Retinoblastoma

Molecular Basis of Cancer

Cancer is a disease that arises from the uncontrolled growth of cells due to genetic mutations and epigenetic changes. Molecular biology has provided valuable insights into cancer development and progression mechanisms. Cancer cells have alterations in the genes that regulate cell growth, division, and death, leading to the accumulation of mutations that confer a survival advantage. Oncogenes promote cell growth and division, while tumour suppressor genes inhibit cell proliferation and induce cell death. Alterations in these genes and changes in DNA methylation and histone modifications lead to the dysregulation of cell signalling pathways, which contribute to cancer development. In addition, the tumour microenvironment plays a critical role in cancer progression by providing growth factors, cytokines, and extracellular matrix components that promote tumour growth and invasion. Molecular biology techniques such as DNA sequencing, gene expression profiling, and epigenetic analysis have facilitated the identification of driver mutations and key molecular pathways involved in cancer development, leading to targeted therapies that exploit these vulnerabilities. Understanding the molecular basis of cancer can revolutionize cancer diagnosis, treatment, and prevention.

Genome Editing and Genetically Engineered Bacteria for Bioremediation of Heavy Metals

Genetic engineering involves the manipulation of DNA to either improve, enhance or repair a function by using recombinant DNA technology, which has contributed greatly to the fields of medicine and agriculture. In recent times, the CRISPR-Cas system of gene editing has come to the forefront of genome engineering, transforming disease treatment strategies and the production of modified crops. Industrial activities cause environmental pollution by releasing heavy metal-containing xenobiotic compounds into the environment and affect animal health by causing organ dysfunction and even cancer. Although plants utilize heavy metals from soil in small quantities for their growth, excessive exposure leads to disruption of plant cell machinery and reduces productivity. Similarly, heavy metals degrade soil health by interfering with microbial processes that contribute to soil fertility. Apart from existing methods available for the remediation of contaminated sites, bioremediation is emerging as a potent technique due to its high efficacy, cost-effectiveness and ecofriendly nature. Microbes possess a number of physiological and biochemical properties that have been exploited for the removal and detoxification of metal pollutants. This chapter elaborates on the approaches of gene editing and the development of genetically engineered bacteria to modify the expression of specific genes coding for enzymes that take part in the degradative or detoxification pathway of metals and xenobiotic compounds. It is crucial to address the scope as well as limitations involved in the use of genetically engineered microbes to ensure a safe and cost-effective method for the bioremediation of heavy metal contaminants.

Animal Models in Dentistry

Dentistry is a medical specialty that deals with teeth and gums, and animal models play an important part in its research and teaching. The use of animal models dates back centuries, and animals such as dogs, cats, rabbits, and horses have been utilized to investigate dental diseases and the anatomy and function of teeth. The selection criteria for animal models include their human-like physiology, the accessibility of relevant genetic resources, and usability and affordability. Animals are employed for research on various dental conditions, such as periodontal disease, dental caries, and oral cancer. Periodontitis is a dangerous gum infection that can lead to tooth loss, frequently brought on by a lack of oral hygiene. Dental caries are studied in animal models, and new preventative and therapeutic methods are explored. Oral cancer is studied, and its course and therapies are tested using animal models. The use of test methods specified by the International Organization for Standardization has helped to evaluate the biological reaction of various dental substances. Hamsters, which are usually correlated to mice, are employed to examine the features of periodontal and cariogenic diseases. Disease transmission can be studied in these animals as well. The dog periodontium is the one that most closely resembles that of humans. Canine periodontal disease is highly reflective of its human counterpart, and gingival recession is a hallmark of periodontitis in dogs, as it is in humans. Although animal models have been instrumental in the field of dentistry, there is not a single animal model that adequately replicates human soft and hard tissues, and it is crucial to choose an experimental model in light of the goals of the study.

Animal Models for Cancer

Cancer is a complex multifactorial disease that affects many people worldwide. Animal models play an important role in deciphering cancer biology and developing new therapies. The animal models widely used in cancer research include tumor xenografts, genetically engineered mice, chemically induced models, and spontaneous tumor models. These models provide a controlled environment to study cancer progression, the interaction of cancer and the immune system, and the effectiveness of new therapies. Although animal models have several advantages, it is important to identify their limitations and use them in conjunction with other preclinical models, such as in-vitro cell culture and patient-derived xenografts, to ensure that results are transferable to humans. In this chapter, we discuss the importance of animal models in cancer research, the different types of animal models, and their advantages and disadvantages. We also provide some examples of animal models used in cancer research. Collectively, animal models have been invaluable in advancing our understanding of cancer and will continue to be important tools in the development of new therapies.

Cancer Pathophysiology

Cancer prevalence across the globe has increased substantially in the last two decades despite significant progress in inpatient care. Cancer, a multifactorial disease, evolved several theories to establish pathophysiological conditions. Uncontrolled proliferation, dedifferentiation and metastasis mainly describe the cancer progression, which must be characterized by cellular and molecular changes. Understanding these processes helps devise the strategy for effectively delivering the drugs to the target sites. The present review described the essential features of cancer pathophysiology and challenges to achieving drug concentration in the targeted area.

Stem Cell Models: Novel Experimental Approach for Testable Alternatives against Therapy-resistant Breast and Colon Cancer

Breast and colon cancer represent the leading causes of mortality in developed countries. The treatment options for these organ site cancers differ depending on the status of hormone/growth factor receptors in molecular subtypes that exhibit altered expression of oncogenes/tumor suppressor genes and growth factormediated molecular pathways. Conventional cytotoxic chemo-endocrine therapy traditionally includes the use of anthracyclin, taxol, cisplatin, anti-estrogens, antifolates and DNA anti-metabolites. Additionally, the use of molecular pathway-specific small molecule inhibitors represents evidence-based targeted therapy. Long-term conventional or targeted therapy using pharmacological agents is frequently associated with systemic toxicity, acquired tumor resistance and the emergence of drug-resistant cancer stem cells. These limitations are associated with the progression of the therapyresistant disease.

Natural products such as dietary phytochemicals, their respective bioactive agents, botanicals, nutraceuticals and nutritional herbs are widely used in complementary and alternative medicine in women for estrogen-related issues, osteoporosis and breast diseases. Unlike conventional or targeted chemo-endocrine therapeutics, natural products, mainly due to their low systemic toxicity, may not lead to acquired tumor resistance and therefore, represent testable alternatives against therapy-resistant cancer.

These aspects emphasize a need to develop reliable experimental approaches, and specific and sensitive biomarkers that facilitate the identification of effective testable alternatives against therapy-resistant cancer.

Models for drug-resistant stem cells have been developed and characterized from the parental breast and colon carcinoma-derived cell lines, as well as from the cell lines derived from genetically predisposed colon cancer models. These stem cell models are characterized by the quantifiable expression status of select stem cell-specific cellular and molecular markers.

Mechanistically distinct natural products have documented growth-inhibitory effects on parental cell lines. Some of these agents also exhibit stem cell targeted growth inhibitory efficacy.

Recognizing clinical evidence for the role of estrogens in breast and colon cancer, future investigations include the development of tumor organoid models of therapyresistant breast and colon cancer from female patient-derived xenografts. These investigations support a scientifically robust rationale to provide clinical translatability for patient-derived preclinical data.

This chapter summarizes the evidence relevant to experimental models systems, natural products and efficacy of lead compounds as stem cell-targeted testable alternatives against breast and colon cancer. Collectively, discussed evidence and its clinical relevance support the hypothesis that natural products may benefit patients that are diagnosed for therapy resistant cancers.

Chromosome 21

The significance of human chromosome 21 is that the trisomy of human chromosome 21 causes Down syndrome in children. There are about 235 protein-coding genes on chromosome 21. Mutations like translocation in human chromosome 21 cause different conditions such as partial monosomy 21, core binding factor acute myeloid leukemia, ring chromosome 21, and other types of cancers such as acute lymphoblastic leukemia. Mutation in the DSCAM gene causes mental retardation and facial deformities in down syndrome. The human chromosome 21 also comprises the APP gene, where the expression of the gene causes Alzheimer's disease. The genes that are involved in causing Down syndrome and Alzheimer's diseases are also involved in cancer. This chapter discusses 63 genes of human chromosome 21 that are involved in different types of cancer.

Chromosome 20

Over the years, many scientists and doctors have been treating the deadly disease of cancer but are not able to find a permanent treatment for this disease. Also, sometimes it becomes very difficult to understand the mechanisms and causes of cancer as it is a very complex disease that involves many biological processes. Due to the redundancy in our biological system, cancer progression becomes very easy, thus making it difficult to cure. To find the root cause of this disease, we should know what genetic alterations are undergoing, which is causing cancer to progress, and know who is participating in these alterations, like proteins, signaling pathways, or genes. Cancer is caused due to various reasons; it can be due to genetics but mostly due to carcinogens, causing mutations in the genes, thereby making them an oncogene. The Proto-oncogenes are those genes that usually assist the growth of tumor cells. The alteration, mutation, or increased copy number of a particular gene may turn into a proto-oncogene which could end up completely activated or turned on. Many Tumor-causing alterations or mutations related to oncogenes are usually acquired and not inherited. These tumor-causing mutations often actuate oncogenes via chromosomal rearrangement, or alterations in the chromosome, which sequestrates one gene after another, thereby permitting the first gene to prompt the alternative. Search which genes are involved in different cancer types would help scientists proceed with new methods for finding a cure for this disease. This article will depict which genes and their location on which chromosomes, specifically on chromosome 20, are related to different types of cancer.

Chromosome 18

Cancer is an abnormal or unusual growth of cells in the body with invasive and migrating potential. It leads to loss of function, weakens the immune system, and is the second leading cause of death worldwide. This makes it important to eliminate the disease. Genetic predisposition imposes a high relative risk for several kinds of cancer. Inherited genetic mutations are responsible for causing 5 to 10 percent of all cancers. Scientists have investigated mutations in specific genes with more than 50 hereditary cancer syndromes. For this, chromosome 18 was explored for its genes associated with cancer and this study unveiled 30 genes involved in causing cancer. Of these, the genes DCC, EPB41L3, MBD1 PHLPP1, and RBBP8 were the potential tumor suppressors. This chromosome consists of the target genes of the transforming growth factor-beta (TGF-β) signaling pathway. The SMAD family genes (SMAD4, SMAD7, and SMAD2) are encoded by this chromosome, of which SMAD4 acts as a tumor suppressor. SERPINB5 and TCF-4 were the potential oncogenes. The enzyme coded by TYMS was a potential therapeutic target for chemotherapy. Several fusion genes of this chromosome (SS18-SSX2B, SS18-SSX2, and SS18-SSX4) have been identified to cause cancer. Therefore, this chapter provides a summary of the genes in chromosome 18 that are involved in the initiation and proliferation of cancer and provides an insight into the potential biomarkers and therapeutic targets for clinical application to develop a cancer-free world.

Chromosome 16

Cancer is a heterogeneous disorder with invasive and metastatic potential. It is a deadly disorder affecting 1 in 6 people worldwide. Hence, it is important to eliminate the disease. Genetic alterations remain an underlying cause of cancer, and several gene mutations were involved in causing different types of cancer. Recently, researchers have been investigating the role of genetic mutations in causing cancer. For this reason, the genes associated with chromosome 16 were investigated for their role in causing cancer. This study revealed 70 genes associated with cancer. Of which, the cadherin genes (CDH11, CDH13, and CDH1), AXIN-1, ANKRD11, BANP, CYLD, CBFA2T3, IR8, MVP, MT1F, NQO1 and PYCARD was the tumor suppressor, and the gene MSLN is the potential oncogene. CBFB and MYH11 are well-known fusion genes associated with this chromosome. Loss of heterogeneity was noted in the q arm of this chromosome. The chromosome translocations, t (16;16) (16) (p13q22), t (16;21) (21) (p11;q22), t (12;16) (q13; p13; p11), t(16;21) (p11;q22) and t(7;16) (q33; p11) led to the development of acute myeloid leukemia, leukemia, and sarcoma. Several other genes associated with chromosome 16 responsible for cancer initiation and proliferation are summarized in this chapter. A novel insight into the genetic biomarkers and therapeutic targets has been provided to develop potential therapeutic strategies against cancer.

