Osteosarcoma

Preface

Potential Blue Bioresources to Develop Functional Foods

Functional foods are foods with therapeutic properties that enhance health along with nutritional properties. This review provides information about the potential of using marine ingredients to develop functional foods by elaborating on the nutritional and therapeutic effects of bioactive compounds found in marine bioresources. Microalgae, marine fungi, bacteria, marine invertebrates, vertebrates, and marine plants are marine resources, and some of the bioactive compounds obtained from marine resources are polysaccharides, fatty acids proteins, peptides, amino acids, many types of essential macro and trace elements, pigments, and phenolic compounds. Marine bioactive compounds have shown many therapeutic properties, including anticancer, antimicrobial, antioxidant, anti-proliferative, anti-inflammatory, antidiabetic, and immune regulatory activities. These compounds can be used in the functional food industry in the form of nano or micro-particles, liposomes, gels, liquids, solids, pastes, and emulsions to overcome the challenges that could occur during product formulation and processing. Overall, this book chapter reveals the important facts about marine bioresources (except Seaweeds) and their functional potentials that the majority are unaware of. It also identifies that future research studies should be carried out.

Subject Index

Human Topoisomerases and Caspases: Important Targets in Cancer Therapy

Cancer has always remained a major challenge to humanity with its rising morbidity and mortality rate making it uncontrollable. Current treatments for cancer offer limited efficacy and suffer from serious side effects. With a focus on making treatment safer and more effective, there is a need to identify novel targets and potent drugs for these targets. Recent years have witnessed significant progress in the discovery of targeted cancer therapy. On-going research in this field suggests that human topoisomerases and caspases are important molecular drug targets for anti-cancer drug development. Topoisomerases are DNA processing enzymes essentially required to maintain DNA topology during transcription, replication, recombination and chromosomal decatenation. Several new chemical classes of topoisomerase inhibitors including natural product derivatives are in clinical trials for the treatment of various human cancers. Several topoisomerase inhibitors such as topotecan, irinotecan, camptothecin, teniposide and doxorubicin are clinically approved for various cancers such as colon cancer, lung cancer, breast cancer, and many more. However, many of these inhibitors have also been associated with serious side effects during chemotherapy. Emerging data in recent years also suggests the role of topoisomerase inhibition in immunogenic cell death and activating anticancer immune responses making them potential combinatorial modalities for cancer immunotherapy. Caspases [1-12] belong to the family of cysteine-aspartic proteases responsible for the execution of cell death in apoptotic cells. Caspases play an important role in various non-lethal biological processes like cell proliferation, cell differentiation, intercellular communication, and cell migration. The dysregulation of apoptotic signalling pathways is considered one of the hallmarks of cancer. Hence the focus of cancer therapy is correcting this aberrant behaviour. Natural products such as alkaloids, flavonoids, diterpenoids, sesquiterpenes, and polyphenolics have been reported with various anticancer properties. In this chapter, we have discussed topoisomerases and the regulation of caspase functions through direct or indirect methods for anticancer drug discovery.

Application of d- and f- Block Elements and Their Compounds in Medicine

Recent Synthetic and Biological Advances in Anti-Cancer Ferrocene-Analogues and Hybrids

Cancer is among the most severe risks to the global human population. The enduring crisis of drug-resistant cancer and the limited selectivity of anticancer drugs are significant roadblocks to its control and eradication, requiring the identification of new anticancer entities. The stable aromatic nature, reversible redox properties, and low toxicity of ferrocene revolutionized medicinal organometallic chemistry, providing us with bioferrocene compounds with excellent antiproliferative potential, which has been the focus of persistent efforts in recent years. Substituting the aryl/heteroaryl core for ferrocene in an organic molecule alters its molecular characteristics, including solubility, hydro-/lipophilicity, as well as bioactivities. Ferrocifen (ferrocene analogues of hydroxytamoxifen) has shown antiproliferative potential in both hormone-dependent (MCF-7) and hormone-independent (MDA-MB-231) breast cancer cells. It is now in pre-clinical trials against malignancies. These entities operate through various targets, some of which have been revealed and activated in response to product concentrations. They also react to the cancer cells by diverse mechanisms that can work in concert or in isolation, depending on signaling pathways that promote senescence or death. The behavior of ferrocene-containing hybrids with a range of anticancer targets is explained in this chapter.

Subject Index

Current Trends in Target-Specific Delivery of Phytomedicine: A Possible Strategy for Cancer Treatment

Cancer is a leading source of illness and mortality around the world. Despite the fact that primary cancer treatment has considerably reduced cancer mortality, the survival rate remains low due to tumour metastasis, a variety of adverse medication responses, and drug resistance. Alternative medicines, particularly herbal medications, have piqued the interest of scientists due to their high efficacy and low toxicity. However, their limited water solubility, low stability, poor absorption, and quick metabolism limit their therapeutic usefulness. Due to these constraints, the focus of phytocancer therapy has switched to tailored drug delivery systems. Nanomedicine, which involves using nanoparticles as drug delivery vehicles to boost the therapeutic benefits of phytochemicals, has a wide range of uses in cancer treatment. Many challenges in drug delivery to cancer cells can be overcome by using nanoparticulate drug carriers, including improved solubility and bioavailability, drug targeting, reducing adverse effects in non-target organs, high efficacy, low drug resistance, and high drug concentration at the tumour site. The present review entails the most recent advancements in anticancer phytodrug delivery employing nanocarrier-based technologies.

Allium Species: A Remarkable Repertoire of Nutraceuticals with Anti-cancer Properties

Cancer - the name evokes fear and anxiety. Researchers are working tirelessly to bring hope to countless patients by developing prevention and treatment strategies. One approach is dietary modulation - which is documented to reduce the risk of cancer and increase the benefit of anti-cancer therapy. Allium species are a part of the daily diet in most parts of the world. Important members of this genus - chives, garlic, onions, and shallots add flavour and nutrition to food. These are prized for their organosulphur compounds and flavonoid content which are responsible for their diverse pharmacological activities. Traditional and scientific literature shows that dietary intake of Allium species prevents and aids the treatment of different cancers. In this review, based on an extensive search of available databases, the role of Allium species as nutraceuticals for cancer management was examined to ascertain the truth in the popular claims. Preclinical and clinical investigations show that consumption of the Allium members as a part of the diet and also the functional components (e.g., allicin, diallyl disulphide, diallyl trisulphide, ajoene, S-allyl cysteine, S-allyl mercaptocysteine, tuberoside M, onionin A, fisetin, quercetin, etc.) reduce risk of cancer and have significant antitumor activities. These act by varied mechanisms, including inhibition of gene expression, promotion of apoptosis of cancer cells, antiproliferative activity, and anti-oxidant and anti-inflammatory effects. It is emphasised that standardization of Allium products, their efficacy, dosage, safety profiles and interactions should be ascertained to corroborate their use. This article highlights the importance of Allium species for their prophylactic, therapeutic and immune-boosting ability in cancer management.

