyer, Alain Bruhat, Patricia Chakur Brum, John H. Brumell, Nicola Brunetti Pierri, Robert J. Bryson Richardson, Shilpa Buch, Alastair M. Buchan, Hikmet Budak, Dmitry V. Bulavin, Scott J. Bultman, Geert Bultynck, Vladimir Bumbasirevic, Yan Burelle, Robert E. Burke, Margit Burmeister, Peter Bütikofer, Laura Caberlotto, Ken Cadwell, Monika Cahova, Dongsheng Cai, Jingjing Cai, Qian Cai, Sara Calatayud, Nadine Camougrand, Michelangelo Campanella, Grant R. Campbell, Matthew Campbell, Silvia Campello, Robin Candau, Isabella Caniggia, Lavinia Cantoni, Lizhi Cao, Allan B. Caplan, Michele Caraglia, Claudio Cardinali, Sandra Morais Cardoso, Jennifer S. Carew, Laura A. Carleton, Cathleen R. Carlin, Silvia Carloni, Sven R. Carlsson, Didac Carmona Gutierrez, Leticia AM Carneiro, Oliana Carnevali, Serena Carra, Alice Carrier, Bernadette Carroll, Caty Casas, Josefina Casas, Giuliana Cassinelli, Perrine Castets, Susana Castro Obregon, Gabriella Cavallini, Isabella Ceccherini, Francesco Cecconi, Arthur I. Cederbaum, Valentín Ceña, Simone Cenci, Claudia Cerella, Davide Cervia, CETRULLO, SILVIA, Hassan Chaachouay, Han Jung Chae, Andrei S. Chagin, Chee Yin Chai, Gopal Chakrabarti, Georgios Chamilos, Edmond YW Chan, Matthew TV Chan, Dhyan Chandra, Pallavi Chandra, Chih Peng Chang, Raymond Chuen Chung Chang, Ta Yuan Chang, John C. Chatham, Saurabh Chatterjee, Santosh Chauhan, Yongsheng Che, Michael E. Cheetham, Rajkumar Cheluvappa, Chun Jung Chen, Gang Chen, Guang Chao Chen, Guoqiang Chen, Hongzhuan Chen, Jeff W. Chen, Jian Kang Chen, Min Chen, Mingzhou Chen, Peiwen Chen, Qi Chen, Quan Chen, Shang Der Chen, Si Chen, Steve S. L. Chen, Wei Chen, Wei Jung Chen, Wen Qiang Chen, Wenli Chen, Xiangmei Chen, Yau Hung Chen, Ye Guang Chen, Yin Chen, Yingyu Chen, Yongshun Chen, Yu Jen Chen, Yue Qin Chen, Yujie Chen, Zhen Chen, Zhong Chen, Alan Cheng, Christopher HK Cheng, Hua Cheng, Heesun Cheong, Sara Cherry, Jason Chesney, Chun Hei Antonio Cheung, Eric Chevet, Hsiang Cheng Chi, Sung Gil Chi, Fulvio Chiacchiera, Hui Ling Chiang, Roberto Chiarelli, Mario Chiariello, Marcello Chieppa, Lih Shen Chin, Mario Chiong, Gigi NC Chiu, Dong Hyung Cho, Ssang Goo Cho, William C. Cho, Yong Yeon Cho, Young Seok Cho, Augustine MK Choi, Eui Ju Choi, Eun Kyoung Choi, Jayoung Choi, Mary E. Choi, Seung Il Choi, Tsui Fen Chou, Salem Chouaib, Divaker Choubey, Vinay Choubey, Kuan Chih Chow, Kamal Chowdhury, Charleen T. Chu, Tsung Hsien Chuang, Taehoon Chun, Hyewon Chung, Taijoon Chung, Yuen Li Chung, Yong Joon Chwae, Valentina Cianfanelli, Roberto Ciarcia, Iwona A. Ciechomska, Maria Rosa Ciriolo, Mara Cirone, Sofie Claerhout, Michael J. Clague, Joan Clària, Peter GH Clarke, Robert Clarke, Emilio Clementi, Cédric Cleyrat, Miriam Cnop, Eliana M. Coccia, Tiziana Cocco, Patrice Codogno, Jörn Coers, Ezra EW Cohen, David Colecchia, Luisa Coletto, Núria S. Coll, Emma Colucci Guyon, Sergio Comincini, Maria Condello, Katherine L. Cook, Graham H. Coombs, Cynthia D. Cooper, J. Mark Cooper, Isabelle Coppens, Maria Tiziana Corasaniti, Marco Corazzari, Ramon Corbalan, Elisabeth Corcelle Termeau, Mario D. Cordero, Cristina Corral Ramos, Olga Corti, Andrea Cossarizza, Paola Costelli, Safia Costes, Susan L. Cotman, Ana Coto Montes, Sandra Cottet, Eduardo Couve, Lori R. Covey, L. Ashley Cowart, Jeffery S. Cox, Fraser P. Coxon, Carolyn B. Coyne, Mark S. Cragg, Rolf J. Craven, Tiziana Crepaldi, Jose L. Crespo, Alfredo Criollo, Valeria Crippa, Maria Teresa Cruz, Ana Maria Cuervo, Jose M. Cuezva, Taixing Cui, Pedro R. Cutillas, Mark J. Czaja, Maria F. Czyzyk Krzeska, Ruben K. Dagda, Uta Dahmen, Chunsun Dai, Wenjie Dai, Yun Dai, Kevin N. Dalby, Luisa Dalla Valle, Guillaume Dalmasso, Marcello D'Amelio, Markus Damme, Arlette Darfeuille Michaud, Catherine Dargemont, Victor M. Darley Usmar, Srinivasan Dasarathy, Biplab Dasgupta, Srikanta Dash, Crispin R. Dass, Hazel Marie Davey, Lester M. Davids, David Dávila, Roger J. Davis, Ted M. Dawson, Valina L. Dawson, Paula Daza, Jackie de Belleroche, Paul de Figueiredo, Regina Celia Bressan Queiroz de Figueiredo, José de la Fuente, Luisa De Martino, Antonella De Matteis, Guido RY De Meyer, Angelo De Milito, Mauro De Santi, Wanderley de Souza, Vincenzo De Tata, Daniela De Zio, Jayanta Debnath, Reinhard Dechant, Jean Paul Decuypere, Shane Deegan, Benjamin Dehay, Barbara Del Bello, Dominic P. Del Re, Régis Delage Mourroux, Lea MD Delbridge, Louise Deldicque, Elizabeth Delorme Axford, Yizhen Deng, Joern Dengjel, Melanie Denizot, Paul Dent, Channing J. Der, Vojo Deretic, Benoît Derrien, Eric Deutsch, Timothy P. Devarenne, Rodney J. Devenish, Sabrina Di Bartolomeo, Nicola Di Daniele, Fabio Di Domenico, Alessia Di Nardo, Simone Di Paola, Antonio Di Pietro, Livia Di Renzo, Aaron DiAntonio, Guillermo Díaz Araya, Ines Díaz Laviada, Maria T. Diaz Meco, Javier Diaz Nido, Chad A. Dickey, Robert C. Dickson, Marc Diederich, Paul Digard, Ivan Dikic, Savithrama P. Dinesh Kumar, Chan Ding, Wen Xing Ding, Zufeng Ding, Luciana Dini, Jörg HW Distler, Abhinav Diwan, Mojgan Djavaheri Mergny, Kostyantyn Dmytruk, Renwick CJ Dobson, Volker Doetsch, Karol Dokladny, Svetlana Dokudovskaya, Massimo Donadelli, X. Charlie Dong, Xiaonan Dong, Zheng Dong, Terrence M. Donohue Jr, Kelly S. Doran, Gabriella D'Orazi, Gerald W. Dorn II, Victor Dosenko, Sami Dridi, Liat Drucker, Jie Du, Li Lin Du, Lihuan Du, André du Toit, Priyamvada Dua, Lei Duan, Pu Duann, Vikash Kumar Dubey, Michael R. Duchen, Michel A. Duchosal, Helene Duez, Isabelle Dugail, Verónica I. Dumit, Mara C. Duncan, Elaine A. Dunlop, William A. Dunn Jr, Nicolas Dupont, Luc Dupuis, Raúl V. Durán, Thomas M. Durcan, Stéphane Duvezin Caubet, Umamaheswar Duvvuri, Vinay Eapen, Darius Ebrahimi Fakhari, Arnaud Echard, Leopold Eckhart, Charles L. Edelstein, Aimee L. Edinger, Ludwig Eichinger, Tobias Eisenberg, Avital Eisenberg Lerner, N. Tony Eissa, Wafik S. El Deiry, Victoria El Khoury, Zvulun Elazar, Hagit Eldar Finkelman, Chris JH Elliott, Enzo Emanuele, Urban Emmenegger, Nikolai Engedal, Anna Mart Engelbrecht, Simone Engelender, Jorrit M. Enserink, Ralf Erdmann, Jekaterina Erenpreisa, Rajaraman Eri, Jason L. Eriksen, Andreja Erman, Ricardo Escalante, Eeva Liisa Eskelinen, Lucile Espert, Lorena Esteban Martínez, Thomas J. Evans, Mario Fabri, Gemma Fabrias, Cinzia Fabrizi, Antonio Facchiano, Nils J. Færgeman, Alberto Faggioni, W. Douglas Fairlie, Chunhai Fan, Daping Fan, Jie Fan, Shengyun Fang, Manolis Fanto, Alessandro Fanzani, Thomas Farkas, Mathias Faure, Francois B. Favier, Howard Fearnhead, Massimo Federici, Erkang Fei, Tania C. Felizardo, Hua Feng, Yibin Feng, Yuchen Feng, Thomas A. Ferguson, Álvaro F. Fernández, Maite G. Fernandez Barrena, Jose C. Fernandez Checa, Arsenio Fernández López, Martin E. Fernandez Zapico, Olivier Feron, Elisabetta Ferraro, Carmen Veríssima Ferreira Halder, Laszlo Fesus, Ralph Feuer, Fabienne C. Fiesel, Eduardo C. Filippi Chiela, Giuseppe Filomeni, Gian Maria Fimia, John H. Fingert, Steven Finkbeiner, Toren Finkel, Filomena Fiorito, Paul B. Fisher, Marc Flajolet, FLAMIGNI, FLAVIO, Oliver Florey, Salvatore Florio, R. Andres Floto, Marco Folini, Carlo Follo, Edward A. Fon, Francesco Fornai, Franco Fortunato, Alessandro Fraldi, Rodrigo Franco, Arnaud Francois, Aurélie François, Lisa B. Frankel, Iain DC Fraser, Norbert Frey, Damien G. Freyssenet, Christian Frezza, Scott L. Friedman, Daniel E. Frigo, Dongxu Fu, José M. Fuentes, Juan Fueyo, Yoshio Fujitani, Yuuki Fujiwara, Mikihiro Fujiya, Mitsunori Fukuda, Simone Fulda, Carmela Fusco, Bozena Gabryel, Matthias Gaestel, Philippe Gailly, Malgorzata Gajewska, Sehamuddin Galadari, Gad Galili, Inmaculada Galindo, Maria F. Galindo, Giovanna Galliciotti, Lorenzo Galluzzi, Luca Galluzzi, Vincent Galy, Noor Gammoh, Sam Gandy, Anand K. Ganesan, Swamynathan Ganesan, Ian G. Ganley, Monique Gannagé, Fen Biao Gao, Feng Gao, Jian Xin Gao, Lorena García Nannig, Eleonora García Véscovi, Marina Garcia Macía, Carmen Garcia Ruiz, Abhishek D. Garg, Pramod Kumar Garg, Ricardo Gargini, Nils Christian Gassen, Damián Gatica, Evelina Gatti, Julie Gavard, Evripidis Gavathiotis, Liang Ge, Pengfei Ge, Shengfang Ge, Po Wu Gean, Vania Gelmetti, Armando A. Genazzani, Jiefei Geng, Pascal Genschik, Lisa Gerner, Jason E. Gestwicki, David A. Gewirtz, Saeid Ghavami, Eric Ghigo, Debabrata Ghosh, Anna Maria Giammarioli, Francesca Giampieri, Claudia Giampietri, Alexandra Giatromanolaki, Derrick J. Gibbings, Lara Gibellini, Spencer B. Gibson, Vanessa Ginet, Antonio Giordano, Flaviano Giorgini, Elisa Giovannetti, Stephen E. Girardin, Suzana Gispert, Sandy Giuliano, Candece L. Gladson, Alvaro Glavic, Martin Gleave, Nelly Godefroy, Robert M. Gogal Jr, Kuppan Gokulan, Gustavo H. Goldman, Delia Goletti, Michael S. Goligorsky, Aldrin V. Gomes, Ligia C. Gomes, Hernando Gomez, Candelaria Gomez Manzano, Rubén Gómez Sánchez, Dawit AP Gonçalves, Ebru Goncu, Qingqiu Gong, Céline Gongora, Carlos B. Gonzalez, Pedro Gonzalez Alegre, Pilar Gonzalez Cabo, Rosa Ana González Polo, Ing Swie Goping, Carlos Gorbea, Nikolai V. Gorbunov, Daphne R. Goring, Adrienne M. Gorman, Sharon M. Gorski, Sandro Goruppi, Shino Goto Yamada, Cecilia Gotor, Roberta A. Gottlieb, Illana Gozes, Devrim Gozuacik, Yacine Graba, Martin Graef, Giovanna E. Granato, Gary Dean Grant, Steven Grant, Giovanni Luca Gravina, Douglas R. Green, Alexander Greenhough, Michael T. Greenwood, Benedetto Grimaldi, Frédéric Gros, Charles Grose, Jean Francois Groulx, Florian Gruber, Paolo Grumati, Tilman Grune, Jun Lin Guan, Kun Liang Guan, Barbara Guerra, Carlos Guillen, Kailash Gulshan, Jan Gunst, Chuanyong Guo, Lei Guo, Ming Guo, Wenjie Guo, Xu Guang Guo, Andrea A. Gust, Åsa B. Gustafsson, Elaine Gutierrez, Maximiliano G. Gutierrez, Ho Shin Gwak, Albert Haas, James E. Haber, Shinji Hadano, Monica Hagedorn, David R. Hahn, Andrew J. Halayko, Anne Hamacher Brady, Kozo Hamada, Ahmed Hamai, Andrea Hamann, Maho Hamasaki, Isabelle Hamer, Qutayba Hamid, Ester M. Hammond, Feng Han, Weidong Han, James T. Handa, John A. Hanover, Malene Hansen, Masaru Harada, Ljubica Harhaji Trajkovic, J. Wade Harper, Abdel Halim Harrath, Adrian L. Harris, James Harris, Udo Hasler, Peter Hasselblatt, Kazuhisa Hasui, Robert G. Hawley, Teresa S. Hawley, Congcong He, Cynthia Y. He, Fengtian He, Gu He, Rong Rong He, Xian Hui He, You Wen He, Yu Ying He, Joan K. Heath, Marie Josée Hébert, Robert A. Heinzen, Gudmundur Vignir Helgason, Michael Hensel, Elizabeth P. Henske, Chengtao Her, Paul K. Herman, Agustín Hernández, Carlos Hernandez, Sonia Hernández Tiedra, Claudio Hetz, P. Robin Hiesinger, Katsumi Higaki, Sabine Hilfiker, Bradford G. Hill, Joseph A. Hill, William D. Hill, Keisuke Hino, Daniel Hofius, Paul Hofman, Günter U. Höglinger, Jörg Höhfeld, Marina K. Holz, Yonggeun Hong, David A. Hood, Jeroen JM Hoozemans, Thorsten Hoppe, Chin Hsu, Chin Yuan Hsu, Li Chung Hsu, Dong Hu, Guochang Hu, Hong Ming Hu, Hongbo Hu, Ming Chang Hu, Yu Chen Hu, Zhuo Wei Hu, Fang Hua, Ya Hua, Canhua Huang, Huey Lan Huang, Kuo How Huang, Kuo Yang Huang, Shile Huang, Shiqian Huang, Wei Pang Huang, Yi Ran Huang, Yong Huang, Yunfei Huang, Tobias B. Huber, Patricia Huebbe, Won Ki Huh, Juha J. Hulmi, Gang Min Hur, James H. Hurley, Zvenyslava Husak, Sabah NA Hussain, Salik Hussain, Jung Jin Hwang, Seungmin Hwang, Thomas IS Hwang, Atsuhiro Ichihara, Yuzuru Imai, Carol Imbriano, Megumi Inomata, Takeshi Into, Valentina Iovane, Juan L. Iovanna, Renato V. Iozzo, Nancy Y. Ip, Javier E. Irazoqui, Pablo Iribarren, Yoshitaka Isaka, Aleksandra J. Isakovic, Harry Ischiropoulos, Jeffrey S. Isenberg, Mohammad Ishaq, Hiroyuki Ishida, Isao Ishii, Jane E. Ishmael, Ciro Isidoro, Ken ichi Isobe, Erika Isono, Shohreh Issazadeh Navikas, Koji Itahana, Eisuke Itakura, Andrei I. Ivanov, Anand Krishnan V. Iyer, José M. Izquierdo, Yotaro Izumi, Valentina Izzo, Marja Jäättelä, Nadia Jaber, Daniel John Jackson, William T. Jackson, Tony George Jacob, Thomas S. Jacques, Chinnaswamy Jagannath, Ashish Jain, Nihar Ranjan Jana, Byoung Kuk Jang, Alkesh Jani, Bassam Janji, Paulo Roberto Jannig, Patric J. Jansson, Steve Jean, Marina Jendrach, Ju Hong Jeon, Niels Jessen, Eui Bae Jeung, Kailiang Jia, Lijun Jia, Hong Jiang, Hongchi Jiang, Liwen Jiang, Teng Jiang, Xiaoyan Jiang, Xuejun Jiang, Ying Jiang, Yongjun Jiang, Alberto Jiménez, Cheng Jin, Hongchuan Jin, Lei Jin, Meiyan Jin, Shengkan Jin, Umesh Kumar Jinwal, Eun Kyeong Jo, Terje Johansen, Daniel E. Johnson, Gail VW Johnson, James D. Johnson, Eric Jonasch, Chris Jones, Leo AB Joosten, Joaquin Jordan, Anna Maria Joseph, Bertrand Joseph, Annie M. Joubert, Dianwen Ju, Jingfang Ju, Hsueh Fen Juan, Katrin Juenemann, Gábor Juhász, Hye Seung Jung, Jae U. Jung, Yong Keun Jung, Heinz Jungbluth, Matthew J. Justice, Barry Jutten, Nadeem O. Kaakoush, Kai Kaarniranta, Allen Kaasik, Tomohiro Kabuta, Bertrand Kaeffer, Katarina Kågedal, Alon Kahana, Shingo Kajimura, Or Kakhlon, Manjula Kalia, Dhan V. Kalvakolanu, Yoshiaki Kamada, Konstantinos Kambas, Vitaliy O. Kaminskyy, Harm H. Kampinga, Mustapha Kandouz, Chanhee Kang, Rui Kang, Tae Cheon Kang, Tomotake Kanki, Thirumala Devi Kanneganti, Haruo Kanno, Anumantha G. Kanthasamy, Marc Kantorow, Maria Kaparakis Liaskos, Orsolya Kapuy, Vassiliki Karantza, Md Razaul Karim, Parimal Karmakar, Arthur Kaser, Susmita Kaushik, Thomas Kawula, A. Murat Kaynar, Po Yuan Ke, Zun Ji Ke, John H. Kehrl, Kate E. Keller, Jongsook Kim Kemper, Anne K. Kenworthy, Oliver Kepp, Andreas Kern, Santosh Kesari, David Kessel, Robin Ketteler, Isis do Carmo Kettelhut, Bilon Khambu, Muzamil Majid Khan, Vinoth KM Khandelwal, Sangeeta Khare, Juliann G. Kiang, Amy A. Kiger, Akio Kihara, Arianna L. Kim, Cheol Hyeon Kim, Deok Ryong Kim, Do Hyung Kim, Eung Kweon Kim, Hye Young Kim, Hyung Ryong Kim, Jae Sung Kim, Jeong Hun Kim, Jin Cheon Kim, Jin Hyoung Kim, Kwang Woon Kim, Michael D. Kim, Moon Moo Kim, Peter K. Kim, Seong Who Kim, Soo Youl Kim, Yong Sun Kim, Yonghyun Kim, Adi Kimchi, Alec C. Kimmelman, Tomonori Kimura, Jason S. King, Karla Kirkegaard, Vladimir Kirkin, Lorrie A. Kirshenbaum, Shuji Kishi, Yasuo Kitajima, Katsuhiko Kitamoto, Yasushi Kitaoka, Kaio Kitazato, Rudolf A. Kley, Walter T. Klimecki, Michael Klinkenberg, Jochen Klucken, Helene Knævelsrud, Erwin Knecht, Laura Knuppertz, Jiunn Liang Ko, Satoru Kobayashi, Jan C. Koch, Christelle Koechlin Ramonatxo, Ulrich Koenig, Young Ho Koh, Katja Köhler, Sepp D. Kohlwein, Masato Koike, Masaaki Komatsu, Eiki Kominami, Dexin Kong, Hee Jeong Kong, Eumorphia G. Konstantakou, Benjamin T. Kopp, Tamas Korcsmaros, Laura Korhonen, Viktor I. Korolchuk, Nadya V. Koshkina, Yanjun Kou, Michael I. Koukourakis, Constantinos Koumenis, Attila L. Kovács, Tibor Kovács, Werner J. Kovacs, Daisuke Koya, Claudine Kraft, Dimitri Krainc, Helmut Kramer, Tamara Kravic Stevovic, Wilhelm