Download or read book The Metabolic Epigenetic Role of IDH1 In The Initiation And Progression Of High Grade Serous Ovarian Cancer written by Erika Dahl and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer and is composed of several histological subtypes. High-grade serous carcinoma (HGSC) is the most common histosubtype, accounting for approximately 70% of all EOC diagnoses. Almost all HGSC patients have a mutation in TP53, which is an initiating factor in the hypothesized cell-type of origin, the fallopian tube fimbriae. In addition, 20% of HGSC patients have an amplification in the oncogene cyclin E1 (CCNE1), which canonically regulates the G1 to S-phase of the cell cycle. Due to the lack of symptoms and current screening methods, HGSC is typically diagnosed at late stages when it has disseminated from the fallopian tube and ovarian surface epithelium into the peritoneal cavity. Standard-of-care treatments for these patients include debulking surgery, which aims to remove visible tumor, and platinum and taxol-based chemotherapies. Poly(ADP-ribose) polymerase (PARP) inhibitors have recently emerged as a novel therapeutic for women with homologous recombination pathway defects. Unfortunately, 75% of these patients will relapse with chemoresistant disease for which there are limited second-line therapies currently available. As metabolic adaptations are known to occur in cancer and can be specifically targeted, I aimed to identify and target metabolic vulnerabilities in HGSC as novel therapeutic strategies. I found that compared to normal fallopian tube (FT) cells, HGSC cells have increased TCA cycle enzymes and metabolites, suggesting that the TCA cycle may be a novel target for these ovarian cancers. Through further analysis, I identified wildtype isocitrate dehydrogenase I (wtIDH1) to be associated with poor HGSC progression-free survival. Therefore, I hypothesized that targeting wtIDH1 in HGSC may be a novel therapeutic for this patient population. wtIDH1 reversibly converts isocitrate to alpha-ketoglutarate ([alpha]KG), a co-substrate for several DNA and histone demethylases, which can effectively alter gene expression. I found that knockdown of wtIDH1 in HGSC cells depleted whole cell [alpha]KG pools. Decreased [alpha]KG availability increased repressive histone methylation at proliferation-promoting gene loci, which led to a stable cell cycle arrest, termed senescence, in vitro. These data suggest that wtIDH1 is necessary for HGSC proliferation and targeting wtIDH1 may be a pro-senescent therapeutic strategy. Additionally, cyclin E1 amplifications have been identified in FT lesions, suggesting they occur early in ovarian cancer initiation. Cyclin E1 amplifications are mutually exclusive for HR mutations and, therefore, are not sensitive to FDA-approved PARP inhibitors, a currently used therapeutic for HGSC patients. Oncogene activation typically induces senescence; however, it is hypothesized that these cells bypass senescence to progress into HGSC. I found a positive correlation between cyclin E1 and wtIDH1 in FT cells, HGSC cells, and patient data from The Cancer Genome Atlas (TCGA). Defects in HR are known to increase DNA damage in cells and are a hallmark of senescence. Knockdown of wtIDH1 exacerbated DNA damage markers and induced senescence of FT cells, suggesting it is in part necessary for cyclin E1-high FT proliferation. Knockdown of wtIDH1 in cyclin E1-high cells depleted expression of several HR genes, including Breast Cancer Susceptibility Type 1 and 2 (BRCA1/2). To determine whether reduced BRCA1/2 expression is due to epigenetic alterations, I performed histone proteomic screening and found an increase in repressive marks such as H3K9me2 and H4K20me2/3 upon wtIDH1 knockdown. It is well-known that tumors that are HR-deficient are hypersensitive to PARP inhibitors. Interestingly, combination treatment of wtIDH1 and PARP inhibitors increased cell death in vitro, suggesting that changes in HR gene expression due to wtIDH1 inhibition may sensitize these cells to PARP inhibitors. Altogether, these data suggest that wtIDH1 is necessary for proliferation of cyclin E1-high FT cells. Targeting wtIDH1 induces senescence, depletes HR gene expression, and may be a novel combinatorial strategy with PARP inhibitors. Together, these studies identified the critical role of wtIDH1 in the proliferation of HGSC and FT cells with high cyclin E1 expression. wtIDH1 was responsible for regulating key proliferation-promoting and HR genes. Future studies will determine whether inhibition of wtIDH1 alone or in combination with PARP inhibitors may lead to senescence or apoptosis, respectively, of ovarian cancer cells in vivo.