Polymer Composites in Tissue Engineering

A composite is a multiphase material made of layers of stacked phase i.e., a matrix, an interface and a reinforced phase. The matrix phase is the main constituent of a composite. The interface binds the matrix and the reinforced phase, whereas, the latter provides strength to the material. Based on the matrix and the reinforced phase, it may be classified into various types such as fibers, particles, polymers, ceramics and metals. Polymer composite is a sub-type of composite having a polymer matrix and different reinforced materials. Due to its biocompatible nature, it is widely used in the field of biomedical applications. Many manufacturing methods are used in composites, but some of the commonly used manufacturing techniques include hand lay-up, reinforced reaction injection molding (RRIM), centrifugal casting, etc. High strength, and ductility with lightweight, cytocompatibility, and non-toxicity are some of the properties due to which composite materials are widely used in various industries such as automobile, aerospace, sports equipment, and tissue engineering. In tissue engineering (TE), a biomaterial called a scaffold, is developed that evolves into a functional tissue. Enhanced cell proliferation, cell adhesion and cell viability are observed with the composite-developed scaffold. Scaffold is fabricated using two types of composites; natural and synthetic composites. The applications of polymer composites at the bioengineering level are of great interest nowadays. This chapter intends to study various physicochemical properties of polymer composites including their bioengineering/tissue engineering applications elaborately. The study investigating the physicochemical properties and bioengineering/tissue engineering applications of polymer composites may bestow valuable insight into the potential of polymer composites in modern science.

Subject Index

Chromosome X

X Chromosome is the sex chromosome that is found in many organisms. Both males and females, including mammalians, have X Chromosomes. Females have XX sets of chromosomes, and males have XY sets of chromosomes. X Chromosome aids in identifying the sex of the organism. The Human X chromosome contains approximately 1500 genes. These genes may undergo some genetic alterations and eventually lead to complex diseases. Genetic mutations in some of the genes of the X chromosome are associated with cancer. Some specific mutations are observed in human cancer cells. This chapter specifically relayed on X chromosomal genes that are associated with different types of cancer and gave information on the location of the gene in the X chromosome. Moreover, the function of the specific gene and information regarding how many types of cancers were associated with a particular gene, has also been provided.

Chromosome 22

When the collection of human Chromosome 22 was first suggested in 1999, it became the most extended, non-stop stretch of DNA ever decoded and assembled. Chromosome 22 became the first of the 23 human chromosomes to decode due to its minimal length and affiliation with numerous diseases. Chromosome 22 involves several genes that contribute to cancer genetics in one way or the other. The contribution of chromosome 22 in abnormalities is evident through somatic translocations, germline and somatic, and in certain cases, overexpression of genes. One famous example is the Philadelphia translocation, particularly in chronic myeloid leukemia cells. Various gene contributions about types of cancer such as Acute Myeloid Leukemia, colorectal, lung, breast cancer and many more have been reported in studies related to chromosome 22. This chapter takes a run-through of important targeted studies of a gene that facilitates itself as a part of cancer genetics.

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 19

Gene is considered discrete coding units that contain the information for individual proteins. These lot of genes were combined and named DNA which is tightly coiled many times over the histone protein to form Chromosomes. Humans have got 23pairs of chromosomes, including the sex chromosome. The current study is about the major genes and their functions that are present in chromosome 19. There are approximately 1500 genes present in this chromosome, and changes in chromosome 19 are identified in many cancers. Dislocation of the chromosome, a mutation in genes that are present in a chromosome (rearrangements, deletions, or duplications) of DNA in the chromosome, epigenetic modification, and lifestyle changes are some of the chromosomal abnormalities that are responsible for cancer-causing. These changes will trigger the growth of normal cells and induce cancer cell proliferation, migration, invasion, angiogenesis, and metastasis. The signaling pathways like PI3K/AKT, JAK/STAT, NF-κB, and TGF-β are responsible for the various cellular functions with the result of autocrine, juxtacrine, intracrine, paracrine, or endocrine. When the dysregulation of these signaling pathways leads to cancer progression and metastasis. Prostate cancer, breast cancer, gastric cancer, pancreatic cancer, colon cancer, gastric cancer, lung cancer, leukemia, and cervical cancer are the major cancers that are caused because of mutation that occurs in chromosome 19.

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 17

Cancer is a disease in which the body's cells divide disorderly and are likely to spread to other organs. It has always been one of the world's top causes of death. A growing population, low mortality rate, and lifestyle changes lead to an increase in the number of cancer cases. It can be caused by genetic or environmental factors or a combination of both. The risk of cancer increases with age as the body loses its ability to eliminate the damaged cells. Cancer-causing genes can be inherited or acquired due to exposure to carcinogens. Cancers are inherited when a mutation occurs in the germ cells. The carcinogens can alter the DNA of a normal gene (a proto-oncogene) converting it into a cancerous oncogene. Genes that slow cell division, fix DNA errors, or undergo programmed cell death (apoptosis) are tumor suppressor genes. Tumor suppressor genes that don't function properly can cause cells to develop out of control, leading to cancer. Cancer expresses itself differently in each individual, making it challenging to identify and treat. Studying the types of genetic mutations, as well as the genes, proteins, and signaling pathways involved in cancer formation will help better understand the underlying cause of cancer. Identifying which genes are expressed in various cancer types will enable scientists to develop novel techniques for curing the disease. This chapter will explain how different cancer types are linked to specific genes and their locations on chromosome 17.

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.

Subject Index

Herbs for Cancer

In the present era of modernization, the new generation differs from the lifestyle maintained in the ancient period. A few decades ago, it was a regular practice of major community, i.e., Early to bed and early to rise, where the body’s clock and nature's clock were more or less similar. During this period of modernization, there was a tremendous change in lifestyle, including daily activities. This results in an early facing of severe problems. Modern medicines very well deal with such issues, but long-term regular use of such medication can affect vital organs in the future. Medicinal herbs have been used worldwide as supportive treatment to minimize the toxic effects of chemotherapy and radiotherapy. Many clinical studies have reported the beneficial results of herbs in combination with conventional therapeutics on the patients' survival, immune modulation, and quality of life. One such disease is cancer, wherein medicines have various side effects and immunity suppression effects. The present chapter deals with different herbs, their role in cancer treatment, and the side effects of their treatment. Here in this chapter, herbs are briefly reviewed that are used for treating various cancers. Different research work and clinical studies are mentioned here that showed the anticancer activities and their effect on various biological pathways. The use of a dietary regime along with medicinal herbs for better results is also a part of Ayurveda to be followed. The state of balance between doshas and dhatus is essential while using herbs in all aspects. This review may help to provide the utility of various herbs in various aspects of cancer and its treatment.

The Utilisation of Animal By-products for the Production of Potential Biomaterial in Tissue Engineering and Regenerative Medicine

The development of biomaterials in tissue engineering has already started decades ago. A wide variety of biomaterials are being used as alternatives in clinical applications. Lately, animal by-products have increased in demand for natural substrates in various sectors. As in tissue engineering, animal-based biomaterials are from different resources or origins of animal species that are being studied and applied for disease treatments. In addition to this, novel biomaterials are being produced that could imitate the physiology of natural healing mechanisms or the regeneration of certain tissues. Thus, the efficiency in utilising animal by-products could alleviate the waste management cost and scarcity of materials, which could reduce environmental pollution. This book chapter discusses different classifications of animal byproducts, their unique characteristics, and the advantages of these products that could embark as new alternative approaches for treating diseases.