Chromosome 15

The genomic alteration at chromosome 15 has been widely recognized as the utmost significant and prevalent alteration in several cancers, including non-small-cell lung cancer, breast cancer, ovarian cancer, prostate cancer, gastrointestinal cancer, acute lymphoblastic leukemia, colorectal carcinoma, hepatocellular carcinoma, myeloma, pituitary adenomas, etc. Emerging reports suggest that the abnormalities of prime genes in chromosome 15 have drastic effects on tumor development and progression, and can be candidate biomarkers of disease prognosis, disease progression, and response to treatment. The translocations involving chromosome 15 and other chromosomes have been found in tumors, including mucoepidermoid carcinomas, mixed-lineage leukemia, colorectal cancer, pancreatic cancer, sarcoma, lung adenocarcinoma, melanoma, brain cancer, cholangiocarcinoma, spitz tumor, congenital mesoblastic nephroma, papillary thyroid cancer, pontine glioma tumors, and acute promyelocytic leukemia. The tumor suppressor genes such as C15orf65, CSK, CRABP1, DAPK2, FES, GREM1, KNSTRN, NEDD4-1, NTRK3, PML, SPRED1, TPM1, and TCF12 under chromosome 15 play a crucial role by enhancing cellular growth, proliferation, migration, invasion, metastasis, cellular differentiation, and development in various cancer, including colorectal cancer, acute promyelocytic leukemia, myeloid leukemia, breast cancer, thyroid carcinoma, glioblastoma, intrahepatic cholangiocarcinoma, chondrosarcoma, cartilaginous cancer, Squamous cell carcinoma, non- small-cell lung carcinomas, mucosal melanoma, and oral squamous cell carcinoma. Chapter 15 discusses the significance of each important gene under chromosome 15 in mediating oncogenesis. The elevated or attenuated expression levels of these cardinal genes can either act as an oncogene or a tumor suppressor. Thus, shedding light on these genes would be a game changer in the field of cancer genetics and theragnostic.

Chromosome 14

Cancer genetics has focused on several mutational events within a tumor cell for many years. Recently, the study on cancer genetics has been widened by concentrating on the importance of intercellular communication and epigenetic events causing tumor progression and development. The translocation of genetic material betwixt chromosome 14 and other chromosomes may engender the formation of various types of tumors. Recent studies emphasize that these chief translocations between two chromosomes may disrupt the genes crucial for controlling cell growth and cell division. The translocations involving chromosome-14 and other chromosomes have been found in tumors including acute myeloid Leukemia, acute lymphoblastic leukemia, acute bilineal leukemia, follicular lymphoma, small cell lung cancer, non-Hodgkin’s lymphoma, Burkitt lymphoma and multiple myeloma. The tumor suppressor genes, such as ARID4A, ARID4B, BCL11B, BMP4, CCNB1IP1, CEBPE, DICER1, DLK1, ESR2, FOXN3, HIF1A, MAX, MEG3, NDRG2 and TTF-1/NKX2-1 under chromosome 14, play a hypercritical role by enhancing cellular differentiation, migration, proliferation, metastasis, invasion, cellular growth, and development in several tumors, including breast cancer, pancreatic tumor, osteosarcoma, lung cancer, endocrine tumor, T-ALL, cystic nephroma, Hodgkin lymphoma, pleuropulmonary blastomas, Sertoli Leydig ovarian tumors and rhabdomyosarcoma. Chapter 14 meticulously discusses the importance of each predominant gene under chromosome 14 in mediating tumorigenesis. In cancer genetics, these cardinal genes play a crucial role by acting as an oncogene or a tumor suppressor in several cancers. Thus, targeting these tumor-causing genes would provide a breakthrough in cancer biology and oncology when concerned with future perspectives.

Chromosome 13

Chromosome 13 represents around 4 percent of the total cellular DNA with 115 million base pairs. It is home to various tumor suppressors and oncogenes, such as ADP ribosylation factors like GTPase-11 (ARL11), Retinoblastoma-1 (RB1), Ras-related protein Rap-2a (RAP2A), etc. Most of the somatic mutations in this chromosome lead to cancer development. Further, deletion in this chromosome has been reported to support the cancer of leukemias, lymphomas, etc. In this chapter, we have tried to list cancer-causing genes and their possible oncogenesis in cancer development.

Plant Cardenolides: Multifunctional Medicinal Agents

Cardenolides are a class of compounds steroidal in nature, belonging to the cardiac glycoside group of secondary metabolites. They consist of a sugar part and a non-sugar part consisting of a steroidal cyclopentanoperhydrophenanthrene ring with lactone substitution at the β-17 position. Cardenolides are found in angiosperm plant families like Plantiginaceae, Asclepiadaceae, Apocynaceae, Brassicaceae, Cruciferae, Liliaceae, Moraceae, Ranunculaceae, and Scrophulariaceae. These include some important glycosides, such as digitoxin, digoxin, Ouabain, Calotropin, etc. with profound pharmacological potential. Moreover, cardenolides have toxic effects for which these have been used in poison arrows and for self-harm purposes. Traditionally, these were used to treat congestive heart failure. However, recently they have emerged as promising agents to exhibit anticancer, antiviral, anti-inflammatory, neuroprotective, and various other therapeutic roles. Cardenolides like Digoxin and Digitoxin have been used in the treatment of heart failure and atrial fibrillation. Toxicarioside A, and Calotropin have been reported to suppress tumor growth and are used as anticancer agents, Strophalloside and Oubain are reported to be involved in apoptosis. Oleandrin is an antiproliferative agent and can inhibit IL-8 which is responsible for cystic fibrosis.

Chromosome 6

Chromosome 6 is among the 23 pairs of chromosomes in humans and it spans about 170 million base pairs. Several cancer genes have been identified to have a role in cancer development. Cancer is also a genetic disease caused due to changes in the genes that control cell function, such as cell division and cell growth. Most of these cancer genes either act as tumor suppressors or possess an oncogenic potential. Oncogenes like ROS1, MYB, HMGA1, etc., induce tumorigenesis by playing a role in DNA repair, replication, transcriptional regulation, and mRNA splicing. When these genes are highly expressed, they result in the transformation of normal cells to malignant cells; on the other side, tumor suppressor genes like IGF2R, AIM1, IRF4, etc., reduce tumorigenicity and invasive potential. Thus, reduced expression of these genes due to loss of heterozygosity, deletion or any epigenetic modifications can induce tumor formation. Also, some genes can either suppress or induce tumor formation given the cellular location and condition, such as CCN2, TNF, etc. Along with these, different types of structural abnormalities can be observed on chromosome 6, such as chromosomal translocation, deletion, duplication, and inversion. These abnormalities on both p and q arms have been known to contribute to the growth and spread of cancer by impacting the expression of cancer genes. Aberrant expression of the genes can also be influenced by fusions, missense mutations, non-missense mutations, silent mutations, frame-shift deletions, and insertion at the molecular level. Some genes can maintain stem-cell-like properties by regulating the expression of cell surface markers like Oct4, Nanog, Sox4, etc. This chapter explains important cancer genes, genetic mutations, and gene variations that can influence the risk of having cancer and induces cancer formation.

Probiotics-based Anticancer Immunity In Cervical Cancer

In the recent past, many investigations have been directed toward finding the possible relationship between probiotic preventive-therapeutic effects and different cancers. Among different cancers, human papillomavirus (HPV)-induced cancer is the third most frequent cancer among women, resulting in being the second cause of death worldwide. Current treatments, such as chemotherapy and radiotherapy, have been shown to have some limitations, and the available effective cervical vaccines are costly, particularly in developing countries. Therefore, the researchers seek alternatives, such as natural components, as a new approach to treating and cure HPVinduced cancer. Among several natural components, probiotics have increasingly gained more attention due to the probiotic-associated immunomodulation and therapeutic efficacy shown in several studies, as well as their lower risk for human health. In this chapter, we have reviewed the association between probiotics and cervical cancer and discussed how probiotics could exert their effects to suppress or even inhibit the growth of cervical tumors, preclinically or clinically. The different aspects of probiotic application have been precisely studied to assess the potential of probiotics in improving or treating HPV-induced cancer. In addition, the effects of probiotics on immune responses have been described.

Probiotics Based Anticancer Immunity in Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer, originating in the colon and rectal region, leading to abnormal growth in the colon or rectal region. The gut microbiota plays a critical role in the maintenance of gut homeostasis, and dysbiosis in the gut microbiota has been associated with CRC pathogenesis. Probiotics can manipulate the gut microbiota, which can be effective in CRC treatment. Additionally, probiotics, through the modulation of host immune response, inhibition of tumor growth, reduction of microbial infection, inhibition of cancerogenic compounds, and regulation of apoptosis, can become a novel therapeutic option for the prevention and treatment of CRC. Therefore, this chapter mainly focuses on the mechanisms of probiotics-based anticancer immunity in CRC, so the existing knowledge could help in developing a safe and effective treatment for CRC.

Treatment of Cancer

Surgery, the oldest cancer treatment, is a mainstay in the cure and control of most cancers. Indeed, for many patients, surgery, usually in combination with chemotherapy, is the only hope for long-term survival or cure. But surgery can do more than treat cancer; it can also diagnose cancer (diagnostic surgery), investigate cancer further (staging surgery), debulk tumors (debulking surgery), relieve pain (palliative surgery), prevent cancer from occurring in the first place (preventative surgery), restore the appearance or function of the body after cancer surgery (reconstructive surgery) and help medical staff to administer chemotherapy (access surgery). This chapter looks at each of these purposes of cancer surgery in detail.

Biology of Cancer

Loss of genomic stability in the cell due to defects in the checkpoint of DNA damage, mitotic checkpoint, and telomere maintenance led to increased incidences of base pair alterations. Therefore, that genomic instability plays a critical role in tumor initiation and progression. Tumor progression requires a dynamic tumor/normal exchange in their microenvironment to support tumor growth. The histological alteration seen in the tumor at early stages confirms that the surface between the epithelium and the stroma undergoes progressive disturbance. Tumor progression is also affected by the immune system in which chronic inflammations promote the growth of tumor. Tumor cells experience altered metabolic profiling to support their growth. Cancer cells are characterized by uncontrolled cell division. For that, they utilize glucose as a source of energy to help them grow faster than normal cells. Hence, Glycolysis is a key metabolomics pathway consumed at a high rate during carcinogenesis.

Exogenous Factors and Cancer

The causation of cancer, whether exogenous or endogenous, is a cornerstone of cancer prevention and treatment. Many intrinsic factors are discussed in other chapters of this book; this chapter will shed light on exogenous factors influencing cancer with detailed specific examples of microbial, physical and chemical factors. Microbial role in cancer has been debated over many centuries, whether as an antagonist or a cause, since Imhotep’s time through the mid-17th century when cancer was considered contagious, and later cancer hospitals were forcefully moved out of the cities as isolation camps. There are now vivid evidences that specific microbial pathogens are causing up to 25% of cancer cases (lymphoma, solid or others), and in some cases, a single pathogen was found in association with many types of cancer, such as HPV and EBV, to a lesser extent. Also, several non-biological factors are classified as carcinogens as humans are exposed to millions of chemicals whether in environment or smoke processed food.

Implication of Biosensors For Cancer Diagnosis And Therapeutics

“Caution is the parent of Safety”. Early-stage diagnosis of Cancer can provide better medicinal therapeutic responses. Currently, a majority of cancer is diagnosed after having metastasized throughout the body. This led to the urgent requirement for potent and precise cancer detection methods for clinical diagnosis. Over the last several decades, the majority of researchers have concentrated their efforts on developing a potential rapid detection technique based on Biosensor technology for a variety of frightening human health-related disorders, such as cardiovascular disease, cancer, diabetes, and others. Significant advances were made in a wide range of fields attributed to the designed techniques having enhanced sensitivity, specificity, and repeatability. The development of diagnostic treatments in medicine was aided by noteworthy advancements in other scientific fields, including genetics, chemistry, micro-electrical engineering, and computational biology. As a result, efficient, accurate, rapid, and steady sensing platforms have been successfully developed for specific and ultrasensitive biomarker-based disease diagnostics. Biosensors are analytical devices designed to detect biological analytes by converting biological entities’ responses (DNA, RNA, Protein) into potent electrical signals. The biosensor device combines a biological component with a physiochemical detector for sensing an analyte (biological samples). The discovery of the Biosensor boosted the potential clinical diagnosis of cancer at a large scale. Biosensors can be designed to detect emerging cancer biomarkers and determine drug efficacy at various target sites. Biosensor technology has the potential to be used as a diagnostic tool for accurate and impressive cancer cell imaging, tracking cancer cell angiogenesis and metastasis, and evaluating the efficacy of treatment for the disease. This chapter will provide a quick overview of the challenges facing the early diagnosis of cancer, get through the depth of how biosensor technology may be used as a reliable diagnostic tool, and highlight potential uses for biosensor technology in the future.

