Investigation Into The Role Of The Par 4 Tumor Suppressor Pathway In B Cell Biology And Chronic Lymphocytic Leukemia
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Author | : Joseph Thomas Greene |
Publisher | : |
Total Pages | : 132 |
Release | : 2018 |
Genre | : B cells |
ISBN | : |
Download Investigation Into the Role of the Par-4 Tumor Suppressor Pathway in B Cell Biology and Chronic Lymphocytic Leukemia Book in PDF, Epub and Kindle
The Eμ-TCL1 mouse is a B cell leukemia model commonly used to test the efficacy of experimental therapeutics and interrogate the functions of oncogenes and tumor suppressors. The CLL-like disease in this mouse shares similar pathology and molecular etiology with the human variant. We therefore hypothesized that overexpression of the human isoform of Par-4 in the B cells of this mouse would impede disease progression through either an anti-proliferative or pro-apoptotic mechanism. Consistent with this hypothesis, results indicated that B cell-specific overexpression of human Par-4 reduced the rate of T Cell Leukemia/Lymphoma 1 (TCL1)-induced leukemogenesis. In addition, B cell-specific knockout of endogenous Par-4 increased the rate of TCL1-induced leukemogenesis. Par-4 activity is regulated through a variety of mechanisms, which seem to give it a pleiotropic property. It is generally thought to act as either an anti-proliferative or pro-apoptotic tumor suppressor. In our study, TCL1 mice overexpressing human Par-4 were found to harbor malignant B cell clones that proliferated at reduced rates when compared to their Par-4 wild-type (WT) littermates. This indicated that Par-4 was reducing the expansion of overexpressing cells; which we found interesting, because Par-4 overexpressing mice null for the TCL1 oncogene exhibited no phenotype when examined in various immune response assays.
Author | : Mary Kathryn McKenna |
Publisher | : |
Total Pages | : 196 |
Release | : 2017 |
Genre | : |
ISBN | : |
Download Novel Role of Prostate Apoptosis Response-4 Tumor Suppressor in B-cell Chronic Lymphocytic Leukemia Book in PDF, Epub and Kindle
Author | : Vivek M. Rangnekar |
Publisher | : Springer |
Total Pages | : 331 |
Release | : 2021-12-21 |
Genre | : Medical |
ISBN | : 9783030805579 |
Download Tumor Suppressor Par-4 Book in PDF, Epub and Kindle
Par-4 is a naturally occurring tumor suppressor. Studies have indicated that overexpression of Par-4 selectively induces apoptosis in cancer cells while leaving normal, health, cells unaffected. Mechanisms contributing to this cancer-selective action of Par-4 have been associated with PKA activation of intracellular Par-4 in cancer cells or GRP78 expression primarily on the surface of cancer cells. On the other hand, endogenous Par-4 sensitizes cells to the action of a broad range of apoptotic inducers acting via the extrinsic and intrinsic pathways. A number of binding partners of Par-4 have been identified and shown to regulate Par-4 function in cancer and other diseases, such as Alzheimer’s and major depression. Recent studies have recognized a number of natural products, dietary supplements, synthetic molecules and FDA-approved drugs that induce the secretion of Par-4 protein to cause apoptosis in primary or metastatic tumors, one of which is in clinical trials. More than 50 different laboratories worldwide are involved in Par-4 based research of this unique protein that has progressed from the bench to clinical trials. This second, companion volume will provide a comprehensive overview of Par-4’s role in cancer and other diseases. Chapters are written by leading researchers, and will be useful for a broad audience across the scientific community, particularly students and trainees, who are the next generation of scientists and clinicians to participate in new studies and discoveries on Par-4.