Krek, Carole Kretz Remy, Roswitha Krick, Malathi Krishnamurthy, Janos Kriston Vizi, Guido Kroemer, Michael C. Kruer, Rejko Kruger, Nicholas T. Ktistakis, Kazuyuki Kuchitsu, Christian Kuhn, Addanki Pratap Kumar, Anuj Kumar, Ashok Kumar, Deepak Kumar, Dhiraj Kumar, Rakesh Kumar, Sharad Kumar, Mondira Kundu, Hsing Jien Kung, Atsushi Kuno, Sheng Han Kuo, Jeff Kuret, Tino Kurz, Terry Kwok, Taeg Kyu Kwon, Yong Tae Kwon, Irene Kyrmizi, Albert R. La Spada, Frank Lafont, Tim Lahm, Aparna Lakkaraju, Truong Lam, Trond Lamark, Steve Lancel, Terry H. Landowski, Darius JR Lane, Jon D. Lane, Cinzia Lanzi, Pierre Lapaquette, Louis R. Lapierre, Jocelyn Laporte, Johanna Laukkarinen, Gordon W. Laurie, Sergio Lavandero, Lena Lavie, Matthew J. LaVoie, Betty Yuen Kwan Law, Helen Ka wai Law, Kelsey B. Law, Robert Layfield, Pedro A. Lazo, Laurent Le Cam, Karine G. Le Roch, Hervé Le Stunff, Vijittra Leardkamolkarn, Marc Lecuit, Byung Hoon Lee, Che Hsin Lee, Erinna F. Lee, Gyun Min Lee, He Jin Lee, Hsinyu Lee, Jae Keun Lee, Jongdae Lee, Juhyun Lee, Jun Hee Lee, Michael Lee, Myung Shik Lee, Patty J. Lee, Sam W. Lee, Seung Jae Lee, Shiow Ju Lee, Stella Y. Lee, Sug Hyung Lee, Sung Sik Lee, Sung Joon Lee, Sunhee Lee, Ying Ray Lee, Yong J. Lee, Young H. Lee, Christiaan Leeuwenburgh, Sylvain Lefort, Renaud Legouis, Jinzhi Lei, Qun Ying Lei, David A. Leib, Gil Leibowitz, Istvan Lekli, Stéphane D. Lemaire, John J. Lemasters, Marius K. Lemberg, Antoinette Lemoine, Shuilong Leng, Guido Lenz, Paola Lenzi, Lilach O. Lerman, Daniele Lettieri Barbato, Julia I. Ju Leu, Hing Y. Leung, Beth Levine, Patrick A. Lewis, Frank Lezoualc'h, Chi Li, Faqiang Li, Feng Jun Li, Jun Li, Ke Li, Lian Li, Min Li, Qiang Li, Rui Li, Sheng Li, Wei Li, Xiaotao Li, Yumin Li, Jiqin Lian, Chengyu Liang, Qiangrong Liang, Yulin Liao, Joana Liberal, Pawel P. Liberski, Pearl Lie, Andrew P. Lieberman, Hyunjung Jade Lim, Kah Leong Lim, Kyu Lim, Raquel T. Lima, Chang Shen Lin, Chiou Feng Lin, Fang Lin, Fangming Lin, Fu Cheng Lin, Kui Lin, Kwang Huei Lin, Pei Hui Lin, Tianwei Lin, Wan Wan Lin, Yee Shin Lin, Yong Lin, Rafael Linden, Dan Lindholm, Lisa M. Lindqvist, Paul Lingor, Andreas Linkermann, Lance A. Liotta, Marta M. Lipinski, Vitor A. Lira, Michael P. Lisanti, Paloma B. Liton, Bo Liu, Chong Liu, Chun Feng Liu, Fei Liu, Hung Jen Liu, Jianxun Liu, Jing Jing Liu, Jing Lan Liu, Ke Liu, Leyuan Liu, Liang Liu, Quentin Liu, Rong Yu Liu, Shiming Liu, Shuwen Liu, Wei Liu, Xian De Liu, Xiangguo Liu, Xiao Hong Liu, Xinfeng Liu, Xu Liu, Xueqin Liu, Yang Liu, Yule Liu, Zexian Liu, Zhe Liu, Juan P. Liuzzi, Gérard Lizard, Mila Ljujic, Irfan J. Lodhi, Susan E. Logue, Bal L. Lokeshwar, Yun Chau Long, Sagar Lonial, Benjamin Loos, Carlos López Otín, Cristina López Vicario, Mar Lorente, Philip L. Lorenzi, Péter Lõrincz, Marek Los, Michael T. Lotze, Penny E. Lovat, Binfeng Lu, Bo Lu, Jiahong Lu, Qing Lu, She Min Lu, Shuyan Lu, Yingying Lu, Frédéric Luciano, Shirley Luckhart, John Milton Lucocq, Paula Ludovico, Aurelia Lugea, Nicholas W. Lukacs, Julian J. Lum, Anders H. Lund, Honglin Luo, Jia Luo, Shouqing Luo, Claudio Luparello, Timothy Lyons, Jianjie Ma, Yi Ma, Yong Ma, Zhenyi Ma, Juliano Machado, Glaucia M. Machado Santelli, Fernando Macian, Gustavo C. MacIntosh, Jeffrey P. MacKeigan, Kay F. Macleod, John D. MacMicking, Lee Ann MacMillan Crow, Frank Madeo, Muniswamy Madesh, Julio Madrigal Matute, Akiko Maeda, Tatsuya Maeda, Gustavo Maegawa, Emilia Maellaro, Hannelore Maes, Marta Magariños, Kenneth Maiese, Tapas K. Maiti, Luigi Maiuri, Maria Chiara Maiuri, Carl G. Maki, Roland Malli, Walter Malorni, Alina Maloyan, Fathia Mami Chouaib, Na Man, Joseph D. Mancias, Eva Maria Mandelkow, Michael A. Mandell, Angelo A. Manfredi, Serge N. Manié, Claudia Manzoni, Kai Mao, Zixu Mao, Zong Wan Mao, Philippe Marambaud, Anna Maria Marconi, Zvonimir Marelja, Gabriella Marfe, Marta Margeta, Eva Margittai, Muriel Mari, Francesca V. Mariani, Concepcio Marin, Sara Marinelli, Guillermo Mariño, Ivanka Markovic, Rebecca Marquez, MARTELLI, ALBERTO MARIA, Sascha Martens, Katie R. Martin, Seamus J. Martin, Shaun Martin, Miguel A. Martin Acebes, Paloma Martín Sanz, Camille Martinand Mari, Wim Martinet, Jennifer Martinez, Nuria Martinez Lopez, Ubaldo Martinez Outschoorn, Moisés Martínez Velázquez, Marta Martinez Vicente, Waleska Kerllen Martins, Hirosato Mashima, James A. Mastrianni, Giuseppe Matarese, Paola Matarrese, Roberto Mateo, Satoaki Matoba, Naomichi Matsumoto, Takehiko Matsushita, Akira Matsuura, Takeshi Matsuzawa, Mark P. Mattson, Soledad Matus, Norma Maugeri, Caroline Mauvezin, Andreas Mayer, Dusica Maysinger, Guillermo D. Mazzolini, Mary Kate McBrayer, Kimberly McCall, Craig McCormick, Gerald M. McInerney, Skye C. McIver, Sharon McKenna, John J. McMahon, Iain A. McNeish, Fatima Mechta Grigoriou, Jan Paul Medema, Diego L. Medina, Klara Megyeri, Maryam Mehrpour, Jawahar L. Mehta, Yide Mei, Ute Christiane Meier, Alfred J. Meijer, Alicia Meléndez, Gerry Melino, Sonia Melino, Edesio Jose Tenorio de Melo, Maria A. Mena, Marc D. Meneghini, Javier A. Menendez, Regina Menezes, Liesu Meng, Ling hua Meng, Songshu Meng, Rossella Menghini, A. Sue Menko, Rubem FS Menna Barreto, Manoj B. Menon, Marco A. Meraz Ríos, Giuseppe Merla, Luciano Merlini, Angelica M. Merlot, Andreas Meryk, Stefania Meschini, Joel N. Meyer, Man tian Mi, Chao Yu Miao, Lucia Micale, Simon Michaeli, Carine Michiels, FRANCO MIGLIACCIO, ANNA RITA, Anastasia Susie Mihailidou, Dalibor Mijaljica, Katsuhiko Mikoshiba, Enrico Milan, Leonor Miller Fleming, Gordon B. Mills, Ian G. Mills, Georgia Minakaki, Berge A. Minassian, Xiu Fen Ming, Farida Minibayeva, Elena A. Minina, Justine D. Mintern, Saverio Minucci, Antonio Miranda Vizuete, Claire H. Mitchell, Shigeki Miyamoto, Keisuke Miyazawa, Noboru Mizushima, Katarzyna Mnich, Baharia Mograbi, Simin Mohseni, Luis Ferreira Moita, Marco Molinari, Maurizio Molinari, Andreas Buch Møller, Bertrand Mollereau, Faustino Mollinedo, Marco Mongillo, Martha M. Monick, Serena Montagnaro, Craig Montell, Darren J. Moore, Michael N. Moore, Rodrigo Mora Rodriguez, Paula I. Moreira, Etienne Morel, Maria Beatrice Morelli, Sandra Moreno, Michael J. Morgan, Arnaud Moris, Yuji Moriyasu, Janna L. Morrison, Lynda A. Morrison, Eugenia Morselli, Jorge Moscat, Pope L. Moseley, Serge Mostowy, Elisa Motori, Denis Mottet, Jeremy C. Mottram, Charbel E. H. Moussa, Vassiliki E. Mpakou, Hasan Mukhtar, Jean M. Mulcahy Levy, Sylviane Muller, Raquel Muñoz Moreno, Cristina Muñoz Pinedo, Christian Münz, Maureen E. Murphy, James T. Murray, Aditya Murthy, Indira U. Mysorekar, Ivan R. Nabi, Massimo Nabissi, Gustavo A. Nader, Yukitoshi Nagahara, Yoshitaka Nagai, Kazuhiro Nagata, Anika Nagelkerke, Péter Nagy, Samisubbu R. Naidu, Sreejayan Nair, Hiroyasu Nakano, Hitoshi Nakatogawa, Meera Nanjundan, Gennaro Napolitano, Naweed I. Naqvi, Roberta Nardacci, Derek P. Narendra, Masashi Narita, Anna Chiara Nascimbeni, Ramesh Natarajan, Luiz C. Navegantes, Steffan T. Nawrocki, Taras Y. Nazarko, Volodymyr Y. Nazarko, Thomas Neill, Luca M. Neri, Mihai G. Netea, Romana T. Netea Maier, Bruno M. Neves, Paul A. Ney, Ioannis P. Nezis, Hang TT Nguyen, Huu Phuc Nguyen, Anne Sophie Nicot, Hilde Nilsen, Per Nilsson, Mikio Nishimura, Ichizo Nishino, Mireia Niso Santano, Hua Niu, Ralph A. Nixon, Vincent CO Njar, Takeshi Noda, Angelika A. Noegel, Elsie Magdalena Nolte, Erik Norberg, Koenraad K. Norga, Sakineh Kazemi Noureini, Shoji Notomi, Lucia Notterpek, Karin Nowikovsky, Nobuyuki Nukina, Thorsten Nürnberger, Valerie B. O'Donnell, Tracey O'Donovan, Peter J. O'Dwyer, Ina Oehme, Clara L. Oeste, Michinaga Ogawa, Besim Ogretmen, Yuji Ogura, Young J. Oh, Masaki Ohmuraya, Takayuki Ohshima, Rani Ojha, Koji Okamoto, Toshiro Okazaki, F. Javier Oliver, Karin Ollinger, Stefan Olsson, Daniel P. Orban, Paulina Ordonez, Idil Orhon, Laszlo Orosz, Eyleen J. O'Rourke, Helena Orozco, Angel L. Ortega, Elena Ortona, Laura D. Osellame, Junko Oshima, Shigeru Oshima, Heinz D. Osiewacz, Takanobu Otomo, Kinya Otsu, Jing hsiung James Ou, Tiago F. Outeiro, Dong yun Ouyang, Hongjiao Ouyang, Michael Overholtzer, Michelle A. Ozbun, P. Hande Ozdinler, Bulent Ozpolat, Consiglia Pacelli, Paolo Paganetti, Guylène Page, Gilles Pages, Ugo Pagnini, Beata Pajak, Stephen C. Pak, Karolina Pakos Zebrucka, Nazzy Pakpour, Zdena Palková, Francesca Palladino, Kathrin Pallauf, Nicolas Pallet, Marta Palmieri, Søren R. Paludan, Camilla Palumbo, Silvia Palumbo, Olatz Pampliega, Hongming Pan, Wei Pan, Theocharis Panaretakis, Aseem Pandey, Areti Pantazopoulou, Zuzana Papackova, Daniela L. Papademetrio, Issidora Papassideri, Alessio Papini, Nirmala Parajuli, Julian Pardo, Vrajesh V. Parekh, Giancarlo Parenti, Jong In Park, Junsoo Park, Ohkmae K. Park, Roy Parker, Rosanna Parlato, Jan B. Parys, Katherine R. Parzych, Jean Max Pasquet, Benoit Pasquier, Kishore BS Pasumarthi, Daniel Patschan, Cam Patterson, Sophie Pattingre, Scott Pattison, Arnim Pause, Hermann Pavenstädt, Flaminia Pavone, Zully Pedrozo, Fernando J. Peña, Miguel A. Peñalva, Mario Pende, Jianxin Peng, Fabio Penna, Josef M. Penninger, Anna Pensalfini, Salvatore Pepe, Gustavo JS Pereira, Paulo C. Pereira, Verónica Pérez de la Cruz, María Esther Pérez Pérez, Diego Pérez Rodríguez, Dolores Pérez Sala, Celine Perier, Andras Perl, David H. Perlmutter, Ida Perrotta, Shazib Pervaiz, Maija Pesonen, Jeffrey E. Pessin, Godefridus J. Peters, Morten Petersen, Irina Petrache, Basil J. Petrof, Goran Petrovski, James M. Phang, Mauro Piacentini, Marina Pierdominici, Philippe Pierre, Valérie Pierrefite Carle, Federico Pietrocola, Felipe X. Pimentel Muiños, Mario Pinar, Benjamin Pineda, Ronit Pinkas Kramarski, Marcello Pinti, Paolo Pinton, Bilal Piperdi, James M. Piret, Leonidas C. Platanias, Harald W. Platta, Edward D. Plowey, Stefanie Pöggeler, Marc Poirot, Peter Polčic, Angelo Poletti, Audrey H. Poon, Hana Popelka, Blagovesta Popova, Izabela Poprawa, Shibu M. Poulose, Joanna Poulton, Scott K. Powers, Ted Powers, Mercedes Pozuelo Rubio, Krisna Prak, Reinhild Prange, Mark Prescott, Muriel Priault, Sharon Prince, Richard L. Proia, Tassula Proikas Cezanne, Holger Prokisch, Vasilis J. Promponas, Karin Przyklenk, Rosa Puertollano, Subbiah Pugazhenthi, Luigi Puglielli, Aurora Pujol, Julien Puyal, Dohun Pyeon, Xin Qi, Wen bin Qian, Zheng Hong Qin, Yu Qiu, Ziwei Qu, Joe Quadrilatero, Frederick Quinn, Nina Raben, Hannah Rabinowich, Flavia Radogna, Michael J. Ragusa, Mohamed Rahmani, Komal Raina, Sasanka Ramanadham, Rajagopal Ramesh, Abdelhaq Rami, Sarron Randall Demllo, Felix Randow, Hai Rao, V. Ashutosh Rao, Blake B. Rasmussen, Tobias M. Rasse, Edward A. Ratovitski, Pierre Emmanuel Rautou, Swapan K. Ray, Babak Razani, Bruce H. Reed, Fulvio Reggiori, Markus Rehm, Andreas S. Reichert, Theo Rein, David J. Reiner, Eric Reits, Jun Ren, Xingcong Ren, Maurizio Renna, Jane EB Reusch, Jose L. Revuelta, Leticia Reyes, Alireza R. Rezaie, Robert I. Richards, Des R. Richardson, Clémence Richetta, Michael A. Riehle, Bertrand H. Rihn, Yasuko Rikihisa, Brigit E. Riley, Gerald Rimbach, Maria Rita Rippo, Konstantinos Ritis, Federica Rizzi, Elizete Rizzo, Peter J. Roach, Jeffrey Robbins, Michel Roberge, Gabriela Roca, Maria Carmela Roccheri, Sonia Rocha, Cecilia MP Rodrigues, Clara I. Rodríguez, Santiago Rodriguez de Cordoba, Natalia Rodriguez Muela, Jeroen Roelofs, Vladimir V. Rogov, Troy T. Rohn, Bärbel Rohrer, Davide Romanelli, Luigina Romani, Patricia Silvia Romano, M. Isabel G. Roncero, Jose Luis Rosa, Alicia Rosello, Kirill V. Rosen, Philip Rosenstiel, Magdalena Rost Roszkowska, Kevin A. Roth, Gael Roué, Mustapha Rouis, Kasper M. Rouschop, Daniel T. Ruan, Diego Ruano, David C. Rubinsztein, Edmund B. Rucker III, Assaf Rudich, Emil Rudolf, Ruediger Rudolf, Markus A. Ruegg, Carmen Ruiz Roldan, Avnika Ashok Ruparelia, Paola Rusmini, David W. Russ, Gian Luigi Russo, Giuseppe Russo, Rossella Russo, Tor Erik Rusten, Victoria Ryabovol, Kevin M. Ryan, Stefan W. Ryter, David M. Sabatini, Michael Sacher, Carsten Sachse, Michael N. Sack, Junichi Sadoshima, Paul Saftig, Ronit Sagi Eisenberg, Sumit Sahni, Pothana Saikumar, Tsunenori Saito, Tatsuya Saitoh, Koichi Sakakura, Machiko Sakoh Nakatogawa, Yasuhito Sakuraba, María Salazar Roa, Paolo Salomoni, Ashok K. Saluja, Paul M. Salvaterra, Rosa Salvioli, Afshin Samali, Anthony MJ Sanchez, José A. Sánchez Alcázar, Ricardo Sanchez Prieto, Marco Sandri, Miguel A. Sanjuan, Stefano Santaguida, Laura Santambrogio, Giorgio Santoni, Claudia Nunes dos Santos, Shweta Saran, Marco Sardiello, Graeme Sargent, Pallabi Sarkar, Sovan Sarkar, Maria Rosa Sarrias, Minnie M. Sarwal, Chihiro Sasakawa, Motoko Sasaki, Miklos Sass, Ken Sato, Miyuki Sato, Joseph Satriano, Niramol Savaraj, Svetlana Saveljeva, Liliana Schaefer, Ulrich E. Schaible, Michael Scharl, Hermann M. Schatzl, Randy Schekman, Wiep Scheper, Alfonso Schiavi, Hyman M. Schipper, Hana Schmeisser, Jens Schmidt, Ingo Schmitz, Bianca E. Schneider, E. Marion Schneider, Jaime L. Schneider, Eric A. Schon, Miriam J. Schönenberger, Axel H. Schönthal, Daniel F. Schorderet, Bernd Schröder, Sebastian Schuck, Ryan J. Schulze, Melanie Schwarten, Thomas L. Schwarz, Sebastiano Sciarretta, Kathleen Scotto, A. Ivana Scovassi, Robert A. Screaton, Mark Screen, Hugo Seca, Simon Sedej, Laura Segatori, Nava Segev, Per O. Seglen, Jose M. Seguí Simarro, Juan Segura Aguilar, Ekihiro Seki, Iban Seiliez, Christian Sell, Clay F. Semenkovich, Gregg L. Semenza, Utpal Sen, Andreas L. Serra, Ana Serrano Puebla, Hiromi Sesaki, Takao Setoguchi, Carmine Settembre, John J. Shacka, Ayesha N. Shajahan Haq, Irving M. Shapiro, Shweta Sharma, Hua She, C. K. James Shen, Chiung Chyi Shen, Han Ming Shen, Sanbing Shen, Weili Shen, Rui Sheng, Xianyong Sheng, Zu Hang Sheng, Trevor G. Shepherd, Junyan Shi, Qiang Shi, Qinghua Shi, Yuguang Shi, Shusaku Shibutani, Kenichi Shibuya, Yoshihiro Shidoji, Jeng Jer Shieh, Chwen Ming Shih, Yohta Shimada, Shigeomi Shimizu, Dong Wook Shin, Mari L. Shinohara, Michiko Shintani, Takahiro Shintani, Tetsuo Shioi, Ken Shirabe, Ronit Shiri Sverdlov, Orian Shirihai, Gordon C. Shore, Chih Wen Shu, Deepak Shukla, Andriy A. Sibirny, Valentina Sica, Christina J. Sigurdson, Einar M. Sigurdsson, Puran Singh Sijwali, Beata Sikorska, Wilian A. Silveira, Sandrine Silvente Poirot, Gary A. Silverman, Jan Simak, Thomas Simmet, Anna Katharina Simon, Hans Uwe Simon, Cristiano Simone, Matias Simons, Anne Simonsen, Rajat Singh, Shivendra V. Singh, Shrawan K. Singh, Debasish Sinha, Sangita Sinha, Frank A. Sinicrope, Agnieszka Sirko, Kapil Sirohi, Balindiwe JN Sishi, Annie Sittler, Parco M. Siu, Efthimios Sivridis, Anna Skwarska, Ruth Slack, Iva Slaninová, Nikolai Slavov, Soraya S. Smaili, Keiran SM Smalley, Duncan R. Smith, Stefaan J. Soenen, Scott A. Soleimanpour, Anita Solhaug, Kumaravel