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Immune Checkpoint Molecules and Cancer Immunotherapy

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889457328 Year: Pages: 197 DOI: 10.3389/978-2-88945-732-8 Language: English
Publisher: Frontiers Media SA
Subject: Oncology --- Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2019-01-23 14:53:43
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For the faultless function of the immune system, tight regulation of immune cell activation, immuno-suppression and the strength and efficiency of the immune response is essential. Immune checkpoint (ICP) molecules can amplify or dampen signals that lead to the modulation of specific immune activities. Under physiological conditions, immune checkpoints are essential to prevent autoimmune manifestations and to preserve self-tolerance. They help modulate immune responses by either promoting or inhibiting T-cell activation. However, in the context of cancer, malignant cells can dysregulate the expression of immune checkpoint proteins on immune cells in order to suppress anti-tumor immune responses and to gain immune resistance. Moreover, tumor cells themselves can also express some checkpoints proteins, thereby enabling these cells to externally orchestrate immune regulatory mechanisms. Several recent studies have confirmed that the expression of immune checkpoints could be an important prognostic parameter for cancer development and for patient outcome. Therefore, cancer immunotherapy based on the modulation of immune checkpoint molecules alone, or in combination with conventional tumor therapy (chemo- or/and radiotherapy), is now in focus as a means of developing new therapeutic strategies for different types of cancer. The two well-known molecules – CTLA4 and PD-1 - serve as important examples of such checkpoint proteins of important therapeutic potential. Thus far, inhibitors of CTLA4 and PD-1 have been approved to treat only a limited number of malignancies (e.g. malignant Melanoma, Non-Small Cell Lung Cancer). Many others are currently under investigation and the list of immune checkpoint molecules for potential therapeutic targeting is still growing. However, the clinical response to inhibitors of checkpoint molecules is not sufficient in all cases. Therefore, further studies are needed to improve our knowledge of such immunomodulatory proteins and their associated signaling pathways. Several key signaling pathways which are involved in the regulation of expression of checkpoint molecules in immune cells and in cancer cells have already been identified including MAPK, PI3K, NF-kB, JAKs and STATs. These (and future discovered) signaling pathways could give rise to the development of new strategies for modulating the expression of ICPs and thereby, improving anti-cancer immune responses. The main aim of the Research Topic is to collect novel findings from scientists involved in basic research on immune checkpoints as well as in translational studies investigating the use of checkpoint inhibtors in immunotherapy in experimental settings. We welcome the submission of Review, Mini-Review and Original Research articles that cover the following topics: 1. Molecular mechanisms underlying regulation of ICP expression in immune and/or cancer cells.2. Characterization of signaling pathways downstream ICP molecules.3. Cellular responses to ICP blockade.4. Identification of new compounds interfering with ICP expression and/or signaling.5. ICP-mediated interactions between cancer cells and immune cells. 6. Functional links between ICP and cytokines/chemokines.7. Molecular mechanisms of ICP inhibition in the context of experimental cancer immunotherapy.

Cancer-associated defects in the DNA damage response: drivers for malignant transformation and potential therapeutic targets