Download or read book Role of Epigenetic Regulators in the Initiation Progression and Metastasis of Cancer written by Ritu Kulshreshtha and published by Frontiers Media SA. This book was released on 2022-11-30 with total page 207 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Role of Ovarian Cancer initiating Cells in High grade Serous Ovarian Carcinogenesis written by Rohit Jadhav and published by . This book was released on 2011 with total page 172 pages. Available in PDF, EPUB and Kindle. Book excerpt: A subpopulation of tumor cells known as ovarian cancer initiating cells (OCICs) have been shown to be the cells that propagate the tumor phenotype in ovarian cancer. Studies have showed that a very small population (100) of these cells is sufficient to induce a tumor phenotype; while a large quantity of tumor cells (5 X 105) are required to induce such a phenotype. In this study we studied the functional changes in genes expressed in the OCIC phenotype which were important for such efficient propagation of cancers. To enable this analysis, we generated mRNA expression and DNA methylation profiles of OCICs and compared them with those of tumor and normal ovarian surface epithelial cells. We identified four pathways which regulated most of the observed changes and were predicted to be important factors in distinguishing the OCICs from tumors and normal cells. The gene signatures for these pathways were analyzed by unsupervised clustering in order to determine the similarities of OCICs with respect to tumor and normal samples. We further believed that the OCICs can be used as indicators towards the genesis and progression of early events in the ovarian cancers. In light of this, we considered two hypotheses which are currently addressing the genesis of ovarian cancer. The first hypothesis proposed ovarian surface epithelial cells to be cells of origin of the ovarian cancer while the other proposed the fallopian tube cells to be contributing the cell of origin for these cancers. It is also believed that these two cells can be reciprocal cells of origin for the cancer phenotype. In order to test these hypotheses, we integrated the in-house dataset with a public domain fallopian tube gene expression data. The integration of the results obtained from these analyses provided better understanding of the early events in ovarian carcinogenesis.

Download or read book Modeling High grade Serous Ovarian Carcinoma HGSC Using a Combination of in Vivo Oviductal Electroporation and CRISPR Cas9 Mediated Genome Editing written by Katie Teng and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Ovarian cancer remains the most lethal gynecological cancer that affect women today. High-grade serous ovarian carcinoma (HGSC) is the most common and lethal type of ovarian cancer and is most frequently diagnosed at advanced stages when metastasis has occurred. Despite its name, the origin for HGSC remains controversial. There have been many studies that support ovarian surface epithelial origin (OSE) while others support fallopian tube epithelial (FTE) origin.Approximately 70% of HGSC patients show a decrease in liver kinase B1 (LKB1) protein expression suggesting that loss-of-LKB1 plays a role in the mechanism for its initiation and progression. In order to investigate the role of Lkb1 in HGSC tumorigenesis, we developed a novel in vivo oviductal electroporation method to modulate tumor suppressor genes directly in the distal oviductal luminal epithelial cells in mice. Cre and PX330 CRISPR plasmids targeting Brca1, Tp53 and Pten were electroporated into the oviductal epithelial cells of Rosa- LSLtdTomato and Lkb1flox/flox ; Rosa-LSLtdTomato mice. Early precancerous lesions, such as PAX8+ secretory cell outgrowths, were detected in the oviductal epithelium in both cohorts 4 months post electroporation, however, loss-of-Lkb1 significantly facilitated the initiation and progression of HGSC.The HGSC tumours formed in the Lkb1 intact and deletion group recapitulated human and current animal models of HGSC, however many of the tumours formed in the Lkb1 deletion group were PAX8-. By performing salpingectomies immediately following in vivo oviductal electroporation in Lkb1flox/flox ; Rosa-LSLtdTomato mice, we observed the development of ovarian tumours and peritoneal metastasis at a similar onset and penetrance as non-salpinectomized mice. This suggested that these tumours originated from a minor population of electroporated cells outside of the FTE. Upon careful examination of the ovaries and surrounding tissues, the tumours in the Lkb1 deletion cohort appear to be emerging from the epithelium of the ovary and hilum region.Taken together, these results revealed that depending on the mutation combinations present in the cell-of-origin, HGSC tumours can originate from the FTE, OSE and the epithelium of the hilum. Additionally, following sequencing analysis of ovarian tumours and peritoneal metatstasic tumours, we found that frameshift mutations were predominantly selected during HGSC disease progression.Determining and defining the cell-of-origin for HGSC has been an ongoing challenge. Continuing to define and create animal models with various origins is critical in determining effective strategies for prevention, prognosis, diagnosis and treatment of HGSC"--