Protein Cancer Biomarkers

Cancer is one of the leading causes of death worldwide and it is becoming increasingly important to be able to efficiently identify and map the progression of cancers. The study of the diagnostic, predictive and prognostic value of protein biomarkers has become one of the main aspects at the forefront of cancer research. The diversity of various biomarkers for different cancers and their varying roles in each disease presents a continual challenge for researchers to understand, with new biomarkers still being discovered today. Understanding the role of protein biomarkers ensures patients are diagnosed with greater confidence and helps clinicians with treatment regimes. This chapter aims to discuss the clinical significance of various protein biomarkers in terms of their diagnostic, prognostic, and predictive value in the treatment of their respective cancers.

DNA Methylation Landscapes in Cancer and Non-Cancer Cells

Epigenetic modifications are heritable changes to gene expression without physical changes to the actual DNA sequence. The most widely studied epigenetic modification is DNA methylation, as it is influenced by aging, diet, diseases and the environment. DNA methylation involves direct chemical modification to the DNA and plays an important role in gene regulation by preventing proteins from binding to certain regions of the DNA, which causes these regions to be repressed. It is essential for normal development, cell differentiation and regulation of cellular biology. The DNA methylation landscape of each unique cell type helps to determine which genes are expressed and silenced. It is well known today that the accumulation of both genetic and epigenetic abnormalities contributes to the development of cancers. Aberrant DNA methylation is a hallmark of cancer. During cancer development and progression, the methylation landscape undergoes aberrant remodelling. Recently within cancer research, the advancements in DNA methylation mapping technologies have enabled methylation landscapes to be studied in greater detail, sparking new interest in how the methylation landscape undergoes a change in cancer and possible applications of DNA methylation. This chapter focuses on reviewing DNA methylation landscapes in normal cells and then how they are altered in cancer. It also discusses the applications of DNA methylation as cancer biomarkers.

Subject Index

Preimplantation, Prenatal, and Postnatal Diagnosis

Pre-implantation genetic diagnosis (PGD) is a practical alternate evolving approach to prenatal diagnosis and termination of pregnancies in families with a high risk of Mendelian monogenetic and polygenetic disorders. Pre-implantation genetic diagnosis testing is continuing to extend immensely, along with a novel genetic analysis and in vitro fertilization approaches are in practice in the medical field throughout the world. However, PGD is regarded as ethically sensitive because repetitive termination of pregnancy causes huge psychological effects on the couples, and also because the low rate of pregnancy and birth makes it unreliable compared to prenatal testing. But it is also helpful in achieving additional goals e.g., improved embryo and gender selection, overcoming the chances of birth of a child with an unknown genetic defect, better understanding of epigenomic regulations and reduction in the monetary burden of society. This chapter focuses on PGD, its procedure, utility and advantages, goals and objectives and the various issues surrounding it. We also discuss the future of this technology at the end of the chapter

Subject Index

Heterocyclic Anti-cancer Compounds Derived from Natural Sources with their Mechanism of Action

The variety of natural compounds is indispensable due to their mechanism of action. For many years, natural compounds have been used to develop new classes of chemotherapeutic agents. Chemotherapeutic agents derived and synthesised from natural sources could be the best possible alternatives to minimise the harmful aftereffects of conventionally used agents against cancer, especially oral and maxillofacial carcinoma and tumors. The proposed chapter concentrates on recent research on various classes of natural scaffolds and their analogues that possess potent antitumor activity. Moreover, we would like to provide an analysis of preclinical and/or clinically investigated natural compounds. These compounds and their synthetic heterocyclic analogues were found to be obtained through bioactivity and mechanism of actiondirected isolation and characterization, conjoined with modification using rational drug design-based approaches and analogue synthesis. Structure-activity relationships, structural change, and molecular mechanisms of action will all be examined.

Management of Colorectal Cancer

Management of colorectal cancer is a very important part of treatment as improper procedures may cause certain complications. Many decisions regarding the treatment depend on the condition of the tumour and the patient, and also the focus is on the treatment to be perform without complications. Management is done by first preparing the patient with different procedures, like stomal therapy, bowel preparation, or nutritional intervention. Then, the tumour is further evaluated, and accordingly, the treatment option is selected. Possible treatment options could be electrocoagulation, touch radiotherapy, local excision with or without neoadjuvant/adjuvant therapy; they all are local treatment methods for rectal cancer and endoscopic treatment. The results may vary with the selection of the procedure and the prognosis.

Phytochemistry and Pharmacology of Terminalia chebula: An Update

Various plants and shrubs with enormous medicinal values are easily found in India. These are mostly used in routine home remedies and the treatment of various diseases or ailments. Since the ancient era, medicinal plants are being used in various traditional systems of medicine to treat minor to major diseases or disorders. Considering their valuable contribution at various levels of treatment, these medicinal plants have gained importance and emerged as one of the most cost-effective remedies in the current health care system. Ayurveda, an ancient system of Indian medicine, has mentioned several important medicinal plants; out of all these, Terminalia chebula has owned its importance because of its phytoconstituents and potent action on enormous diseases. It is also an important part of Triphala churna, which is one of the important formulations in the Ayurvedic system of medicine. The current review focuses on the phytochemistry and pharmacological effects of Terminalia chebula. The literature search was performed using various datasets like EBSCO, PubMed, Scopus, ProQuest, and selected websites, such as the World Health Organization (WHO) and the National Institutes of Health (NIH). Terminalia chebula shows the presence of tannins like ellagic acid, gallic acid, ethyl gallate, chebulinic acid, tannic acid, chebulin, arjungenin, arjunglucoside I, terflavin A, punicalagin, and luteolin, which is mainly responsible for showing their pharmacological effects. The various parts of the plant have been reported for the treatment of various ailments. It has laxative, antiseptic, antidiabetic, and hepatoprotective properties. It is also used in the treatment of upper respiratory tract infections and bronchitis. Half ripe fruits are used as purgative and ripe fruit as tonic, astringent, antipyretic, expectorant, dyspepsia, diarrhoea, allergic eruptions, biliousness, cough, and leprosy. The dry powder form of fruit is used for emesis, hoarseness of voice, and worm infestation, as an anthelmintic, asthma, useful in hepatitis, eye diseases, and piles. Kernels of Terminalia chebula have been reported as anodyne.
Kernel oil has been reported for its purgative action. Gum of the bark is a painkiller and laxative. In conclusion, Terminalia chebula contains important phytochemicals like tannins, gallic acid, and ellagic acid. These indicate that the plant and its different parts have a wide range of pharmacological effects. This book chapter provides detailed information on the recent studies for pharmacological activities of T. chebula and its active components.

Quercetin, A Flavonoid with Remarkable Anticancer Activity

Cancer is the second leading cause of death globally and is responsible for

about 10 million deaths per year. Several therapeutic options are available currently to

treat this deadly disease by targeting various enzymes, receptors, signaling pathways,

and nucleic acids. Development of drug resistance, new oncogenic proteins, and

recurrence demands sustained discovery of new therapeutic options. Flavonoids are a

class of plant polyphenols consisting of 15 carbon skeletons with two benzene rings

linked together to a heterocyclic pyrone ring. So far, more than 4,000 flavonoids of

different types have been discovered from nature. Flavonoids exhibit several biological

activities, including cancer. Quercetin (QCT) is one of the most studied flavonoids that

belongs to the flavones subclass. In the recent five years, immense efforts have been

made in discovering the anticancer aspect of QCT. This book chapter summarizes the

anticancer activities of QCT on various cancer cells (in vitro) and tumors (in vivo)

reported in the last five years.

Introduction

Nanotherapeutics for the Treatment of Hepatocellular Carcinoma

Currently, hepatocellular carcinoma (HCC) is the third leading cause of

mortality among cancerous diseases. It is a primary type of liver cancer possessing

unique features like solid malignant tumor type growth, leaky vasculature, and

angiogenesis. The success of conventional treatment in the management of HCC is

constrained due to unresponsiveness to particular approaches, drug resistance, systemic

side effects, and recurrence of malignancy. The development of nanotherapeutics offers

an impending key for overcoming these challenges. Nanotherapeutics utilizes

nanosized or nanostructured materials to attain particular therapeutic and

pharmacokinetic purposes. The diverse targeting strategies and site-specific drug

release patterns of this approach enlighten the hope for effective management of HCC.

Scientists have developed several nanomaterials like nanoparticles, nanogel, and

liposomes to deliver chemotherapeutic agents specifically to HCC sites with improved

efficacy, safety, and selectivity. Active targeting has remained most common and

effective in HCC management among active, passive, and stimuli-responsive targeting

strategies. Hopefully, some nanoformulations for HCC treatment have proved their

promising effects in clinical trials. In this chapter, an attempt is made to illustrate the

overview of HCC, the impact of nanotherapeutics, along with recent developments,

suitability, and challenges of various nanotherapeutic approaches for HCC

management.

Hepatocellular Carcinoma: Diagnosis, Molecular Pathogenesis, Biomarkers, and Conventional Therapy

Hepatocellular carcinoma (HCC), the most common liver malignancy, has

been a significant cause of cancer-related deaths worldwide. Cirrhosis, hepatic viral

infections, fatty liver, and alcohol consumption are notable risk factors associated with

HCC. Furthermore, a crucial challenge in the therapeutic management of HCC patients

is the late-stage diagnosis, primarily due to the asymptomatic early stage. Despite the

availability of various preventive techniques, diagnoses, and several treatment options,

the mortality rate persists. Ongoing investigation on exploring molecular pathogenesis

of HCC and identifying different prognostic and diagnostic markers may intervene in

the conventional mode of treatment option for better therapeutic management of the

disease. Subsequently, tumor site and its size, extrahepatic spread, and liver function

are the underlying fundamental factors in treating treatment modality. The development

in both surgical and non-surgical methods has resulted in admirable benefits in the

survival rates. Understanding the mechanism(s) of tumor progression and the ability of

the tumor cells to develop resistance against drugs is extremely important for designing

future therapy concerning HCC. This chapter has accumulated the current literature and

provided a vivid description of HCC based on its classification, risk factors, stagebased

diagnosis systems, molecular pathogenesis, prognostic/diagnostic markers, and

the existing conventional treatment approaches.

Brain Tumor: An Insight into In-vitro and In-vivo Experimental Models

Despite intensive research, brain tumor remains one of the deadliest forms of cancer with rapid progression and poor prognosis. A brain tumor is physically, emotionally, socially, and financially challenging not only for the patient but also for the caregiver. Morbid conditions like seizures, paralysis, cognitive impairment, and permanent neurological damage are the potential impacts of either the disease or therapy. Poor long-term survival with the 5-year and 10-year survival rates of almost 36% and 31%, respectively, adds to the burden. Animal models have undergone constant development with time and remain an indispensable tool for exploring the underlying pathophysiological mechanism and evaluating potential therapeutic strategies. Initial brain tumor models used chemical carcinogens to induce brain tumors, with nitrosourea derivatives being the favorable choice. These tumors could be maintained easily under in vitro conditions as cell lines and grafted in suitable syngeneic or xenogeneic hosts to study the cellular and physiological features of different types of brain tumors. The advent of transgenic technology has revolutionized animal modeling by allowing the manipulation of the host genome. Transgenic animals with gain/loss of function (knock-in/knockout) can be produced to investigate the role of any specific protein/gene involved in the cell cycle, metabolism, and signal transduction. Since the first oncomice in the 1980s, the transgenic technique and the subsequent expression of the transgene have been carefully worked out in mice. The role of different mutations, tumor suppressors, and oncogenes has also been studied. 2D and 3D in vitro techniques for faster evaluation and pre-screening of drugs have been established to mimic the brain microenvironment by manipulation of the culture conditions. Furthermore, a brief summary of non-rodent models and their potential applications has been discussed.

MDM2-p53 Antagonists Under Clinical Evaluation: A Promising Cancer Targeted Therapy for Cancer Patients Harbouring Wild-Type TP53

Mutation of TP53 occurs in about 50% of both sporadic and familial cancer cases. In the remaining malignant tumours harbouring wild-type TP53, it seems that p53 function is suppressed via other mechanisms, including MDM2 upregulation. In addition to frequent loss of p53 function in most types of tumours, the multi-functional transcription activity and tumour suppressor impact of p53 encouraged an enormous effort to introduce novel anti-cancer agents targeting p53. Different synthetic nongenotoxic inhibitors have been advanced to prevent the interaction between p53 and MDM2 and correct p53 dysfunction, of which some are still at early stages of development, and many have recently entered into clinical trials. In spite of the potential merits of targeting p53, including less damage to normal cells, fewer adverse events, and more efficiency, it has its potential drawbacks, which are needed to be addressed. Moreover, activated p53 impacts other biological processes making p53 restoration therapy more complicated. This issue can be resolved through the identification of biomarkers that predict sensitivity to these anti-cancer drugs, combined treatment, and optimization of p53-targeted therapy.