Somasundaram, Jin H. Son, Avinash Sonawane, Chunjuan Song, Fuyong Song, Hyun Kyu Song, Ju Xian Song, Wei Song, Kai Y. Soo, Anil K. Sood, Tuck Wah Soong, Virawudh Soontornniyomkij, Maurizio Sorice, Federica Sotgia, David R. Soto Pantoja, Areechun Sotthibundhu, Maria João Sousa, Herman P. Spaink, Paul N. Span, Anne Spang, Janet D. Sparks, Peter G. Speck, Stephen A. Spector, Claudia D. Spies, Wolfdieter Springer, Daret St Clair, Alessandra Stacchiotti, Bart Staels, Michael T. Stang, Daniel T. Starczynowski, Petro Starokadomskyy, Clemens Steegborn, John W. Steele, Leonidas Stefanis, Joan Steffan, Christine M. Stellrecht, Harald Stenmark, Tomasz M. Stepkowski, Stęphan T. Stern, Craig Stevens, Brent R. Stockwell, Veronika Stoka, Zuzana Storchova, Björn Stork, Vassilis Stratoulias, Dimitrios J. Stravopodis, Pavel Strnad, Anne Marie Strohecker, Anna Lena Ström, Per Stromhaug, Jiri Stulik, Yu Xiong Su, Zhaoliang Su, Carlos S. Subauste, Srinivasa Subramaniam, Carolyn M. Sue, Sang Won Suh, Xinbing Sui, Supawadee Sukseree, David Sulzer, Fang Lin Sun, Jiaren Sun, Jun Sun, Shi Yong Sun, Yang Sun, Yi Sun, Yingjie Sun, Vinod Sundaramoorthy, Joseph Sung, Hidekazu Suzuki, Kuninori Suzuki, Naoki Suzuki, Tadashi Suzuki, Yuichiro J. Suzuki, Michele S. Swanson, Charles Swanton, Karl Swärd, Ghanshyam Swarup, Sean T. Sweeney, Paul W. Sylvester, Zsuzsanna Szatmari, Eva Szegezdi, Peter W. Szlosarek, Heinrich Taegtmeyer, Marco Tafani, Emmanuel Taillebourg, Stephen WG Tait, Krisztina Takacs Vellai, Yoshinori Takahashi, Szabolcs Takáts, Genzou Takemura, Nagio Takigawa, Nicholas J. Talbot, Elena Tamagno, Jerome Tamburini, Cai Ping Tan, Lan Tan, Mei Lan Tan, Ming Tan, Yee Joo Tan, Keiji Tanaka, Masaki Tanaka, Daolin Tang, Dingzhong Tang, Guomei Tang, Isei Tanida, Kunikazu Tanji, Bakhos A. Tannous, Jose A. Tapia, Inmaculada Tasset Cuevas, Marc Tatar, Iman Tavassoly, Nektarios Tavernarakis, Allen Taylor, Graham S. Taylor, Gregory A. Taylor, J. Paul Taylor, Mark J. Taylor, Elena V. Tchetina, Andrew R. Tee, Fatima Teixeira Clerc, Sucheta Telang, Tewin Tencomnao, Ba Bie Teng, Ru Jeng Teng, Faraj Terro, Gianluca Tettamanti, Arianne L. Theiss, Anne E. Theron, Kelly Jean Thomas, Marcos P. Thomé, Paul G. Thomes, Andrew Thorburn, Jeremy Thorner, Thomas Thum, Michael Thumm, Teresa LM Thurston, Ling Tian, Andreas Till, Jenny Pan yun Ting, Vladimir I. Titorenko, Lilach Toker, Stefano Toldo, Sharon A. Tooze, Ivan Topisirovic, Maria Lyngaas Torgersen, Liliana Torosantucci, Alicia Torriglia, Maria Rosaria Torrisi, Cathy Tournier, Roberto Towns, Vladimir Trajkovic, Leonardo H. Travassos, Gemma Triola, Durga Nand Tripathi, Daniela Trisciuoglio, Rodrigo Troncoso, Ioannis P. Trougakos, Anita C. Truttmann, Kuen Jer Tsai, Mario P. Tschan, Yi Hsin Tseng, Takayuki Tsukuba, Allan Tsung, Andrey S. Tsvetkov, Shuiping Tu, Hsing Yu Tuan, Marco Tucci, David A. Tumbarello, Boris Turk, Vito Turk, Robin FB Turner, Anders A. Tveita, Suresh C. Tyagi, Makoto Ubukata, Yasuo Uchiyama, Andrej Udelnow, Takashi Ueno, Midori Umekawa, Rika Umemiya Shirafuji, Benjamin R. Underwood, Christian Ungermann, Rodrigo P. Ureshino, Ryo Ushioda, Vladimir N. Uversky, Néstor L. Uzcátegui, Thomas Vaccari, Maria I. Vaccaro, Libuše Váchová, Helin Vakifahmetoglu Norberg, Rut Valdor, Enza Maria Valente, Francois Vallette, Angela M. Valverde, Greet Van den Berghe, Ludo Van Den Bosch, Gijs R. van den Brink, F. Gisou van der Goot, Ida J. van der Klei, Luc JW van der Laan, Wouter G. van Doorn, Marjolein van Egmond, Kenneth L. van Golen, Luc Van Kaer, Menno van Lookeren Campagne, Peter Vandenabeele, Wim Vandenberghe, Ilse Vanhorebeek, Isabel Varela Nieto, M. Helena Vasconcelos, Radovan Vasko, Demetrios G. Vavvas, Ignacio Vega Naredo, Guillermo Velasco, Athanassios D. Velentzas, Panagiotis D. Velentzas, Tibor Vellai, Edo Vellenga, Mikkel Holm Vendelbo, Kartik Venkatachalam, Natascia Ventura, Salvador Ventura, Patrícia ST Veras, Mireille Verdier, Beata G. Vertessy, Andrea Viale, Michel Vidal, Helena LA Vieira, Richard D. Vierstra, Nadarajah Vigneswaran, Neeraj Vij, Miquel Vila, Margarita Villar, Victor H. Villar, Joan Villarroya, Cécile Vindis, Giampietro Viola, Maria Teresa Viscomi, Giovanni Vitale, Dan T. Vogl, Olga V. Voitsekhovskaja, Clarissa von Haefen, Karin von Schwarzenberg, Daniel E. Voth, Valérie Vouret Craviari, Kristina Vuori, Jatin M. Vyas, Christian Waeber, Cheryl Lyn Walker, Mark J. Walker, Jochen Walter, Lei Wan, Xiangbo Wan, Bo Wang, Caihong Wang, Chao Yung Wang, Chengshu Wang, Chenran Wang, Chuangui Wang, Dong Wang, Fen Wang, Fuxin Wang, Guanghui Wang, Hai jie Wang, Haichao Wang, Hong Gang Wang, Hongmin Wang, Horng Dar Wang, Jing Wang, Junjun Wang, Mei Wang, Mei Qing Wang, Pei Yu Wang, Peng Wang, Richard C. Wang, Shuo Wang, Ting Fang Wang, Xian Wang, Xiao jia Wang, Xiao Wei Wang, Xin Wang, Xuejun Wang, Yan Wang, Yanming Wang, Ying Wang, Ying Jan Wang, Yipeng Wang, Yu Wang, Yu Tian Wang, Yuqing Wang, Zhi Nong Wang, Pablo Wappner, Carl Ward, Diane McVey Ward, Gary Warnes, Hirotaka Watada, Yoshihisa Watanabe, Kei Watase, Timothy E. Full Terms, Conditions of access, use can be found at h.t.t.p.:././.w.w.w. t.a.n.d.f.o.n.l.i.n.e. com/action/journalInformation?journalCode=kaup20 Download by: [Alma Mater Studiorum Università di Bologna] Date: 23 September 2016, At: 06:43 Weaver, Colin D. Weekes, Jiwu Wei, Thomas Weide, Conrad C. Weihl, Günther Weindl, Simone Nardin Weis, Longping Wen, Xin Wen, Yunfei Wen, Benedikt Westermann, Cornelia M. Weyand, Anthony R. White, Eileen White, J. Lindsay Whitton, Alexander J. Whitworth, Joëlle Wiels, Franziska Wild, Manon E. Wildenberg, Tom Wileman, Deepti Srinivas Wilkinson, Simon Wilkinson, Dieter Willbold, Chris Williams, Katherine Williams, Peter R. Williamson, Konstanze F. Winklhofer, Steven S. Witkin, Stephanie E. Wohlgemuth, Thomas Wollert, Ernst J. Wolvetang, Esther Wong, G. William Wong, Richard W. Wong, Vincent Kam Wai Wong, Elizabeth A. Woodcock, Karen L. 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Zhao, Dexian Zheng, Xi Long Zheng, Xiaoxiang Zheng, Boris Zhivotovsky, Qing Zhong, Guang Zhou Zhou, Guofei Zhou, Huiping Zhou, Shu Feng Zhou, Xu jie Zhou, Hongxin Zhu, Hua Zhu, Wei Guo Zhu, Wenhua Zhu, Xiao Feng Zhu, Yuhua Zhu, Shi Mei Zhuang, Xiaohong Zhuang, Elio Ziparo, Christos E. Zois, Teresa Zoladek, Wei Xing Zong, Antonio Zorzano, Susu M. Zughaier, Life Sciences Institute and Department of Molecular, Cellular, and Developmental Biology and Biological Chemistry, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Tokyo Medical University, The Hebrew University of Jerusalem (HUJ), Mammalian Genetics Unit, Medical Research Council Harwell, University of Occupational and Environmental Health School of Medicine, Partenaires INRAE, University of Toronto, Ben-Gurion University of the Negev (BGU), University of Colorado [Boulder], Cell Death Research & Therapy (CDRT) Lab, Université Catholique de Louvain = Catholic University of Louvain (UCL), University of Vienna [Vienna], Conway Institute of Biomolecular and Biomedical Research and School of Chemical and Bioprocess Engineering, University College Dublin [Dublin] (UCD), Georgetown University, Candiolo Cancer Institute (IRCCS), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Ikerbasque - Basque Foundation for Science, Cleveland Clinic, Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University), Universidad de Buenos Aires (UBA), Department of Clinical Neurosciences, University College of London [London] (UCL)-Institute of Neurology, Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Consiglio Nazionale delle Ricerche (CNR), Osaka University, Department of Experimental Medicine and Public Health, University of Camerino, University of Barcelona, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-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), Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Physics, Technical University of Denmark [Lyngby] (DTU), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Department of Pharmaco-Biology, Università della Calabria [Arcavacata di Rende] (Unical), Fondation Universitaire Notre Dame de la Paix (FUNDP), Facultés Universitaires Notre Dame de la Paix (FUNDP), USC Neuromuscular Center, Department of Neurology, University of Southern California (USC), Physiopathologie de la survie et de la mort cellulaire et infection virale, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Giannina Gaslini Institute, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, Inner Mongolia Agricultural University (IMAU), Politecnico di Milano [Milan] (POLIMI), Department of Civil, Geological, and Mining Engineering, École Polytechnique de Montréal (EPM)-NSERC Industrial Chair on Drinking Water, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Molecular Medicine, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Experimental Virology - Department of Medical Microbiology [Amsterdam, The Netherlands], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Center for Infection and Immunity Amsterdam - CINIMA [Amsterdam, The Netherlands], Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Department of Internal Medicine, Hospital Universitario Infanta Sofía, Celullar and Molecular Medicine, Infection bactérienne, inflammation, et carcinogenèse digestive, University of Edinburgh, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Faculty of Engineering and Natural Sciences, Sabanci University [Istanbul], University of Science and Technology Beijing [Beijing] (USTB), Centre for Computational and Systems Biology (COSBI), Sun Yat-Sen University [Guangzhou] (SYSU), Dynamique Musculaire et Métabolisme (DMEM), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), CAS Institute of Oceanology (IOCAS), Chinese Academy of Sciences [Beijing] (CAS), Polytechnic University of Marche, 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), Cell Biology, Physiology and Immunology, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Pisa - Università di Pisa, Dulbecco Telethon Institute/Department of Biology, Fondation de Recherche Cancer et Sang - Hôpital Kirchberg, China University of Petroleum, Unilever R&D, University of Queensland [Brisbane], University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Laboratoire de Génie des Procédés et Matériaux - EA 4038 (LGPM), CentraleSupélec, Institute for Advanced Study [Tsinghua], Tsinghua University [Beijing] (THU), Nanayang Technological University (NTU), Nanayang Technological University, Institute of Microelectronics [Beijing] (IMETU), Laboratoire de photonique et de nanostructures (LPN), Centre National de la Recherche Scientifique (CNRS), Institut de biologie moléculaire des plantes (IBMP), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Northwestern Polytechnical University [Xi'an] (NPU), University of Pennsylvania [Philadelphia], City University of Hong Kong (CityU), Department of Mathematics [Berkeley], University of California [Berkeley], University of California-University of California, ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, University of Cincinnati (UC), Réponses immunes : régulation et développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), The University of New Mexico [Albuquerque], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), Dipartimento di Scienze Biomediche, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Department of Experimental Medicine and Oncology, University of Turin, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), CNV, University of Valparaiso, Université Paris 1 Panthéon-Sorbonne - UFR d'Arts plastiques et sciences de l'art (UP1 UFR04), Université Paris 1 Panthéon-Sorbonne (UP1), Department of General, Visceral and Vascular Surgery [Jena], Friedrich-Schiller-Universität Jena, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Réseau International des Instituts Pasteur (RIIP), Macrophages et Développement de l’Immunité, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris], Trafic membranaire et Division cellulaire - Membrane Traffic and Cell Division, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Cibles thérapeutiques, formulation et expertise pré-clinique du médicament (CITHEFOR), Université de Lorraine (UL), This work was supported in part by the National Institutes of Health, including Public Health Service grant GM053396 to D.J.K. Due to space and other limitations, it is not possible to include all other sources of financial support., In a rapidly expanding and highly dynamic field such as autophagy, it is possible that some authors who should have been included on this article have been missed. D.J.K. extends his apologies to researchers in the field of autophagy who, due to oversight or any other reason, could not be included on this article. I also note that two of our colleagues on this manuscript have passed away: Arlette Darfeuille-Michaud and Wouter van Doorn., Life Sciences Institute [Ann Arbor, MI, USA], Laboratoire de Biogenèse Membranaire, CNRS UMR 5200, Université de Bordeaux, INRA Bordeaux Aquitaine, Villenave d'Ornon, France., Amelio, Ivano [0000-0002-9126-5391], Beale, Rupert [0000-0002-6705-8560], Floto, Andres [0000-0002-2188-5659], Frezza, Christian [0000-0002-3293-7397], Ktistakis, Nicholas [0000-0001-9397-2914], Melino, Gerry [0000-0001-9428-5972], Narita, Masashi [0000-0001-7764-577X], Rubinsztein, David [0000-0001-5002-5263], Underwood, Benjamin [0000-0003-3427-9487], Whitworth, Alex [0000-0002-1154-6629], Apollo - University of Cambridge Repository, Université Catholique de Louvain, Facultés Universitaires Notre-Dame de la Paix, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR50-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-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 Nice Sophia Antipolis (... - 2019) (UNS), Department of Clinical and Molecular Medicine, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' [Rome], Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Sun Yat-Sen University (SYSU), 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), University of Minnesota [Twin Cities], Tsinghua University [Beijing], Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université Panthéon-Sorbonne - UFR d'Arts plastiques et sciences de l'art (UP1 UFR04), Université Panthéon-Sorbonne (UP1), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Necker - Enfants Malades [AP-HP], Trafic membranaire et Division