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Cytotoxic lymphocytes, comprised of NK cells and cytotoxic T cells, play a pivotal role in immune defense. By directed release of perforin-containing lytic granules, NK and cytotoxic T cells can eradicate pathogen-infected, tumorigenic, and otherwise stressed cells. By the virtue of cytokine and chemokine secretion, they can influence other cells of the immune system. Through these processes, cytotoxic lymphocytes also contribute to the maintenance of immune homeostasis. In recent years, much progress has been made with respect to the mechanisms by which cytotoxic lymphocytes develop, differentiate, and exert their effector functions. In a clinical perspective, a wide variety of mutations impairing cytotoxic lymphocyte development and/or function have been associated with immunodeficiency and severe diseases in humans. Aberrant activity of cytotoxic T cells and/or NK cells has been linked to an increased susceptibility to viral infections, persistent inflammation, cancer and autoimmunity. In addition, lymphocyte cytotoxic activity may be harnessed therapeutically to target tumor cells in different adoptive cellular therapy regimes, or through the use of recombinant antibodies. Still, a number of questions remain in regards to how cytotoxic lymphocytes develop, their relationships and plasticity, as well as the mechanisms dictating target cell discrimination, lytic granule release and induction of target cell death. In this Research Topic we encourage submission of research articles, reviews, perspectives, or methods on cytotoxic lymphocyte development and function, their relation to the pathogenesis or treatment of different diseases, as well as comparison between similarities and/or differences in their effector functions. Considering the clinical significance of NK cells and cytotoxic T cells, we aim to provide a range of articles summarizing the current knowledge on the identification and elucidation of the mechanisms governing cytotoxic lymphocyte activity.

Microbiology & Immunology --- Biology --- Health & Biological Sciences --- secretory lysosomes --- NK cells --- hemophagocytic histiocytosis --- immune therapy --- granzyme --- lytic granules --- Cytotoxicity --- anti-tumor response --- Immunological Synapse --- Perforin

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Natural Killer (NK) cells are innate lymphocytes, now recognized as members of a larger family of “Innate lymphoid cells” (ILCs). Both murine and human NK cells are well characterized effector cells with cytotoxic as well as cytokine production ability which mainly react in response to microbial and cell stress stimuli, thus playing a central role in the defense against pathogen infection, in tumor surveillance and in regulating immune homeostasis. Despite these established concepts, our understanding of the complexity of NK cells, also in view of their developmental and functional relationship with other ILC subsets, is only recently emerging. This Research Topic highlights the recent advances in NK cell (and ILC) research in human and mouse from basic research to clinical applications.

natural killer cells --- ILC --- NK cells --- immune therapy --- viral infection --- NK cell education --- immunotherapy --- MHC-I --- cancer --- immune regulation --- adaptive immunity

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Malignant mesothelioma (MM) is a rare and aggressive cancer, related to chronic inflammation and oxidative stress caused mainly by exposure to asbestos. Although this mineral has been banned for decades in many countries, epidemiologists predict the MM epidemic will last past 2040, raising many concerns in public health given its late diagnosis, dismal prognosis, and lack of current efficient therapies.To deal with this situation, important breakthroughs have recently been made in the understanding of MM’s complex biology and the carcinogenic process of the different patterns of the disease. Examples of these include the development of new biomarkers and the deciphering of gene–environment interactions, molecular mechanisms of invasiveness, deregulated pathways, altered expression of miRNAs, DNA damage repair, or metabolic profile. From now on, MM’s aggressive and chemoresistant character appears linked to a polyclonal malignancy, and heterogeneity in molecular alterations.Given these improvements, new therapeutic targets are being explored to solve the double challenge faced by clinicians. The first is to reduce tumor development and its wasting consequences as soon as possible, without resistance and with limited toxicity. The second is to stimulate the recognition of tumor cells by the induction of a specific immune response. This Special Issue will highlight all these aspects.