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889199495 Year: Pages: 107 DOI: 10.3389/978-2-88919-949-5 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Genetics
Added to DOAB on : 2016-01-19 14:05:46
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For this eBook, and the associated Research Topic in Frontiers in Genetics, entitled: ‘Cancer-associated defects in the DNA damage response: drivers for malignant transformation and potential therapeutic targets’ we have selected 10 papers that each discusses important, yet distinct aspects of the response to DNA damage in normal cells and cancer cells. Using an evolutionary conserved signaling network called the ‘DNA damage response (DDR)’ cells maintain the integrity of their genome, and thus safeguard cellular functioning and the ability to create viably progeny. Initially, the DDR appeared to consist of few linear kinase-driven pathways. However, research over the past decades in model organisms, as well as in the human system has revealed that the DDR is a complex signaling network, wired by multiple parallel pathways and displaying extensive crosstalk. Besides phosphorylation, multiple other post-translational modifications, including ubiquitination and sumoylation, are involved to achieve chromatin remodeling and initiation of DNA repair. Also, rather than being a cell-intrinsic phenomenon, we increasingly appreciate that cell-cell communication is involved. The recognition and repair of DNA damage is essential to maintain normal physiology. Multiple pathological conditions have been attributed to defective DNA repair, most notably accelerated aging, neurodegeneration and cancer. In the context of cancer, through repair of DNA damage or elimination of irreparably damaged cells, the DDR clearly has a tumor-suppressive role. Indeed, many tumor cells show partially inactivated DDR signaling, which allows proliferation in the context of DNA damage-inducing oncogenes. Simultaneously, loss of specific DDR signaling nodes creates a specific dependence of tumor cells on their remaining DDR components, and thus creates therapeutic opportunities. Especially in the context of cancer treatment, numerous targeted agents are under investigation, either to potentiate the cytotoxic effects of chemo-radiotherapy, or to induce synthetic lethality with cancer-specific alterations, with the treatment of BRCA1/2 mutant cancers with PARP1 inhibitors as a prototype example. We have selected four review articles that provide insight into the key components and the wiring of the DDR and DNA repair. Torgovnick and Schumacher review the involvement of DNA repair in the initiation and treatment of cancer, Brinkmann et al., describe the involvement of ubiquitination in DNA damage signaling and Jaiswal and Lindqvist discuss how cell-extrinsic signaling participates in communication of DNA damage to neighboring cells. In addition, Shatneyeva and colleagues review the connection between the cellular response to DNA damage and escape from immune surveillance. Concerning the therapeutic application of targeting the DDR and DNA repair, three articles were included. Krajewska and van Vugt review the wiring of homologous recombination and how this offers therapeutic opportunities. Additionally, Knittel and colleagues describe how genetic loss of the central DDR component ATM in chronic lymphocytic leukemia can be exploited therapeutically by targeting certain parallel DNA repair pathways. Syljuasen and colleagues report on how targeting of the DDR can be used as a therapeutic strategy in lung cancer. Finally, three chapters describe newly identified regulators of the cellular response to DNA damage. Von Morgen et al. describe the R2TP complex, Lezzi and Fanciluuli review the involvement of Che-1/AATF in the DDR, and Ohms and co-authors describe how retrotransposons are at the basis of increased genomic instability. Altogether, these articles describe how defective responses to DNA damage underlie disease - and especially in the context of cancer -can be exploited to better treat disease.

DNA Replication Controls

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ISBN: 9783038425724 9783038425731 Year: Volume: 2 Pages: X, 346 DOI: 10.3390/books978-3-03842-573-1 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Biology
Added to DOAB on : 2017-12-27 08:38:10
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The conditions for DNA replication are not ideal, owing to endogenous and exogenous replication stresses that lead to arrest of the replication fork. Arrested forks are among the most serious threats to genomic integrity because they can break or rearrange, leading to genomic instability, which is a hallmark of cancers and aging-related disorders. This title, “DNA Replication Controls”, presents series of new reviews and original research articles, providing a comprehensive guide to theoretical advancements in the field of DNA replication research in both prokaryotic and eukaryotic systems. The topics include DNA polymerases and helicases; replication initiation; replication timing; replication-associated DNA repair; and replication of difficult-to-replicate genomic regions, including telomeres, centromeres and highly-transcribed regions. This title also provides recent advancements in studies of cellular processes that are coordinated with DNA replication and how defects in the DNA replication program result in genetic disorders, including cancer. Written by leading experts in DNA replication regulation, this book will be an important resource for a wide variety of audiences, including junior graduate students and established investigators who have interests in DNA replication and genome maintenance mechanisms.

DNA Replication Controls

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ISBN: 9783038425687 9783038425694 Year: Volume: 1 Pages: X, 304 DOI: 10.3390/books978-3-03842-569-4 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Biology
Added to DOAB on : 2018-01-02 15:17:59
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The conditions for DNA replication are not ideal, owing to endogenous and exogenous replication stresses that lead to arrest of the replication fork. Arrested forks are among the most serious threats to genomic integrity because they can break or rearrange, leading to genomic instability, which is a hallmark of cancers and aging-related disorders.

Is the Recent Burst of Therapeutic Anti-Tumor Antibodies the Tip of an Iceberg?