Download or read book Signal Transduction in Cancer written by David A. Frank and published by Springer Science & Business Media. This book was released on 2002-12-31 with total page 358 pages. Available in PDF, EPUB and Kindle. Book excerpt: One of the most exciting areas of cancer research now is the development of agents which can target signal transduction pathways that are activated inappropriately in malignant cells. The understanding of the molecular abnormalities which distinguish malignant cells from their normal counterparts has grown tremendously. This volume summarizes the current research on the role that signal transduction pathways play in the pathogenesis of cancer and how this knowledge may be used to develop the next generation of more effective and less toxic anticancer agents. Series Editor comments: "The biologic behavior of both normal and cancer cells is determined by critical signal transduction pathways. This text provides a comprehensive review of the field. Leading investigators discuss key molecules that may prove to be important diagnostic and/or therapeutic targets."

Download or read book DNA Damage DNA Repair and Disease written by Miral Dizdaroglu and published by Royal Society of Chemistry. This book was released on 2020-11-11 with total page 509 pages. Available in PDF, EPUB and Kindle. Book excerpt: The DNA of all organisms is constantly being damaged by endogenous and exogenous sources. Oxygen metabolism generates reactive species that can damage DNA, proteins and other organic compounds in living cells. Exogenous sources include ionizing and ultraviolet radiations, carcinogenic compounds and environmental toxins among others. The discovery of multiple DNA lesions and DNA repair mechanisms showed the involvement of DNA damage and DNA repair in the pathogenesis of many human diseases, most notably cancer. These books provide a comprehensive overview of the interdisciplinary area of DNA damage and DNA repair, and their relevance to disease pathology. Edited by recognised leaders in the field, this two-volume set is an appealing resource to a variety of readers including chemists, chemical biologists, geneticists, cancer researchers and drug discovery scientists.

Download or read book Epigenetics and Metabolomics written by Paban K. Agrawala and published by Elsevier. This book was released on 2021-08-25 with total page 478 pages. Available in PDF, EPUB and Kindle. Book excerpt: Epigenetics and Metabolomics, a new volume in the Translational Epigenetics series, offers a synthesized discussion of epigenetic control of metabolic activity, and systems-based approaches for better understanding these mechanisms. Over a dozen chapter authors provide an overview of epigenetics in translational medicine and metabolomics techniques, followed by analyses of epigenetic and metabolomic linkage mechanisms likely to result in effective identification of disease biomarkers, as well as new therapies targeting the removal of the inappropriate epigenetic alterations. Epigenetic interventions in cancer, brain damage, and neuroendocrine disease, among other disorders, are discussed in-depth, with an emphasis on exploring next steps for clinical translation and personalized healthcare. Offers a synthesized discussion of epigenetic regulation of metabolic activity and systems-based approaches to power new research Discusses epigenetic control of metabolic pathways and possible therapeutic targets for cancer, neurodegenerative, and neuroendocrine diseases, among others Provides guidance in epigenomics and metabolomic research methodology

Download or read book Primary Central Nervous System Tumors written by Andrew D. Norden and published by Springer Science & Business Media. This book was released on 2010-12-15 with total page 568 pages. Available in PDF, EPUB and Kindle. Book excerpt: This comprehensive, yet practical, text is a ready collection of the most up-to-date information on primary CNS tumors. Authored by a carefully selected group of the world’s leading clinicians and scientists, the book is divided into three sections. The opening chapters cover general principles, including epidemiology, pathogenesis, tumor stem cells, supportive care, complications of therapy, and quality of life. The remaining two sections are comprised of treatment-oriented chapters covering the spectrum of gliomas and rarer tumor types. Each of these chapters presents multi-disciplinary therapeutic approaches and addresses specific disease concerns. Throughout, the authors incorporate the cutting-edge advances in molecular biology and genomics that are revolutionizing neuro-oncology. The result is an important clinical resource which provides evidence-based data and interpretation essential to intelligent therapeutic decision making.