cellulaire, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Klionsky, D., Abdelmohsen, K., Abe, A., Abedin, M., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C., Adams, P., Adeli, K., Adhihetty, P., Adler, S., Agam, G., Agarwal, R., Aghi, M., Agnello, M., Agostinis, P., Aguilar, P., Aguirre-Ghiso, J., Airoldi, E., Ait-Si-Ali, S., Akematsu, T., Akporiaye, E., Al-Rubeai, M., Albaiceta, G., Albanese, C., Albani, D., Albert, M., Aldudo, J., Algül, H., Alirezaei, M., Alloza, I., Almasan, A., Almonte-Beceril, M., Alnemri, E., Alonso, C., Altan-Bonnet, N., Altieri, D., Alvarez, S., Alvarez-Erviti, L., Alves, S., Amadoro, G., Amano, A., Amantini, C., Ambrosio, S., Amelio, I., Amer, A., Amessou, M., Amon, A., An, Z., Anania, F., Andersen, S., Andley, U., Andreadi, C., Andrieu-Abadie, N., Anel, A., Ann, D., Anoopkumar-Dukie, S., Antonioli, M., Aoki, H., Apostolova, N., Aquila, S., Aquilano, K., Araki, K., Arama, E., Aranda, A., Araya, J., Arcaro, A., Arias, E., Arimoto, H., Ariosa, A., Armstrong, J., Arnould, T., Arsov, I., Asanuma, K., Askanas, V., Asselin, E., Atarashi, R., Atherton, S., Atkin, J., Attardi, L., Auberger, P., Auburger, G., Aurelian, L., Autelli, R., Avagliano, L., Avantaggiati, M., Avrahami, L., Awale, S., Azad, N., Bachetti, T., Backer, J., Bae, D., Bae, J., Bae, O., Bae, S., Baehrecke, E., Baek, S., Baghdiguian, S., Bagniewska-Zadworna, A., Bai, H., Bai, J., Bai, X., Bailly, Y., Balaji, K., Balduini, W., Ballabio, A., Balzan, R., Banerjee, R., Bánhegyi, G., Bao, H., Barbeau, B., Barrachina, M., Barreiro, E., Bartel, B., Bartolomé, A., Bassham, D., Bassi, M., Bast, R., Basu, A., Batista, M., Batoko, H., Battino, M., Bauckman, K., Baumgarner, B., Bayer, K., Beale, R., Beaulieu, J., Beck, G., Becker, C., Beckham, J., Bédard, P., Bednarski, P., Begley, T., Behl, C., Behrends, C., Behrens, G., Behrns, K., Bejarano, E., Belaid, A., Belleudi, F., Bénard, G., Berchem, G., Bergamaschi, D., Bergami, M., Berkhout, B., Berliocchi, L., Bernard, A., Bernard, M., Bernassola, F., Bertolotti, A., Bess, A., Besteiro, S., Bettuzzi, S., Bhalla, S., Bhattacharyya, S., Bhutia, S., Biagosch, C., Bianchi, M., Biard-Piechaczyk, M., Billes, V., Bincoletto, C., Bingol, B., Bird, S., Bitoun, M., Bjedov, I., Blackstone, C., Blanc, L., Blanco, G., Blomhoff, H., Boada-Romero, E., Böckler, S., Boes, M., Boesze-Battaglia, K., Boise, L., Bolino, A., Boman, A., Bonaldo, P., Bordi, M., Bosch, J., Botana, L., Botti, J., Bou, G., Bouché, M., Bouchecareilh, M., Boucher, M., Boulton, M., Bouret, S., Boya, P., Boyer-Guittaut, M., Bozhkov, P., Brady, N., Braga, V., Brancolini, C., Braus, G., Bravo-San Pedro, J., Brennan, L., Bresnick, E., Brest, P., Bridges, D., Bringer, M., Brini, M., Brito, G., Brodin, B., Brookes, P., Brown, E., Brown, K., Broxmeyer, H., Bruhat, A., Brum, P., Brumell, J., Brunetti-Pierri, N., Bryson-Richardson, R., Buch, S., Buchan, A., Budak, H., Bulavin, D., Bultman, S., Bultynck, G., Bumbasirevic, V., Burelle, Y., Burke, R., Burmeister, M., Bütikofer, P., Caberlotto, L., Cadwell, K., Cahova, M., Cai, D., Cai, J., Cai, Q., Calatayud, S., Camougrand, N., Campanella, M., Campbell, G., Campbell, M., Campello, S., Candau, R., Caniggia, I., Cantoni, L., Cao, L., Caplan, A., Caraglia, M., Cardinali, C., Cardoso, S., Carew, J., Carleton, L., Carlin, C., Carloni, S., Carlsson, S., Carmona-Gutierrez, D., Carneiro, L., Carnevali, O., Carra, S., Carrier, A., Carroll, B., Casas, C., Casas, J., Cassinelli, G., Castets, P., Castro-Obregon, S., Cavallini, G., Ceccherini, I., Cecconi, F., Cederbaum, A., Ceña, V., Cenci, S., Cerella, C., Cervia, D., Cetrullo, S., Chaachouay, H., Chae, H., Chagin, A., Chai, C., Chakrabarti, G., Chamilos, G., Chan, E., Chan, M., Chandra, D., Chandra, P., Chang, C., Chang, R., Chang, T., Chatham, J., Chatterjee, S., Chauhan, S., Che, Y., Cheetham, M., Cheluvappa, R., Chen, C., Chen, G., Chen, H., Chen, J., Chen, M., Chen, P., Chen, Q., Chen, S., Chen, W., Chen, X., Chen, Y., Chen, Z., Cheng, A., Cheng, C., Cheng, H., Cheong, H., Cherry, S., Chesney, J., Cheung, C., Chevet, E., Chi, H., Chi, S., Chiacchiera, F., Chiang, H., Chiarelli, R., Chiariello, M., Chieppa, M., Chin, L., Chiong, M., Chiu, G., Cho, D., Cho, S., Cho, W., Cho, Y., Choi, A., Choi, E., Choi, J., Choi, M., Choi, S., Chou, T., Chouaib, S., Choubey, D., Choubey, V., Chow, K., Chowdhury, K., Chu, C., Chuang, T., Chun, T., Chung, H., Chung, T., Chung, Y., Chwae, Y., Cianfanelli, V., Ciarcia, R., Ciechomska, I., Ciriolo, M., Cirone, M., Claerhout, S., Clague, M., Clària, J., Clarke, P., Clarke, R., Clementi, E., Cleyrat, C., Cnop, M., Coccia, E., Cocco, T., Codogno, P., Coers, J., Cohen, E., Colecchia, D., Coletto, L., Coll, N., Colucci-Guyon, E., Comincini, S., Condello, M., Cook, K., Coombs, G., Cooper, C., Cooper, J., Coppens, I., Corasaniti, M., Corazzari, M., Corbalan, R., Corcelle-Termeau, E., Cordero, M., Corral-Ramos, C., Corti, O., Cossarizza, A., Costelli, P., Costes, S., Cotman, S., Coto-Montes, A., Cottet, S., Couve, E., Covey, L., Cowart, L., Cox, J., Coxon, F., Coyne, C., Cragg, M., Craven, R., Crepaldi, T., Crespo, J., Criollo, A., Crippa, V., Cruz, M., Cuervo, A., Cuezva, J., Cui, T., Cutillas, P., Czaja, M., Czyzyk-Krzeska, M., Dagda, R., Dahmen, U., Dai, C., Dai, W., Dai, Y., Dalby, K., Dalla Valle, L., Dalmasso, G., D'Amelio, M., Damme, M., Darfeuille-Michaud, A., Dargemont, C., Darley-Usmar, V., Dasarathy, S., Dasgupta, B., Dash, S., Dass, C., Davey, H., Davids, L., Dávila, D., Davis, R., Dawson, T., Dawson, V., Daza, P., de Belleroche, J., de Figueiredo, P., de Figueiredo, R., de la Fuente, J., De Martino, L., De Matteis, A., De Meyer, G., De Milito, A., De Santi, M., de Souza, W., De Tata, V., De Zio, D., Debnath, J., Dechant, R., Decuypere, J., Deegan, S., Dehay, B., Del Bello, B., Del Re, D., Delage-Mourroux, R., Delbridge, L., Deldicque, L., Delorme-Axford, E., Deng, Y., Dengjel, J., Denizot, M., Dent, P., Der, C., Deretic, V., Derrien, B., Deutsch, E., Devarenne, T., Devenish, R., Di Bartolomeo, S., Di Daniele, N., Di Domenico, F., Di Nardo, A., Di Paola, S., Di Pietro, A., Di Renzo, L., Diantonio, A., Díaz-Araya, G., Díaz-Laviada, I., Diaz-Meco, M., Diaz-Nido, J., Dickey, C., Dickson, R., Diederich, M., Digard, P., Dikic, I., Dinesh-Kumar, S., Ding, C., Ding, W., Ding, Z., Dini, L., Distler, J., Diwan, A., Djavaheri-Mergny, M., Dmytruk, K., Dobson, R., Doetsch, V., Dokladny, K., Dokudovskaya, S., Donadelli, M., Dong, X., Dong, Z., Donohue, T., Doran, K., D'Orazi, G., Dorn, G., Dosenko, V., Dridi, S., Drucker, L., Du, J., Du, L., du Toit, A., Dua, P., Duan, L., Duann, P., Dubey, V., Duchen, M., Duchosal, M., Duez, H., Dugail, I., Dumit, V., Duncan, M., Dunlop, E., Dunn, W., Dupont, N., Dupuis, L., Durán, R., Durcan, T., Duvezin-Caubet, S., Duvvuri, U., Eapen, V., Ebrahimi-Fakhari, D., Echard, A., Eckhart, L., Edelstein, C., Edinger, A., Eichinger, L., Eisenberg, T., Eisenberg-Lerner, A., Eissa, N., El-Deiry, W., El-Khoury, V., Elazar, Z., Eldar-Finkelman, H., Elliott, C., Emanuele, E., Emmenegger, U., Engedal, N., Engelbrecht, A., Engelender, S., Enserink, J., Erdmann, R., Erenpreisa, J., Eri, R., Eriksen, J., Erman, A., Escalante, R., Eskelinen, E., Espert, L., Esteban-Martínez, L., Evans, T., Fabri, M., Fabrias, G., Fabrizi, C., Facchiano, A., Færgeman, N., Faggioni, A., Fairlie, W., Fan, C., Fan, D., Fan, J., Fang, S., Fanto, M., Fanzani, A., Farkas, T., Faure, M., Favier, F., Fearnhead, H., Federici, M., Fei, E., Felizardo, T., Feng, H., Feng, Y., Ferguson, T., Fernández, Á., Fernandez-Barrena, M., Fernandez-Checa, J., Fernández-López, A., Fernandez-Zapico, M., Feron, O., Ferraro, E., Ferreira-Halder, C., Fesus, L., Feuer, R., Fiesel, F., Filippi-Chiela, E., Filomeni, G., Fimia, G., Fingert, J., Finkbeiner, S., Finkel, T., Fiorito, F., Fisher, P., Flajolet, M., Flamigni, F., Florey, O., Florio, S., Floto, R., Folini, M., Follo, C., Fon, E., Fornai, F., Fortunato, F., Fraldi, A., Franco, R., Francois, A., François, A., Frankel, L., Fraser, I., Frey, N., Freyssenet, D., Frezza, C., Friedman, S., Frigo, D., Fu, D., Fuentes, J., Fueyo, J., Fujitani, Y., Fujiwara, Y., Fujiya, M., Fukuda, M., Fulda, S., Fusco, C., Gabryel, B., Gaestel, M., Gailly, P., Gajewska, M., Galadari, S., Galili, G., Galindo, I., Galindo, M., Galliciotti, G., Galluzzi, L., Galy, V., Gammoh, N., Gandy, S., Ganesan, A., Ganesan, S., Ganley, I., Gannagé, M., Gao, F., Gao, J., García Nannig, L., García Véscovi, E., Garcia-Macía, M., Garcia-Ruiz, C., Garg, A., Garg, P., Gargini, R., Gassen, N., Gatica, D., Gatti, E., Gavard, J., Gavathiotis, E., Ge, L., Ge, P., Ge, S., Gean, P., Gelmetti, V., Genazzani, A., Geng, J., Genschik, P., Gerner, L., Gestwicki, J., Gewirtz, D., Ghavami, S., Ghigo, E., Ghosh, D., Giammarioli, A., Giampieri, F., Giampietri, C., Giatromanolaki, A., Gibbings, D., Gibellini, L., Gibson, S., Ginet, V., Giordano, A., Giorgini, F., Giovannetti, E., Girardin, S., Gispert, S., Giuliano, S., Gladson, C., Glavic, A., Gleave, M., Godefroy, N., Gogal, R., Gokulan, K., Goldman, G., Goletti, D., Goligorsky, M., Gomes, A., Gomes, L., Gomez, H., Gomez-Manzano, C., Gómez-Sánchez, R., Gonçalves, D., Goncu, E., Gong, Q., Gongora, C., Gonzalez, C., Gonzalez-Alegre, P., Gonzalez-Cabo, P., González-Polo, R., Goping, I., Gorbea, C., Gorbunov, N., Goring, D., Gorman, A., Gorski, S., Goruppi, S., Goto-Yamada, S., Gotor, C., Gottlieb, R., Gozes, I., Gozuacik, D., Graba, Y., Graef, M., Granato, G., Grant, G., Grant, S., Gravina, G., Green, D., Greenhough, A., Greenwood, M., Grimaldi, B., Gros, F., Grose, C., Groulx, J., Gruber, F., Grumati, P., Grune, T., Guan, J., Guan, K., Guerra, B., Guillen, C., Gulshan, K., Gunst, J., Guo, C., Guo, L., Guo, M., Guo, W., Guo, X., Gust, A., Gustafsson, Å., Gutierrez, E., Gutierrez, M., Gwak, H., Haas, A., Haber, J., Hadano, S., Hagedorn, M., Hahn, D., Halayko, A., Hamacher-Brady, A., Hamada, K., Hamai, A., Hamann, A., Hamasaki, M., Hamer, I., Hamid, Q., Hammond, E., Han, F., Han, W., Handa, J., Hanover, J., Hansen, M., Harada, M., Harhaji-Trajkovic, L., Harper, J., Harrath, A., Harris, A., Harris, J., Hasler, U., Hasselblatt, P., Hasui, K., Hawley, R., Hawley, T., He, C., He, F., He, G., He, R., He, X., He, Y., Heath, J., Hébert, M., Heinzen, R., Helgason, G., Hensel, M., Henske, E., Her, C., Herman, P., Hernández, A., Hernandez, C., Hernández-Tiedra, S., Hetz, C., Hiesinger, P., Higaki, K., Hilfiker, S., Hill, B., Hill, J., Hill, W., Hino, K., Hofius, D., Hofman, P., Höglinger, G., Höhfeld, J., Holz, M., Hong, Y., Hood, D., Hoozemans, J., Hoppe, T., Hsu, C., Hsu, L., Hu, D., Hu, G., Hu, H., Hu, M., Hu, Y., Hu, Z., Hua, F., Hua, Y., Huang, C., Huang, H., Huang, K., Huang, S., Huang, W., Huang, Y., Huber, T., Huebbe, P., Huh, W., Hulmi, J., Hur, G., Hurley, J., Husak, Z., Hussain, S., Hwang, J., Hwang, S., Hwang, T., Ichihara, A., Imai, Y., Imbriano, C., Inomata, M., Into, T., Iovane, V., Iovanna, J., Iozzo, R., Ip, N., Irazoqui, J., Iribarren, P., Isaka, Y., Isakovic, A., Ischiropoulos, H., Isenberg, J., Ishaq, M., Ishida, H., Ishii, I., Ishmael, J., Isidoro, C., Isobe, K., Isono, E., Issazadeh-Navikas, S., Itahana, K., Itakura, E., Ivanov, A., Iyer, A., Izquierdo, J., Izumi, Y., Izzo, V., Jäättelä, M., Jaber, N., Jackson, D., Jackson, W., Jacob, T., Jacques, T., Jagannath, C., Jain, A., Jana, N., Jang, B., Jani, A., Janji, B., Jannig, P., Jansson, P., Jean, S., Jendrach, M., Jeon, J., Jessen, N., Jeung, E., Jia, K., Jia, L., Jiang, H., Jiang, L., Jiang, T., Jiang, X., Jiang, Y., Jiménez, A., Jin, C., Jin, H., Jin, L., Jin, M., Jin, S., Jinwal, U., Jo, E., Johansen, T., Johnson, D., Johnson, G., Johnson, J., Jonasch, E., Jones, C., Joosten, L., Jordan, J., Joseph, A., Joseph, B., Joubert, A., Ju, D., Ju, J., Juan, H., Juenemann, K., Juhász, G., Jung, H., Jung, J., Jung, Y., Jungbluth, H., Justice, M., Jutten, B., Kaakoush, N., Kaarniranta, K., Kaasik, A., Kabuta, T., Kaeffer, B., Kågedal, K., Kahana, A., Kajimura, S., Kakhlon, O., Kalia, M., Kalvakolanu, D., Kamada, Y., Kambas, K., Kaminskyy, V., Kampinga, H., Kandouz, M., Kang, C., Kang, R., Kang, T., Kanki, T., Kanneganti, T., Kanno, H., Kanthasamy, A., Kantorow, M., Kaparakis-Liaskos, M., Kapuy, O., Karantza, V., Karim, M., Karmakar, P., Kaser, A., Kaushik, S., Kawula, T., Kaynar, A., Ke, P., Ke, Z., Kehrl, J., Keller, K., Kemper, J., Kenworthy, A., Kepp, O., Kern, A., Kesari, S., Kessel, D., Ketteler, R., Kettelhut, I., Khambu, B., Khan, M., Khandelwal, V., Khare, S., Kiang, J., Kiger, A., Kihara, A., Kim, A., Kim, C., Kim, D., Kim, E., Kim, H., Kim, J., Kim, K., Kim, M., Kim, P., Kim, S., Kim, Y., Kimchi, A., Kimmelman, A., Kimura, T., King, J., Kirkegaard, K., Kirkin, V., Kirshenbaum, L., Kishi, S., Kitajima, Y., Kitamoto, K., Kitaoka, Y., Kitazato, K., Kley, R., Klimecki, W., Klinkenberg, M., Klucken, J., Knævelsrud, H., Knecht, E., Knuppertz, L., Ko, J., Kobayashi, S., Koch, J., Koechlin-Ramonatxo, C., Koenig, U., Koh, Y., Köhler, K., Kohlwein, S., Koike, M., Komatsu, M., Kominami, E., Kong, D., Kong, H., Konstantakou, E., Kopp, B., Korcsmaros, T., Korhonen, L., Korolchuk, V., Koshkina, N., Kou, Y., Koukourakis, M., Koumenis, C., Kovács, A., Kovács, T., Kovacs, W., Koya, D., Kraft, C., Krainc, D., Kramer, H., Kravic-Stevovic, T., Krek, W., Kretz-Remy, C., Krick, R., Krishnamurthy, M., Kriston-Vizi, J., Kroemer, G., Kruer, M., Kruger, R., Ktistakis, N., Kuchitsu, K., Kuhn, C., Kumar, A., Kumar, D., Kumar, R., Kumar, S., Kundu, M., Kung, H., Kuno, A., Kuo, S., Kuret, J., Kurz, T., Kwok, T., Kwon, T., Kwon, Y., Kyrmizi, I., La Spada, A., Lafont, F., Lahm, T., Lakkaraju, A., Lam, T., Lamark, T., Lancel, S., Landowski, T., Lane, D., Lane, J., Lanzi, C., Lapaquette, P., Lapierre, L., Laporte, J., Laukkarinen, J., Laurie, G., Lavandero, S., Lavie, L., Lavoie, M., Law, B., Law, H., Law, K., Layfield, R., Lazo, P., Le Cam, L., Le Roch, K., Le Stunff, H., Leardkamolkarn, V., Lecuit, M., Lee, B., Lee, C., Lee, E., Lee, G., Lee, H., Lee, J., Lee, M., Lee, P., Lee, S., Lee, Y., Leeuwenburgh, C., Lefort, S., Legouis, R., Lei, J., Lei, Q., Leib, D., Leibowitz, G., Lekli, I., Lemaire, S., Lemasters, J., Lemberg, M., Lemoine, A., Leng, S., Lenz, G., Lenzi, P., Lerman, L., Lettieri Barbato, D., Leu, J., Leung, H., Levine, B., Lewis, P., Lezoualc'H, F., Li, C., Li, F., Li, J., Li, K., Li, L., Li, M., Li, Q., Li, R., Li, S., Li, W., Li, X., Li, Y., Lian, J., Liang, C., Liang, Q., Liao, Y., Liberal, J., Liberski, P., Lie, P., Lieberman, A., Lim, H., Lim, K., Lima, R., Lin, C., Lin, F., Lin, K., Lin, P., Lin, T., Lin, W., Lin, Y., Linden, R., Lindholm, D., Lindqvist, L., Lingor, P., Linkermann, A., Liotta, L., Lipinski, M., Lira, V., Lisanti, M., Liton, P., Liu, B., Liu, C., Liu, F., Liu, H., Liu, J., Liu, K., Liu, L., Liu, Q., Liu, R., Liu, S., Liu, W., Liu, X., Liu, Y., Liu, Z., Liuzzi, J., Lizard, G., Ljujic, M., Lodhi, I., Logue, S., Lokeshwar, B., Long, Y., Lonial, S., Loos, B., López-Otín, C., López-Vicario, C., Lorente, M., Lorenzi, P., Lõrincz, P., Los, M., Lotze, M., Lovat, P., Lu, B., Lu, J., Lu, Q., Lu, S., Lu, Y., Luciano, F., Luckhart, S., Lucocq, J., Ludovico, P., Lugea, A., Lukacs, N., Lum, J., Lund, A., Luo, H., Luo, J., Luo, S., Luparello, C., Lyons, T., Ma, J., Ma, Y., Ma, Z., Machado, J., Machado-Santelli, G., Macian, F., Macintosh, G., Mackeigan, J., Macleod, K., Macmicking, J., MacMillan-Crow, L., Madeo, F., Madesh, M., Madrigal-Matute, J., Maeda, A., Maeda, T., Maegawa, G., Maellaro, E., Maes, H., Magariños, M., Maiese, K., Maiti, T., Maiuri, L., Maiuri, M., Maki, C., Malli, R., Malorni, W., Maloyan, A., Mami-Chouaib, F., Man, N., Mancias, J., Mandelkow, E., Mandell, M., Manfredi, A., Manié, S., Manzoni, C., Mao, K., Mao, Z., Marambaud, 