well-differentiated papillary mesothelioma --- WDPM --- malignant mesothelioma --- DNA sequencing --- mutation --- mesothelioma --- tumor suppressor --- targeted therapy --- immunotherapy --- biomarkers --- proteomics --- macrophage-capping protein --- fatty acid-binding protein --- laminin subunit beta-2 --- selenium-binding protein 1 --- carcinogenesis --- malignant pleural mesothelioma --- asbestos exposure --- DNA methylation --- lymphocyte-to-monocyte ratio --- epigenome-wide analysis --- survival analysis --- metabolomics --- radiotherapy --- cancers --- inflammation --- infiltrating immune cells --- prognostic biomarker --- predictive biomarker --- immune therapy --- VATS --- extrapleural pneumonectomy --- pleurectomy decortication --- therapy response --- survival --- FDG --- PET-CT --- mesothelium --- oxidative stress --- redox-sensitive factors --- asbestos --- carbon nanotubes --- protein-protein interactions --- systems biology --- network analysis --- drug repurposing --- pleural mesothelioma --- gene expression --- immunogenicity --- sarcomatoid --- epithelioid --- first line --- meta-analysis --- systematic review --- MPM --- lurbinectedin --- DNA damage response --- histotype --- Hippo pathway --- NF2 --- BAP1 --- CDKN2A --- PTCH1 --- SETD2 --- MTAP --- liquid biopsies --- circulating tumor DNA --- plasma --- cancer-specific mutations --- genomics --- cancer biomarkers --- tumor microenvironment --- tumor-associated macrophages --- dendritic cells --- immunohistochemistry --- interaction analysis --- pleural effusion --- n/a

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Malignant mesothelioma (MM) is a rare and aggressive cancer, related to chronic inflammation and oxidative stress caused mainly by exposure to asbestos. Although this mineral has been banned for decades in many countries, epidemiologists predict the MM epidemic will last past 2040, raising many concerns in public health given its late diagnosis, dismal prognosis, and lack of current efficient therapies.To deal with this situation, important breakthroughs have recently been made in the understanding of MM’s complex biology and the carcinogenic process of the different patterns of the disease. Examples of these include the development of new biomarkers and the deciphering of gene–environment interactions, molecular mechanisms of invasiveness, deregulated pathways, altered expression of miRNAs, DNA damage repair, or metabolic profile. From now on, MM’s aggressive and chemoresistant character appears linked to a polyclonal malignancy, and heterogeneity in molecular alterations.Given these improvements, new therapeutic targets are being explored to solve the double challenge faced by clinicians. The first is to reduce tumor development and its wasting consequences as soon as possible, without resistance and with limited toxicity. The second is to stimulate the recognition of tumor cells by the induction of a specific immune response. This Special Issue will highlight all these aspects.

Medicine --- well-differentiated papillary mesothelioma --- WDPM --- malignant mesothelioma --- DNA sequencing --- mutation --- mesothelioma --- tumor suppressor --- targeted therapy --- immunotherapy --- biomarkers --- proteomics --- macrophage-capping protein --- fatty acid-binding protein --- laminin subunit beta-2 --- selenium-binding protein 1 --- carcinogenesis --- malignant pleural mesothelioma --- asbestos exposure --- DNA methylation --- lymphocyte-to-monocyte ratio --- epigenome-wide analysis --- survival analysis --- metabolomics --- radiotherapy --- cancers --- inflammation --- infiltrating immune cells --- prognostic biomarker --- predictive biomarker --- immune therapy --- VATS --- extrapleural pneumonectomy --- pleurectomy decortication --- therapy response --- survival --- FDG --- PET-CT --- mesothelium --- oxidative stress --- redox-sensitive factors --- asbestos --- carbon nanotubes --- protein-protein interactions --- systems biology --- network analysis --- drug repurposing --- pleural mesothelioma --- gene expression --- immunogenicity --- sarcomatoid --- epithelioid --- first line --- meta-analysis --- systematic review --- MPM --- lurbinectedin --- DNA damage response --- histotype --- Hippo pathway --- NF2 --- BAP1 --- CDKN2A --- PTCH1 --- SETD2 --- MTAP --- liquid biopsies --- circulating tumor DNA --- plasma --- cancer-specific mutations --- genomics --- cancer biomarkers --- tumor microenvironment --- tumor-associated macrophages --- dendritic cells --- immunohistochemistry --- interaction analysis --- pleural effusion