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889454624 Year: Pages: 305 DOI: 10.3389/978-2-88945-462-4 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2018-11-16 17:17:57
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The high effectiveness of antibodies as anti-tumor therapeutic agents has led to a burst of research aiming to increase their therapeutic applications by the use of antibodies against new targets, new antibody formats or new combinations. In this e-book we present relevant research depicting the current efforts in the field.

Tailoring NK Cell Receptor-Ligand Interactions: An Art in Evolution

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889454648 Year: Pages: 407 DOI: 10.3389/978-2-88945-464-8 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2018-11-16 17:17:57
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Recognition and killing of aberrant, infected or tumor targets by Natural Killer (NK) cells is mediated by positive signals transduced by activating receptors upon engagement of ligands on target surface. These stimulatory pathways are counterbalanced by inhibitory receptors that raise NK cell activation threshold through negative antagonist signals. While regulatory effects are necessary for physiologic control of autoimmune aggression, they may restrain the ability of NK cells to activate against disease. Overcoming this barrier to immune surveillance, multiple approaches to enhance NK-mediated responses are being investigated since two decades. Propelled by considerable advances in the understanding of NK cell biology, these studies are critical for effective translation of NK-based immunotherapy principles into the clinic. In humans, dominant inhibitory signals are transduced by Killer Immunoglobulin Like Receptors (KIR) recognizing cognate HLA class I on target cells. Conversely, KIR recognition of “missing self-HLA” - due to HLA loss or HLA/ KIR mismatch - triggers NK-mediated tumor rejection. Initially observed in murine transplant models, these antitumor effects were later found to have important implications for the clinical outcome of haplotype-mismatched stemcell transplantation. Here, donor NK subsets protect against acute myeloid leukemia (AML) relapse through missing self recognition of donor HLA-C allele groups (C1 or C2) and/or Bw4 epitope. These studies were subsequently extended by trials investigating the antileukemia effects of adoptively transferred haplotype-mismatched NK cells in non-transplant settings. Other mechanisms have been found to induce clinically relevant NK cell alloreactivity in transplantation, e.g., post-reconstitution functional reversal of anergic NK cells. More recently, activating KIR came into the spotlight for their potential ability to directly activate donor NK cells through in vivo recognition of HLA or other ligands. Novel therapeutic monoclonal antibodies (mAb) may optimize NK-mediated effects. Examples include obinutuzumab (GA101), a glyco-engineered anti-CD20 mAb with increased affinity for the FcγRIIIA receptor, enhancing antibody-dependent cellular cytotoxicity; lirilumab (IPH2102), a first-in-class NK-specific checkpoint inhibitor, blocking the interaction between the major KIR and cognate HLA-C antigens; and elotuzumab (HuLuc63), a humanized monoclonal antibody specific for SLAMF7, whose anti-myeloma therapeutic effects are partly due to direct activation of SLAMF7-expressing NK cells. In addition to conventional antibodies, NK cell-targeted bispecific (BiKEs) and trispecific (TriKEs) killer engagers have also been developed. These proteins elicit potent effector functions by binding target ligands (e.g., CD19, CD22, CD30, CD133, HLA class II, EGFR) on one arm and NK receptors on the other. An additional innovative approach to direct NK cell activity is genetic reprogramming with chimeric antigen receptors (CAR). To date, primary NK cells and the NK92 cell line have been engineered with CAR specific for antigens expressed on multiple tumors. Encouraging preclinical results warrant further development of this approach. This Research Topic welcomes contributions addressing mechanisms of NK-mediated activation in response to disease as well as past and contemporary strategies to enhance NK mediated reactivity through control of the interactions between NK receptors and their ligands.

