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Recent advances in the understanding of the biological basis of pediatric soft-tissue and bone tumors, especially owing to the advent of “omics” technologies, have led to an exponential increase in the current knowledge on the genetic and cellular patho-mechanisms that drive these diseases. This offers the unprecedented opportunity to develop and implement targeted therapies such as monoclonal antibodies, small molecules, oncolytic viruses, and immunotherapies in standard and/or personalized treatment regimens. However, to date only a few examples document a successful translation of discoveries from the bench to the bedside. Recent international expert congresses such as the “Pediatric Cancer Translational Genomics” conference (Phoenix, Arizona, 2012), the ESF-EMBO workshop on “Molecular Biology and Innovative Therapies in Sarcomas” (Pultusk, Poland, 2012), and the AACR special meeting on “Pediatric Cancer at the Crossroads – Translating Discovery into Improved Outcomes” (San Diego, California, 2013) further emphasize the urgent need for a more rapid and especially more successful translational process. Hence, we strongly believe that a Frontiers Research Topic aiming at this aspect would fit just in time and that it would have great potential to receive numerous contributions of outstanding experts of the field. The proposed Frontiers Research Topic shall provide a platform for active and interdisciplinary discussion, summarize current state-of-the-art knowledge on all basic research and translational aspects in pediatric soft-tissue and bone tumors, and offer new perspectives of how to further promote and accelerate the translational process. We welcome high-quality original research articles, brief reports, as well as opinion, hypothesis, and review articles, and especially encourage submissions from early-career scientists.

Oncology --- Cancer in children --- Research. --- Treatment. --- targeted therapy --- Translational research --- Ewing sarcoma --- Sarcoma --- pediatric oncology --- Osteosarcoma --- Immunotherapy --- bone tumor --- Rhabdomyosarcoma --- epithelioid sarcoma

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Ewing sarcoma is an aggressive cancer of the bone and soft tissues that affects mostly adolescents and young adults. Metastatic and relapsed Ewing tumors are still associated with a dismal prognosis, which emphasizes the need for new therapeutic perspectives. Ewing tumor cells are characterized by a chromosomal translocation that leads to the formation of a novel fusion oncogene called EWS-FLI1. The resulting oncoprotein acts as an aberrant transcription factor and completely rewires the gene expression programs of the cell through both transcriptional and post-transcriptional mechanisms. Recently, a role in mRNA decay was highlighted that is thought to occur via the recruitment by the oncoprotein of the CCR4-NOT deadenylase complex at the 3’ end of target mRNAs. The interaction between the transactivation
domain of EWS-FLI1, called the EAD, and CNOT2, part of the CCR4-NOT complex, seems to be the basis of this new role in gene regulation. Therefore, disruption of this specific protein-protein
interaction could be of high clinical relevance. Here, I aim to describe a detailed framework of how such disruption could be achieved by applying two distinct but complementary methods: high-throughput and virtual screening.
High-throughput screening is a large-scale process that requires the use of robot-automated equipment to screen large chemical libraries of compounds for a desired biological activity. In this context, a comprehensive experimental protocol will be developed and optimized on the basis of luciferase-fragment protein complementation in a stable cell line expressing both protein partners. Quality control assessments will then be necessary to probe the robustness of our assay controls. Later, the primary screen is to be conducted following the careful selection of focused chemical libraries. Finally, secondary or counter-screens that aim to validate true active compounds will be performed.
Virtual screening broadly describes the process of computationally docking large libraries of ligands onto a protein structure. Compounds that bind with high affinity are then selected for further experimental validations. Prior to large-scale screening however, it is important to map the EAD/CNOT2 interaction as precisely as possible to identify docking-relevant conformations. To that aim, two approaches were considered: in silico molecular dynamics simulations and in vitro mutagenesis experiments. The combination of the two methods has led to a precise characterization of the binding interface.
In both high-throughput and virtual screening, biological validation and structure-activity relationship studies must be performed with the top-performing molecules identified. While currently ambitious in its scope, the framework presented in this master thesis provides relevant guidelines that would hopefully lead to the discovery of highly efficient and specific inhibitory small molecules for Ewing sarcoma. Le sarcome d’Ewing est un cancer agressif des os et des tissus mous qui affecte principalement les adolescents et les jeunes adultes. Les tumeurs d’Ewing métastatiques ou récurrentes sont associées à un faible taux de survie, ce qui souligne l’importance de la recherche de nouvelles pistes thérapeutiques. Les cellules tumorales de sarcome d’Ewing sont caractérisées par une translocation chromosomique qui entraîne la formation d’un nouvel oncogène appelé EWS-FLI1. L’oncoprotéine résultante se comporte comme un facteur de transcription aberrant qui reprogramme l’expression génique des cellules, en agissant tant au niveau transcriptionnel que post-transcriptionnel. Récemment, un rôle dans la dégradation de l’ARNm a été mis en avant. Cette nouvelle fonction serait basée sur le recrutement par l’oncoprotéine du complexe de déadénylation CCR4-NOT à l’extrémité 3’ des ARNm cibles, dont le fondement serait l’interaction entre le domaine de trans-activation de EWS-FLI1, appelé l’EAD, et CNOT2, membre du complexe CCR4-NOT. Par conséquent, la perturbation de cette intéraction protéine-protéine pourrait être de haute pertinence clinique. L’objectif principal de ce travail consiste à décrire un cadre qui permettrait une telle inhibition via deux méthodes distinctes mais complémentaires: le criblage haut-débit et virtuel. Le criblage haut-débit est un procédé à grande échelle qui requiert l’utilisation d’équipements robotisés afin de cribler des bibliothèques de composés chimiques (chimiothèques) contre une activité biologique spécifique. Selon ce cadre, un protocole complet sera développé et optimisé sur base d’une
méthode de complémentation de fragments de luciférase dans une lignée cellulaire stable exprimant les deux protéines (EAD et CNOT2). Des évaluations de contrôle qualité seront ensuite nécessaires afin de mesurer la robustesse de nos contrôles. Par après, le crible primaire sera réalisé selon la sélection de chimiothèques pertinente. Enfin, un crible secondaire et un contre-crible auront pour but de valider les composés actifs.
Le criblage virtuel est un processus informatique qui permet l’amarrage moléculaire de grandes
chimiothèques sur la structure tridimensionnelle d’une protéine. Les composés qui se lient avec haute affinité sont ensuite sélectionnés pour des validations expérimentales. Avant cela cependant, il est important de caractériser l’interaction EAD/CNOT2 aussi précisément que possible afin d’identifier des potentiels sites de liaisons des ligands. Dans ce but, deux approches ont été considérées: des simulations de dynamiques moléculaires in silico, et des expériences de mutagénèse in vitro. La combinaison des deux méthodes a permis une analyse précise de l’interface de liaison entre les deux protéines.
Dans le cas des deux méthodes décrites, la pertinence biologique et pharmacologique des composés les plus prometteurs devra être évaluée expérimentalement. Bien qu’ambitieux de par sa portée, le cadre présenté dans ce mémoire fournit des lignes directrices importantes qui pourraient amener à la découverte de nouvelles molécules inhibitrices dans le traitement du sarcome d’Ewing.