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.

Biosynthesis of Nanomaterials via Plant Extracts

Nanoparticles (NPs) have become a hot research material in many fields, such as catalysis, sensing, clinical diagnosis, medical treatment, antimicrobial agents, and environmental remediation, due to their small size, high surface area, high reactivity, and unique optical, electrical, and thermodynamic properties. The type, morphology, size, and surface function modification of NPs determine their performance and application scope. The development of green, simple, and controllable NP synthesis methods is an important research direction at present. The biosynthesis of NPs is a kind of green synthesis method that uses organisms or biomolecules to reduce NP precursors. The reaction conditions are mild, the energy consumption is low, and there is no need for expensive equipment or harmful chemicals. It has been developed into an important branch of nanobiotic technology. This chapter summarizes the latest progress in the synthesis of NPs from different plant tissue extracts. It also summarizes the biosynthesis mechanism and application of NPs, analyzes the main problems faced by the biosynthesis method, and prospects its future research direction.

Chromosome 10

Chromosome 10 contains various genes that are significantly involved in tumorigenesis. These genes described herein that play roles in cancer comprise receptor tyrosine kinases (FGFR2), proto-oncogenes (FRAT1, RET), tumor suppressor genes (PTEN, KLF6), and also genes involved in signal transduction (MAPK8), gene fusions (CCDC6, KIF5B, VTI1A), developmental processes (GATA3, NODAL), Epithelial- Mesenchymal transition (ZEB1, VIM) and epigenetic regulation (MLLT10). This chapter provides a compilation of many such genes from Chromosome 10 that are associated with cancer, with vivid delineations of the underlying molecular mechanisms of each gene in its contribution to cancer initiation, progression and metastasis. Genes that are insufficiently investigated but implicated in tumorigenesis have also been described in this chapter.

Chromosome 8

Chromosome 8 spans more than 146 million DNA base pairs, and represents between 4.5 and 5 percent of the total DNA in cells. Sixteen percent of these genes and their mutations have been identified to play a role in cancer development. Cancer is a genetic disease at the somatic cell level. Multiple gene mutations usually precede them throughout one’s life. Oncogenes such as Myc, Lyn, Atad2, etc., from chromosome 8 promoted cancer cell proliferation, invasion, and migration. The increased expression of these proteins can transform a normal cell into a cancer cell. Chromosome 8 also houses multiple tumor suppressor genes, such as Dlc1, E2f5, Gata4, Ido1, etc. These proteins, when expressed, reduce the chances of tumor initiation within cells. Thus, mutations leading to the reduced expression of these genes are associated with multiple cancers. Mutation of other functional genes like Ank1, Ctsb, Ext1, Il7, etc., has also been implicated in various cancers for their role in increasing the invasive nature of cancers by regulating angiogenesis and facilitating cancer metastasis. Cancers can also stem from the translocational mutations of genes in chromosome 8. This chapter explains essential cancer genes, genetic mutations, and gene variations that can cause an increased risk of cancer and its progression.

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.

Chromosome 5

Chromosome 5 presents an extensive collection of genes, and includes several cancer-associated ones. The contribution of chromosome 5 in abnormalities is evident through somatic translocations, germline, somatic, and, in some instances, expression of genes. Various syndromes are associated with chromosome 5, such as 5q minus syndrome, leading to the development of acute myeloid leukemia, PDGFRBassociated chronic eosinophilic leukemia contributing to acute myeloid leukemia, and myelodysplastic syndromes. Studies propose that a few genes on chromosome 5 play important roles withinside the increase and department of cells. When chromosome segments are deleted, as in a few instances of AML and MDS, those crucial genes are missing. Without those genes, cells can develop and divide too speedy and in an out-o- -control way. Researchers are trying to perceive the genes on chromosome five that might be associated with AML and MDS.

Chromosome 3

Myriad genes in the genome have been implicated in cancer. However, a focused compilation of genes from the same chromosome would provide a valuable detailed yet succinct catalog for researchers, advantageous in quickly understanding the leading roles played by these genes in cancer. This chapter fulfills the above aim of furnishing a pocket dictionary- like a concise yet meticulous explanation of many genes from Chromosome 3, describing these genes’ functional essentialities in various cancers. Such a judicious collection of genes from a single chromosome is probably the first of its kind. The multiple inputs in this chapter from Chromosome 3 include oncogenes (BCL6, RAF1), tumor suppressor genes (SRGAP3, FHIT), transcription factors (FOXP1, MITF), fusion genes (MECOM), and many other types. With approximately 1085 genes spanning 198 million base pairs, Chromosome 3 constitutes 6.5% of the total DNA.

Application of Bioceramics to Cancer Therapy

Despite the great medical developments, cancer remains the main cause of death amongst individuals under 85 years. Novel therapeutic approaches for cancer therapy are constantly being developed, and bioactive ceramics show great promise in this respect. Bioceramics contain inorganic components, which help in the repair, replacement, and regeneration of human cells; for that reason, their use is growing in scope. Bioceramics have a flexible nature and can be modified with biologically active substances for a particular treatment or improvement of tissue or organ functionality. Materials, including glass-ceramics and calcium phosphate, can be loaded with specific drugs, growth factors, peptides, and hormones in a particular fashion. Also, for the elimination of infections and inflammations after surgery, the surface of bioceramics can be modified, and antibiotics can be introduced to prevent bacterial biofilm formation. In the context of bone cancer diagnosis and treatment, mesoporous bioceramics have demonstrated excellent properties not only for being osteoinductive and osteoconductive but also for drug delivery, therefore, being rendered as a remarkable platform for the creation of bone tissue engineering scaffolds for the purpose of bone cancer treatment. Furthermore, the creation of ceramic magnetic nanoparticles as thermoseeds for hyperthermia exhibits promising development for cancer treatment. The conjugation of ceramic nanoparticles with therapeutic agents and heat treatment via different magnetic fields improve the efficacy of hyperthermia to the extent that it makes them an alternative to chemotherapy. This chapter discusses the therapeutic value of bioceramics.

Anticancer Delivery: Nanocarriers and Nanodrugs

Cancer is a disease in which cells grow uncontrollably and spread to different tissues. Existing treatment methods developed for cancer do not allow this disease to be completely cured, and these methods have various side effects. The search for effective cancer treatment has encouraged scientists to produce new ideas with nanotechnological methods. With the help of nanotechnological methods, which are becoming more popular day by day, the material is reduced to nano size, where it shows quantum effect, and gains unique physicochemical, mechanical, and biological properties. Thanks to the large surface area of the nanocarriers, more drug loading can be achieved on the unit surface, and their easy modification procedures enable these materials to be conjugated with biological molecules to become more specific structures. Due to the several advantages of nanocarriers, such as different synthesis methods, being open to modification, and relatively easy production, these materials can provide effective delivery of cancer drugs and even increase their efficacy. Moreover, there are also many nanodrugs approved for different routes of administration. Thanks to all these features, nanocarriers are promising ways to develop new drug formulations for cancer treatment. In this chapter, the anticancer activity of nanocarriers synthesized by different methods is clarified. Besides, the effects of the nanocarriers on different types of cancer, the targeting strategies of nanocarriers, and the effects of their size, surface charge, and shape, on their anticancer activity are summarized.