In this chapter, we review the role of TP53 as a tumour suppressor gene, targeting the interaction between p53 and MDM2 as a strategy for the treatment of malignancies and p53-MDM2 antagonists with emphasis on those that have been used in clinical trials. Other aspects of MDM2 inhibitors, including their predictive biomarkers, their side effects, resistance mechanisms, and combined treatment of MDM2 antagonists with other anti-cancer drugs, which potentially improve their clinical efficacy and patient stratification, will also be discussed briefly.

Analysis of Retinoblastoma Treatment Techniques with Fuzzy PROMETHEE

Retinoblastoma is the most common primary intraocular malignancy in children (1 in 15.000-20.000 live birth). It involves an uncontrollable growth and division of cells in the retina (neurosensory layer of nerve cells lining the back of the eye). The most common first sign of retinoblastoma is a visible whiteness in the pupil called “cat's eye reflex” or leukocoria. Another sign is strabismus; eyes do not point in the same direction. Children with retinoblastoma may have inherited a gene from their parents that causes this disease. Retinoblastoma is a curable disease with a very low mortality rate; early diagnosis can result in a 95% chance of treatment success and survival of the patient, with a likelihood of saving 70 to 80% of the vision in the affected eye(s). This study aims to shed more light on the parameters that affect the different treatment alternatives of retinoblastoma and how these parameters affect the preference ranking of each technique. In this study, we analyzed and ranked the most common treatment techniques of retinoblastoma using fuzzy PROMETHEE (Preference ranking organization method for enrichment evaluations), a multi-criteria decision-making tool using some parameters. The analysis results based on the parameters, criteria, and weights used suggest that cryotherapy is the most favorable treatment technique for treating retinoblastoma, followed by thermotherapy, chemotherapy, photocoagulation, enucleation, and, finally, radiation therapy. Using fuzzy PROMETHEE allows the decision-maker to change the parameters, criteria, and weights according to the situation and the desired outcome. However, fuzzy PROMETHEE for this application is to aid the decision-maker in arriving at a decision and not be followed blindly without an expert opinion.

Tau-Targeted Therapy in Alzheimer's Disease - History and Current State

The two main histopathological hallmarks still required for the diagnosis of Alzheimer's disease are the presence of amyloid plaques and intraneuronal neurofibrillary tangles formed mainly of tau protein. Normally, tau protein regulates intracellular trafficking and provides microtubule stability. However, in AD as well as in other tauopathies, there is a disruption in the normal function of tau, leading to the development of neurofibrillary tangles with disease-dependent ultrastructure of the tau filaments.

After several failures of trials with drugs trying to prevent the accumulation of amyloid, tau protein became another target of molecules designed to modify the course of AD.

Each stage in the development of tau pathology, from the expression of tau protein to its post-translational modifications, with the protein’s aggregation and impaired clearance, presents opportunities for therapeutic intervention: reducing tau expression with antisense oligonucleotides, reducing tau phosphorylation with kinase inhibitors, inhibiting tau acetylation, tau deglycosylation, tau aggregation, modulating tau degradation, stabilizing the microtubules, as well as active or passive anti-tau immunotherapies (with various monoclonal antibodies), have been attempted or are still in trials, with rather inconclusive results so far. It appears that an efficient diseasemodifying therapy is not yet available. Given the complex pathophysiology of Alzheimer’s disease, most likely, a multi-targeted approach would be more effective.

Subject Index

Breast Surgery

At the end of week 4 of human embryonic development, paired thickenings appear in the ectoderm on the ventral aspect of the torso. Extending from the axilla to the inguinal region, they form the mammary ridges or “milk lines.” Subsequently they regress and leave a pair of primary mammary buds at the level of the fourth and fifth inter- costal spaces. The primary buds thicken into lens-shaped mammary placodes. Epithelial cells invade the underlying mesenchyme during weeks 7 and 8 to form the primitive mammary disk. In week 9, a surge of mesenchymal proliferation occurs, coincident with a thinning of the overlying epithelium. A dense mesenchymal stroma then coalesces around the bud. Between weeks 10 and 12, epithelial buds form, begin to branch, and extend into the epithelial–mesenchyme bound- ary. By the first half of the second trimester (weeks 13–20), there are 15–20 solid epithelial cords that converge at the nipples. Ramification processes continue to week 32, when the cords undergo apoptosis to establish tubules and alveoli. At birth, male and female mammary glands are equally formed. There are 20 lactiferous ducts draining into the dimple. In later stages of the final trimester, the mesoderm underlying the dimple changes it into a true nipple with an areola. Placental estrogens during the final weeks of gestation cause breast buds to enlarge to create a true breast nodule at birth, about 1 cm in size, in both genders.

Pediatric Malignancy

Cancer is the second leading cause of death in children after trauma and accounts for approximately 11% of all pediatric deaths in the United States. In the western countries, leukemia, central nervous system (CNS) tumors, lymphomas, neuroblastomas and nephroblastomas account for most pediatric malignancies. Neuroblastoma and nephroblastoma are among the more common solid abdominal tumors. The prognoses for these cancers have improved after numerous multicentre trials. The following description will be restricted to the most commonly encountered tumors in children.

Key Proteins and Their Roles in COVID-19

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is a novel member of the Coronaviridae family that is the causative agent of coronavirus disease- 19 (COVID-19), which is now pandemic in the world. Various proteins characteristically responsible for pathogenesis are categorized as structural proteins (S, M, E, and N), non-structural proteins, and accessory proteins (ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10). Substitution of 380 amino acids and mutations in SARSCoV- 2 compared to other SARS-like coronaviruses characteristically plays a key role in entering the development of infection. S1/S2 of S protein has a specific differential role in SARS-CoV-2 stabilization and resultant infection. In addition to these key proteins, the host and virus-related proteins play risk factors in the spread of this disease. The current chapter will describe the structure of key proteins, their role in pathogenesis, starting from viral attachment leading to the infection in the host compared to the viruses belonging to Betacoronaviruses.

Pathophysiology

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal pathogen of the novel coronavirus disease 2019. This novel Covid-19 has created a serious public health crisis throughout the world. The primary symptoms of coronavirus infection are common cold and influenza-like illness and with time it causes pneumonia. Although various studies are going on throughout the world, its actual pathophysiology is not very well clear to date. The Coronavirus is a positively charged single-stranded RNA virus. This virus gets easily transmitted from human to human. Numerous investigations have been found that the virus enters into the human body via its spike (S) proteins. The S-protein binds to ACE2 receptors and silently comes in contact with alveoli via blood. This entry hypersensitizes various receptors, epithelial cells, macrophages, T-cells, dendritic cells and thus implants proinflammatory cytokines and chemokines, resulting in stressful conditions. Studies found that Hemagglutinin-Esterase protein, Spike protein, Nucleocapsid protein, small envelope protein, internal proteins, group-specific proteins take part in viral pathogenesis, whereas, replication proteins (eIF4A, Cyclophilin, 3CLpro, RdRp) participates in Coronaviruses (CoVs) replication and translation phases, influencing both pathogenesis and pathophysiological conditions. In this chapter, we elaborate on viral pathogenesis, the various functions of proteins, structural, enzymatic, and accessory that are linked with the pathological conditions and will also highlight the correlation causing physiological alteration associated with this infection.

Clinical Milestones in Nanotherapeutics: Current Status and Future Prospects

An aging population and poor clinical solutions for several diseases have propelled the rapid emergence of nanotherapeutics. Advanced drug delivery has turned out to be an important aspect of the medical field. A targeted delivery system transports the drug to the place of action hence, minimizing its adverse side effects on other vital tissues. Cell-specific targeting can be achieved by coupling drugs to specially framed carriers. Various nanoparticles, including solid lipid nanoparticles, nanosuspensions, nanoliposomes, micelles, polymeric nanoparticles, magnetic nanoparticles, dendrimers, carbon nanotubes, and fullerenes have been developed as carriers in drug delivery systems. In this chapter, the aforementioned nanocarriers and their clinical milestones achieved in various arenas including cancer, CNS disorder, rheumatoid arthritis, thyroid, cardiac diseases, ocular drug delivery, and vaccines so far, are scrutinized. This chapter outlines the current status of pharmacological and clinical studies of nanoparticles in the development process.

Artificial Intelligence Played an Active Role in the COVID-19 Epidemic in China

This perspective aims to summarize the COVID-19 experience of the Chinese people, which included psychological assistance and open datasets. We hope that countries across the world can utilize the lessons learned and tools developed by China in response to the COVID-19 pandemic and share their fighting experience in academic publication freely so the world can solve this crisis. This perspective focuses on psychological assistance and open datasets in China's COVID-19 pandemic; they played an important role in fighting with COVID-19 and acquired major contributions to calm people in the restless environment. We hope other countries can absorb the quintessence from this experience and utilize their situation to prevent and protect citizens from being infected and get rid of sequela in the COVID-19 epidemic.

Applications and Implementations of 6G Internet of Things

The Internet of things (IoT) has been the information infrastructure of a digitalized society and drives the newest wave of industrial development. With the rise of smart vehicular IoT applications, such as intelligent transport, smart navigation, and automatic driving, vehicular IoT is gaining some new features that cannot be fully addressed by current 5G networks. This chapter presents an overview of the vehicular IoT developing trend and discusses its relationship to 5G and the coming generation. It also presents some survey results from recent literature on the challenges and promising technologies for vehicular massive IoT.

Histological Classification of Head and Neck Tumors

Head and neck constituency tumor display many types of cell depending on the lineages, which can develop in a variety of tumor types. Nodaway, all these types and variants of tumor have been recognized based on histomorphological features and their molecular behavior. The most updated and receptive classification is provided by the World Health Organization (WHO) and the American Joint Committee on Cancer (AJCC). In the chapter, the discussion will include the common neoplasm, which can occur in oropharynx, nasopharynx, sinonasal region, salivary gland, thyroid gland and other adjacent structures. A brief overview, clinical presentation, histomorphology, genetic profile and outcome/prognosis will be highlighted.

Types of Head and Neck Malignancy

Head and neck cancer (HNC) is a heterogeneous group of malignant neoplasms, and its classification is a challenge. Based on the primary site, most literature comprehends five types of HNCs: laryngeal, pharyngeal, oral cavity, nasal cavity, and salivary gland cancer. More than 90% of HCNs are of epithelial origin, making squamous cell carcinoma the most common histological type. The prototypic HNC is a moderately differentiated squamous cell carcinoma associated with tobacco and alcohol consumption that affects older men more frequently. They are usually treated in a similar fashion. Currently, the human papillomavirus epidemic and a shift in tobacco consumption patterns are changing this trend. HNCs have a high rate of genetic heterogeneity, and molecular profiling has gained importance in the classification and future treatment of HNCs.

Molecular Biology

Introducing the ¹⁸⁸W/¹⁸⁸Re and ¹⁴⁴Ce/¹⁴⁴Pr Plaques for Eye Cancers Brachytherapy

Background: Plaque brachytherapy has been introduced as a treatment for ocular melanoma, an intraocular tumor, and is an available alternative to eye enucleation. Brachytherapy is one of the radiotherapy methods, which uses radioactive sources near or on the tumor.

Introduction: So far, various plaques have been used to treat eye tumors. The aim of this research is the development of radioactive material for brachytherapy plaques.

Method: In order to introduce and produce new brachytherapy plaques, all the isotopes of the periodic table of elements have been identified, and the mother and daughter of elements whose mother had long half-life beta decay and its daughter had a short halflife have been identified and the method of mother production has been examined.

Result: After reviewing, two new ¹⁸⁸W/¹⁸⁸Re and ¹⁴⁴Ce/¹⁴⁴Pr plaques have been selected for use in brachytherapy.

Conclusion: Each of the new plaques has a special advantage in comparison with old plaques. The 2D dose distribution of ¹⁸⁸W/¹⁸⁸Re and ¹⁴⁴Ce/¹⁴⁴Pr plaques in eye and tumor was obtained and was compared with old plaques.

Potential Natural Products For Prostate Cancer Management: Prospects For Castration-Resistant Patients

Prostate Cancer (PCa) is a major global health burden with alarming epidemiological indices. Research advances in this area have revealed complex molecular aspects associated with the disease, thus necessitating the novel development of diagnostic methods and therapeutic strategies. The main molecular target is the androgen receptor (AR), which is involved in both normal development and malignant transformation. However, many patients become resistant to conventional treatments, and the disease progresses to a castration-resistant stage (CRPC) in which tumor aggressiveness is driven by a constitutive activation of AR signaling. Tremendous effort has been made for elucidating CRPC and chemoresistance. In fact, multiple signaling pathways are related to the insurgence and maintenance of CRPC, highlighting the need for continuously updating such a complex scenario. Different drugs have been tested and used for CRPC treatment, facing unfavorable heterogeneity and leading to substantial morbidity and mortality. Thus, the clinical impact of advanced PCa with poorer outcomes still underscores the need for new compounds. The discovery and current use of natural products has given way to promising possibilities, offering alternative tools that aim to control the disease and to better manage patients. These natural products are versatile and effective molecules with different mechanisms of action and structures. In the present chapter, we explore the challenges of PCa and describe recent scientific contributions in this field, with special attention devoted to CRPC. We also discuss and suggest natural products as potential novel anti-tumor agents to overcome clinical limits and to treat and cure CRPC patients.