Ewing sarcoma --- EWS-FLI1 --- EAD --- mRNA decay --- CNOT2 --- CCR4-NOT --- high-throughput screening --- virtual screening --- protein-protein interaction --- small molecule inhibitor --- drug discovery --- Sarcome d'Ewing --- EWS-FLI1 --- EAD --- dégradation de l'ARNm --- CNOT2 --- CCR4-NOT --- criblage haut-débit --- criblage virtuel --- intéraction protéine-protéine --- découverte de médicament --- inhibiteur moléculaire --- Sciences du vivant > Biochimie, biophysique & biologie moléculaire

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Metastasis is the dissemination of neoplastic cells from the primary tumor, and their colonization and growth in another part of the body. The process of metastasis is orchestrated by a complex network of biological events, and our understanding of the processes that regulate metastasis has significantly improved. This open access book provides an in-depth analysis of our understanding of the molecular mechanisms, detection, and clinical management of metastatic cancer. Updates are given on molecular imaging of brain metastasis and recurrence, management of pulmonary nodules for the early diagnosis of lung cancer, surgical management of both primary and metastatic lung cancers, genomic landscapes and tumor evolution of metastatic gynecological cancers, epigenetic changes in metastatic ovarian cancer, microRNAs in metastasis of prostate cancer, hematological toxicity of radiation therapy for bone metastasis, DNA damage response in cancer metastasis, tumor endothelial cells and angiogenesis in cancer metastasis, apoptosis-induced compensatory proliferation in cancer, the potential of targeting apoptosis to overcome chemotherapy resistance, and features of metastatic Ewing sarcoma. This open access book is aimed primarily at clinicians and scientists, but many areas will also be of interest to the layperson.