Innovative Approaches to Prosthetics and Implants

The use of prosthesis plays an important role in rehabilitation in the case of congenital absence or loss of an extremity. Apart from lower and upper extremity prostheses, there is a wide variety of prostheses used in different parts of the body. Unlike limb prostheses, these are permanently placed in the body by surgical intervention and are also called implants. New studies emerge every day in the development of innovative prostheses and implants. These innovations include material selection, new material development, control strategies, feedback system development, sensor and actuator development, power supply methods, and power equipment development work. Besides, many studies aim to increase user comfort as well as acceptance rate and the useful life of prostheses. Some researchers are working to develop prostheses exclusively for the use of children. Innovative developments in prostheses and implants are examined in this section. Developments are presented from various aspects, and information is given about the research that has made significant contributions to the field. As an example of technological development in prosthetics, an autonomic tumor prosthesis developed for children with bone cancer is introduced at the end of the section as a case study.

Functionalization of Graphene and Factors Affecting Catalytic Performance

Carbon and its driven materials have been a foundation of living and nonliving systems for centuries due to their amazing experimental expressions in light, temperature, pressure, and pH. Being light-weighted and electronically active with equal energy partitioning in its four orbitals (2s12px12py12pz1), the C atoms have been at the core of natural sciences, providing valuable resources like high-grade wood, cotton, and many others. Thus, carbon-driven materials like diamond, graphite, and graphene ink have been attracting the attention of scientists, researchers, and industries. The chapter reviews recent chemical methodologies for the synthesis and structural investigation of graphene and its derivatives by various analytical techniques that provide information about basic knowledge to understand the role of graphene and graphene-based composites in various qualitative and quantitative applications. Here, several methods have been enlisted for the surface alteration of graphene oxide by a synthetic approach, such as ultrasound, a microwave-assisted synthesis that avoids the use of hazardous chemicals. Also, conventional methods have been discussed, including various types of reactions, such as nucleophilic, electrophilic, condensation, and cycloaddition. This review article highlights the key points to understanding the 2D carbon material for researchers and users to learn about the chemical modification of graphene at the initial stage. This write-up also discusses a brief explanation of various carbon nanomaterials that concern graphene and its oxide forms. We have explained the synthetic value of 2D carbon materials so that it covers a lot of the needs of researchers for synthetic aspects in graphene and allied fields of interest. Currently, such unique experiments are noted as milestones in the field of material synthesis for various applications. So, a review of chemically altered graphene materials reinforced with structural multi-functionalities is highly informative as a ready reckoner for needed information and understanding.

Natural Immunomodulators in Cancer Therapy

Cancer is a complex disease, ranking among the top causes of mortality worldwide. There are numerous therapies available however, they are showing limited success in a complete cure. The advanced treatment regime includes immunotherapy that improves the body's natural defences. The approved immunotherapies are imiquimod (Zyclara®), lenalidomide (Revlimid®) pomalidomide (Pomalyst®), and thalidomide (Thalomid®). However, these therapies have severe side effects like nausea, high blood pressure, blood clot, severe allergies, etc. Hence, natural products with immunomodulatory properties are being widely used as adjuvant therapy in cancer treatment. Plant secondary metabolites, such as curcumin, resveratrol, zerumbone, quercetin, genistein and betulinic acid, which are used as a member of the cancer medications and possess immunomodulatory potential, have been described in this chapter. We have discussed the mode of action, in vitro, in vivo, formulation studies and plant source of these natural immunomodulators. This chapter also discusses the current state of these pure compounds in context to their development as anticancer treatments in the future.

Saponins in the Treatment of Gastrointestinal Tract Cancer

The natural glycosides with triterpenoid or spirostaneaglycones are the saponins, which are associated with a wide range of therapeutic activities, inclusive of gastrointestinal anticancer activities. To promote research and development of novel cytotoxic agents against GIT cancer, this chapter focused on the anticancer potentia l of the naturally occurring triterpenoid and steroidal saponins. The in vitro assays and in vivo studies authenticated the anticancer potential of these compounds through antiangiogenic, anti-proliferative, anti-metastatic and anti-multidrug resistance activities. The protein targets and signaling cascades behind the anticancer effect of these compounds in GIT cancer are also discussed in this chapter.

Immunotherapy and Cancer Stem Cells

Immunotherapy is one of the important modalities in the treatment of cancer since it can directly target the tumor and its microenvironment with lesser side effects and cytotoxicity. The main goal of immunotherapy in the treatment of cancer is the reactivation of the immune system against cancer cells. In this way, the body fights against cancer using its immune system rather than relying on external agents which might be harmful to other healthy parts of the body. The development of monoclonal antibodies (Mabs) has delivered a significant therapeutic effect. Mab therapy is one of the most evolving techniques in cancer immunotherapy and has shown efficacy in controlling several types of malignancies. There are several other methods by which the activation of the immune system can be achieved, such as by using small molecules or by targeting ligands. Interestingly, studies have demonstrated that cancer stem cells have also been found as a target for effective immunotherapy. Additionally, the complete elimination of the cancer cells requires longer sustainability of tumor-specific T cells. Primitive results suggest that these T cells can be localized to tumor cells, mediating highly effective immunotherapy. However, despite these huge successes, several problems still persist and must be overcome. This chapter discusses the current and cutting-edge immunotherapeutic approaches to fight against cancer cells.

Cancer Types

Normally, to replace damaged cells or for the purpose of growth, healthy cells can divide according to the proliferation potency, in a systematic and controlled manner. When this mechanism is interfered with in such a way that the cell multiplies beyond the control system, a neoplasm may originate. The name (neoplasm) comes from the ancient Greek words neo, which means “new,” and plasma, which means “creation, formation.”. Even after the underlying trigger is removed, a neoplasm's growth is disorganized with that of the healthy surrounding tissue, and it continues to grow abnormally. When this abnormal neoplastic growth creates a mass, it is referred to as a ” tumor”. There are four primary types of neoplasms (tumor): benign (noncancerous), in situ, malignant (cancerous), and neoplasms of unclear or unidentified behaviour, which follow the pattern of cell development. Oncology is concerned with malignant neoplasms, which are commonly known as malignancies or cancers. In Oncology, many cancer classifications emerged, however, the most notable of which is based on the nomenclature by the type of tissue from which it arises, or by the primary site in the body where it originally appeared. Herein, this chapter will go over the definition of cancer, classifications as well as the key differences between the types of cancers. This chapter will also cover the pathophysiology and epidemiology of the many types of cancers.

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.

Swellings of Orofacial Structures in Children

Orofacial swelling is clinically a common problem found in pediatric dental patients. The causes of these swellings are mostly diverse, and the knowledge about specific clinical as well as imaging manifestations along with the most affected sites of these swelling is needed for the formulation of a differential diagnosis. Mid-facial nonprogressive swelling is usually suggestive of a congenital defect (like a cephalocele, nasal glioma, epidermoid cyst or nasal dermoid). Swelling that is slowly progressive, may be indicative of a neurofibroma, hemangioma, vascular malformation, lymph angioma, pseudocyst or fibrous dysplasia. In cases of facial swellings that are rapidly progressive and associated with cranial nerve deficits, rhabdomyosarcoma, Ewing sarcoma, Langerhans cell histiocytosis, metastatic neuroblastoma and osteogenic sarcoma should also be included in the differential diagnosis.