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L, Chen, Wei, Chen, Wei Jung, Chen, Wen Qiang, Chen, Wenli, Chen, Xiangmei, Chen, Yau Hung, Chen, Ye Guang, Chen, Yin, Chen, Yingyu, Chen, Yongshun, Chen, Yu Jen, Chen, Yue Qin, Chen, Yujie, Chen, Zhen, Chen, Zhong, Cheng, Alan, Cheng, Christopher Hk, Cheng, Hua, Cheong, Heesun, Cherry, Sara, Chesney, Jason, Cheung, Chun Hei Antonio, Chevet, Eric, Chi, Hsiang Cheng, Chi, Sung Gil, Chiacchiera, Fulvio, Chiang, Hui Ling, Chiarelli, Roberto, Chiariello, Mario, Chieppa, Marcello, Chin, Lih Shen, Chiong, Mario, Chiu, Gigi Nc, Cho, Dong Hyung, Cho, Ssang Goo, Cho, William C, Cho, Yong Yeon, Cho, Young Seok, Choi, Augustine Mk, Choi, Eui Ju, Choi, Eun Kyoung, Choi, Jayoung, Choi, Mary E, Choi, Seung Il, Chou, Tsui Fen, Chouaib, Salem, Choubey, Divaker, Choubey, Vinay, Chow, Kuan Chih, Chowdhury, Kamal, Chu, Charleen T, Chuang, Tsung Hsien, Chun, Taehoon, Chung, Hyewon, Chung, Taijoon, Chung, Yuen Li, Chwae, Yong Joon, Cianfanelli, Valentina, Ciarcia, Roberto, Ciechomska, Iwona A, Ciriolo, Maria Rosa, Cirone, Mara, Claerhout, Sofie, Clague, Michael J, Clària, Joan, Clarke, Peter Gh, Clarke, Robert, Clementi, Emilio, Cleyrat, Cédric, Cnop, Miriam, Coccia, Eliana M, Cocco, Tiziana, Codogno, Patrice, Coers, Jörn, Cohen, Ezra Ew, Colecchia, David, Coletto, Luisa, Coll, Núria S, Colucci Guyon, Emma, Comincini, Sergio, Condello, Maria, Cook, Katherine L, Coombs, Graham H, Cooper, Cynthia D, Cooper, J. Mark, Coppens, Isabelle, Corasaniti, Maria Tiziana, Corazzari, Marco, Corbalan, Ramon, Corcelle Termeau, Elisabeth, Cordero, Mario D, Corral Ramos, Cristina, Corti, Olga, Cossarizza, Andrea, Costelli, Paola, Costes, Safia, Cotman, Susan L, Coto Montes, Ana, Cottet, Sandra, Couve, Eduardo, Covey, Lori R, Cowart, L. 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Tony, El Deiry, Wafik S, El Khoury, Victoria, Elazar, Zvulun, Eldar Finkelman, Hagit, Elliott, Chris Jh, Emanuele, Enzo, Emmenegger, Urban, Engedal, Nikolai, Engelbrecht, Anna Mart, Engelender, Simone, Enserink, Jorrit M, Erdmann, Ralf, Erenpreisa, Jekaterina, Eri, Rajaraman, Eriksen, Jason L, Erman, Andreja, Escalante, Ricardo, Eskelinen, Eeva Liisa, Espert, Lucile, Esteban Martínez, Lorena, Evans, Thomas J, Fabri, Mario, Fabrias, Gemma, Fabrizi, Cinzia, Facchiano, Antonio, Færgeman, Nils J, Faggioni, Alberto, Fairlie, W. 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Berghe, G, Van Den Bosch, L, van den Brink, Gr, van der Goot, Fg, van der Klei, Ij, van der Laan, Lj, van Doorn, Wg, van Egmond, M, van Golen, Kl, Van Kaer, L, van Lookeren Campagne, M, Vandenabeele, P, Vandenberghe, W, Vanhorebeek, I, Varela Nieto, I, Vasconcelos, Mh, Vasko, R, Vavvas, Dg, Vega Naredo, I, Velasco, G, Velentzas, Ad, Velentzas, Pd, Vellai, T, Vellenga, E, Vendelbo, Mh, Venkatachalam, K, Ventura, N, Ventura, S, Veras, P, Verdier, M, Vertessy, Bg, Viale, A, Vidal, M, Vieira, H, Vierstra, Rd, Vigneswaran, N, Vij, N, Vila, M, Villar, M, Villar, Vh, Villarroya, J, Vindis, C, Viola, G, Viscomi, Mt, Vitale, G, Vogl, Dt, Voitsekhovskaja, Ov, von Haefen, C, von Schwarzenberg, K, Voth, De, Vouret Craviari, V, Vuori, K, Vyas, Jm, Waeber, C, Walker, Cl, Walker, Mj, Walter, J, Wan, L, Wan, X, Wang, B, Wang, C, Wang, Cy, Wang, D, Wang, F, Wang, G, Wang, Hj, Wang, H, Wang, Hg, Wang, Hd, Wang, J, Wang, M, Wang, Mq, Wang, Py, Wang, P, Wang, Rc, Wang, S, Wang, Tf, Wang, X, Wang, Xj, 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Yang, W, Yang, Wy, Yang, X, Yang, Y, Yang, Z, Yao, Mc, Yao, Pj, Yao, X, Yao, Z, Yasui, L, Ye, M, Yedvobnick, B, Yeganeh, B, Yeh, E, Yeyati, Pl, Yi, F, Yi, L, Yin, Xm, Yip, Ck, Yoo, Ym, Yoo, Yh, Yoon, Sy, Yoshida, Ki, Yoshimori, T, Young, Kh, Yu, H, Yu, Jj, Yu, Jt, Yu, J, Yu, L, Yu, Wh, Yu, Xf, Yu, Z, Yuan, J, Yuan, Zm, Yue, By, Yue, J, Yue, Z, Zacks, Dn, Zacksenhaus, E, Zaffaroni, N, Zaglia, T, Zakeri, Z, Zecchini, V, Zeng, J, Zeng, M, Zeng, Q, Zervos, A, Zhang, Dd, Zhang, F, Zhang, G, Zhang, Gc, Zhang, H, Zhang, J, Zhang, Jp, Zhang, L, Zhang, My, Zhang, X, Zhang, Xd, Zhang, Y, Zhao, M, Zhao, Wl, Zhao, X, Zhao, Yg, Zhao, Y, Zhao, Yx, Zhao, Z, Zhao, Zj, Zheng, D, Zheng, Xl, Zheng, X, Zhivotovsky, B, Zhong, Q, Zhou, Gz, Zhou, G, Zhou, H, Zhou, Sf, Zhou, Xj, Zhu, H, Zhu, Wg, Zhu, W, Zhu, Xf, Zhu, Y, Zhuang, Sm, Zhuang, X, Ziparo, E, Zois, Ce, Zoladek, T, Zong, Wx, Zorzano, A, Zughaier, Sm, AII - Amsterdam institute for Infection and Immunity, Medical Microbiology and Infection Prevention, Other departments, CCA -Cancer Center Amsterdam, Center of Experimental and Molecular Medicine, Radiotherapy, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biochemistry, ANS - Cellular & Molecular Mechanisms, Cell Biology and Histology, Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Daniel J Klionsky, Kotb Abdelmohsen, Akihisa Abe, Md Joynal Abedin, Hagai Abeliovich, Abraham Acevedo Arozena, Hiroaki Adachi, Christopher M Adam, Peter D Adam, Khosrow Adeli, Peter J Adhihetty, Sharon G Adler, Galila Agam, Rajesh Agarwal, Manish K Aghi, Maria Agnello, Patrizia Agostini, Patricia V Aguilar, Julio Aguirre-Ghiso, Edoardo M Airoldi, Slimane Ait-Si-Ali, Takahiko Akematsu, Emmanuel T Akporiaye, Mohamed Al-Rubeai, Guillermo M Albaiceta, Chris Albanese, Diego Albani, Matthew L Albert, Jesus Aldudo, Hana Algül, Mehrdad Alirezaei, Iraide Alloza, Alexandru Almasan, Maylin Almonte-Beceril, Emad S Alnemri, Covadonga Alonso, Nihal Altan-Bonnet, Dario C Altieri, Silvia Alvarez, Lydia Alvarez- Erviti, Sandro Alve, Giuseppina Amadoro, Atsuo Amano, Consuelo Amantini, Santiago Ambrosio, Ivano Amelio, Amal O Amer, Mohamed Amessou, Angelika Amon, Zhenyi An, Frank A Anania, Stig U Andersen, Usha P Andley, Catherine K Andreadi, Nathalie Andrieu- Abadie, Alberto Anel, David K Ann, Shailendra Anoopkumar-Dukie, Manuela Antonioli, Hiroshi Aoki, Nadezda Apostolova, Saveria Aquila, Katia Aquilano, Koichi Araki, Eli Arama, Agustin Aranda, Jun Araya, Alexandre Arcaro, Esperanza Aria, Hirokazu Arimoto, Aileen R Ariosa, Jane L Armstrong, Thierry Arnould, Ivica Arsov, Katsuhiko Asanuma, Valerie Askana, Eric Asselin, Ryuichiro Atarashi, Sally S Atherton, Julie D Atkin, Laura D Attardi, Patrick Auberger, Georg Auburger, Laure Aurelian, Riccardo Autelli, Laura Avagliano, Maria Laura Avantaggiati, Limor Avrahami, Suresh Awale, Neelam Azad, Tiziana Bachetti, Jonathan M Backer, Dong- Hun Bae, Jae-sung Bae, Ok-Nam Bae, Soo Han Bae, Eric H Baehrecke, Seung-Hoon Baek, Stephen Baghdiguian, Agnieszka Bagniewska-Zadworna, Hua Bai, Jie Bai, Xue-Yuan Bai, Yannick Bailly, Kithiganahalli Narayanaswamy Balaji, Walter Balduini, Andrea Ballabio, Rena Balzan, Rajkumar Banerjee, Gábor Bánhegyi, Haijun Bao, Benoit Barbeau, Maria D Barrachina, Esther Barreiro, Bonnie Bartel, Alberto Bartolomé, Diane C Bassham, Maria Teresa Bassi, Robert C Bast Jr, Alakananda Basu, Maria Teresa Batista, Henri Batoko, Maurizio Battino, Kyle Bauckman, Bradley L Baumgarner, K Ulrich Bayer, Rupert Beale, Jean-François Beaulieu, George R. Beck Jr, Christoph Becker, J David Beckham, Pierre-André Bédard, Patrick J Bednarski, Thomas J Begley, Christian Behl, Christian Behrend, Georg MN Behren, Kevin E Behrn, Eloy Bejarano, Amine Belaid, Francesca Belleudi, Giovanni Bénard, Guy Berchem, Daniele Bergamaschi, Matteo Bergami, Ben Berkhout, Laura Berliocchi, Amélie Bernard, Monique Bernard, Francesca Bernassola, Anne Bertolotti, Amanda S Be, Sébastien Besteiro, Saverio Bettuzzi, Savita Bhalla, Shalmoli Bhattacharyya, Sujit K Bhutia, Caroline Biagosch, Michele Wolfe Bianchi, Martine Biard-Piechaczyk, Viktor Bille, Claudia Bincoletto, Baris Bingol, Sara W Bird, Marc Bitoun, Ivana Bjedov, Craig Blackstone, Lionel Blanc, Guillermo A Blanco, Heidi Kiil Blomhoff, Emilio Boada-Romero, Stefan Böckler, Marianne Boe, Kathleen Boesze-Battaglia, Lawrence H Boise, Alessandra Bolino, Andrea Boman, Paolo Bonaldo, Matteo Bordi, Jürgen Bosch, Luis M Botana, Joelle Botti, German Bou, Marina Bouché, Marion Bouchecareilh, Marie- Josée Boucher, Michael E Boulton, Sebastien G Bouret, Patricia Boya, Michaël Boyer-Guittaut, Peter V Bozhkov, Nathan Brady, Vania MM Braga, Claudio Brancolini, Gerhard H Brau, José M Bravo-San Pedro, Lisa A Brennan, Emery H Bresnick, Patrick Brest, Dave Bridge, MarieAgnès Bringer, Marisa Brini, Glauber C Brito, Bertha Brodin, Paul S Brooke, Eric J Brown, Karen Brown, Hal E Broxmeyer, Alain Bruhat, Patricia Chakur Brum, John H Brumell, Nicola Brunetti-Pierri, Robert J Bryson-Richardson, Shilpa Buch, Alastair M Buchan, Hikmet Budak, Dmitry V Bulavin, Scott J Bultman, Geert Bultynck, Vladimir Bumbasirevic, Yan Burelle, Robert E Burke, Margit Burmeister, Peter Bütikofer, Laura Caberlotto, Ken Cadwell, Monika Cahova, Dongsheng Cai, Jingjing Cai, Qian Cai, Sara Calatayud, Nadine Camougrand, Michelangelo Campanella, Grant R Campbell, Matthew Campbell, Silvia Campello, Robin Candau, Isabella Caniggia, Lavinia Cantoni, Lizhi Cao, Allan B Caplan, Michele Caraglia, Claudio Cardinali, Sandra Morais Cardoso, Jennifer S Carew, Laura A Carleton, Cathleen R Carlin, Silvia Carloni, Sven R Carlsson, Didac Carmona-Gutierrez, Leticia AM Carneiro, Oliana Carnevali, Serena Carra, Alice Carrier, Bernadette Carroll, Caty Casa, Josefina Casa, Giuliana Cassinelli, Perrine Castet, Susana Castro-Obregon, Gabriella Cavallini, Isabella Ceccherini, Francesco Cecconi, Arthur I Cederbaum, Valentín Ceña, Simone Cenci, Claudia Cerella, Davide Cervia, Silvia Cetrullo, Hassan Chaachouay, Han-Jung Chae, Andrei S Chagin, Chee-Yin Chai, Gopal Chakrabarti, Georgios Chamilo, Edmond YW Chan, Matthew TV Chan, Dhyan Chandra, Pallavi Chandra, Chih-Peng Chang, Raymond Chuen-Chung Chang, Ta Yuan Chang, John C Chatham, Saurabh Chatterjee, Santosh Chauhan, Yongsheng Che, Michael E Cheetham, Rajkumar Cheluvappa, Chun-Jung Chen, Gang Chen, Guang-Chao Chen, Guoqiang Chen, Hongzhuan Chen, Jeff W Chen, Jian-Kang Chen, Min Chen, Mingzhou Chen, Peiwen Chen, Qi Chen, Quan Chen, Shang- Der Chen, Si Chen, Steve S-L Chen, Wei Chen, Wei-Jung Chen, Wen Qiang Chen, Wenli Chen, Xiangmei Chen, Yau-Hung Chen, Ye-Guang Chen, Yin Chen, Yingyu Chen, Yongshun Chen, Yu- Jen Chen, Yue-Qin Chen, Yujie Chen, Zhen Chen, Zhong Chen, Alan Cheng, Christopher HK Cheng, Hua Cheng, Heesun Cheong, Sara Cherry, Jason Chesney, Chun Hei Antonio Cheung, Eric Chevet, Hsiang Cheng Chi, Sung-Gil Chi, Fulvio Chiacchiera, Hui-Ling Chiang, Roberto Chiarelli, Mario Chiariello, Marcello Chieppa, Lih-Shen Chin, Mario Chiong, Gigi NC Chiu, Dong-Hyung Cho, Ssang-Goo Cho, William C Cho, Yong-Yeon Cho, Young-Seok Cho, Augustine MK Choi, Eui-Ju Choi, Eun-Kyoung Choi, Jayoung Choi, Mary E Choi, Seung-Il Choi, Tsui-Fen Chou, Salem Chouaib, Divaker Choubey, Vinay Choubey, Kuan-Chih Chow, Kamal Chowdhury, Charleen T Chu, Tsung-Hsien Chuang, Taehoon Chun, Hyewon Chung, Taijoon Chung, Yuen-Li Chung, Yong-Joon Chwae, Valentina Cianfanelli, Roberto Ciarcia, Iwona A Ciechomska, Maria Rosa Ciriolo, Mara Cirone, Sofie Claerhout, Michael J Clague, Joan Clària, Peter GH Clarke, Robert Clarke, Emilio Clementi, Cédric Cleyrat, Miriam Cnop, Eliana M Coccia, Tiziana Cocco, Patrice Codogno, Jörn Coer, Ezra EW Cohen, David Colecchia, Luisa Coletto, Núria S Coll, Emma Colucci-Guyon, Sergio Comincini, Maria Condello, Katherine L Cook, Graham H Coomb, Cynthia D Cooper, J Mark Cooper, Isabelle Coppen, Maria Tiziana Corasaniti, Marco Corazzari, Ramon Corbalan, Elisabeth Corcelle-Termeau, Mario D Cordero, Cristina Corral-Ramo, Olga Corti, Andrea Cossarizza, Paola Costelli, Safia Coste, Susan L Cotman, Ana Coto-Monte, Sandra Cottet, Eduardo Couve, Lori R Covey, L Ashley Cowart, Jeffery S Cox, Fraser P Coxon, Carolyn B Coyne, Mark S Cragg, Rolf J Craven, Tiziana Crepaldi, Jose L Crespo, Alfredo Criollo, Valeria Crippa, Maria Teresa Cruz, Ana Maria Cuervo, Jose M Cuezva, Taixing Cui, Pedro R Cutilla, Mark J Czaja, Maria F Czyzyk-Krzeska, Ruben K Dagda, Uta Dahmen, Chunsun Dai, Wenjie Dai, Yun Dai, Kevin N Dalby, Luisa Dalla Valle, Guillaume Dalmasso, Marcello D'Amelio, Markus Damme, Arlette Darfeuille-Michaud, Catherine Dargemont, Victor M Darley-Usmar, Srinivasan Dasarathy, Biplab Dasgupta, Srikanta Dash, Crispin R Da, Hazel Marie Davey, Lester M David, David Dávila, Roger J Davi, Ted M Dawson, Valina L Dawson, Paula Daza, Jackie de Belleroche, Paul de Figueiredo, Regina Celia Bressan Queiroz de Figueiredo, José de la Fuente, Luisa De Martino, Antonella De Mattei, Guido RY De Meyer, Angelo De Milito, Mauro De Santi, Wanderley de Souza, Vincenzo De Tata, Daniela De Zio, Jayanta Debnath, Reinhard Dechant, Jean-Paul Decuypere, Shane Deegan, Benjamin Dehay, Barbara Del Bello, Dominic P Del Re, Régis Delage-Mourroux, Lea MD Delbridge, Louise Deldicque, Elizabeth Delorme-Axford, Yizhen Deng, Joern Dengjel, Melanie Denizot, Paul Dent, Channing J Der, Vojo Deretic, Benoît Derrien, Eric Deutsch, Timothy P Devarenne, Rodney J Devenish, Sabrina Di Bartolomeo, Nicola Di Daniele, Fabio Di Domenico, Alessia Di Nardo, Simone Di Paola, Antonio Di Pietro, Livia Di Renzo, Aaron DiAntonio, Guillermo Díaz-Araya, Ines Díaz-Laviada, Maria T Diaz-Meco, Javier Diaz-Nido, Chad A Dickey, Robert C Dickson, Marc Diederich, Paul Digard, Ivan Dikic, Savithrama P Dinesh-Kumar, Chan Ding, Wen-Xing Ding, Zufeng Ding, Luciana Dini, Jörg HW Distler, Abhinav Diwan, Mojgan Djavaheri-Mergny, Kostyantyn Dmytruk, Renwick CJ Dobson, Volker Doetsch, Karol Dokladny, Svetlana Dokudovskaya, Massimo Donadelli, X Charlie Dong, Xiaonan Dong, Zheng Dong, Terrence M Donohue Jr, Kelly S Doran, Gabriella D'Orazi, Gerald W Dorn II, Victor Dosenko, Sami Dridi, Liat Drucker, Jie Du, Li-Lin Du, Lihuan Du, André du Toit, Priyamvada Dua, Lei Duan, Pu Duann, Vikash Kumar Dubey, Michael R Duchen, Michel A Duchosal, Helene Duez, Isabelle Dugail, Verónica I Dumit, Mara C Duncan, Elaine A Dunlop, William A Dunn Jr, Nicolas Dupont, Luc Dupui, Raúl V Durán, Thomas M Durcan, Stéphane Duvezin-Caubet, Umamaheswar Duvvuri, Vinay Eapen, Darius Ebrahimi-Fakhari, Arnaud Echard, Leopold Eckhart, Charles L Edelstein, Aimee L