Advances of the Current Therapeutic Approach for the Management of Breast Cancer

Breast cancer is the most common type of malignancy in women worldwide. There are several factors associated with breast cancer for manifesting a heterogeneous disease in nature. Chemotherapeutic drugs significantly reduce the mortality rate of breast cancer. The recent development of chemotherapeutic drugs is targeting heterogeneity by including hormone receptors, expression of genes, epidermal growth factors, etc. The therapeutic response is dependent on a variety of factors, including stages, subtypes, metastasis, etc. For example,- endocrine therapy is preferred for positive hormone response in luminal breast cancer. In the recent therapeutic regimens, CDK4/6 quenchers are emerged, which regulate cell cycle by interacting with cyclin D1. It is also because, in the case of resistant hormonal therapy, tumors still showed its dependency on CDK4/6- cyclin D1 for proliferation. Apart from chemotherapy, immunotherapy is one of the emerging therapeutical regimens for breast cancer. There are also a number of vaccination approaches against breast cancer, including Nelipepimut–S, derived from the extracellular domain of the human epidermal factor receptor, which is used as a vaccine to prevent the reoccurrence of refractory breast cancer. Epithelial-to-mesenchymal transition (EMT) is a crucial mechanism for breast cancer progression. Currently, EMT inhibitor is used for preclinical testing to further used as a drug molecule to treat breast cancer. Thus, the advancement of chemo- or immunotherapy can substitute over invasive treatment strategies such as the surgical method for the treatment of breast cancer.

Sodium Bisulfite Conversion of Human Genome for DNA Methylation Studies

The regulation of transcription and translation of a gene under a given environment is dependent on several factors and epigenetics is one such factor, responsible for the differential expression of several genes in health and in various diseases. DNA methylation, an important epigenetics mechanism has been shown to play a vital role in numerous cellular processes, and the abnormal patterns of methylation have been linked to the number of human diseases. CpG islands, a short stretch of DNA enriched with CpG sites in the 5’ end of a gene, although remains unmethylated but tends to methylate aberrantly upon certain environmental exposures. The methylation of the promoter region bearing transcriptional start sites of those genes that encodes tumor suppressors such as tumor protein p53, retinoblastoma-associated protein 1, tumor protein p16, breast cancer 1 and many more result in the reduced expression of these genes and have been implicated in a large number of cancers like retinoblastoma, colon, lung and ovarian. A growing number of human diseases have been found to be associated with the aberrant DNA methylation. Hence, a deep insight into the individual’s epigenetic profile is the need of the hour. Several approaches have been developed to map DNA methylation patterns genome-wide. Some of these approaches include enzymatic digestion with methylation-sensitive restriction enzymes, the capture of 5-mC by methylated DNA-binding proteins followed by nextgeneration sequencing and methyl-DNA immunoprecipitation followed by sequencing of precipitated fragments. However, this chapter is going to describe the most recommended method for studying DNA methylation pattern, the method based on bisulfite sequencing. The bisulfite treatment of DNA converts unmethylated cytosine(s) to uracil(s), which are subsequently amplified as Ts by PCR. Hence, the bisulfitetreated DNA has mutations specifically at unmethylated Cs that can be mapped by Next-Generation sequencing.

Subject Index

Indirubins as Multi-target Anti-Tumor Agents

The traditional use of indirubin for the treatment of leukaemia has opened a vast field of research, studying the anti-tumor properties of indirubin and its derivatives (IRDs) against a wide range of malignancies. The cytotoxic effects of indirubin has been primarily attributed to its inhibitory function on a number of protein kinases, including cyclin-dependent kinases (CDKs), glycogen-synthase kinase 3 (GSK-3), and receptor tyrosine kinases (RTKs). In the past few decades, a lot of effort has been directed to the chemical modification of indirubin’s backbone towards better pharamcokinetic properties. This has led to the synthesis of various derivatives with new biological activities. We here review from the discovery of indirubin to the development of novel IRDs, and highlight the recent progress on how indirubins influence multiple cancer-associated signaling networks, leading to anti-proliferative and pro-apoptotic effects. Furthermore, we discuss the therapeutic use of indirubins in anti-cancer settings, as well as their potential for future clinical application.

The Prospects of CDK Targeting and Clinical Application of CDK Inhibitors in Cancer

CDKs (Cyclin-Dependent Kinases) are protein kinases that regulate cell cycle progression. In cancer cells, which are characterised by unregulated proliferation, CDK expression and activity are often deregulated. CDKs are potential therapeutic targets in cancer therapy. However, the inhibition of CDKs is a complicated affair and has been the subject of drug discovery for decades. With the preclinical and clinical phases of CDK inhibitor discovery confronted by drug resistance, low selectivity, and the need for selective inhibitors, and the successful development of CDK inhibitors is challenging. The application of proper patient selection has shown promise in the identification of highly selective CDK inhibitors. Promising results from clinical studies have led to the rapid approval of CDK dual inhibitors by the FDA and EMA; clinical guidelines from the NCCN and ESMO advocate their use in advanced breast cancer in combination with aromatase inhibitors in hormone receptor positive patients. Rapidly evolving data indicate that dual CDK inhibitors may favorably modulate the immune microenvironment and thus may be good partners for checkpoint blockade. Although promising, dual inhibitors will not offer an ultimate cure and tumour cells will engineer a way around them. A key challenge to therapeutic application is determining appropriate biomarkers to identify patients who may benefit most. An area of concern, as with all targeted therapy, is the study of mechanisms of acquired resistance to these drugs. Defining the mechanisms of resistance will be critical for designing future strategies. The inhibition of CDKs thus presents a complicated yet promising line of anticancer therapy. After a brief introduction to the molecular biology of CDKs and CDK inhibition, the chapter will focus on the present status and future prospects of targeting CDKs for cancer therapy, taking lessons from the failures and success stories of clinical trials in CDK inhibition.

Pro-Apoptotic and Anti-Telomerase Activity of Naturally Occurring Compounds

A common hallmark of human cancers is the over expression of telomerase, a ribonucleoprotein complex that is responsible for maintaining the length and integrity of chromosome ends and often directly correlated with the uncontrolled growth of cancer cells. Telomerase activity is present in 85-90% of all cancers, but absent in normal cells, which makes telomerase a good marker for cancer diagnosis and prognosis. Also, telomerase inhibition can be used as a novel anticancer therapy with reduced probability of toxicity than present antimalignancy drugs. However, current treatments used for cancer such as radiation, anti-hormonal therapy, surgery and chemotherapy using synthetic drugs, have been reported to produce various side effects. Therefore, it is crucial to reveal the beneficial effects of natural compounds with lesser side effects on normal cells and potential anticancer activity. In recent years, several natural molecules have been discovered so far that arrest proliferation of cancer cells by inhibiting telomerase. In this book chapter, we highlighted the effect of natural compounds on cancer cell proliferation, telomerase activity and their mechanism of action.

Alzheimer’s Disease and Proteasome: The Therapeutic Development and Management

The proteasome system is a cellular machinery that is responsible for the degradation of nearly 90% of the proteins in cells and is crucial in protein metabolism involved in physiological and pathological developments, especially in aging and aging-related disorders. Numerous reports indicate that impaired proteasome is involved in the pathological process of Alzheimer’s disease (AD), which is a leading form of dementia. It is well known that the pathological hallmarks of the AD are the aggregated proteins such as plaques, tangles and Lewy bodies. The formation of these aggregates is tightly associated with the dysfunction of the proteasome system, which is responsible for the degradation of oxidized, misfolded, aged and other damaged proteins. In fact, the proteasome system plays a major role in quality and quantity control in cellular protein homeostasis, and in responses to inflammatory signals, oxidative stress, and other cellular signals. This chapter will summarize the basic information and updates on the proteasome system and related cellular complexes, such as lysosome and ribosome and their alterations during aging and AD pathogenesis. In addition, some clinical trials and practical management for the AD will be discussed to explore possible strategies for pharmaceutical and clinical development associated with the proteasome system.

Ribavirin Against Viral, Neoplastic and Inflammatory Diseases: Focus on Mechanisms of Action

Discovered 45 years ago, ribavirin still proves useful as a broad-spectrum anti-viral drug against different RNA and DNA viruses. Although many cellular and molecular mechanisms of ribavirin action have been proposed during several decades of the extensive research, the complete spectrum of its actions is still not fully known. The direct mechanisms of ribavirin anti-viral action involve RNA polymerase inhibition and lethal mutagenesis. The main intracellular target of ribavirin action is inosine 5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in a de novo synthesis of guanine nucleotides. The inhibition of IMPDH activity leads to depletion of the guanine nucleotide pool and the consequent attenuation of GTPdependent cellular processes, inducing cell cycle arrest, and the interruption of DNA and RNA synthesis. Since these processes are essential for the normal as well as mitogenic functions of all cells, the inhibition of IMPDH probably represents the central mechanism of ribavirin action, including its cytotoxic effect. Recent data suggest that ribavirin may also be effective as an anti-cancer drug. By inhibiting the eukaryotic translation initiation factor e4E (eIF4E), ribavirin impedes eIF4E-mediated oncogenic transformation. Additionally, immunomodulatory and immunosuppressive actions of ribavirin have been shown in different in vivo and in vitro models of neuroinflammation. Accumulating evidence points to important cell type-specific differences in response to ribavirin that may arise from cell specific variations in ribavirin metabolism, as well as the functional status of targeted cells. This chapter reviews the antiviral, anticancer and anti-inflammatory activities of ribavirin and its metabolites, and discusses the possible mechanisms of action.

Reactive Oxygen Species (ROS)

The reactive oxygen species produced endogenously are essential to life, being involved in several biological functions. However, when produced at higher levels, these reactive species become highly harmful, causing oxidative stress through the oxidation of biomolecules, leading to cellular damage. The study in the field of ROS associated biological functions and/or deleterious effects requires new sensitive and specific tools in order to enable a deeper insight on its action mechanisms. Here, we discuss several methods related to the detection of reactive oxygen species.

Pediatric Hematological Malignancies – Clinical Manifestation, Treatment and Follow-Up

Hematological malignancies are the forms of cancer that begin in the cells of the blood- forming tissue, such as the bone marrow. Childhood blood cancers are relatively rare but are still found to be the major cause of death in children aged 1-14. Early detection increases the chances of successful treatment which paves the way to reduce the rate of mortality. Leukemias and lymphomas account for more than one half of new cancer cases in children. Despite major advances – from an overall survival rate of 10 percent to nearly 90 percent today, for many rare cancers, the survival rate is much lower. Enhancement of anti-leukemic efficacy and reduction of treatment related morbidity or mortality can be achieved by targeted therapy, but requires detailed understanding of pathways and genetic defects involved in leukemogenesis.

The Life Cycle and Transmission of HPV Types

Genital HPV infections are the most common of all sexually transmissible agents. The HPV life cycle is dependent on host cell differentiation with late viral events such as structural gene expression and viral genome amplification in the upper layers of the stratified epithelium. Indeed, the virus destabilizes host chromatinremodeling factors to facilitate viral replication and transcription. Generally, the life cycle of the virus is divided into major steps including entry, establishment of the nonproductive infectious state, maintenance of the non-productive infectious state, and productive stage. In this chapter, we briefly explain transmission and the life cycle of HPVs in host cells.

HPV Proteins and Their Functions

Papillomaviruses (PVs) are small non-enveloped viruses with a circular DNA genome encoding the viral early and late genes. The expression of late gene generates the structural L1 and L2 proteins, whereas early gene expression produces the regulatory proteins (E1-E8). The L1 and L2 proteins have important roles in virion assembly. Among the regulatory proteins, E7 and E6 oncoproteins play an important role in benign and also malignant transformation. For instance, a variant of HPV16 with the minimal differences in E6 sequence (Q14H/H78Y/L83V) found in cervical cancers is more effective for virus replication and maintenance as well as cell immortalization compared to other HPV types. Regarding the role of early proteins in the HPV life cycle, all proteins encoded by the HPV genome and their functions will be described in this chapter.