Subject Index

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.

Herbal Medicine: Prejudice to Realm of Reality Against TNBC

In triple-negative breast cancers, there exist tumor-specific vulnerabilities that can be targeted to avoid compensatory adaptation of cancer cells in response to standard pharmaceutical therapies. Natural moieties are well-known to possess a multitude of medicinal properties and deserve attention for TNBC prevention and therapy. To overcome drug resistance and efficacy issues, the exploration of natural moieties as targeting agents may emerge as dynamic, promising, and new therapeutic strategies to benefit TNBC patients. This chapter summarizes the role of polysaccharides, flavonoids, phenols, saponins, and taxanes in targeting TNBC. The potent role of herbal medicine in targeting molecular signalling pathways with special emphasis on their ability to target uncontrolled proliferation, metastasis, angiogenesis, and autophagy has also been discussed. Furthermore, the ability of herbal medicine in inhibiting PI3K/Akt/mTOR, STAT3, and Wnt/β-Catenin has also been explored. Combinational therapy comprising chemotherapeutic drugs and active plant constituents was also explored to overcome the complications of TNBC.

Neuroprotective Sri Lankan Plants: Back to the Future with Phytomedicine

Sri Lanka is listed as the top 34th biodiversity hotspot globally and has the highest biodiversity per unit area of terrestrial in the Asian continent. Intriguingly, it has been reported that 3771 flowering plant species are grown in Sri Lanka, of which 927 (24%) are endemic to the country, and 1430 species are considered medicinal plants. Surprisingly, it is reported that up to 40% of all new molecular entities submitted to the Food and Drug Administration (FDA) approval are either natural products or natural product-derived compounds. This chapter aims to explore the therapeutic potential of Sri Lankan plants/natural products in neuroprotection as possible synergistic targets of the nuclear factor erythroid (NF-E2)-related factor 2 (Nrf2) pathway. Nonetheless, the symptoms of neurological diseases are different; oxidative stress plays a central role in pathogenesis, thus, Nrf2 activation will counteract common pathogenic processes involved in neurodegener-ative/neuromuscular disorders. Therefore, targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurological disorders. However, when translating from the bench to the bedside, the knowledge of the timing of Nrf2 modulating compounds and dosage is crucial to define at which point should an Nrf2 activator be used versus an Nrf2 inhibitor. In this scenario, blends of natural products that synergize and provide multi-site action on Nrf2 regulation via different pathways are vital and will pave the way for the development of evidencebased effective neuro-nutraceuticals with a stride of innovation.

Combretastatin Derivatives as Tubulin Inhibitors: A Fascinating Journey from Nature to Drug Discovery Strategies

The combretastatins are a family of stilbene phenolic natural products isolated from the bark of the South African bush willow tree Combretum caffrum. Since their isolation and structural elucidation, these molecules have attracted a lot of interest due to their potent cytotoxic activity against several human cancer cell lines. Combretastatin A-4, a cis-stilbene, is the most potent member of these natural products, has the ability to strongly inhibit tubulin polymerization, resulting in high cytotoxic activity. Indeed, it also displays an additional activity as a potent vascular disrupting agent. This interesting double bioactive profile accounts for the potent antiproliferative and antivascular action in tumors. However, combretastatin A-4, due to the sensitive cis-stilbene moiety, is prone to isomerization giving the less bioactive trans-isomer and exhibits diminished water solubility. Hence, a wide panel of synthetic derivatives were therefore developed with the aim of overcoming these limitations. The development of prodrugs such as fosbretabulin, ombrabulin and Oxi4503 isrepresentative of successful attempts to overcome pharmacokinetic disadvantages, whereas the most recent approaches aim to develop combretastatin prodrugs able to selectively target tumor site, possessing also theranostic properties. Herein, miscellaneous and the most potent synthetic analogues are presented. In addition, a general outlook on combretastatin derivatives and drug delivery approaches based on innovative nanoformulations is also presented.

Subject Index

Additive Manufacturing in Developing Localized Controlled Drug Delivery Systems (LCDDSs)

Patients may show various defects to medications depending on race, gender, fitness, age, pharmacokinetic and health conditions. To address this challenge, there is a need to establish personalized, on-demand, programable and smart carriers that can control drug release with new and robust techniques. Additive manufacturing (AM) is the key sustenance of digital technology that has been developing and growing recently. AM offers several opportunities in localized controlled drug delivery systems (LCDDS), including materials recycling as well as on-site manufacturing, design freedom and full customization. Moreover, the industrial, biomedical and academic requests for AM for LCDDS have been continually rising, demonstrating significant marks for an extensive range of products. This chapter outlines AM approaches and their functions for LCDDS and describes AM technologies, such as recent advances in controlled drug release, as well as their processed materials and working principles. Furthermore, the benefits of 3D printing in the progressions of the LCDDS, the advantages of 4D printing, the impression of designing and material selection in these techniques are discussed. Finally, the potentials of AM approaches and their LCDD applications that designate a promising healthcare future are described.

Subject Index

The Fluoride Adsorption Isothermal Studies of Activated Alumina Modified with Different Materials: A Critical Review

Fluoride in drinking water has become a global problem that has a profound effect on teeth and bones, fostering various health problems. Adsorption is a potential defluoridation technique because of flexibility, cost-effectiveness, environmental friendliness, simplicity in design, relative ease of operation, and capability of producing high water quality. Although activated alumina is an appropriate adsorbent, it has a narrow favorable pH range, a tendency to form toxic aluminum fluoride complexes, and the problem of aluminum metal leaching. This article critically reviews the applicability of activated alumina and its modification by metal oxides, rare earth elements, organic materials, alkaline earth metals, and acid treatment. The effect of process parameters like pH, contact time, adsorbent dose, initial fluoride concentration, and the presence of coexisting ions on the adsorption capacity of fluoride ions is discussed. The adsorption reaction rates were discussed by fitting various rate models into the experimental data and the model equations. The adsorption isotherm models like Langmuir, Freundlich, Temkin, and Dubinin-Radushkevich tested on the adsorption equilibrium data to identify the best fit model for adsorption isotherm are discussed in this chapter. The chapter finally discusses the advantages, disadvantages, and future prospects of all the adsorbents in order to improve their fluoride removal capacity.

Subject Index

Insights into the Recent Application of Rosmarinic Acid in Therapy

Herbs are key players in many traditional health care systems that have been used in medical practices since ancient times. The beneficial therapeutic effects of these medicinal plants resulted from the combinations of their secondary metabolite. Nowadays, the use of natural compounds is increasing around the world due to their relatively mild potentials and low side effects, Polyphenols are the most important compounds that exhibit diverse activities. Among these polyphenols, rosmarinic acid (RA) attracted much attention from the researchers since it was isolated as the main compound in many plants, like those of the Boraginaceae and Lamiaceae families such as Rosmarinus officinalis (rosemary) and Ocimum baslicum (sweet basil). It is an ester of caffeic acid and 3,4-dihydroxy phenyl lactic acid, which has a wide spectrum of biological, pharmacological and medicinal properties that can be useful in many pathological conditions. Moreover, it presents anti-inflammatory effects, which are attributed to the inhibition of lipoxygenase and cyclooxygenases and interference with the complement cascade. Furthermore, RA has been shown to prevent cell damage caused by free radicals, thereby reducing the risk of cancer. On the other hand, it also exerts powerful hypolipidemic, antioxidant, anti-atherosclerotic, anticancer and even hepato-protective activities. The current chapter aims to highlight the therapeutic potential of RA against a wide range of diseases. Given the current evidence, rosmarinic acid can be used as part of the daily intake in the treatment of several diseases, with predefined doses preventing cytotoxicity.