Edinger, Ludwig Eichinger, Tobias Eisenberg, Avital Eisenberg-Lerner, N Tony Eissa, Wafik S El-Deiry, Victoria El-Khoury, Zvulun Elazar, Hagit Eldar-Finkelman, Chris JH Elliott, Enzo Emanuele, Urban Emmenegger, Nikolai Engedal, Anna-Mart Engelbrecht, Simone Engelender, Jorrit M Enserink, Ralf Erdmann, Jekaterina Erenpreisa, Rajaraman Eri, Jason L Eriksen, Andreja Erman, Ricardo Escalante, Eeva- Liisa Eskelinen, Lucile Espert, Lorena Esteban-Martínez, Thomas J Evan, Mario Fabri, Gemma Fabria, Cinzia Fabrizi, Antonio Facchiano, Nils J Færgeman, Alberto Faggioni, W Douglas Fairlie, Chunhai Fan, Daping Fan, Jie Fan, Shengyun Fang, Manolis Fanto, Alessandro Fanzani, Thomas Farka, Mathias Faure, Francois B Favier, Howard Fearnhead, Massimo Federici, Erkang Fei, Tania C Felizardo, Hua Feng, Yibin Feng, Yuchen Feng, Thomas A Ferguson, Álvaro F Fernández, Maite G Fernandez-Barrena, Jose C Fernandez-Checa, Arsenio Fernández-López, Martin E Fernandez-Zapico, Olivier Feron, Elisabetta Ferraro, Carmen Veríssima Ferreira-Halder, Laszlo Fesu, Ralph Feuer, Fabienne C Fiesel, Eduardo C Filippi-Chiela, Giuseppe Filomeni, Gian Maria Fimia, John H Fingert, Steven Finkbeiner, Toren Finkel, Filomena Fiorito, Paul B Fisher, Marc Flajolet, Flavio Flamigni, Oliver Florey, Salvatore Florio, R Andres Floto, Marco Folini, Carlo Follo, Edward A Fon, Francesco Fornai, Franco Fortunato, Alessandro Fraldi, Rodrigo Franco, Arnaud Francoi, Aurélie Françoi, Lisa B Frankel, Iain DC Fraser, Norbert Frey, Damien G Freyssenet, Christian Frezza, Scott L Friedman, Daniel E Frigo, Dongxu Fu, José M Fuente, Juan Fueyo, Yoshio Fujitani, Yuuki Fujiwara, Mikihiro Fujiya, Mitsunori Fukuda, Simone Fulda, Carmela Fusco, Bozena Gabryel, Matthias Gaestel, Philippe Gailly, Malgorzata Gajewska, Sehamuddin Galadari, Gad Galili, Inmaculada Galindo, Maria F Galindo, Giovanna Galliciotti, Lorenzo Galluzzi, Luca Galluzzi, Vincent Galy, Noor Gammoh, Sam Gandy, Anand K Ganesan, Swamynathan Ganesan, Ian G Ganley, Monique Gannagé, Fen-Biao Gao, Feng Gao, Jian-Xin Gao, Lorena García Nannig, Eleonora García Véscovi, Marina Garcia-Macía, Carmen Garcia- Ruiz, Abhishek D Garg, Pramod Kumar Garg, Ricardo Gargini, Nils Christian Gassen, Damián Gatica, Evelina Gatti, Julie Gavard, Evripidis Gavathioti, Liang Ge, Pengfei Ge, Shengfang Ge, Po-Wu Gean, Vania Gelmetti, Armando A Genazzani, Jiefei Geng, Pascal Genschik, Lisa Gerner, Jason E Gestwicki, David A Gewirtz, Saeid Ghavami, Eric Ghigo, Debabrata Ghosh, Anna Maria Giammarioli, Francesca Giampieri, Claudia Giampietri, Alexandra Giatromanolaki, Derrick J Gibbing, Lara Gibellini, Spencer B Gibson, Vanessa Ginet, Antonio Giordano, Flaviano Giorgini, Elisa Giovannetti, Stephen E Girardin, Suzana Gispert, Sandy Giuliano, Candece L Gladson, Alvaro Glavic, Martin Gleave, Nelly Godefroy, Robert M Gogal Jr, Kuppan Gokulan, Gustavo H Goldman, Delia Goletti, Michael S Goligorsky, Aldrin V Gome, Ligia C Gome, Hernando Gomez, Candelaria Gomez-Manzano, Rubén Gómez-Sánchez, Dawit AP Gonçalve, Ebru Goncu, Qingqiu Gong, Céline Gongora, Carlos B Gonzalez, Pedro Gonzalez-Alegre, Pilar Gonzalez-Cabo, Rosa Ana González-Polo, Ing Swie Goping, Carlos Gorbea, Nikolai V Gorbunov, Daphne R Goring, Adrienne M Gorman, Sharon M Gorski, Sandro Goruppi, Shino Goto- Yamada, Cecilia Gotor, Roberta A Gottlieb, Illana Goze, Devrim Gozuacik, Yacine Graba, Martin Graef, Giovanna E Granato, Gary Dean Grant, Steven Grant, Giovanni Luca Gravina, Douglas R Green, Alexander Greenhough, Michael T Greenwood, Benedetto Grimaldi, Frédéric Gro, Charles Grose, Jean-Francois Groulx, Florian Gruber, Paolo Grumati, Tilman Grune, Jun-Lin Guan, Kun-Liang Guan, Barbara Guerra, Carlos Guillen, Kailash Gulshan, Jan Gunst, Chuanyong Guo, Lei Guo, Ming Guo, Wenjie Guo, Xu-Guang Guo, Andrea A Gust, Åsa B Gustafsson, Elaine Gutierrez, Maximiliano G Gutierrez, Ho-Shin Gwak, Albert Haa, James E Haber, Shinji Hadano, Monica Hagedorn, David R Hahn, 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L Semenza, Utpal Sen, Andreas L Serra, Ana Serrano-Puebla, Hiromi Sesaki, Takao Setoguchi, Carmine Settembre, John J Shacka, Ayesha N Shajahan-Haq, Irving M Shapiro, Shweta Sharma, Hua She, C-K James Shen, Chiung-Chyi Shen, Han-Ming Shen, Sanbing Shen, Weili Shen, Rui Sheng, Xianyong Sheng, Zu-Hang Sheng, Trevor G Shepherd, Junyan Shi, Qiang Shi, Qinghua Shi, Yuguang Shi, Shusaku Shibutani, Kenichi Shibuya, Yoshihiro Shidoji, Jeng- Jer Shieh, Chwen-Ming Shih, Yohta Shimada, Shigeomi Shimizu, Dong Wook Shin, Mari L Shinohara, Michiko Shintani, Takahiro Shintani, Tetsuo Shioi, Ken Shirabe, Ronit Shiri-Sverdlov, Orian Shirihai, Gordon C Shore, Chih-Wen Shu, Deepak Shukla, Andriy A Sibirny, Valentina Sica, Christina J Sigurdson, Einar M Sigurdsson, Puran Singh Sijwali, Beata Sikorska, Wilian A Silveira, Sandrine Silvente-Poirot, Gary A Silverman, Jan Simak, Thomas Simmet, Anna Katharina Simon, Hans-Uwe Simon, Cristiano Simone, Matias Simon, Anne Simonsen, Rajat Singh, Shivendra V Singh, Shrawan K Singh, Debasish Sinha, Sangita Sinha, Frank A Sinicrope, Agnieszka Sirko, Kapil Sirohi, Balindiwe JN Sishi, Annie Sittler, Parco M Siu, Efthimios Sivridi, Anna Skwarska, Ruth Slack, Iva Slaninová, Nikolai Slavov, Soraya S Smaili, Keiran SM Smalley, Duncan R Smith, Stefaan J Soenen, Scott A Soleimanpour, Anita Solhaug, Kumaravel Somasundaram, Jin H Son, Avinash Sonawane, Chunjuan Song, Fuyong Song, Hyun Kyu Song, Ju-Xian Song, Wei Song, Kai Y Soo, Anil K Sood, Tuck Wah Soong, Virawudh Soontornniyomkij, Maurizio Sorice, Federica Sotgia, David R Soto-Pantoja, Areechun Sotthibundhu, Maria João Sousa, Herman P Spaink, Paul N Span, Anne Spang, Janet D Spark, Peter G Speck, Stephen A Spector, Claudia D Spie, Wolfdieter Springer, Daret St Clair, Alessandra Stacchiotti, Bart Stael, Michael T Stang, Daniel T Starczynowski, Petro Starokadomskyy, Clemens Steegborn, John W Steele, Leonidas Stefani, Joan Steffan, Christine M Stellrecht, Harald Stenmark, Tomasz M Stepkowski, Stęphan T Stern, Craig Steven, Brent R Stockwell, Veronika Stoka, Zuzana Storchova, Björn Stork, Vassilis Stratoulia, Dimitrios J Stravopodi, Pavel Strnad, Anne Marie Strohecker, Anna- Lena Ström, Per Stromhaug, Jiri Stulik, Yu-Xiong Su, Zhaoliang Su, Carlos S Subauste, Srinivasa Subramaniam, Carolyn M Sue, Sang Won Suh, Xinbing Sui, Supawadee Sukseree, David Sulzer, Fang-Lin Sun, Jiaren Sun, Jun Sun, Shi-Yong Sun, Yang Sun, Yi Sun, Yingjie Sun, Vinod Sundaramoorthy, Joseph Sung, Hidekazu Suzuki, Kuninori Suzuki, Naoki Suzuki, Tadashi Suzuki, Yuichiro J Suzuki, Michele S Swanson, Charles Swanton, Karl Swärd, Ghanshyam Swarup, Sean T Sweeney, Paul W Sylvester, Zsuzsanna Szatmari, Eva Szegezdi, Peter W Szlosarek, Heinrich Taegtmeyer, Marco Tafani, Emmanuel Taillebourg, Stephen WG Tait, Krisztina Takacs-Vellai, Yoshinori Takahashi, Szabolcs Takát, Genzou Takemura, Nagio Takigawa, Nicholas J Talbot, Elena Tamagno, Jerome Tamburini, Cai-Ping Tan, Lan Tan, Mei Lan Tan, Ming Tan, Yee-Joo Tan, Keiji Tanaka, Masaki Tanaka, Daolin Tang, Dingzhong Tang, Guomei Tang, Isei Tanida, Kunikazu Tanji, Bakhos A Tannou, Jose A Tapia, Inmaculada Tasset-Cueva, Marc Tatar, Iman Tavassoly, Nektarios Tavernaraki, Allen Taylor, Graham S Taylor, Gregory A Taylor, J Paul Taylor, Mark J Taylor, Elena V Tchetina, Andrew R Tee, Fatima Teixeira-Clerc, Sucheta Telang, Tewin Tencomnao, Ba-Bie Teng, Ru-Jeng Teng, Faraj Terro, Gianluca Tettamanti, Arianne L Thei, Anne E Theron, Kelly Jean Thoma, Marcos P Thomé, Paul G Thome, Andrew Thorburn, Jeremy Thorner, Thomas Thum, Michael Thumm, Teresa LM Thurston, Ling Tian, Andreas Till, Jenny Pan-yun Ting, Vladimir I Titorenko, Lilach Toker, Stefano Toldo, Sharon A Tooze, Ivan Topisirovic, Maria Lyngaas Torgersen, Liliana Torosantucci, Alicia Torriglia, Maria Rosaria Torrisi, Cathy Tournier, Roberto Town, Vladimir Trajkovic, Leonardo H Travasso, Gemma Triola, Durga Nand Tripathi, Daniela Trisciuoglio, Rodrigo Troncoso, Ioannis P Trougako, Anita C Truttmann, Kuen-Jer Tsai, Mario P Tschan, Yi-Hsin Tseng, Takayuki Tsukuba, Allan Tsung, Andrey S Tsvetkov, Shuiping Tu, Hsing-Yu Tuan, Marco Tucci, David A Tumbarello, Boris Turk, Vito Turk, Robin FB Turner, Anders A Tveita, Suresh C Tyagi, Makoto Ubukata, Yasuo Uchiyama, Andrej Udelnow, Takashi Ueno, Midori Umekawa, Rika Umemiya-Shirafuji, Benjamin R Underwood, Christian Ungermann, Rodrigo P. Ureshino, Ryo Ushioda, Vladimir N Uversky, Néstor L Uzcátegui, Thomas Vaccari, Maria I Vaccaro, Libuše Váchová, Helin Vakifahmetoglu-Norberg, Rut Valdor, Enza Maria Valente, Francois Vallette, Angela M Valverde, Greet Van den Berghe, Ludo Van Den Bosch, Gijs R van den Brink, F Gisou van der Goot, Ida J van der Klei, Luc JW van der Laan, Wouter G van Doorn, Marjolein van Egmond, Kenneth L van Golen, Luc Van Kaer, Menno van Lookeren Campagne, Peter Vandenabeele, Wim Vandenberghe, Ilse Vanhorebeek, Isabel Varela-Nieto, M Helena Vasconcelo, Radovan Vasko, Demetrios G Vavva, Ignacio Vega- Naredo, Guillermo Velasco, Athanassios D Velentza, Panagiotis D Velentza, Tibor Vellai, Edo Vellenga, Mikkel Holm Vendelbo, Kartik Venkatachalam, Natascia Ventura, Salvador Ventura, Patrícia ST Vera, Mireille Verdier, Beata G Vertessy, Andrea Viale, Michel Vidal, Helena LA Vieira, Richard D Vierstra, Nadarajah Vigneswaran, Neeraj Vij, Miquel Vila, Margarita Villar, Victor H Villar, Joan Villarroya, Cécile Vindi, Giampietro Viola, Maria Teresa Viscomi, Giovanni Vitale, Dan T Vogl, Olga V Voitsekhovskaja, Clarissa von Haefen, Karin von Schwarzenberg, Daniel E Voth, Valérie Vouret-Craviari, Kristina Vuori, Jatin M Vya, Christian Waeber, Cheryl Lyn Walker, Mark J Walker, Jochen Walter, Lei Wan, Xiangbo Wan, Bo Wang, Caihong Wang, Chao-Yung Wang, Chengshu Wang, Chenran Wang, Chuangui Wang, Dong Wang, Fen Wang, Fuxin Wang, Guanghui Wang, Hai-jie Wang, Haichao Wang, Hong-Gang Wang, Hongmin Wang, Horng-Dar Wang, Jing Wang, Junjun Wang, Mei Wang, Mei-Qing Wang, Pei-Yu Wang, Peng Wang, Richard C Wang, Shuo Wang, Ting-Fang Wang, Xian Wang, Xiao-jia Wang, Xiao-Wei Wang, Xin Wang, Xuejun Wang, Yan Wang, Yanming Wang, Ying Wang, Ying-Jan Wang, Yipeng Wang, Yu Wang, Yu Tian Wang, Yuqing Wang, Zhi-Nong Wang, Pablo Wappner, Carl Ward, Diane McVey Ward, Gary Warne, Hirotaka Watada, Yoshihisa Watanabe, Kei Watase, Timothy E Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kaup20 Download by: [Alma Mater Studiorum - Università di Bologna] Date: 23 September 2016, At: 06:43 Weaver, Colin D Weeke, Jiwu Wei, Thomas Weide, Conrad C Weihl, Günther Weindl, Simone Nardin Wei, Longping Wen, Xin Wen, Yunfei Wen, Benedikt Westermann, Cornelia M Weyand, Anthony R White, Eileen White, J Lindsay Whitton, Alexander J Whitworth, Joëlle Wiel, Franziska Wild, Manon E Wildenberg, Tom Wileman, Deepti Srinivas Wilkinson, Simon Wilkinson, Dieter Willbold, Chris William, Katherine William, Peter R Williamson, Konstanze F Winklhofer, Steven S Witkin, Stephanie E Wohlgemuth, Thomas Wollert, Ernst J Wolvetang, Esther Wong, G William Wong, Richard W Wong, Vincent Kam Wai Wong, Elizabeth A Woodcock, Karen L Wright, Chunlai Wu, Defeng Wu, Gen Sheng Wu, Jian Wu, Junfang Wu, Mian Wu, Min Wu, Shengzhou Wu, William KK Wu, Yaohua Wu, Zhenlong Wu, Cristina PR Xavier, Ramnik J Xavier, Gui-Xian Xia, Tian Xia, Weiliang Xia, Yong Xia, Hengyi Xiao, Jian Xiao, Shi Xiao, Wuhan Xiao, Chuan-Ming Xie, Zhiping Xie, Zhonglin Xie, Maria Xilouri, Yuyan Xiong, Chuanshan Xu, Congfeng Xu, Feng Xu, Haoxing Xu, Hongwei Xu, Jian Xu, Jianzhen Xu, Jinxian Xu, Liang Xu, Xiaolei Xu, Yangqing Xu, Ye Xu, Zhi-Xiang Xu, Ziheng Xu, Yu Xue, Takahiro Yamada, Ai Yamamoto, Koji Yamanaka, Shunhei Yamashina, Shigeko Yamashiro, Bing Yan, Bo Yan, Xianghua Yan, Zhen Yan, Yasuo Yanagi, Dun-Sheng Yang, Jin-Ming Yang, Liu Yang, Minghua Yang, Pei-Ming Yang, Peixin Yang, Qian Yang, Wannian Yang, Wei Yuan Yang, Xuesong Yang, Yi Yang, Ying Yang, Zhifen Yang, Zhihong Yang, Meng-Chao Yao, Pamela J Yao, Xiaofeng Yao, Zhenyu Yao, Zhiyuan Yao, Linda S Yasui, Mingxiang Ye, Barry Yedvobnick, Behzad Yeganeh, Elizabeth S Yeh, Patricia L Yeyati, Fan Yi, Long Yi, Xiao-Ming Yin, Calvin K Yip, Yeong-Min Yoo, Young Hyun Yoo, Seung-Yong Yoon, Ken-Ichi Yoshida, Tamotsu Yoshimori, Ken H Young, Huixin Yu, Jane J Yu, Jin-Tai Yu, Jun Yu, Li Yu, W Haung Yu, Xiao-Fang Yu, Zhengping Yu, Junying Yuan, Zhi-Min Yuan, Beatrice YJT Yue, Jianbo Yue, Zhenyu Yue, David N Zack, Eldad Zacksenhau, Nadia Zaffaroni, Tania Zaglia, Zahra Zakeri, Vincent Zecchini, Jinsheng Zeng, Min Zeng, Qi Zeng, Antonis S Zervo, Donna D Zhang, Fan Zhang, Guo Zhang, Guo-Chang Zhang, Hao Zhang, Hong Zhang, Hongbing Zhang, Jian Zhang, Jiangwei Zhang, Jianhua Zhang, Jing-pu Zhang, Li Zhang, Lin Zhang, Long Zhang, Ming-Yong Zhang, Xiangnan Zhang, Xu Dong Zhang, Yan Zhang, Yang Zhang, Yanjin Zhang, Yingmei Zhang, Yunjiao Zhang, Mei Zhao, Wei-Li Zhao, Xiaonan Zhao, Yan G Zhao, Ying Zhao, Yongchao Zhao, Yu-xia Zhao, Zhendong Zhao, Zhizhuang J Zhao, Dexian Zheng, Xi-Long Zheng, Xiaoxiang Zheng, Boris Zhivotovsky, Qing Zhong, Guang-Zhou Zhou, Guofei Zhou, Huiping Zhou, Shu-Feng Zhou, Xu-jie Zhou, Hongxin Zhu, Hua Zhu, Wei- Guo Zhu, Wenhua Zhu, Xiao-Feng Zhu, Yuhua Zhu, Shi-Mei Zhuang, Xiaohong Zhuang, Elio Ziparo, Christos E Zoi, Teresa Zoladek, Wei-Xing Zong, and Antonio Zorzano & Susu M Zughaier
Subjects: [SDV]Life Sciences [q-bio], autophagosome, Review Article, ddc:616.07, stress, stre, LC3, MESH: Animals, Settore MED/49 - Scienze Tecniche Dietetiche Applicate, Settore BIO/06 - Anatomia Comparata E Citologia, chaperone-mediated autophagy, ComputingMilieux_MISCELLANEOUS, Settore BIO/11, Pharmacology. Therapy, Settore BIO/13, standards [Biological Assay], autolysosome, MESH: Autophagy*/physiology, lysosome, methods [Biological Assay], Biological Assay, Settore BIO/17 - ISTOLOGIA, Erratum, Human, Biochemistry & Molecular Biology, Settore BIO/06, physiology [Autophagy], Chaperonemediated autophagy, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, NO, autophagy, guidelines, molecular biology, ultrastructure, flux, macroautophagy, phagophore, vacuole, MESH: Biological Assay/methods, MESH: Computer Simulation, ddc:570, Autolysosome, Autophagosome, Chaperonemediated autophagy, Flux, LC3, Lysosome, Macroautophagy, Phagophore, Stress, Vacuole, Autophagy, Animals, Humans, Computer Simulation, Settore BIO/10, ddc:612, Biology, MESH: Humans, Animal, 0601 Biochemistry And Cell Biology, MESH: Biological Assay/standards, Human medicine
Abstract: Seuls les 100 premiers auteurs dont les auteurs INRA ont été entrés dans la notice. La liste complète des auteurs et de leurs affiliations est accessible sur la publication.; International audience; In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
Published: 2016