Author | : Jérôme Paggetti |
Publisher | : Frontiers Media SA |
Total Pages | : 164 |
Release | : 2022-01-31 |
Genre | : Medical |
ISBN | : 2889742415 |
Download New Insights into the Complexity of Tumor Immunology in B-cell Malignancies: Disease Biology and Signaling Book in PDF, Epub and Kindle
Author | : Owen A. O'Connor |
Publisher | : John Wiley & Sons |
Total Pages | : 516 |
Release | : 2023-03-09 |
Genre | : Medical |
ISBN | : 1119819946 |
Download Precision Cancer Therapies, Volume 1 Book in PDF, Epub and Kindle
Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies A thorough compilation of the many scientific breakthroughs in the ongoing development of precision cancer therapies related to lymphoma Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies: From Concept to Practice focuses on lymphoma, an area which has seen a remarkable number of breakthroughs in the ongoing development of precision cancer therapies. Each section on a specific biology or class of drugs has an introductory chapter written by an authority in the field, exclusively focused on the science and its relevance to cancer biology. This approach addresses the need for scientists, physicians, and the private sector to understand the broader context of the extraordinary advances that have produced such astonishing advances in the disease. The work primarily focuses on how to understand and translate fundamental principles of basic science into information that can be directly applied to patients – hence the subtitle, From Concept to Practice. To aid in readers’ comprehension, the first page of each chapter contains a box entitled ‘Take Home Points’. This short text will highlight the major unique points about the information contained within the chapter. Some of the key topics addressed in the work are as follows: Biological basis of the lymphoid malignancies: fundamental principles of lymphomagenesis and molecular classification of lymphoid malignancies Targeting programmed cell death: principles for understanding the many types of cell death and promising combinations of drugs targeting apoptosis Targeting the PI3K pathway: understanding the intricacies of this complex biology and precisely how targeted drugs can be leveraged therapeutically Targeting the cancer epigenome: pharmacologic features of drugs targeting the epigenome and future prospects for targeting various aspects of epigenetic control Targeting the tumour proteome: understanding the mechanisms of protein degradation in cancer including both older drugs like proteasome inhibitors, and newer PROTAC based approaches Written primarily for scientists and physicians in both the public and private sectors, Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies: From Concept to Practice is a comprehensive reference work for those interested in the growing area of Precision Cancer Therapies. Seamlessly integrating the basic and applied science, this volume will be an indispensable reference for those interested in translating the most important advances in science to innovative novel treatments for patients.
Author | : Vivek M. Rangnekar |
Publisher | : |
Total Pages | : 0 |
Release | : 2022 |
Genre | : |
ISBN | : 9783030735739 |
Download Tumor Suppressor Par-4 Book in PDF, Epub and Kindle
Par-4 is a tumor suppressor protein first discovered and identified in 1993 by Dr. Vivek Rangnekar's laboratory in prostate cancer cells undergoing apoptosis. Par-4 (later also known as PAWR) is a naturally occurring tumor suppressor. Studies have indicated that Par-4 selectively induces apoptosis in cancer cells while leaving normal, healthy, cells unaffected. Mechanisms contributing to the cancer-selective action of Par-4 have been associated with protein kinase A activation of intracellular Par-4 in cancer cells or GRP78 expression primarily on the surface of cancer cells. Par-4 is downregulated, inactivated or mutated in diverse cancers. This first of two volumes will be the first on the market on the topic of Par-4, and will provide the opportunity for researchers to discuss the future direction of studies, broaden the scope of research, and contribute a more complete understanding of the molecule's structural features, key functional domains, regulation and relevant basic and clinical/translational facets.
Author | : Vivek M. Rangnekar |
Publisher | : Springer Nature |
Total Pages | : 329 |
Release | : 2022-01-01 |
Genre | : Medical |
ISBN | : 3030805581 |
Download Tumor Suppressor Par-4 Book in PDF, Epub and Kindle
Par-4 is a naturally occurring tumor suppressor. Studies have indicated that overexpression of Par-4 selectively induces apoptosis in cancer cells while leaving normal, health, cells unaffected. Mechanisms contributing to this cancer-selective action of Par-4 have been associated with PKA activation of intracellular Par-4 in cancer cells or GRP78 expression primarily on the surface of cancer cells. On the other hand, endogenous Par-4 sensitizes cells to the action of a broad range of apoptotic inducers acting via the extrinsic and intrinsic pathways. A number of binding partners of Par-4 have been identified and shown to regulate Par-4 function in cancer and other diseases, such as Alzheimer’s and major depression. Recent studies have recognized a number of natural products, dietary supplements, synthetic molecules and FDA-approved drugs that induce the secretion of Par-4 protein to cause apoptosis in primary or metastatic tumors, one of which is in clinical trials. More than 50 different laboratories worldwide are involved in Par-4 based research of this unique protein that has progressed from the bench to clinical trials. This second, companion volume will provide a comprehensive overview of Par-4’s role in cancer and other diseases. Chapters are written by leading researchers, and will be useful for a broad audience across the scientific community, particularly students and trainees, who are the next generation of scientists and clinicians to participate in new studies and discoveries on Par-4.