General Description of HPVs

Viruses are related to 15-20% of human cancers worldwide. Many studies focused on clarifying the molecular mechanisms and genetic alterations caused by oncogenic viruses. Among different oncoviruses, human papillomaviruses (HPVs) are small, non-enveloped, double-stranded DNA viruses, which can infect mucosal or cutaneous epithelia. Many HPVs have been classified as low-risk viruses associated with benign warts in the general population. Other HPVs entitled as the high-risk HPV types cause several important human cancers including cervical cancer, other anogenital cancers and head and neck tumors. A general description of HPV types and their association with different disorders are presented in this chapter.

Microtubules as Anti-Cancer Drug Targets

In developmental biology, all cellular events are suitably synchronized to ensure proper growth and development of any multicellular organism. A healthy adult tissue is often characterized by stem cells that can undergo orchestrated cell division and differentiation. Disruption of these events often leads to cancer resulting from the accretion or accumulation of the genetic and epigenetic changes that occur at the somatic as well as the germ line levels. In the recent years, significant progress has been made in the early detection, treatment and prevention of cancer. Targeted cancer therapies include the use of apoptosis inducing drugs and drugs that target microtubules among others. Over the past few years, drugs that inhibit microtubule dynamics have been successfully used as anticancer drugs. They can either be microtubule stabilizers (Vincristine, Vinblastine, Colchicine etc.) or microtubule destabilizers (Paclitaxel, Docetaxel, Epithilones, Taccalonolides etc.). Recently, new classes of compounds have been identified that interfere with cell growth and proliferation as a consequence of binding to tubulin αβ- dimers. Natural compounds like Curcumin have shown to inhibit tubulin activity. Whereas some antimitotic agents like Aurora A/B, Pentoxifylline, benzimidazole derivatives, combrestatin, polymeric nanoparticles etc. have been reported to show significant effect in the treating several types of cancer which were previously deemed untreatable. The following chapter acknowledges the presence of these anti-tumor compounds and how they target microtubules and further aid in the treatment of various cancers afflicting human beings.

Perspectives in Breast Cancer Treatment and Principal New Agents

In the last decades, the constant and relevant advances in genetics and molecular biology profoundly changed our knowledge on etiopathology, origin and progression of breast cancer disease. The different spread of program screenings, environmental and lifestyles changes have variously affected the epidemiology of disease in the different geographic areas. In the meanwhile, many new drugs have been experimented and entered into clinical practice. Thus, all the main aspects of the disease are continuously involved and need a regular updating. This chapter faces up with this difficult task and all the issues are discussed taking into account the most important scientific contributions in the field. The first part of the chapter is devoted to epidemiology, etiopathology and origin of the disease; thereafter it focuses on medical treatment and presents the current common lines of therapy in the different settings with particular reference to the more recent target therapies. As to this, the currently proposed treatments to overcome the occurrence of “de novo” or acquired resistance are also described. The last section discusses further innovative biological approaches and suggests a strategy for a more successful antitumoral immune manipulation.

Cancer and its Treatment: Development of Anticancer Chemotherapeutic Agents from Natural Products

Over the last 5 decades, biologically active compounds derived from natural resources have provided a number of useful cancer chemotherapeutic drugs. The search for natural product based drug candidates is growing rapidly with the advancements in drug discovery and development techniques in recent years, with the active fractions and isolates of marine organisms along with terrestrial plants. Microorganisms are also being explored for their anti-cancer activities. The present review highlights the information about occurrence, types, clinical features pathophysiology and etiology of cancer as well as conventional and recent advancements in anticancer drug development along with description of selected medicinal plants and compounds derived from natural sources or their derivatives with potential use as cancer chemotherapeutic agents. It is expected that such promising leads from natural origin tend to create extensive interest among researchers including medicinal chemists and pharmacologists working in anticancer drug research and therefore the availability of a given brief information about cancer and anticancer drug development focused on natural product may be proved useful to develop preliminary ideas of biochemical pathways and key enzymes regulating these pathways as well as new targets involved in different stages of the disease along with chemotherapeutic agents which selectively target a specific signaling pathway through structure-activity relationships and preclinical trials.

Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and the third leading cause of cancer death in the world. HCC has a poor prognosis unless recognized at an early stage, underscoring the importance of prevention. HCC most often develops in cirrhosis associated with chronic viral, toxic, or genetic liver injury. Notably, HCC has a rising incidence in developed societies with an increasing evidence for the role of nonalcoholic fatty liver disease (NAFLD), which has become the most common liver condition mirroring the spread of obesity and type II diabetes. A significant proportion of HCC associated with NAFLD may occur in the absence of advanced fibrosis or cirrhosis, posing a major challenge to cost-efficient risk stratification. Beyond the strong tumorigenic milieu of cirrhosis, molecular mechanisms of hepatocarcinogenesis in NAFLD include adipose tissue expansion with a pro-inflammatory adipokine profile, general and tissue-specific lipotoxicity, and the cell growth promoting effects of elevated insulin levels. Altered gut microbiota and microRNA deregulation may also contribute to HCC development in NAFLD. After reviewing these topics, the chapter provides a brief overview of the clinical characteristics, screening, and novel opportunities in the chemoprevention of NAFLDrelated HCC.

Combined Hamartoma of Retina and Retinal Pigment Epithelium

Subject Index

Astrocytoma Tuberous Sclerosis

Von Hippel-Lindau Disease

Retinoblastoma

Persistent Fetal Vasculature

Coats` Disease

Retinopathy of Prematurity

Aging and β-Cell Proliferation, Molecular and Signaling Changes and What This Means for Targeted Regeneration

Increased age confers a greater risk for the development of type 2 diabetes (T2D), and also has significant consequences for β-cell growth and regeneration. Pancreatic insulin-producing β-cells are long-lived, and exhibit very little turnover in adult life. The severe decline in β-cell proliferation contributes to a decreased capacity for β-cell regeneration with age. β-cell regeneration is dependent on mitogenic signals, receptor and downstream signal transduction, cell cycle progression, and epigenetic regulation of gene expression, all of which are significantly affected by increasing age. Studies suggest that circulating growth factors and their receptors are decreased with age, along with important intracellular signaling molecules, such as Pdx-1 and FoxM1. Cell cycle progression is inhibited by an increased expression of cell cycle inhibitors and a reduction in cell cycle kinase complexes (Cyclin/Cdks). Moreover, decreased expression of epigenetic silencers, such as polycomb group proteins, results in derepression of the cell cycle inhibitor p16, and a significant reduction in β-cell proliferation. Collectively, these age-induced changes present obstacles for the design of β-cell regenerative therapies for diabetes; however, some reports suggest that even very old β-cells can re-enter cell cycle. Future studies will further define the effects of aging on β-cell proliferation and elucidate new drug targets for diabetes therapy.

Fundamental Relationships Between Cancer Stem Cells, the Cancer Stem Cell Niche and Metastasis

Parallels drawn between stem cells and cancer are not new. However, these shared features are becoming increasingly important as our understanding of disseminated, recurrent and metastatic cancer cell biology continues to develop. Indeed, nearly all cancer-related deaths are the result of recurrent and metastatic disease, highlighting the need for a more comprehensive schema of how tumors colonize new sites, resist therapy and evolve. In this chapter, we compare the phenotypes of stem cells, cancer stem cells (CSCs) and metastatic cells, highlighting notable points of contrast. We begin with an introduction to stem cell biology, tumorinitiating CSCs, metastatic cells and discuss shared features. The implication of the stem-like phenotype extends to many characteristics of cell biology: cell division, differentiation, morphology, gene expression, motility, invasion, clonogenicity, capacity for colonization, metabolism and the interaction of these cells with their surrounding microenvironment. Stem cell phenotypes are highly complex and, while there may be a number of shared features, there are important elements that are uniquely tissue-dependent. While staunch definitions based upon a single biomarker of stemness have proven inadequate in broader applications, seeing universal themes of the stem cell phenotype will provide critical insights for studying cancer. Our understanding of this complex biology is critical for developing rational and dynamic therapeutic interventions for patients with recurrent and metastatic cancer.

Cyclin E and its Potential Use for Liver Cancer Prognosis and Therapy

Liver cancer is an aggressive malignancy developed in the liver. Hepatocellular carcinoma (HCC) is the predominant form of liver cancer worldwide. The prognosis of HCC patients remains poor even with the evolving development on technologies for disease diagnosis, prognosis and treatment. New methods to improve the management of HCC patients should be implemented. Cell cycle deregulation is one key mechanism leading to HCC. Cyclin E is a cell cycle molecule regulating G1 to S phase transition of the cell cycle. The prominent cell cycle regulating function of cyclin E has signified its involvement in HCC when its activity is deregulated. This chapter summarizes the current research on cyclin E in HCC and with a special focus on its underlying, well-studied downstream mechanism involving retinoblastoma-E2F transcriptional factor network. Lastly, research on the potential use of cyclin E for HCC prognosis and treatment is also highlighted and discussed.

Malignant Pleural Mesothelioma (MPM): Latent Disease

Malignant pleural mesothelioma (MPM) is a cancer with aggressive nature and poor prognosis (the median survival ranges from 9-18 months). The worldwide incidence of this disease is increasing, with 2180 estimated new cases diagnosed in the United States in 2013. Despite the apparent benefits offered by the multimodal approach (a combination of surgery, chemotherapy -cisplatin/ pemetrexed- and radiotherapy), survival remains poor. As a consequence, multiple therapies aiming to improve the evolution of the disease are under investigation. In this chapter, we will summarize some of the new preclinical and early clinical developments in the treatment of MPM, which include mesothelin specific antibody and toxin therapies, gene therapy, interleukin-4 (IL-4) receptor toxins and dendritic cell vaccines, among others.

Bevacizumab for Glioblastoma Treatment: Reviewing Biological and Clinical Hypothesis for its Success and Failures

Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor in adults with a very poor prognosis. The standard treatment for newly diagnosed glioblastoma is surgical debulking followed by radiotherapy and temozolomide (TMZ) with additional maintenance with TMZ. However, this regimen offers modest benefits with a median survival of less than 15 months, with an inevitable recurrence.

GBM is one of the most vascularized tumors; therefore antiangiogenic therapeutic strategies are very appealing. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, was the first FDA approved angiogenesis inhibitor, based on impressive response rates in recurrent GBM. Recent trials have shown that the combination of bevacizumab with standard radiotherapy–TMZ for the treatment of newly diagnosed glioblastoma resulted in improved median progressionfree survival, without gain in overall survival. Data regarding quality of life and functional status are conflicting. Not surprisingly, there was an increase in adverse events associated with bevacizumab therapy, namely thrombosis, bleeding and hypertension. Therefore, the efficacy of antiangiogenic therapy in the management of GBM remains unclear. To improve outcomes, it has been made a huge effort to better understand the biology underlying angiogenesis and tumor survival, as well as the mechanisms of antiangiogenic resistance in GBM.

Adult Stem Cell Niches and Their Regulatory Molecular Mechanisms

The activation, survival, and quiescence of stem cells (SCs) are dependent on signaling within their niche or microenvironment. There are many types of SCs and SC niches that can be found in the human body. A single organ may contain more than one niche to accommodate for both slow and fast cycling SC populations. It appears that many SC niches possess similarities in both their cellular and molecular components. This chapter focuses on cellular organization, key molecular regulators, and the role of SC niches in aging and cancer.

Antitumor Properties of Honeybee Plant-Derived Products: Honey, Propolis and Pollen

The majority of cancers have no curable treatment and the main available therapies have serious side effects, justifying the need for development of new antitumor agents. Several efforts have been made to identify natural products useful in the cancer setting. This area has emerged as an important research field, providing the possibility to both identify novel potentially useful agents and to study the mechanisms of antitumor action. Honeybee plant-derived products have shown anti-cancer activity in a series of experimental and clinical studies with cell lines, animals and humans. Honey, the viscous, golden and sweet liquid produced by bees from the nectar of flowering plants has proven to display antiproliferative and apoptotic effects, along with other activities that contribute for its antitumor properties. Propolis, a special substance made by honeybees through mixing tree saps with salivary secretions, is used to seal fissures and openings in the hive, strength combs, seal brood cells and protect the hive from infections. Propolis contains phytonutrients that may be useful in different pathological conditions, including cancer.

Bee pollen, the bees´ primary food source, is plant pollen collected from a variety of plants and processed by honeybees. Demand for this natural product is rising since it has effects on a variety of biological functions, which contribute to the fight and prevention of cancer. This review focuses on the antitumor properties of honey, propolis and bee pollen as well as on the potential use of these honeybee plant-derived products to develop new therapeutic approaches for patients with different types of tumors.