36. The potential of neurotrophic tyrosine kinase (NTRK) inhibitors for treating lung cancer

Author: Rafael Caparica, Angela Listì, Christian Caglevic, Luis E. Raez, Christian Rolfo, Elisa Giovannetti, Marco Giallombardo, Patrizia Diana, Francesco Passiglia, Antonio Russo, Girolamo Cirrincione, Medical oncology laboratory, CCA - Target Discovery & Preclinial Therapy Development, Passiglia, F, Caparica,R, Giovannetti, E, Giallombardo, M, Listi, A, Diana, P, Cirrincione, G, Caglevic, C, Raez, LE, Russo, A, and Rolfo C
Subjects: 0301 basic medicine, Lung Neoplasms, NTRKinhibitors, NTRK1/2/3, Settore MED/06 - Oncologia Medica, medicine.medical_treatment, Receptor Protein-Tyrosine Kinases, Entrectinib, Pharmacology, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Medicine, Animals, Humans, Pharmacology (medical), In patient, NTRKinhibitor, Lung cancer, Protein Kinase Inhibitors, TrkA/B/C, targeted therapy, lung cancer, biology, business.industry, Pharmacology. Therapy, General Medicine, medicine.disease, Settore CHIM/08 - Chimica Farmaceutica, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, business, Early phase, Tyrosine kinase, Neurotrophin
Abstract: Introduction: Molecular alterations in neurotrophic tyrosine kinase (NTRK) genes have been identified in several solid tumors including lung cancer. Pre-clinical and clinical evidence suggested their potential role as oncogenic drivers and predictive biomarkers for targeted inhibition, leading to the clinical development of a new class of compounds blocking the NTRK molecular pathway, which are currently undner early clinical investigation. Area covered: This review describes the biology of the NTRK pathway and its molecular alterations in lung cancer. It focuses on the pre-clinical and clinical development of emerging NTRK inhibitors, which have shown very promising activity in early phase I studies. Expert opinion: Among the several NTRK-inhibitors, entrectinib and LOXO-101 are those in more advanced stage of clinical development. Both agents have shown encouraging activity along with a tolerable safety profile in patients with different solid tumors harboring NTRK-fusions, emerging as new promising therapeutic options for molecularly selected patients with advanced Trk-driven lung cancers. Results from ongoing phase II basket trials are eagerly awaited.
Published: 2016

