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Squamous cell carcinoma (SCC) is the most common histological type of cancer in the head and neck region and arises in the epithelial mucosa of the upper aerodigestive tract. Approximately one and a half million people are living with the diagnosis. Despite efforts in prevention and advances in treatment, the 5-year survival rate still lies around 60%, and recurrences and second primary tumors remain a problem. Moreover, treatment responses vary from patient to patient, highlighting the need for individually tailored treatments. To make this possible, biomarkers predicting treatment outcome are needed to better guide treatment decisions. The aim of this thesis was to evaluate the expression of certain proteins and the frequency of certain SNPs (Single nucleotide polymorphisms) in tumor biopsies and cell cultures of head and neck squamous cell carcinomas (HNSCC), and to explore their potential as biomarkers for treatment outcome. Furthermore, we aimed to study the impact of hypoxia on treatment response, epithelial-tomesenchymal transition (EMT), and induction of cancer stem cells (CSC). In papers I and II, we investigated two proteins, survivin and WRAP53?, using immunohistochemistry (IHC) in tumor biopsies from 40 patients categorized as Non-responders or Responders to radiotherapy. High expression of survivin and nuclear expression of WRAP53? were significantly more prevalent in the Responder group. The combination of these two factors correlated strongest to overall survival, but not to a significantly higher extent compared to survivin alone. Moreover, when examined separately, a high percentage of p53-stained cells and the presence of the SNP FGFR4 Gln388Arg correlated to improved overall survival, whereas the SNP XPD Lys751Gln was associated with worse overall survival. The latter three showed no significant correlations to radiotherapy response. In paper III, the two most promising proteins identified in papers I and II were analyzed in a study cohort of 149 tumor biopsies of glottic laryngeal SCC, categorized as T2N0-T3N0. In this patient group, no significant associations between survivin expression and survival could be found. However, expression of cytoplasmic WRAP53? was significantly linked to worse disease-free-survival (DSF) compared to nuclear WRAP53? or negative staining for WRAP53?. Positive expression of p16INK4a was found in 7% of the tumors. The prevalence of p16 INK4a was higher in younger patients (<60) and associated with absence of recurrence and longer DSF. In paper IV, five HNSCC cell lines were cultured in normoxic (20% O2) and hypoxic (1% O2) conditions and changes in treatment response, EMT profile, and expression of CSC markers were examined. As expected, hypoxia induced EMT and to a certain extent expression of CSC markers. Silencing of the hypoxia-inducible-factor-1? (HIF-1?) only partly reversed these effects, suggesting that other mechanisms are involved. Whereas most cell lines became more resistant to treatment in hypoxia, one cell line (LK0412) became more sensitive to cetuximab-treatment in hypoxia, an effect that was revoked by depletion of HIF-1?, suggesting a possible sensitizing effect of HIF-1? to cetuximab-treatment. Taken together, WRAP53? appears to be a promising biomarker candidate for treatment outcome in HNSCC, but further evaluation especially on the subcellular localization of WRAP53? is required. Even though the role of survivin in radiotherapy response in glottic SCC seems to be insignificant, it might have a more important role in other HNSCC subsites. As far as the effects of hypoxia, it appears that hypoxia might have a sensitizing effect on cetuximab-treatment in certain cases, which seems to be HIF1-? –dependent. Further studies are required to clarify the importance of this observation.
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..
Completely revised new edition of the premier reference on pediatric liver disease. Liver Disease in Children, 3rd Edition provides authoritative coverage of every aspect of liver disease affecting infants, children, and adolescents. The book offers an integrated approach to the science and clinical practice of pediatric hepatology and charts the substantial progress in understanding and treating these diseases. Chapters are written by international experts and address the unique pathophysiology, manifestations, and management of these disorders in the pediatric population. The third edition has been thoroughly updated and features new contributions on liver development, cholestatic and autoimmune disorders, fatty liver disease, and inborn errors of metabolism. With the continued evolution of pediatric hepatology as a discipline, this text remains an essential reference for all physicians involved in the care of children with liver disease.
Third in a series of textbooks on pediatric disease primarily based on annual seminars held at the Gant in Aspen, Colorado as part of the Aspen conference on Pediatric Diseases, directed by the Institute for Pediatric Medical Education founded in 1981.