Apoptosis Targeting Therapeutics in Clinical Trials

Apoptosis (called as programmed cell death) is vital for maintaining homeostatic balance between cell survival/cell deaths in metazoan cells. Apoptosis is regulated through extrinsic (or receptor mediated) and intrinsic (or mitochondria mediated) pathways. The pro-apoptotic proteins (e.g. Bax, Bak, Bad, Bcl-Xs, Bid, Bik, Bim and Hrk) and the anti-apoptotic proteins (e.g. Bcl-2, Bcl-XL, Bcl-W, Bfl-1 and Mcl-1) are crucial to control the apoptotic pathways. Dysfunctions of apoptosis pathways are implicated in cancer as defects in these pathways not only promote tumorigenesis but also confer resistance to cancer cells to most conventional chemotherapies as well as radiotherapy. The apoptosis occurs by imbalanced proapoptotic and anti-apoptotic protein levels, impaired or reduced death receptor signalling and caspase function. Hence, targeting apoptosis pathways is considered as an attractive strategy for therapeutic intervention in cancer. The past decade recorded tremendous advances in this area especially small molecular intervention of apoptosis pathways for cancer treatment which resulted in several compounds under clinical development. This chapter reviews the current progressions in the development of bioactive molecules targeting apoptotic pathways with special emphasis on small molecular anticancer drugs under clinical trials. Some excellent examples are; nutlins, MI-888, MI-219 and SM-164 which target MDM2, ABT-263, AT-406 and GX15- 070MS which target Bcl-2 family of proteins, birinapant, GDC-0917, HGS-1029 and LCL-161 which target IAPs (inhibitors of apoptotic proteins). The content of this chapter will be enlightening the readers in academic and research to update their knowledge on the anticancer drugs especially target proteins responsible for apoptosis.

Targeting the Warburg Effect for Cancer Therapy: A Long and Winding Road

In the 1920s, Otto Warburg, one of the leading biochemists of the 20th century, uncovered a striking phenotype of cancer cells: their increased dependence on lactic acid fermentation for energy production compared to that of the normal cells from which they derived. Warburg viewed this metabolic particularity of cancer cells, which came to be known as the Warburg effect, as a driving force in carcinogenesis. This perception suggested a novel path for cancer therapy, a strategy that Warburg himself proposed and defended with passion to his death. However, for many decades, both his metabolic theory of cancer and suggested therapeutic approach were essentially ignored by cancer researchers, who were mostly focused on the genetic basis of the disease and on the intricacies of the pathways known to promote cellular proliferation, differentiation and death. Still, thanks to the combined efforts of those who chose to pursue Warburg’s line of research, experimental evidence supporting and extending Warburg´s findings on the metabolism of cancer cells accumulated. In the 1980s, 18F-deoxyglucose positron emission tomography (18FDG–PET) was implemented in the clinic. This metabolic imaging technique, which is based on the avidity of cancer cells for glucose, represents, to this day, the only successful exploitation of the Warburg effect for medical purposes. The wide success of 18FDG–PET in the diagnosis and staging of tumors is among the factors most responsible for renewing interest in the central carbon metabolism of cancer cells. This renewed interest was further boosted by the discovery of multiple links between central carbon metabolism and cellular proliferation, differentiation and death and culminated in the recent classification, by Weinberg and Hanahan, of tumor metabolism as an emerging cancer hallmark. Tremendous research effort is now being devoted into a more detailed and comprehensive elucidation of the metabolic rewiring that accompanies neoplastic transformation and, unsurprisingly, targeting the metabolic peculiarities of tumors has become a hot topic in drug discovery. This chapter summarizes past and current efforts at targeting the Warburg effect for selective cancer therapies.

Chemotherapy for Uterine Sarcomas: A Review

Uterine sarcomas are relatively rare tumors, constituting only 8%-10% of all uterine malignancies. Its three most common histologic variants are carcinosarcoma (CS), leiomyosarcoma (LMS), and endometrial stromal sarcoma (ESS). Because of its frequent resistance to existing chemotherapeutic drugs (caused by several mechanisms), standard chemotherapeutic regimens have not yet been established. Presently, CSs are treated in the same way as high-grade endometrioid endometrial carcinomas. A combination of carboplatin and paclitaxel is the most commonly used adjuvant therapy regimen in advanced or recurrent CS. For LMS, the key drugs are doxorubicin, ifosfamide, gemcitabine, and docetaxel. These drugs are used as single agents or in combination for the treatment of patients with advanced or recurrent LMS. For ESS treatment, hormonal agents have been used because ESS expresses estrogen and progesterone receptors. Because of its rarity, well-designed random controlled trials are required for future investigations of the efficacy of chemotherapy for patients with uterine sarcoma.

Collaboration of Epithelial Mesenchymal Transition and Cancer Stem Cells: Sinister Routes for Chemoresistant Recurrent Ovarian Cancer

Overcoming intrinsic and acquired chemoresistance is the major challenge in treating ovarian cancer patients. Initially nearly 75% of ovarian cancer patients respond favorably to chemotherapy, but subsequently the majority gain acquired resistance resulting in recurrence, cancer dissemination and death. This chapter summarizes recent advances in our understanding of the cellular origin and the molecular mechanisms defining the basis of cancer initiation and malignant transformation with respect to epithelial-mesenchymal transition (EMT) of ovarian cancer cells. We discuss the critical role of EMT frequently encountered in different phases of ovarian cancer progression and its involvement in regulating cancer growth, survival, migration, invasion and drug resistance. Using model ovarian cancer cell lines we highlight the relationship between EMT and the ‘cancer stem cell (CSC)-like phenotype’ in response to drug treatment, and relate how these processes can impact on chemoresistance and ultimately recurrence. We propose the molecular targeting of distinct ‘EMT transformed CSC-like cells’ and suggest ways that may improve the efficacy of current chemotherapeutic regimens much needed for the management of this disease.

Virus Oncogenesis of Malignant Pleural Mesothelioma

Simian Vacuolating Virus 40 (SV40) was isolated in 1960 from polio vaccines contaminated during the manufacturing process. SV40 is able to induce tumors in animals and is causally associated with human malignant mesothelioma, lymphoma, and bone and brain tumors. SV40 is a co-factor for malignant mesothelioma development in hamsters and mice exposed to asbestos, based on different mechanisms. In addition, SV40 cooperates with asbestos and possibly other mineral fibers, leading to in vitro transformation of primary human mesothelial cells (HM). SV40 induces transformation of HM, rather than cell lysis as occurs in other human cell types, due to the transcription of antisense RNA repressing late viral gene expression. The mechanism of SV40 carcinogenesis relies on the activity of the two SV40 early proteins, large T antigen (Tag) and small t antigen (tag). In SV40-infected mesothelial cells, Tag binds p53 and the resulting complex associates with retinoblastoma protein (Rb), p300, p400 and CREB-binding protein (CBP). This larger complex establishes a potent transcriptional regulator, able to induce IGF-1, Met and Notch-1 expression and the associated downstream signaling pathways. The induction of calretinin expression is also a part of Tag activity in host cells. The interaction of Tag with other binding partners suggests additional mechanisms of interference with cell cycle or survival of the host infected cells.

Chemical Control of Cancer: The Best Way Forward

Ehrlich invented chemotherapy in 1909 with a simple rationale: Chemicals could cure infection by hitting targets in microbes that didn’t exist in hosts. Arsenicals, sulfa drugs, and antibiotics lent credibility to the notion. But now we know it’s oversimplified. Immune and inflammatory responses are essential to curing infection, and continued treatment with any single chemical leads inevitably to resistance. Cancer is more challenging than infection. Host and cancer cells are similar, host responses to cancer are less vigorous than those to microbes, and drugs that inhibit cell division tend not only to suppress inflammation and immunity, but also to erode gastrointestinal mucosa causing nausea, vomiting, and malnutrition. Together these side-effects predispose to infection, and a desperate dilemma: Should the patient die of cancer or it’s treatment? Despite long odds, chemicals remain the only hope for control of disseminated cancer. To realize this hope, however, we must enact a sea-change in our thinking. Rather than searching for new magic bullets, we must focus on overcoming tumor defenses, precluding resistance to treatment, preserving and enhancing host anticancer responses, minimizing toxic side effects, and inspiring patients and their physicians to engage in realistic dialogue about life and death. Combining effective drugs and drug combinations with nutritional manipulations, metabolic modifications, mind-body interventions, and philosophic contemplations holds the most promise for realizing this goal.

Some Natural Products May Represent a Future Alternative to Anti-Neoplastic Medicine

Currently, the main treatments available for cancer include surgery, biological therapy, radiation and chemotherapy. However, these treatments have strong secondary effects on patients, which can prohibit their use. Therefore, the search for alternative treatments is a current challenge for scientists. Several studies have identified compounds from plants that exhibit biological properties compatible with the desired activity of anti-neoplastic drugs. Natural products are thought to be more compatible with the human body and cause fewer side effects. Furthermore, substances present in fruits, vegetables and herbal essential oils have demonstrated important antiproliferative activity, inducing cell and genomic changes favorable for cancer prevention and therapy. Taking into account that the molecular mechanisms by which natural compounds function to prevent cancer are not fully understood and that molecular targets can be important tools for evaluating their effectiveness, this chapter aims to present and discuss potential active compounds as possible anti-cancer agents.

Bayesian Systems for Optimizing Treatment Protocols in Oncology

The development of new pharmacodynamic biomarkers has greatly increased the information content of clinical trials, and made possible the construction of pharmacokinetic/pharmacodynamic (PK-PD) models. A population PK-PD model, in conjunction with a disease model, can then be used to simulate clinical trials in silico. In the case of oncology, the disease model must describe the cancer cell cycle, and such aspects of tumour biology as growth, invasion, metastasis, angiogenesis, and interactions of tumour cells with the immune response. Such models of tumour growth and its response to drug treatment can be used in conjunction with databases of drug PK and PD parameters and with databases of biomarkers, to ask the question: for a tumour with a given biomarker expression profile, what treatment protocol is likely to be most effective? Various treatment options can then be modelled, and the one predicted to be most active selected for clinical evaluation. Since, in practice, many of the tumour growth parameters are still unknown, a Bayesian approach is required: prior assumptions are made, based upon preclinical data and historical precedent. The course of treatment, based upon these prior assumptions, is predicted, compared with the clinical outcome, and the difference fed back to drive model adjustments. The assumptions of the model are thus progressively refined - the system learns from experience. A Bayesian model can be used to devise optimal control strategies for chronic disease. A frequent cause of cancer treatment failure is the rapid development of acquired drug resistance. In silico clinical trials that incorporate the techniques of evolutionary dynamics can be used to predict the incidence of drug resistance, including multi-drug resistance, so that emergence of resistant clones can be minimized and delayed. In due course, the actual clinical outcome can then be compared with the predictions. We review the literature on the use of Bayesian systems in oncology, and discuss their application to development strategies for new drugs, and to developing personalised medicine approaches in oncology.

Ultrasound Compared to Other Ocular Imaging Systems

Ophthalmology in the last decades has seen a great rise in new images techniques. The appearance of fluorescein angiography, optical tomography, etc. Highlight that other image techniques are unnecessary. But in fact in the present years, the ocular echography has become important, and the advances with new probes with higher frequencies, has helped us in a lot of ocular pathologies, as seen in the last chapter. In the present chapter we describe the indications of other image techniques used in medicine, but with poor knowledge in ophthalmology. The authors describe the indications of computer tomography and magnetic resonance, and also define when we use each technique.

Ocular Tumors

The posterior segment tumors are the most important indication for ultrasound examination. Echography is essential in choroid melanoma diagnosis; there are a lot of signs in echography which permit us to make a differential diagnosis with the other most frequent intraocular tumor, metastases which appeared with similar echographic signs in ultrasound examination. In the present chapter we also explain the characteristics of other tumors, as retinoblastoma or choroid hemangioms.

Targeting Interleukin-6 for the Treatment of Castration-Resistant Prostate Cancer

The existence of a crosstalk between the androgen receptor (AR) pathway and interleukin-6 (IL-6) signaling in prostate cancer (PCa) is broadly recognized. IL-6 activates the AR in a ligand-independent manner leading to the transcription of prostatespecific antigen (PSA), the most widely used marker for the detection and monitoring of PCa. IL-6 expression is increased in the malignant epithelium of prostate cancer patients and its levels are enhanced in the plasma of patients with late-stage disease. Interestingly, IL-6 is able to shift from being a paracrine growth inhibitor to an autocrine growth stimulator in PCa cells. Hence, IL-6 has been implicated in the progression towards castration-resistant prostate cancer (CRPC), in which elevated levels are indicative of poor prognosis and predict resistance to chemotherapy with taxanes. We will depict here the IL-6 signaling pathway and its contribution to PCa. For this purpose, we will portray the molecular events that prompted the origin of LNCaPIL- 6+ cells, a model of advanced PCa, upon chronic exposure to IL-6. We will also examine the similarities between LNCaP-IL-6+ cells and late-stage prostatic carcinoma. In addition, we will reveal the effect of CNTO 328, a chimeric monoclonal antibody targeting IL-6, in LNCaP-IL-6+ cells, as well as discuss the latest results from clinical trials with CNTO 328 in CRPC patients. Finally, we will speculate on the possibility, not yet investigated, of administering CNTO 328 to patients before the onset of CRPC.