Tailoring NK Cell Receptor-Ligand Interactions: an Art in Evolution. 2nd Edition

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889456635 Year: Pages: 407 DOI: 10.3389/978-2-88945-663-5 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2019-01-23 14:53:43
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Recognition and killing of aberrant, infected or tumor targets by Natural Killer (NK) cells is mediated by positive signals transduced by activating receptors upon engagement of ligands on target surface. These stimulatory pathways are counterbalanced by inhibitory receptors that raise NK cell activation threshold through negative antagonist signals. While regulatory effects are necessary for physiologic control of autoimmune aggression, they may restrain the ability of NK cells to activate against disease. Overcoming this barrier to immune surveillance, multiple approaches to enhance NK-mediated responses are being investigated since two decades. Propelled by considerable advances in the understanding of NK cell biology, these studies are critical for effective translation of NK-based immunotherapy principles into the clinic. In humans, dominant inhibitory signals are transduced by Killer Immunoglobulin Like Receptors (KIR) recognizing cognate HLA class I on target cells. Conversely, KIR recognition of “missing self-HLA” - due to HLA loss or HLA/ KIR mismatch - triggers NK-mediated tumor rejection. Initially observed in murine transplant models, these antitumor effects were later found to have important implications for the clinical outcome of haplotype-mismatched stemcell transplantation. Here, donor NK subsets protect against acute myeloid leukemia (AML) relapse through missing self recognition of donor HLA-C allele groups (C1 or C2) and/or Bw4 epitope. These studies were subsequently extended by trials investigating the antileukemia effects of adoptively transferred haplotype-mismatched NK cells in non-transplant settings. Other mechanisms have been found to induce clinically relevant NK cell alloreactivity in transplantation, e.g., post-reconstitution functional reversal of anergic NK cells. More recently, activating KIR came into the spotlight for their potential ability to directly activate donor NK cells through in vivo recognition of HLA or other ligands. Novel therapeutic monoclonal antibodies (mAb) may optimize NK-mediated effects. Examples include obinutuzumab (GA101), a glyco-engineered anti-CD20 mAb with increased affinity for the FcγRIIIA receptor, enhancing antibody-dependent cellular cytotoxicity; lirilumab (IPH2102), a first-in-class NK-specific checkpoint inhibitor, blocking the interaction between the major KIR and cognate HLA-C antigens; and elotuzumab (HuLuc63), a humanized monoclonal antibody specific for SLAMF7, whose anti-myeloma therapeutic effects are partly due to direct activation of SLAMF7-expressing NK cells. In addition to conventional antibodies, NK cell-targeted bispecific (BiKEs) and trispecific (TriKEs) killer engagers have also been developed. These proteins elicit potent effector functions by binding target ligands (e.g., CD19, CD22, CD30, CD133, HLA class II, EGFR) on one arm and NK receptors on the other. An additional innovative approach to direct NK cell activity is genetic reprogramming with chimeric antigen receptors (CAR). To date, primary NK cells and the NK92 cell line have been engineered with CAR specific for antigens expressed on multiple tumors. Encouraging preclinical results warrant further development of this approach. This Research Topic welcomes contributions addressing mechanisms of NK-mediated activation in response to disease as well as past and contemporary strategies to enhance NK mediated reactivity through control of the interactions between NK receptors and their ligands.

Methods in Computational Biology

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ISBN: 9783039211630 / 9783039211647 Year: Pages: 214 DOI: 10.3390/books978-3-03921-164-7 Language: eng
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Computer Science
Added to DOAB on : 2019-08-28 11:21:27
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Modern biology is rapidly becoming a study of large sets of data. Understanding these data sets is a major challenge for most life sciences, including the medical, environmental, and bioprocess fields. Computational biology approaches are essential for leveraging this ongoing revolution in omics data. A primary goal of this Special Issue, entitled “Methods in Computational Biology”, is the communication of computational biology methods, which can extract biological design principles from complex data sets, described in enough detail to permit the reproduction of the results. This issue integrates interdisciplinary researchers such as biologists, computer scientists, engineers, and mathematicians to advance biological systems analysis. The Special Issue contains the following sections:•Reviews of Computational Methods•Computational Analysis of Biological Dynamics: From Molecular to Cellular to Tissue/Consortia Levels•The Interface of Biotic and Abiotic Processes•Processing of Large Data Sets for Enhanced Analysis•Parameter Optimization and Measurement

Towards New Promising Discoveries for Lung Cancer Patients: A Selection of Papers from the First Joint Meeting on Lung Cancer of the FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (Houston, TX, USA)