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Viruses in the Parvoviridae family constitute one of the most diverse and intriguing fields of research. While they all share an ssDNA genome and a small capsid, they can differ widely in structure, genome organization and expression, virus–cell interaction, and impact on the host. Exploring such diversity and unraveling the inherent complexity in these apparently simple viruses is an ongoing endeavor and commitment for the scientific community. The translational implications of research on parvoviruses are relevant. Within the family, some viruses are important human and veterinary pathogens, in need of diagnostic methods and antiviral strategies; other viruses have long been studied and engineered as tools for oncolytic therapy, or as sophisticated gene delivery vectors, and can now display their wide and expanding applicative potential. This Special Issue of Viruses collects recent contributions in the field of parvovirus research, with a focus on new insights and research on unresolved issues, as well as new approaches exploiting systemic methodologies. Evolution, structural biology, viral replication, virus–host interaction, pathogenesis and immunity, and viral oncotherapy are a selection of the topics addressed in the issue that can be of relevance to the community involved in parvovirus research and of interest to a wider audience.

antivirals --- Bombyx mori bidensovirus --- Bocaparvovirus --- human bocavirus 1 --- equine parvovirus-hepatitis --- NS2 --- NS1 --- X-ray crystallography --- BIRC3 (cIAP-2) --- glycans --- children --- antibody interactions --- new viruses --- alpaca --- cidofovir --- rodent protoparvoviruses --- clinical trials --- structural biology --- DNA virus --- human bocavirus --- caspase-3 --- viral communities --- uncoating --- PLA2 --- phospholipase-A2 --- oncolytic virus immune therapy --- Parvoviridae --- viral ecology --- Cryo-EM --- AAV --- metagenomics --- phylogeny --- oncolytic viruses --- mite --- parvovirus evolution --- Carnivore protoparvovirus 1 --- adeno-associated virus --- telbivudine --- capsid stability --- virus --- homology modeling --- human airway epithelia --- sequence analysis --- acute gastroenteritis --- bisulfite PCR --- next-generation sequencing --- single stranded DNA virus --- overlapping promoters --- virus diversity --- prognosis --- oncolytic activity --- genome --- hydroxyurea --- Lepidoptera --- genome externalization --- antiviral compounds --- circulating angiogenic cells --- tumor microenvironment --- coumarin derivatives --- nuclear targeting --- densovirus --- receptor interactions --- cell cycle arrest --- transcription profile --- brincidofovir --- canine parvovirus --- endogenous viral elements --- inflammatory cardiomyopathy --- erythroid progenitor cells --- RNA-seq --- insect --- chapparvovirus --- RT-qPCR --- trafficking --- AAV2 --- agricultural pests --- Adeno-associated virus --- myocarditis --- diagnosis --- parvovirus --- feline panleukopenia virus --- chitin --- B19V --- transcription mapping --- flavonoids --- immunomodulation --- erythrovirus --- apoptosis --- adenoviral vector --- anti-cancer --- divalent cations --- protease --- genetics --- preclinical --- arthropod --- peritrophins --- biocontrol --- dilated cardiomyopathy --- insect parvovirus --- combination therapies --- intravenous immunoglobulin (IVIG) --- virus phylogeny --- evolution --- second generation parvovirus treatments --- commercial horse serum --- parvovirus B19 --- canine chapparvovirus --- CpG methylation --- RACE --- H-1PV --- viral metagenomics --- horses