Myocardial Ischemia, Myocardial Infarction

In this chapter, we address the basic notions of myocardial ischemia and myocardial infarction. Cardiac ischemia changes the electrical activity and the genesis of the action potential and of the resting potential. It can be divided into 3 forms; ischemia, lesion and necrosis. Modification of the QRS complex, the ST segment and T wave is observed. Ischemia is a biochemically reversible anomaly. Moreover, it is mainly ionic, notably potassium disturbances which underlie ST and T wave changes. Lesion is a more severe form of cardiac ischemia but is still reversible, with interstitial oedema and biochemical disturbances. Essentially, it is the ST segment, which is modified, in that it becomes displaced from the isoelectric baseline. The ST segment vector is determined in the same manner as that of the QRS complex: it allows for better localization of the site of the stenosis or obstruction of the culprit artey. The more leads exhibit ST changes, the bigger the territory at risk. A sum total of ST depression or elevation greater than 12 mm in the different leads implies widespread ischemia. The most severe stage of cardiac ischemia is necrosis since there is cellular death with cessation of electrical activity. Neither the action potential nor the resting membrane potential exists anymore and the conduction capability has ceased. The start of depolarisation (QRS) is modified with the apparition of an \"electrical hole\" (Q waves), which could progress as far as the total disappearance of the positive forces (R waves) and a QS morphology; the necrosis is transmural affecting therefore the full thickness of the myocardium. Acute coronary syndrome includes STEMI and non-STEMI. STEMI (ST Segment Elevation Myocardial Infarction) is the acute coronary syndrome with ST segment elevation and non-STEMI is associated with other ST segment changes (negative T waves or ST segment depression) but not ST segment elevation. Electrocardiographically, the electrical changes recorded in the different territories differ according to the coronary artery involved. There is a good correlation between the ischemic zone and the coronary artery affected. Ischemia is recorded by the electrode \"exploring\" the territory implicated. Involvement of the right coronary artery gives rise to inferior wall ischemia and this is characterized on the ECG as changes in leads II, III and aVF. Involvement of the left coronary artery gives rise to anterior wall ischemia and this is characterized on the ECG as changes in precordial leads.

Barriers for Posterior Segment Ocular Drug Delivery

Drug delivery for the treatment of posterior segment diseases has become a major challenge in the field of ophthalmology due to its restrictive barrier functionalities. Blood-ocular barriers act as a physical barrier between the local blood vessels, ocular tissues and fluids which restrict the passage of various solutes and fluids. Ocular barriers may be classified as static and dynamic barriers. Static barrier include sclera, Bruch’s membrane-choroid (BC), retinal pigment epithelium (RPE) and conjunctiva while dynamic barriers include drug clearance mechanism through blood and lymphatic vessels. Apart from above mentioned barriers, it is also imperative to understand the role of enzymes and transporters in drug disposition. Overall, it is essential to understand anatomy, physiology and disposition mechanisms of eye and interaction between drug molecules/formulation with various ocular tissues in order to design a successful drug delivery system.

Selective Cyclooxygenase-2 Inhibitors for Malignant Glioma Therapy: Molecular Targets Beyond COX-2

Cyclooxygenase-2 (COX-2) oftentimes is highly expressed in cancer tissues, where it supports tumor development and angiogenesis. Over the past 15 years, newly developed non-steroidal anti-inflammatory drugs (NSAIDs) that are able to highly selectively inhibit this enzyme were hoped to become therapeutic tools for cancer prevention and therapy. However, while chemopreventive effects of certain selective COX-2 inhibitors indeed have been documented, their efficacy for therapy of already established cancers has been unimpressive so far. Intriguingly, the investigation of compounds such valdecoxib, rofecoxib, and in particular celecoxib, has revealed molecular targets besides COX-2, and it appears that some of these non-COX-2 targets may be critically involved in mediating the pro-apoptotic effects of these compounds without any apparent involvement of COX-2. In fact, investigations of a series of close structural analogs of celecoxib demonstrated that it is possible to separate COX-2 inhibitory function from apoptosis-stimulatory function within the molecule. For example, 2,5-dimethyl-celecoxib (DMC) has lost COX-2 inhibitory function, yet still exerts profound cytotoxic potency.

This review will summarize pertinent results from the exploratory therapeutic use of NSAIDs, in particular celecoxib, in preclinical and clinical studies of malignant glioma. Several COX-2 independent targets will be presented, and it will be discussed how DMC has helped to delineate their relevance for the surmised COX-2 independent tumoricidal effects of celecoxib.Angiogenesis, azetazolamide, carbonic anhydrase, celecoxib, diclofenac, 2,5-dimethyl-celecoxib (DMC), endoplasmic reticulum stress, etoricoxib, glucose-regulated protein 78 (GRP78), meloxicam, nimesulide, 3- phosphoinositide-dependent protein kinase-1 (PDK1), rofecoxib, temozolomide, valdecoxib.

Posters

miRNAs in Myocardial Infarction

The aim of this chapter is to provide an overview on the role of miRNAs in myocardial ischemia, ischemia/reperfusion injury and ischemic preconditioning. Myocardial ischemia due to occlusion of coronary arteries constitutes the major cause of mortality and morbidity of humans worldwide by causing an array of injuries. Timely myocardial reperfusion remains the most effective treatment strategy for reducing myocardial infarct size, preventing left ventricular remodelling, preserving left ventricular systolic function and improving clinical outcomes. However, the full benefits of myocardial reperfusion are not realized, given that the actual process of reperfusing ischemic myocardium can independently induce myocardial injury. On the other hand, heart has endogenous cardioprotective capability against myocardial/reperfusion injury, called ischemic preconditioning. Recent studies indicate that miRNAs are implicated in all these different aspects of myocardial ischemia. This chapter describes the role of miR-1 and mR-133 in myocardial ischemia, miR-21, miR-29 and miR-320 in ischemia/reperfusion injury, and miR-21 and miR-199a in preconditioning.

Therapeutic Transfer of DNA Encoding Adenoviral E1A†

E1A is a multifunctional adenoviral protein expressed early after infection that interferes with numerous important regulatory processes by interaction with host cell proteins or direct transcriptional activation of target genes. Although, initially identified as the adenoviral component that can cause malignant conversion of rodent cells, remarkable tumorsuppressive effects of E1A on various types of human cancer cells were observed. Gene therapeutic approaches with E1A are currently evaluated in animal models and early clinical studies. Therapeutic applications of E1A are covered by a series of patents which include the description of small variants (mini-E1A) that can be used for tumor suppression and E1A gene transfer in combination with conventional chemotherapy. In this mini review, we provide an introduction to E1A functions, summarize relevant patents, and discuss potential clinical applications of E1A gene transfer on basis of recent results of clinical and preclinical investigations.

Neurological Complications of Antiangiogenic Therapy

Since the discovery of the principles of angiogenesis and the drugs with antiangiogenic properties, the science has evolved greatly in understanding the pathophysiology of several diseases like cancer and the development of drugs that act in the cascade of mechanisms related to angiogenesis. Due to the systemic action of antiangiogenic therapy, patients may experience several side effects, among them those related to the nervous system. Several neurological complications have been described in patients treated with antiangiogenic therapy. The neurological side effect profile of the new agents is largely unknown and may include central (reversible posterior leukoencephalopathy, strokes, encephalopathy, seizures) and peripheral neurotoxicity (autonomic, sensory or sensorimotor neuropathy) depending on the specific agent. The peripheral neurotoxicity of relatively older agents such as bortezomib and thalidomide is well described and health care professionals dealing with patients treated with such medications need to be aware of these complications. Further research is necessary to understand the mechanisms and foster prevention and treatment of these neurological complications.

Retinoblastoma

Molecular Basis of Cancer

Genome Editing and Genetically Engineered Bacteria for Bioremediation of Heavy Metals

Animal Models in Dentistry

Animal Models for Cancer

Cancer Pathophysiology

Stem Cell Models: Novel Experimental Approach for Testable Alternatives against Therapy-resistant Breast and Colon Cancer

Chromosome 21

Chromosome 20

Chromosome 18

Chromosome 16

Chromosome 15

Chromosome 14

Chromosome 13

Plant Cardenolides: Multifunctional Medicinal Agents

Chromosome 6

Probiotics-based Anticancer Immunity In Cervical Cancer

Probiotics Based Anticancer Immunity in Colorectal Cancer

Treatment of Cancer

Biology of Cancer

Exogenous Factors and Cancer

Implication of Biosensors For Cancer Diagnosis And Therapeutics

Protein Cancer Biomarkers

DNA Methylation Landscapes in Cancer and Non-Cancer Cells

Subject Index

Preimplantation, Prenatal, and Postnatal Diagnosis

Subject Index

Heterocyclic Anti-cancer Compounds Derived from Natural Sources with their Mechanism of Action

Management of Colorectal Cancer

Phytochemistry and Pharmacology of Terminalia chebula: An Update

Quercetin, A Flavonoid with Remarkable Anticancer Activity

Introduction

Nanotherapeutics for the Treatment of Hepatocellular Carcinoma

Hepatocellular Carcinoma: Diagnosis, Molecular Pathogenesis, Biomarkers, and Conventional Therapy

Brain Tumor: An Insight into In-vitro and In-vivo Experimental Models

MDM2-p53 Antagonists Under Clinical Evaluation: A Promising Cancer Targeted Therapy for Cancer Patients Harbouring Wild-Type TP53

Analysis of Retinoblastoma Treatment Techniques with Fuzzy PROMETHEE

Tau-Targeted Therapy in Alzheimer's Disease - History and Current State

Subject Index

Breast Surgery

Pediatric Malignancy

Key Proteins and Their Roles in COVID-19

Pathophysiology

Clinical Milestones in Nanotherapeutics: Current Status and Future Prospects

Artificial Intelligence Played an Active Role in the COVID-19 Epidemic in China

Applications and Implementations of 6G Internet of Things

Histological Classification of Head and Neck Tumors

Types of Head and Neck Malignancy

Molecular Biology

Introducing the 188W/188Re and 144Ce/144Pr Plaques for Eye Cancers Brachytherapy

Potential Natural Products For Prostate Cancer Management: Prospects For Castration-Resistant Patients

Advances of the Current Therapeutic Approach for the Management of Breast Cancer

Sodium Bisulfite Conversion of Human Genome for DNA Methylation Studies

Subject Index

Indirubins as Multi-target Anti-Tumor Agents

The Prospects of CDK Targeting and Clinical Application of CDK Inhibitors in Cancer

Pro-Apoptotic and Anti-Telomerase Activity of Naturally Occurring Compounds

Alzheimer’s Disease and Proteasome: The Therapeutic Development and Management

Ribavirin Against Viral, Neoplastic and Inflammatory Diseases: Focus on Mechanisms of Action

Reactive Oxygen Species (ROS)

Pediatric Hematological Malignancies – Clinical Manifestation, Treatment and Follow-Up

The Life Cycle and Transmission of HPV Types

HPV Proteins and Their Functions

General Description of HPVs

Microtubules as Anti-Cancer Drug Targets

Perspectives in Breast Cancer Treatment and Principal New Agents

Cancer and its Treatment: Development of Anticancer Chemotherapeutic Agents from Natural Products

Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

Combined Hamartoma of Retina and Retinal Pigment Epithelium

Subject Index

Astrocytoma Tuberous Sclerosis

Von Hippel-Lindau Disease

Retinoblastoma

Persistent Fetal Vasculature

Coats` Disease

Retinopathy of Prematurity

Aging and β-Cell Proliferation, Molecular and Signaling Changes and What This Means for Targeted Regeneration

Fundamental Relationships Between Cancer Stem Cells, the Cancer Stem Cell Niche and Metastasis

Cyclin E and its Potential Use for Liver Cancer Prognosis and Therapy

Malignant Pleural Mesothelioma (MPM): Latent Disease

Introducing the ¹⁸⁸W/¹⁸⁸Re and ¹⁴⁴Ce/¹⁴⁴Pr Plaques for Eye Cancers Brachytherapy