In the last decade there has been a growing interest in the study of the interactions between the heart and the brain, especially in the field of cerebral ischemia. The interactions between cardiovascular and cerebrovascular diseases are of relevance not only for research investigation, but also for clinical implications in the daily clinical practice. i.e. A wealth of information has been gathered particularly on three topics, cardiovascular consequences of cerebral injuries, cardioembolic stroke, and association of carotid and coronary artery disease. The available information, however, is still sparse and fragmentary mainly because of the lack of commun ication between neurologists and cardiologists. With the aim of improving communication between several disciplines and technologies, we started to organize since 1987 in Bologna, Italy, an international Symposium on heart brain interactions to be held every 3 years. Our intention was to gather prominent clinicians and researchers from outstanding cardiologic and neuro logic institutions actively involved in the study of heart-brain interactions. The ambitious goal has been to fit different pieces of information like in a puzzle. This book originates from the contributions presented at the 2nd Sympo sium which was held in Bologna on November 30-December 1, 1990. The book is subdivided into three sections: I cardiovascular consequences of cerebral damage, II cardiogenic cerebral ischemia, III cerebrovascular and coronary artery disease.
The book discusses cancer and the potential use of phytochemicals as cancer therapeutics. It begins with the basics of cancer, including the definition, types, etiology and molecular mechanisms involved, before discussing the fundamentals of diagnosis, treatment and associated problems as well as remedial measures. Since cancer is not a single disease, and the mechanisms of carcinogenesis are different for different cancers, it examines the genes and proteins involved in carcinogenesis, and signal transduction pathways for each individual cancer type. Further, the book reviews the latest research on phytochemicals for cancer treatment, highlighting their anti-cancer properties, sources, structure, active biomolecules and probable mechanisms of action, and describing their biochemical properties in the context of cancer prevention and treatment.
DNA Repair and Cancer Therapy: Molecular Targets and Clinical Applications, Second Edition provides a comprehensive and timely reference that focuses on the translational and clinical use of DNA repair as a target area for the development of diagnostic biomarkers and the enhancement of cancer treatment. Experts on DNA repair proteins from all areas of cancer biology research take readers from bench research to new therapeutic approaches. This book provides a detailed discussion of combination therapies, in other words, how the inhibition of repair pathways can be coupled with chemotherapy, radiation, or DNA damaging drugs. Newer areas in this edition include the role of DNA repair in chemotherapy induced peripheral neuropathy, radiation DNA damage, Fanconi anemia cross-link repair, translesion DNA polymerases, BRCA1-BRCA2 pathway for HR and synthetic lethality, and mechanisms of resistance to clinical PARP inhibitors. - Provides a comprehensive overview of the basic and translational research in DNA repair as a cancer therapeutic target - Includes timely updates from the earlier edition, including Fanconi Anemia cross-link repair, translesion DNA polymerases, chemotherapy induced peripheral neuropathy, and many other new areas within DNA repair and cancer therapy - Saves academic, medical, and pharma researchers time by allowing them to quickly access the very latest details on DNA repair and cancer therapy - Assists researchers and research clinicians in understanding the importance of the breakthroughs that are contributing to advances in disease-specific research
Pharmacoepigenetics provides a comprehensive volume on the role of epigenetics and epigenomics in drug discovery and development, providing a detailed, but accessible, view of the field, from basic principles, to applications in disease therapeutics. Leading international researchers from across academia, clinical settings and the pharmaceutical industry discuss the influence of epigenetics and epigenomics in human pathology, epigenetic biomarkers for disease prediction, diagnosis, and treatment, current epigenetic drugs, and the application of epigenetic procedures in drug development. Throughout the book, chapter authors offer a balanced and objective discussion of the future of pharmacoepigenetics and its crucial contribution to the growth of precision and personalized medicine. - Fully examines the influence of epigenetics and epigenomics in human pathology, epigenetic biomarkers for disease prediction, diagnosis, treatment, current epigenetic drugs and the application of epigenetic procedures in drug development - Features chapter contributions from leading international researchers in academia, clinical settings and the pharmaceutical industry - Instructs researchers, students and clinicians on how to better interpret and employ pharmacoepigenetics in drug development, efficiency and safety - Provides a balanced and objective discussion of the future of pharmacoepigenetics and its crucial role in precision medicine
The increase of immigrant population in developed countries (mainly in Europe and North America) together with an important increase of international travel worldwide are the two most important causes that have contributed to the introduction and diagnosis of imported/tropical infectious diseases in these countries. These factors have had an important impact in developed countries in both social and economic aspects. Imported Infectious Diseases focuses not only on describing the infections, but also in evaluating the current epidemiology, the economic and social impact and the possibility to apply immunization measures and vaccines. The main purpose of this book is to give an overview of the current most important and frequent imported infectious diseases in developed countries. The first chapter informs about the medical services that are being offered to the immigrants in the main developed countries depending on the legal situation. Following chapters describe the main surveillance systems for these kinds of diseases, mainly in Europe and North America. Finally, remaining chapters contain sections on epidemiology, pathogenesis, clinical features, diagnosis, treatment and prevention.