37. Risk Groups for Survival in HPV-positive and HPV-negative HNSCC

Author: Rietbergen, MM, Brakenhoff, RH, Leemans, CR, Otolaryngology / Head & Neck Surgery, and CCA - Target Discovery & Preclinial Therapy Development
Published: 2016

38. The role of the blood-brain barrier in drug resistance and central neurotoxicity

Author: Froklage, E.A.M., Lammertsma, Adriaan, Heimans, Jan, Reijneveld, Jacob, Voskuyl, R.A., CCA - Target Discovery & Preclinial Therapy Development, Neurology, Lammertsma, A.A., Heimans, J.J., and Reijneveld, J.C.
Abstract: 12786
Published: 2016

39. Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model

Author: Bakhos A. Tannous, W. Peter Vandertop, Rami S. Kantar, David P. Noske, Casey A. Maguire, Matheus H.W. Crommentuijn, Thomas Wurdinger, Christian E. Badr, CCA - Target Discovery & Preclinial Therapy Development, Neurosurgery, and ANS - Amsterdam Neuroscience
Subjects: 0301 basic medicine, Cancer Research, Pathology, medicine.medical_specialty, Cell type, Transgene, Enolase, Biology, lcsh:RC254-282, Article, Virus, 03 medical and health sciences, Text mining, medicine, Pharmacology (medical), Vector (molecular biology), Gene, business.industry, Promoter, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030104 developmental biology, Oncology, Cancer research, Molecular Medicine, business
Abstract: Adeno-associated virus (AAV) vectors expressing tumoricidal genes injected directly into brain tumors have shown some promise, however, invasive tumor cells are relatively unaffected. Systemic injection of AAV9 vectors provides widespread delivery to the brain and potentially the tumor/microenvironment. Here we assessed AAV9 for potential glioblastoma therapy using two different promoters driving the expression of the secreted anti-cancer agent sTRAIL as a transgene model; the ubiquitously active chicken β-actin (CBA) promoter and the neuron-specific enolase (NSE) promoter to restrict expression in brain. Intravenous injection of AAV9 vectors encoding a bioluminescent reporter showed similar distribution patterns, although the NSE promoter yielded 100-fold lower expression in the abdomen (liver), with the brain-to-liver expression ratio remaining the same. The main cell types targeted by the CBA promoter were astrocytes, neurons and endothelial cells, while expression by NSE promoter mostly occurred in neurons. Intravenous administration of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL vectors to mice bearing intracranial patient-derived glioblastoma xenografts led to a slower tumor growth and significantly increased survival, with the CBA promoter having higher efficacy. To our knowledge, this is the first report showing the potential of systemic injection of AAV9 vector encoding a therapeutic gene for the treatment of brain tumors.
Published: 2016

40. Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

Author: Hui, Kwai Fung, Cheung, Arthur Kwok Leung, Choi, Chung King, Yeung, Po Ling, Middeldorp, Jaap M., Lung, Maria Li, Tsao, Sai Wah, Chiang, Alan Kwok Shing, Pathology, and CCA - Target Discovery & Preclinial Therapy Development
Published: 2016

41. New developments in the management of non-small-cell lung cancer, focus on rociletinib: what went wrong?

Author: Elisa Giovannetti, Christian Rolfo, Godefridus J. Peters, Nele Van Der Steen, Chiara Caparello, Patrick Pauwels, Medical oncology laboratory, CCA - Target Discovery & Preclinial Therapy Development, and CCA - Clinical Therapy Development
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, EGFR, Afatinib, Review, Pharmacology, NSCLC, 03 medical and health sciences, 0302 clinical medicine, Gefitinib, EGFR-TKI, Internal medicine, medicine, Pharmacology (medical), Osimertinib, Rociletinib, Lung cancer, Biology, business.industry, rociletinib, medicine.disease, targeted therapies, respiratory tract diseases, Clinical trial, 030104 developmental biology, Drug development, 030220 oncology & carcinogenesis, Erlotinib, Human medicine, business, Engineering sciences. Technology, medicine.drug
Abstract: Recently, the development of the third-generation epidermal growth factor receptor-small molecule inhibitor (EGFR-TKI) rociletinib had failed. In this review, the wide-ranging aspects of the evolution of EGFR-TKIs were collected, with a special focus on rociletinib. The influence of different oncogenic mutations on EGFR activity was also discussed. Resistance to the first (erlotinib, gefitinib)- and second (afatinib)-generation EGFR-TKIs provided the rationale behind the development of the third-generation inhibitors (rociletinib, osimertinib). On the basis of these data, a comparison of their efficacy on the different mutated EGFRs and the respective resistance mechanisms is further reported. Moreover, the evolution and results of the clinical trials of rociletinib (TIGER trials) are compared with the trials on osimertinib, another third-generation EGFR-TKI that now has been granted US Food and Drug Administration approval. The reasons behind the arrest in the further development of rociletinib are put in the perspective of future drug development., Video abstract
Published: 2016

42. Targeting Serglycin Prevents Metastasis in Murine Mammary Carcinoma

Author: Roy, Ananya, Femel, Julia, Huijbers, Elisabeth J. M., Spillmann, Dorothe, Larsson, Erik, Ringvall, Maria, Olsson, Anna-Karin, Åbrink, Magnus, Medical oncology laboratory, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: Male, Lung Neoplasms, Physiology, Vesicular Transport Proteins, Glycobiology, lcsh:Medicine, Gene Expression, Pathology and Laboratory Medicine, Biochemistry, Lung and Intrathoracic Tumors, Metastasis, Gene Knockout Techniques, Mice, Immune Physiology, Basic Cancer Research, Medicine and Health Sciences, lcsh:Science, Lung, Immune Response, Innate Immune System, Animal Models, Cadherins, Up-Regulation, Gene Expression Regulation, Neoplastic, Oncology, Cytokines, Female, Proteoglycans, Research Article, Epithelial-Mesenchymal Transition, Immunology, Mouse Models, Research and Analysis Methods, Model Organisms, Signs and Symptoms, Diagnostic Medicine, Genetics, Animals, Inflammation, Cancer och onkologi, Gene Expression Profiling, lcsh:R, Mammary Neoplasms, Experimental, Cancers and Neoplasms, Biology and Life Sciences, Molecular Development, Immune System, Cancer and Oncology, lcsh:Q, Secondary Lung Tumors, Developmental Biology
Abstract: In hematopoietic cells, serglycin proteoglycans mainly contribute to proper storage and secretion of inflammatory mediators via their negatively charged glycosaminoglycans. Serglycin proteoglycans are also expressed in cancer cells where increased expression has been linked to poor prognosis. However, the serglycin-dependent mediators promoting cancer progression remain to be determined. In the present study we report that genetic ablation of serglycin proteoglycan completely blocks lung metastasis in the MMTV-PyMT-driven mouse breast cancer model, while serglycin-deficiency did not affect primary tumour growth or number of mammary tumours. Although E-cadherin expression was higher in the serglycin-deficient primary tumour tissue, indicating reduced invasiveness, serglycin-deficient tumour cells were still detected in the circulation. These data suggest that serglycin proteoglycans play a role in extravasation as well as colonization and growth of metastatic cells. A microarray expression analysis and functional annotation of differentially expressed genes identified several biological pathways where serglycin may be important. Our results suggest that serglycin and serglycin-dependent mediators are potential drug targets to prevent metastatic disease/dissemination of cancer.
Published: 2016

43. Minimally invasive diagnostics for occult lymph node metastases in head and neck cancer

Author: Flach, G.B., de Bree, R., Leemans, C.R., de Bree, Remco, CCA - Target Discovery & Preclinial Therapy Development, and Otolaryngology / Head & Neck Surgery
Abstract: 13120
Published: 2016

44. Tissue distribution of crizotinib and gemcitabine combination in a patient-derived orthotopic mouse model of pancreatic cancer

Author: Richard J. Honeywell, Elisa Giovannetti, Amir Avan, Godefridus J. Peters, Medical oncology laboratory, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: Oncology, medicine.medical_specialty, medicine.drug_class, tissue distribution, Medicine (miscellaneous), Antimetabolite, Pharmacokinetics, Crizotinib, gemcitabine, Pancreatic cancer, Internal medicine, medicine, Anaplastic lymphoma kinase, Pharmacology (medical), General Pharmacology, Toxicology and Pharmaceutics, Whole blood, business.industry, lcsh:RM1-950, medicine.disease, Gemcitabine, medicine.anatomical_structure, lcsh:Therapeutics. Pharmacology, Chemistry (miscellaneous), Cancer research, Pancreas, business, medicine.drug
Abstract: Pharmacokinetics focuses on the question whether a drug actually reaches its target in therapeutic concentrations or accumulates elsewhere, potentially causing toxicological or unpredictable side effects. We determined tissue distribution of gemcitabine, an antimetabolite, and crizotinib, a tyrosine-kinase inhibitor targeted against the anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor (c-Met) receptors, in a validated orthotopic mouse model for pancreatic cancer. Mice with pancreatic cancer were treated with either oral crizotinib at 25 mg/kg, gemcitabine at 100 mg/kg or with their combination. Two hours after the last gemcitabine dose mice were sacrificed and all available blood/organs/tissues were sampled. Tissue was subsequently analyzed for drug concentrations using a validated liquid chromatography-mass spectrometry (LC-MS/MS) technique. In whole blood gemcitabine was about 1.0 µM and crizotinib 2.4 µM in the single treatment, whereas in the combination crizotinib increased the levels of gemcitabine. Crizotinib was found in all major tissues, being highest in the intestine. Comparison of crizotinib alone to the gemcitabine-crizotinib combination showed that crizotinib tissue concentrations were 3-6 fold lower in liver, lung, kidney and spleen, 30-fold lower in the skin, heart and pancreas and 200-fold lower in the brain. Tissue gemcitabine was highest in spleen and skin, being about 5-10 fold higher than in the other tissues, including brain, which still had a relatively high accumulation. In conclusion, both gemcitabine and crizotinib accumulate at clinically active but variable levels in tissues, possibly relating to the effects exerted by these drugs.
Published: 2016

45. Using RNA-sequencing to detect novel splice variants related to drug resistance in in vitro cancer models

Author: Sciarrillo, Rocco, Wojtuszkiewicz, Anna, Kooi, Irsan E, Gómez, Valentina E, Boggi, Ugo, Jansen, Gerrit, Kaspers, Gert-Jan, Cloos, Jacqueline, Giovannetti, Elisa, Hematology laboratory, CCA - Target Discovery & Preclinial Therapy Development, Human genetics, Rheumatology, and Medical oncology laboratory
Subjects: Genetics and Molecular Biology (all), Thyroid Hormones, Immunology and Microbiology (all), Cytotoxicity, Resistance, Drug Resistance, Cancer research, Biochemistry, DEAD-box RNA Helicases, Neoplasms, Chemotherapy, Issue 118, Humans, Protein Isoforms, Chemical Engineering (all), Transcriptomics, Protein Processing, Neuroscience (all), Sequence Analysis, RNA, Post-Translational, Membrane Proteins, DNA Methylation, Drug Resistance, Neoplasm, Alternative splicing, RNA-seq, Carrier Proteins, Protein Processing, Post-Translational, RNA, Biochemistry, Genetics and Molecular Biology (all), Neoplasm, Sequence Analysis
Abstract: Drug resistance remains a major problem in the treatment of cancer for both hematological malignancies and solid tumors. Intrinsic or acquired resistance can be caused by a range of mechanisms, including increased drug elimination, decreased drug uptake, drug inactivation and alterations of drug targets. Recent data showed that other than by well-known genetic (mutation, amplification) and epigenetic (DNA hypermethylation, histone post-translational modification) modifications, drug resistance mechanisms might also be regulated by splicing aberrations. This is a rapidly growing field of investigation that deserves future attention in order to plan more effective therapeutic approaches. The protocol described in this paper is aimed at investigating the impact of aberrant splicing on drug resistance in solid tumors and hematological malignancies. To this goal, we analyzed the transcriptomic profiles of several in vitro models through RNA-seq and established a qRT-PCR based method to validate candidate genes. In particular, we evaluated the differential splicing of DDX5 and PKM transcripts. The aberrant splicing detected by the computational tool MATS was validated in leukemic cells, showing that different DDX5 splice variants are expressed in the parental vs. resistant cells. In these cells, we also observed a higher PKM2/PKM1 ratio, which was not detected in the Panc-1 gemcitabine-resistant counterpart compared to parental Panc-1 cells, suggesting a different mechanism of drug-resistance induced by gemcitabine exposure.
Published: 2016

46. Valproate in adjuvant glioblastoma treatment

Author: Peter Sminia, Stephen E. Rose, Richard Head, Leah J. Cosgrove, Nicholas Dowson, Jenny H Martin, Michael Fay, Fay, Michael F, Head, Richard, Sminia, Peter, Dowson, Nicholas, Cosgrove, Leah, Rose, Stephen, Martin, Jenny H, Radiation Oncology, CCA - Cancer biology and immunology, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Dacarbazine, medicine.medical_treatment, Treatment outcome, gliobastome, 03 medical and health sciences, 0302 clinical medicine, Text mining, Internal medicine, medicine, Humans, Combined Modality Therapy, Antineoplastic Agents, Alkylating, Valproic Acid, Brain Neoplasms, business.industry, medicine.disease, Treatment Outcome, letter to the editor, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Glioblastoma, business, Adjuvant, 030217 neurology & neurosurgery, medicine.drug
Abstract: Refereed/Peer-reviewed
Published: 2016

47. Contemporary reviews on cancer treatment INTRODUCTION

Author: Peters, Godefridus J., Raymond, Eric, Medical oncology laboratory, CCA - Target Discovery & Preclinial Therapy Development, CCA - Clinical Therapy Development, and CCA - Cancer biology
Published: 2016

48. Tumor cell resistance to antiangiogenic receptor tyrosine kinase inhibitors

Author: Gotink, K.J., Verheul, H.M.W., Peters, G.J., Verheul, Henk, Peters, Godefridus, CCA - Target Discovery & Preclinial Therapy Development, Medical oncology, and Medical oncology laboratory
Subjects: Tyrosine Kinase Inhibitor, Tumor cell, Resistance, Sunitinib, Lysosome
Abstract: 14173
Published: 2016

49. Advances in purine and pyrimidine metabolism in health and diseases

Author: Michio Hirano, Godefridus J. Peters, Medical oncology laboratory, and CCA - Target Discovery & Preclinial Therapy Development
Subjects: Purine, Pyrimidine, 010405 organic chemistry, Chemistry, education, Columbia university, General Medicine, 010402 general chemistry, 01 natural sciences, Biochemistry, Article, 0104 chemical sciences, chemistry.chemical_compound, Pyrimidine metabolism, Genetics, Molecular Medicine, Purine metabolism
Abstract: In June, 2015, the Purine and Pyrimidine Society (PPS) organized the 16th biennial symposium on Purine and Pyrimidine metabolism at the Faculty House of Columbia University, New York City. This exciting meeting focused on these important molecules, new developments in inborn errors of metabolism; therapeutic analogs. In addition, the biochemistry of mammalian and non-mammalian systems were discussed. Due to significant advances in molecular medicine, the boundaries between clinical and basic sciences have merged into exciting translational research, of which a small portion was highlighted in the pre-symposium.
Published: 2016

50. Recent developments in the use of immunotherapy in non-small cell lung cancer

Author: Christian Rolfo, Maria Gonzalez-Cao, Mariacarmela Santarpia, Elisa Giovannetti, Niki Karachaliou, Rafael Rosell, Giuseppe Altavilla, Medical oncology laboratory, CCA - Target Discovery & Preclinial Therapy Development, and CCA - Clinical Therapy Development
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Long lasting, Oncology, medicine.medical_specialty, Lung Neoplasms, medicine.medical_treatment, Immune checkpoint inhibitors, 03 medical and health sciences, 0302 clinical medicine, Acquired resistance, Immune system, Carcinoma, Non-Small-Cell Lung, Internal medicine, medicine, Humans, Immunologic Factors, Immunology and Allergy, Lung cancer, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), immune checkpoint inhibitors, Non-small-cell lung cancer, programmed cell death ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), Pulmonary and Respiratory Medicine, Immunology and Allergy, Public Health, Environmental and Occupational Health, business.industry, Public Health, Environmental and Occupational Health, Immunotherapy, medicine.disease, Disease control, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunology, Human medicine, Non small cell, business
Abstract: Introduction: Targeted therapies have significantly improved the prognosis of subsets of patients with advanced non-small-cell lung cancer (NSCLC) harboring somatically activated oncogenes, such as mutant EGFR and rearranged ALK. However, the efficacy of these agents is limited by the development of acquired resistance which occurs after variable periods of time. Therefore, there is an urgent need for novel therapeutic strategies to achieve long lasting disease control, as well as new therapies for those patients without targetable driver mutations. A deeper understanding of interactions between the immune system and tumor cells has led to the development of a number of immunotherapeutic agents. Areas covered: We review current data on immunotherapy for lung cancer treatment, with a focus on checkpoint inhibitors and therapeutic vaccines. References for this review were identified through searches of PubMed, congress proceedings and reference lists from key original and review papers. Expert commentary: While most vaccines have been unsuccessful, inhibitors of specific immune checkpoints, including CTLA-4 and PD-1/ PD-L1 pathway, have shown significant clinical activity and manageable toxicities and recently, two anti-PD-1 monoclonal antibodies have been approved by the FDA for treatment of patients with advanced NSCLC. Identification of reliable predictive biomarkers for patient selection and novel rational combinations are currently active areas of research to further improve the efficacy of immunotherapy.
Published: 2016

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