MJCL --- Molecular Imaging of Brain Metastases; Imaging Tests for the Diagnosis of Lung Nodules; Thoracic Surgery for Lung Cancer; Pulmonary Metastases; Surgery for Pulmonary Metastasis; Metastatic Gynecological Cancers; Epigenetic Changes in Ovarian Cancer Metastasis; Tumor Microenvironment in Ovarian Cancer Metastasis; MetastamiRs; MicroRNAs in Metastatic Prostate Cancer; Hematological Toxicity; Bone Metastasis Radiation Therapy; DNA Damage Response; Cancer Metastasis; Tumor Endothelial Cells in Cancer Metastasis; Apoptosis-Induced Compensatory Proliferation; Targeting Apoptosis to Overcome Chemotherapy Resistance; Metastatic Ewing Sarcoma

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Metastasis is the dissemination of neoplastic cells from the primary tumor, and their colonization and growth in another part of the body. The process of metastasis is orchestrated by a complex network of biological events, and our understanding of the processes that regulate metastasis has significantly improved. This open access book provides an in-depth analysis of our understanding of the molecular mechanisms, detection, and clinical management of metastatic cancer. Updates are given on molecular imaging of brain metastasis and recurrence, management of pulmonary nodules for the early diagnosis of lung cancer, surgical management of both primary and metastatic lung cancers, genomic landscapes and tumor evolution of metastatic gynecological cancers, epigenetic changes in metastatic ovarian cancer, microRNAs in metastasis of prostate cancer, hematological toxicity of radiation therapy for bone metastasis, DNA damage response in cancer metastasis, tumor endothelial cells and angiogenesis in cancer metastasis, apoptosis-induced compensatory proliferation in cancer, the potential of targeting apoptosis to overcome chemotherapy resistance, and features of metastatic Ewing sarcoma. This open access book is aimed primarily at clinicians and scientists, but many areas will also be of interest to the layperson.

Molecular Imaging of Brain Metastases; Imaging Tests for the Diagnosis of Lung Nodules; Thoracic Surgery for Lung Cancer; Pulmonary Metastases; Surgery for Pulmonary Metastasis; Metastatic Gynecological Cancers; Epigenetic Changes in Ovarian Cancer Metastasis; Tumor Microenvironment in Ovarian Cancer Metastasis; MetastamiRs; MicroRNAs in Metastatic Prostate Cancer; Hematological Toxicity; Bone Metastasis Radiation Therapy; DNA Damage Response; Cancer Metastasis; Tumor Endothelial Cells in Cancer Metastasis; Apoptosis-Induced Compensatory Proliferation; Targeting Apoptosis to Overcome Chemotherapy Resistance; Metastatic Ewing Sarcoma

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In the landscape of the design of carbon nanomaterials, the fine-tuning of their functionalities and physico-chemical properties has increased their potential for therapeutic, diagnostic, and biosensing applications. In this editorial, we will provide a brief overview of the contents of this Special Issue. In particular, nanoplatforms originating from the synergistic combination of carbon-based nanomaterials (i.e., nanotubes, graphene, graphene oxide, carbon quantum dots, nanodiamond, etc.) with various functional molecules such as drugs, natural compounds, biomolecules, polymers, metal nanoparticles, and macrocycles that have useful applications in drug delivery, multi-targeted therapies, theranostic as well as scaffolds in tissue engineering, and as sensing materials have been selected for publication as Articles or Mini Reviews. The variety of applications covered by the nine articles published in this Special Issue of Nanomaterials are proof of the growing attention that the use of carbon nanomaterials in the biomedical/pharmaceutical field has received in recent years. We hope that readers find the contents of this Special Issue useful for their research, which is aimed to advance carbon nanomaterials from the laboratory to clinical nanomedicine.

Technology: general issues --- Chemical engineering --- graphene oxide --- covalent functionalization --- cortical membranes --- calcium phosphate deposition --- graphene/gold nanocomposite --- SERS --- Dopamine --- Rhodamine 6G --- nanodiamond --- tritium --- biodistribution --- Ewing sarcoma --- drug delivery --- siRNA --- nanomedicine --- porphyrin --- J-aggregates --- carbon nanotubes --- nanohybrids --- graphene --- liquid biopsy --- circulating tumor cells --- exosomes --- circulating nucleic acids --- COVID-19 --- pyrrole --- cancer --- doxorubicin --- drug delivery systems --- nanoparticles --- carbon dots --- platelet aggregation --- arterial thrombosis --- signaling molecules --- bleeding disorder --- cytotoxicity --- carbon nanomaterials --- camptothecin --- Caco-2 --- MCF-7 --- NanoHy-GPS --- antibacterial nanosystems --- one-pot microwave-assisted reaction --- silver nanoparticles --- polyvinyl alcohol --- n/a