Author | : Tasuku Honjo |
Publisher | : Academic Press |
Total Pages | : 0 |
Release | : 2014-12-22 |
Genre | : Science |
ISBN | : 9780123979339 |
Download Molecular Biology of B Cells Book in PDF, Epub and Kindle
Molecular Biology of B Cells, Second Edition is a comprehensive reference to how B cells are generated, selected, activated and engaged in antibody production. All of these developmental and stimulatory processes are described in molecular, immunological, and genetic terms to give a clear understanding of complex phenotypes. Molecular Biology of B Cells, Second Edition offers an integrated view of all aspects of B cells to produce a normal immune response as a constant, and the molecular basis of numerous diseases due to B cell abnormality. The new edition continues its success with updated research on microRNAs in B cell development and immunity, new developments in understanding lymphoma biology, and therapeutic targeting of B cells for clinical application. With updated research and continued comprehensive coverage of all aspects of B cell biology, Molecular Biology of B Cells, Second Edition is the definitive resource, vital for researchers across molecular biology, immunology and genetics.
Author | : Tomohiro Kurosaki |
Publisher | : Springer |
Total Pages | : 231 |
Release | : 2015-12-26 |
Genre | : Medical |
ISBN | : 3319261339 |
Download B Cell Receptor Signaling Book in PDF, Epub and Kindle
This volume details our current understanding of the architecture and signaling capabilities of the B cell antigen receptor (BCR) in health and disease. The first chapters review new insights into the assembly of BCR components and their organization on the cell surface. Subsequent contributions focus on the molecular interactions that connect the BCR with major intracellular signaling pathways such as Ca2+ mobilization, membrane phospholipid metabolism, nuclear translocation of NF-kB or the activation of Bruton’s Tyrosine Kinase and MAP kinases. These elements orchestrate cytoplasmic and nuclear responses as well as cytoskeleton dynamics for antigen internalization. Furthermore, a key mechanism of how B cells remember their cognate antigen is discussed in detail. Altogether, the discoveries presented provide a better understanding of B cell biology and help to explain some B cell-mediated pathogenicities, like autoimmune phenomena or the formation of B cell tumors, while also paving the way for eventually combating these diseases.
Author | : Shuai Dong |
Publisher | : |
Total Pages | : |
Release | : 2017 |
Genre | : Chronic lymphocytic leukemia |
ISBN | : |
Download Pharmacologic and Genetic Investigation of PI3K P110delta in Chronic Lymphocytic Leukemia Book in PDF, Epub and Kindle
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the western world. The treatment strategies of CLL have undergone a paradigm shift in the last decade. Without a disease defining gene abnormality, the Achilleas heels of CLL is its microenvironment dependency. Upon discovering the importance of CLL-microenvironment cross-talk and essential survival B cell receptor (BCR) pathways, small molecule inhibitors that target BCR pathways were soon developed and showed profound activity in preclinical and clinical studies. Several agents that target BCR pathways also reverse tumor related immune suppression. Idelalisib is one such therapy directed at phosphoinositide 3-kinase isoform d, an essential component of BCR signaling in normal and transformed B-cells and essential for the activation of regulatory T cells. CLL is dependent upon BCR signaling and mediates profound immune suppression and tumor tolerance. Idelalisib is a PI3K p110d inhibitor with significant clinical benefit and also toxicities resembling autoimmunity. Using a PI3K p110delta and p110gamma inhibitor IPI-145, we show that PI3K p110delta/p110gamma blockade in leukemia cells overcomes microenvironmental BCR- and CD40L- stimulation, antagonizes pro-survival AKT pathway and induces selective cytotoxicity to leukemia cells. PI3K p110delta/p110gamma blockade reduces TCR-induced T cell proliferation and cytokine production, suggesting PI3K p110delta/p110gamma have dual roles in the leukemic and normal immune compartment. PI3K p110delta/p110gamma inhibition does not impair natural killer cell- mediated cellular cytotoxicity. Most importantly, PI3K p110delta/p110gamma inhibition can overcome ibrutinib resistance due to the BTK C481S mutation. Using different genetic mouse models, we demonstrate that global inactivation of p110delta blocks leukemia development, confirming that p110delta is critical for CLL initiation and progression. Additionally, blocking p110delta activity in the microenvironment protects against both murine CLL and acute myeloid leukemia due to the lack of regulatory T cell immunosuppression. These data suggest a separate immunomodulatory effect of p110delta blockade independent of BCR signaling or direct tumor efficacy. Collectively, these data suggest p110delta blockade may have a broader immune modulatory role across other types of leukemia.