Heliotropium, an Ethnomedicinal Plant: Past and Present Uses

The genus Heliotropium is formed of herbaceous plants belonging to the family Boraginaceae. In Chile and around the world, many Heliotropium species are commonly used in traditional and complementary medicine to treat various diseases. Members of this genus are also recognized for unique biosynthesized phytochemicals, mainly terpenoids, phenolics and alkaloids. Due to important phyto-constituents, as well as their therapeutic potential, many Heliotropium species have been subjected to chemical, biological and pharmacological investigations. This review details the many ethnomedicinal uses for Heliotropium, with an emphasis on Chilean species, and analyzes their scientific validation based on the chemical constituents and pharmacological properties of Heliotropium reported in academic publications. In addition, we discuss the critical conclusions, as well as some suggestions for future phytochemical and biological studies with Heliotropium species.

Natural Products as Anticancer Agents: Recent Advancement and Future Directions

Cancer is one of the biggest health-care challenges to human race and requires an innovative treatment strategy for cure. Undesirable side effects and rapid development of resistance to the conventional therapy have made the scenario more alarming. The chemical diversity of the natural products is immense and therefore is an amazing reserve for the finding of novel anticancer agents. Further, natural products have played a significant role in providing the novel and effective treatment inputs in the field on anticancer research. The compounds obtained from these sources range from a simple peptide, Dolastatin 10, to a complex polyether, Halichonrin B. Natural products have been source of many anticancer agents that are being used in clinical or pre-clinical trials. Further, many compounds derived from natural products have shown potential to be future anticancer agents. Due to their actions on numerous targets natural products are considered ideal for anticancer drug development. Further, their selectivity towards cancer cells is more in comparison to conventional treatment, so their toxicity is lower. This chapter summarizes the progress and ongoing developments in natural products and their analogs as anticancer agents. The challenges and future prospects of natural products based anticancer agents are also discussed.

Subject Index

Recent Advances in Synthesis and the Anticancer Activity of Benzothiazole Hybrids as Anticancer Agents

Cancer is known as a silent killer that wreaks havoc on our immune systems. Cancer is the leading cause of death in the majority of cases. Resistance to anticancer drugs is becoming more agile, which encourages researchers to develop more effective cancer therapies. Heterocyclic compounds have long been important in advanced medicinal chemistry. Among the various heterocyclic scaffolds, benzothiazole (BT) is one of the most privileged moieties with a diverse range of biological activities such as anticancer, antidiabetic, anti-inflammatory, antiviral, antifungal, and so on. A large number of novel benzothiazole derivatives have been synthesized. Some of the mechanisms used by BT to treat cancer include tyrosine-kinase inhibitors, topoisomerase II inhibitors, CYP450 enzyme inhibitors, Abl kinase inhibitors, tubulin polymerase inhibitors, and HSP90 inhibitors. In this chapter, we will discuss various benzothiazole-hybrid compounds that optimise potency as well as anticancer activity in a concise manner. The goal of this chapter is to highlight recent research on benzothiazole scaffolds and their anticancer activity against various biological targets. The chapter will also provide updates on benzothiazole-containing drugs that are currently in clinical trials as well as those that have recently been granted patents.

Role of Terpenoids as Anticancer Compounds: An Insight into Prevention and Treatment

The human population is affected by the wide range of malignant cancers. Several cancer treatment options, including surgery, radiation, chemotherapy, immunotherapy, and others, are available or within our reach. However, the excessive toxic effects that assimilate the negative impact on patients and thus impede progress in cancer treatment have yet to be identified. Recent efforts in the research and development of anticancer drugs derived from natural products have led to the identification of numerous heterocyclic terpenes that inhibit cell proliferation, metastasis, apoptosis, and other mechanisms. The anticancer activity of the terpenoids is quite promising, and it could lead to more opportunities for cancer therapy. The current chapter provides an overview of recent developments in the field of heterocyclic terpenes and their analogues as anticancer compounds. As a result, this provides an overview of the progress made in developing terpenes and analogues as potential anticancer agents, including their synthetic modification, SAR, and action mechanisms. The current studies are hoped to help researchers in increasing their chances of gaining breakthrough insights in the field that can be used in cancer therapeutic practise.

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.

Conclusion, Outlook, and Prospects: Bionanomaterials in Clinical Utilization

Nanomaterials have contributed to significant advancements in the realms of biotechnology and medicine. A holistic examination of the different biocompatible nanocomposites is discussed in this chapter. Their compatibility with state-of-the-art engineering techniques, such as additive manufacturing to design practical surgical implants, is also discussed. The importance and potential of nanocomposites and manufacturing processes in implantable medical device industries are also thoroughly considered. Nanomaterials' unique characteristics contrast with their large counterparts, such as high surfaces, reactivity, and reproducibility. Their incorporation in matrices has shown that the resultant composites' mechanical, chemical, and physical properties can be improved.Consequently, a wide variety of technical technologies, such as energy products, biomedical applications, micro-electrical equipment etc., have been intensively researched. Furthermore, the foundation for many new medicines and surgical instruments, including nanorobots, has been built on nanobiotechnology. It has been utilized in almost every medical sector, and its usage in the treatment of different diseases, such as cancer, neurobiology, cardiovascular disorders, joint and bone disorders, eye diseases, and infectious diseases, has been evident through different studies. Nanobiotechnology can promote diagnostics and the advancement of customized medicine, i.e., prescribing unique therapeutics that are tailored to an individual's needs. Many advances have already begun, and a definite effect on medicine practice will be felt in a decade.

Polymeric Nanomaterials for Cancer Theranostics

Despite global efforts for decades, the number of cancer cases is still on the rise. Although in recent times there has been significant improvement in immunotherapy, chemotherapy remains standard care for cancer patients alongside radiation and surgery. Chemotherapeutic drugs and diagnostic agents (MRI, PET, Ultrasound) lack specificity and often suffer from poor solubility and unwanted biodistribution. This results in unnecessary high dose requirements, systemic toxicity, and compromised quality of life for the patients. Beside therapy, early diagnosis is essential for the successful treatment and cure of cancer patients, just like any other disease. Therefore, a suitable delivery vehicle is always needed for the theranostic agents. Viral vectors are routinely used for the delivery of genetic material. But parallelly, nanoparticles made with biodegradable, non-toxic, and non-immunogenic polymers are often used as a carrier of chemotherapy drugs, diagnostic agents as well as genetic materials. Once decorated with specific ligands, these nanocontainers can deliver cargo molecules to target tissue and organs with high precision.