Download or read book Systems Biology of Cancer written by Sam Thiagalingam and published by Cambridge University Press. This book was released on 2015-04-09 with total page 597 pages. Available in PDF, EPUB and Kindle. Book excerpt: An overview of the current systems biology-based knowledge and the experimental approaches for deciphering the biological basis of cancer.

Download or read book DNA Methyltransferases Role and Function written by Albert Jeltsch and published by Springer. This book was released on 2016-11-08 with total page 537 pages. Available in PDF, EPUB and Kindle. Book excerpt: DNA methyltransferases are important enzymes in a broad range of organisms. Dysfunction of DNA methyltransferases in humans leads to many severe diseases, including cancer. This book focuses on the biochemical properties of these enzymes, describing their structures and mechanisms in bacteria, humans and other species, including plants, and also explains the biological processes of reading of DNA methylation and DNA demethylation. It covers many emerging aspects of the biological roles of DNA methylation functioning as an essential epigenetic mark and describes the role of DNA methylation in diseases. Moreover, the book explains modern technologies, like targeted rewriting of DNA methylation by designed DNA methyltransferases, as well as technological applications of DNA methyltransferases in DNA labelling. Finally, the book summarizes recent methods for the analysis of DNA methylation in human DNA. Overall, this book represents a comprehensive state-of-the-art- work and is a must-have for advanced researchers in the field of DNA methylation and epigenetics.

Download or read book Toxicoepigenetics written by Shaun D. McCullough and published by Academic Press. This book was released on 2018-11-02 with total page 430 pages. Available in PDF, EPUB and Kindle. Book excerpt: Toxicoepigenetics: Core Principles and Applications examines the core aspects of epigenetics, including chromatin biology, DNA methylation, and non-coding RNA, as well as fundamental techniques and considerations for studying each of these mechanisms of epigenetic regulation. Although its integration into the field of toxicology is in its infancy, epigenetics have taken center stage in the study of diseases such as cancer, diabetes, and neurodegeneration. Increasing the presence of epigenetics in toxicological research allows for a more in-depth understanding of important aspects of toxicology such as the role of the environment and lifestyle influencing the individual susceptibility to these effects and the trans-generational transmission of these health effects and susceptibilities. Methods chapters are included to help improve efficacy and efficiency of protocols in both the laboratory and the classroom. Toxicoepigenetics: Core Principles and Applications is an essential book for researchers and academics using epigenetics in toxicology research and study. Introduces the fundamental principles and practices for understanding the role of the epigenome in toxicology Presents the foundation of epigenetics for toxicologists with a broad range of backgrounds Discusses the incorporation of epigenetics and epigenomics into current toxicological studies and interpretation of epigenetic data in toxicological applications

Download or read book Leong s Manual of Diagnostic Antibodies for Immunohistology written by Runjan Chetty and published by Cambridge University Press. This book was released on 2016-11-28 with total page 525 pages. Available in PDF, EPUB and Kindle. Book excerpt: Providing a unique A-Z guide to antibodies for immunohistology, this is an indispensable source for pathologists to ensure the correct application of immunohistochemistry in daily practice. Each entry includes commercial sources, clones, descriptions of stained proteins/epitopes, the full staining spectrum of normal and tumor tissues, staining pattern and cellular localization, the range of conditions of immunoreactivity, and pitfalls of the antibody's immunoprofile, giving pathologists a truly thorough quick-reference guide to sources, preparation and applications of specific antibodies. Appendices provide useful quick-reference tables of antibody panels for differential diagnoses, as well as summaries of diagnostic applications. Expanded from previous editions with over forty new entries, this handbook for diagnostic, therapeutic, prognostic and research applications of antibodies is an essential desktop book for practicing pathologists as well as researchers, residents and trainees.