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ISBN: 9783039214518 / 9783039214525 Year: Pages: 230 DOI: 10.3390/books978-3-03921-452-5 Language: eng
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Medicine (General) --- Oncology
Added to DOAB on : 2019-12-09 11:49:15
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This Special Issue of Cancers (Basel) is mainly dedicated to selecting papers from the talks given during the first Joint Meeting on Lung Cancer (JMLC) between the MD Anderson Cancer Center (Houston, Texas USA) and the Hospital University Federation (HUF) OncoAge (University Côte d’Azur, Nice, France) (Nice, September 2018). The central theme of JMLC is to discuss new advances and exchange ideas regarding lung cancer. Notably, the talks covered different topics on new therapeutic strategies (targeted therapy and immuno-oncology), molecular and cellular biology, biomarkers, and the epidemiology of lung cancer. Special attention was also given to lung cancer in elderly patients. The articles published in this Special Issue covered subjects such as the assessment of new biomarkers and new approaches for the early detection of lung cancer, epidemiological data, and emphasized a place for the newly characterized cellular pathways in lung cancer, which opens room for therapeutic perspectives for lung cancer patients.

The Interplay of Microbiome and Immune Response in Health and Diseases

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ISBN: 9783039216468 / 9783039216475 Year: Pages: 206 DOI: 10.3390/books978-3-03921-647-5 Language: eng
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Medicine (General) --- Internal medicine
Added to DOAB on : 2019-12-09 11:49:16
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[Increasing evidence suggests that microbiota and especially the gut microbiota (the microbes inhabiting the gut including bacteria, archaea, viruses, and fungi) plays a key role in human physiology and pathology. Recent findings indicate how dysbiosis—an imbalance in the composition and organization of microbial populations—could severely impact the development of different medical conditions (from metabolic to mood disorders), providing new insights into the comprehension of diverse diseases, such as IBD, obesity, asthma, autism, stroke, diabetes, and cancer. Given that microbial cells in the gut outnumber host cells, microbiota influences human physiology both functionally and structurally. Microbial metabolites bridge various—even distant—areas of the organism by way of the immune and hormone system. For instance, it is now clear that the mutual interaction between the gastrointestinal tract and the brain (gut–brain axis), often involves gut microbiota, indicating that the crosstalk between the organism and its microbial residents represents a fundamental aspect of both the establishment and maintenance of healthy conditions. Moreover, it is crucial to recognize that beyond the intestinal tract, microbiota populates other host organs and tissues (e.g., skin and oral mucosa). We have edited this eBook with the aim of publishing manuscripts focusing on the impact of microbiota in the development of different diseases and their associated treatments.]

Keywords

microbiota --- rheumatoid arthritis --- anti-TNF-? --- methotrexate --- etanercept --- disease activity --- microbiome --- health --- precision medicine --- genomics --- bacteriocins --- bacteriophages --- antibiotics --- gastrointestinal diseases --- dysbiosis --- gut barrier --- gut microbiota --- virus --- vaginal microbiota --- HIV --- HPV --- HSV2 --- cytokines --- chemokines --- innate immunity --- adaptive immunity --- microbiota --- autoimmunity --- etiopathogenesis --- Candida albicans --- 2,3-dihydroxy-4-methoxyBenzaldehyde --- melanin --- colitis --- anaerobic bacteria --- aerobic bacteria --- gut microbiota --- gut-liver axis --- chronic liver diseases --- fecal transplantation --- probiotics --- gut microbiota --- immunological niche --- dysbiosis --- cancer --- immune system --- cutaneous immunity --- microbiome --- Staphylococcus spp., T cells --- Staphylococcus aureus --- Staphylococcus epidermis --- commensals --- atopic dermatitis --- intravenous immunoglobulin G --- colitis --- dextran sulfate sodium --- mice --- inflammation --- cytokines --- Candida albicans --- Escherichia coli --- Enterococcus faecalis --- gut microbiota --- chemo free treatment --- lymphoid malignancies --- 16S rRNA gene --- chondroitin sulfate disaccharide --- co-occurrence network --- global network --- microbial interactions --- microbiome --- modularity --- superoxide dismutase --- gut microbiota --- macrophages --- TLR mimicry --- immune epigenetics --- metabolism --- sterile inflammation --- microbiota --- microbiome --- immunotherapy --- adoptive cell transfer (ACT) --- CAR T-cell --- TCR --- TIL --- checkpoint inhibitors --- immuno-oncology --- cancer --- diet --- n/a

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