Subject Index

Fenugreek (Trigonella foenum-graecum L.): A Palatable Spice, An Active Herb, A Promising Functional Food, and Even More

Since ancient times, Trigonella foenum-graecum (fenugreek), a plant from the legume family (Fabaceae), is one of the most popular spices worldwide. Medicinal benefits and properties of this plant have been recognized. Fenugreek has a long history as a remedy for diabetes mellitus with a known effective anti-diabetic plant. The studies indicated that T. foenum-graecum has several important biological activities, such as potent immunomodulation-associated anticancer and anti-inflammatory effects. Besides the healing properties, it is stated as a functional food for promoting well-being and a tasty spice often used in the kitchens and the industrial fields. However, to the best of our knowledge, no research has been done so far concerning this plant as a comprehensive literature search. In this chapter, we discuss how fenugreek may be beneficial in clinical and prophylactic health and what further research is necessary to understand whether regular consumption can contribute to healthy living generally

Phenolic Compounds and their Biological and Pharmaceutical Activities

Phenolic compounds play an essential role in plants and foods. These

compounds are well known for their biological and pharmaceutical activities. These

compounds act as colorants and antioxidants. Research on phenolic compounds is

mainly focused on their antioxidant properties. These compounds showed significant

effects on chronic degenerative diseases, such as central neurodegenerative disorders,

cataracts, macular degeneration (age-related), diabetes mellitus, cardiovascular

complication, and cancer. These compounds also showed implications on human health

since increased exposure to free radicals might lead to an increased risk of degenerative

diseases. Fruits and vegetables are rich in phenolic compounds. The phenolic

compound consists of one (phenolic acids) or more polyphenols aromatic structures

attached to a hydroxyl group. The phenolic compound is found in combination with

mono or polysaccharides, and they can occur in the group as an ester or methyl ester.

Their biological and pharmaceutical activities are based on their phenolic ring and a

hydroxyl group. Apart from antioxidant activity, they have many other therapeutic

effects on human health. Among the several classes of phenolic compounds, flavonoids,

tannins, and phenolic acids are considered as main dietary phenolic compounds. In this

chapter, we have summarized the biological and pharmaceutical activities related to

different classes of phenolic compounds.

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.

APPENDIX: KALEVI KAIREMO’S LIFE

FDG Uptake by Brown Adipose Tissue in Paediatric and Adolescent Hodgkin Lymphoma, Visualised on PET/CT Performed at Diagnosis

We aimed to shed some light on the relation between brown adipose tissue

(BAT) visualisation on FDG PET/CT at diagnosis in children with Hodgkin lymphoma

(HL) and the main determinants reported in adult HL, outside temperature, gender, age,

but also with the metabolic activity of HL lesions and of some organs that did not look

to be invaded by HL.

Pre therapeutic FDG PET/CT was performed in 135 children or adolescents suffering

from HL and was centrally blind read, in search for BAT visualisation, determination

of SUVmax of the liver, the bone marrow at the iliac crest and the spinal cord at Th12,

providing those sites did not show focal uptake evocative of HL. The maximum

SUVmax, total metabolic tumour volume, and total lesion glycolysis of HL were also

determined.

The visualisation of BAT as foci of FDG uptake in those patients with paediatric HL

was not significantly associated with gender, age, the outside temperature on the day of

PET/CT, the intensity of FDG in non-invaded organs and maximum SUVmax of HL

tumours. There was a trend for an association with lower tumour volume and lower

total lesion glycolysis of HL that did not reach the statistical significance level.

Our study confirms, in 135 paediatric HL patients at diagnosis, i.e. a homogeneous

clinical status, previous evidence derived from heterogeneous conditions, that the

epidemiology of BAT activation is quite different between paediatric patients and

adults. In relation to HL, BAT activation was not linked with the metabolic activation

of the liver, the bone marrow, and the spinal cord, which may be observed as a consequence of HL presence in the patient. Nevertheless, our results suggest that BAT

visualisation could be associated with a lower HL tumour mass.

Subject Index

References

Introduction

Abstract

Osteosarcoma (OS) is a rare and aggressive bone tumor that impacts mostly children and

young adults. In spite of the numerous efforts made to date in the therapeutic field, OS still

presents a low patient survival rate, high metastasis and relapse occurrence, mostly due to

multidrug resistant cells. To surpass that, nanomedicine has been extensively investigated for

the targeted delivery of genetic material, drugs or both. Polymeric micelles (PM) are

nanosystems that facilitate the targeted transportation of poorly water-soluble drugs to cancer

cells. These nanocomposites are composed of amphiphilic block copolymers, such as

poloxamers, or Pluronics®, that self-assemble into a micellar structure when in contact with an

aqueous solution. Pluronics® F68, and P123 are widely used poloxamers in the

pharmaceutical area due to their advantageous characteristics. A micelleplex is formed from

the interactions of cationic amphiphilic copolymers with genetic material and/or drugs.

Cationic components of micelleplexes can be of natural or synthetic origin, such as chitosan

or polyethyleneimine (PEI), respectively.

miRNAs have been implicated as participators in the development, metastasis and

progression of OS. miRNA-145 is underexpressed in this disease and associated with a worse

cancer prognosis. We hypothesize that the delivery of miRNA-145 to OS cells via a

micelleplex composed of Pluronic® F68 and either chitosan or PEI, will be able to inhibit

tumor proliferation and migration.

In this work, we aim to elucidate the application of a micelleplex encapsulating miRNA-145

in order to achieve a targeted delivery to OS cells and overcome multidrug resistance, as a

new and viable treatment option. As such, we have developed and optimized a mixed PM

consisting of Pluronics® P123 and F68 and cationic graft copolymer F68-PEI.

Foreword

Nanoformulations and Their Therapeutic Advantages

Cancer therapy involves nanomedicine, which can provide a plethora of

advantages unattainable via conventional medicine as the materials of nano-level

exhibit unique physicochemical and biological properties. Both cancer therapy and

cancer therapy research utilize nanoformulations based on liposomes, polymeric

nanoparticles, solid lipid nanoparticles, metal nanoparticles, dendrimers, and

nanoemulsions for facilitating high specificity negating off-target toxicity, prolongedrelease

maintaining drug concentration and reducing dosing frequency, increased

solubilization and absorption, and penetration of impermeable barriers. The entrée to

this chapter is thus made with a brief description of nanomedicine, which is followed

by a description of the designing of nanoformulations for therapeutics. Explanations on

the types and advantages of nanoformulations are also given. The second section of the

chapter describes nanoformulations as therapeutics for cancer, explaining the different

targeting strategies and novel approaches involving nanoparticles. Like numerous other

cancers, nanoformulations are researched extensively in therapy for hepatocellular

carcinoma, the second leading cause of cancer-related deaths. The final section of the

chapter deals with the therapeutic advantages of nanoformulations in hepatocellular

carcinoma. The prominent nanomaterials investigated in hepatocellular carcinoma

therapy include nanoparticles of biopolymers, nanoparticles of artificial biodegradable

polymers, metallic nanoparticles, carbon nanotubes, and mesoporous nanoparticles.