Download or read book Nanobiosensors written by Aiguo Wu and published by John Wiley & Sons. This book was released on 2020-06-02 with total page 412 pages. Available in PDF, EPUB and Kindle. Book excerpt: Containing cutting edge research on the hot topic of nanobiosensor, this book will become highly read Biosensor research has recently re-emerged as most vibrant area in recent years particularly after the advent of novel nanomaterials of multidimensional features and compositions. Nanomaterials of different types and striking properties have played a positive role in giving the boost and accelerated pace to biosensors development technology. Nanobiosensors - From Design to Applications covers several aspects of biosensors beginning from the basic concepts to advanced level research. It will help to bridge the gap between various aspects of biosensors development technology and applications. It covers biosensors related material in broad spectrum such as basic concepts, biosensors & their classification, biomarkers & their role in biosensors, nanostructures-based biosensors, applications of biosensors in human diseases, drug detection, toxins, and smart phone based biosensors. Nanobiosensors - From Design to Applications will prove a source of inspiration for research on biosensors, their local level development and consequently using for practical application in different industries such as food, biomedical diagnosis, pharmaceutics, agriculture, drug discovery, forensics, etc. * Discusses the latest technology and advances in the field of nanobiosensors and their applications in human diseases, drug detection, toxins * Offers a broad and comprehensive view of cutting-edge research on advanced materials such as carbon materials, nitride based nanomaterials, metal and metal oxide based nanomaterials for the fast-developing nanobiosensors research * Goes to a wide scientific and industry audience Nanobiosensors - From Design to Applications is a resource for polymer chemists, spectroscopists, materials scientists, physical chemists, surface chemists, and surface physicists.

Download or read book Cancer RNome Nature Evolution written by Mansi Arora and published by Springer. This book was released on 2018-11-02 with total page 323 pages. Available in PDF, EPUB and Kindle. Book excerpt: In the last decade, researchers working in the field of cancer biology have shifted their focus from genetic defects to epigenetic dysregulation, especially that of non-coding RNAs (ncRNAs). This book encompasses a comprehensive review of the transcriptional landscape of the cell and its involvement in the cancer pathophysiology. The first two chapters elucidate the basics of biosynthesis, mechanism of action and modulation of the epigenetic regulation of gene expression by coding as well as non-coding RNAs. The third chapter discusses the aberrant expression of the cellular RNome in the cancer cells and highlights its role in the orchestration of processes involved in evolution as well as the sustenance of cancer cells. The fourth chapter describes the recent advances in the field of translating the transcriptome into diagnostic/prognostic biomarkers and as targets for novel anti-cancer therapies. The final chapter then reviews the emerging experimental approaches to screen, identify and explore the functions of ncRNAs. Providing valuable insights into the field of RNome in the context of cancer, this book is helpful to students, researchers and clinicians..

Download or read book Diffuse Low Grade Gliomas in Adults written by Hugues Duffau and published by Springer Science & Business Media. This book was released on 2013-03-19 with total page 498 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents the latest research pertaining to the diagnosis, therapy and management of diffuse low-grade gliomas (DLGG) in adults, with a particular focus on the path towards individualised therapy for this kind of tumour. Recent research on the natural history of DLGGs and their interaction with the brain has led to new diagnostic and therapeutic strategies which increase survival and quality of life of the patient, and these methods are described in this book.

Download or read book The Practice of Surgical Pathology written by Diana Weedman Molavi and published by Springer. This book was released on 2017-08-24 with total page 399 pages. Available in PDF, EPUB and Kindle. Book excerpt: In pathology education within North America, there exists a wide gap in the pedagogy between medical school and residency. As a result, the pathology intern often comes into residency unprepared. Completely illustrated in color, this book lays the foundation of practical pathology and provides a scaffold on which to build a knowledge base. It includes basic introductory material and progresses through each organ system. Within each chapter, there is a brief review of salient normal histology, a discussion of typical specimen types, a strategic approach to the specimen, and a discussion of how the multitude of different diagnoses relate to each other.

Download or read book Cancer Cell Metabolism written by and published by . This book was released on 2020 with total page 190 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book illustrates various aspects of cancer cell metabolism, including metabolic regulation in solid tumours vs. non-solid tumours, the molecular pathways involved in its metabolism, and the role of the tumour microenvironment in the regulation of cancer cell metabolism. It summarizes the complexity of cancer cell metabolism in terms of the switch from anaerobic to aerobic glycolysis and how mitochondrial damage promotes aerobic glycolysis in cancer cells. The respective chapters provide the latest information on the metabolic remodelling of cancer cells and elucidate the important role of the signalling pathways in reprogramming of cancer cell metabolism. In addition, the book highlights the role of autophagy in cancer cell metabolism, and how metabolic crosstalk between cancer cells and cancer-associated fibroblasts promotes cancer cell progression. In closing, it summarizes recent advancements in drug development through targeting cancer metabolism.