Targeting of drug-loaded nanoparticles is achieved in therapy for hepatocellular

carcinoma via passive targeting and/or active targeting. A key milestone in

hepatocellular carcinoma therapy is the approval of the drug Zinostatin stimalamer, an

emulsion-based formulation, by the Japanese Ministry of Labour, Health, and Welfare.

Monitoring Therapeutic Response in Cancers: A Raman Spectroscopy Approach

Cancer is a multifactorial disease that is often asymptomatic and is thus

detected at an advanced stage. Late detection and resistance to treatment are two of the

major reasons for poor prognosis. The inherent limitations of conventional tools in

evaluating therapeutic responses, raise the need to monitor such responses during

treatment. Raman spectroscopy is a rapid, label-free, minimally invasive optical

vibrational spectroscopy technique that has been widely employed for cancer detection.

There is also significant literature on its applications in intraoperative surgical margin

assessment, chemotherapeutic drug monitoring, and prediction of radiation response.

However, most books and reviews focus on the diagnostic and screening applications

of Raman spectroscopy. This chapter describes the role of Raman spectroscopy in the

therapeutic monitoring of cancers and discusses its prospective applications. The

present work provides a brief introduction to the basic principles of Raman

spectroscopy, concise information on cancer aetiology, pathogenesis, diagnosis and

therapeutics, and applications of Raman spectroscopy in the therapeutic monitoring of

cancers. The role of Raman spectroscopy in monitoring conventional treatment

modalities such as surgery, radiotherapy, and chemotherapy, along with novel

treatment approaches such as immunotherapy and cold atmospheric plasma therapy, is

discussed in detail. The chapter concludes with a brief introduction to the emerging

field of Raman spectroscopy and artificial intelligence.

Subject Index

Marine Natural Products as a Source of Novel Anticancer Agents: A Treasure from the Ocean

One of the most deadly illnesses in the world remains cancer. New drugs with novel modes of action are urgently needed, recently, much work has been done on novel anticancer molecules derived from natural origins, particularly plants, microorganism and marine organisms. Marine natural products are repositories of novel bioactive metabolites containing different classes of bioactive substances and drug leads. This book chapter highlights the influence of marine organisms, with a specific focus on the ocean resources of marine plants, bacteria, algae, fungi, actinomycetes, sponges, soft corals, diatoms and ascidians, calculating above 90% of the overall ocean biomass. The cell lines and preclinical anti-cancerous effects of marine natural products were first introduced; their activity in preventing tumour development and associated compound-induced apoptosis and cytotoxicity was addressed. They are taxonomically distinct, having a high degree of efficiency and novel chemical structures that are pharmacologically active, creating tremendous potential for the progress of new anticancer molecules. These molecules have numerous pharmacological potentials, such as antioxidant, anti-tumour and antibacterial. Several marine anticancer agents have recently been extracted, characterized, described and are currently being studied for a clinical study. In this book chapter, we have attempted to assemble knowledge about the anticancer potential of marine products in a diversity of flora and fauna, as well as their probable mechanism of action. The molecular mechanisms that underpin the biological effects are also discussed. Finally, it addresses therapeutic methods and the present use of drugs extracted from the marine source, its future direction and limitations.

Chimeric Antigen Receptor (CAR) T Cell for Pediatric Solid Tumors: The Next Frontier in Cancer Treatment

Combiningthe advancements in genetic engineering technologies and the principle knowledge of cancer immunology, chimeric antigen receptor (CAR) T cell therapy has emerged as a promising therapeutic modality for cancers. The function of CARs is to redirect the immune response to attack cancer cells in a specific manner. Up to date, multiple CAR configurations have been designed to ensure safety and to enhance in vivo persistence and therapeutic potency. A number of clinical trials of CAR T therapy for pediatric solid tumors are underway, mainly focusing on neuroblastoma patients. Although CAR T therapy has been approved by the US Food and Drug Administration (FDA) for hematological malignancies, disappointing response rates have been reported in solid cancers due to several hindrances. Proper target antigen selection, inefficient T cell trafficking, and the immunosuppressive nature of the tumor microenvironment (TME) are the main factors limiting CAR T function. In order for CAR T therapy to become successful in this matter, these challenges must be addressed. The future of CAR T therapy is moving toward the development of the “off-the-shelf” universal CAR T product in the hope of providing cancer treatment to a large population. This chapter reviews the principles of CAR design, current clinical trials, limitations, and future prospects of CAR T cells for pediatric solid tumors.

Molecular Therapeutic Approach Focusing on Kinases

So far, there are 538 kinases found in the human proteome. Most of these kinases play a critical role in normal and aberrant signaling biology. In the last three decades, the kinase research field has exploded with myriad unknown findings related to kinases and their disease association. Based on these seminal findings, we can now assert that >85% of identified kinases are dysregulated in at least one or more diseases. Due to these remarkable statistics, novel kinase targeting strategies have been utilized, primarily involving small molecule inhibitors. So far, the FDA has approved around 80 kinase inhibitors (mostly small molecule inhibitors). Here in this chapter, we provide a description of kinases and their families, kinase-disease association and an up-to-date status of kinase-based therapeutics.

Bioinformatics in Precision Medicine

Bioinformatics plays an essential role in precision medicine. By developing analytical and computational frameworks, bioinformatics identifies and analyzes gene variants, altered patterns of transcripts and proteins, as well as other omics profiles generated by high-throughput platforms. The big data generated from biological samples require scalable algorithms, efficient computational workflows, and tools for interpretations. Precise diagnoses can be made upon identifying a particular pathogenic variant/mutation. Candidate (or actionable) targets for precise treatment can be obtained by analyzing molecular expression profiles from the disease states. This chapter describes the basis of bioinformatics and common workflows used to analyze and interpret omics datasets for precision medicine. This chapter also serves as the introduction to genomics, transcriptomics, proteomics, and metabolomics profiling, and thus complements other omics related chapters within this book.

Pharmacotherapy of Emerging Antiviral Agents

Anti-infective agents have been one of the greatest accomplishments of modern medicine, which has led to a decrease in the number of deaths caused by various infectious diseases. The anti-infective agents are a broad family consisting of antimicrobials, antifungals, antimalarials, antiprotozoal, antituberculosis, and antiviral agents. Viral infections have caused millions of casualties worldwide, leading to the need for the development of effective antiviral agents. Although the replication mechanism differs significantly between the viruses, all viruses undergo steps like attachment, entry, genome replication, gene expression, and assembly for the release of the virions into the body of the host. Treatment with antiviral agents is essential for blocking the replication of the virus, and the currently available antiviral therapies are directed according to the disease. Furthermore, the treatment with antiviral agents aims to eradicate the viral pathogen from the host and prevent the clinical manifestation. Infectious diseases, such as human immunodeficiency virus (HIV), hepatitis B, and hepatitis C virus (HBV and HCV), and influenza, are of significant global concern. On the contrary, the outbreak of newer strains of influenza virus and Zika virus, Ebola virus, strains of coronavirus (CoV) like severe acute respiratory syndrome (SARS – CoV), Middle East respiratory syndrome (MERS – CoV) and novel Coronavirus (2019-nCoV) are life-threatening viral infections that exhibit major challenges to the humanity. As of date, multiple effective virostatics that target specific viral replication steps are approved for the treatment of viral infections. However, the use of such agents is restricted given the rapid emergence of antiviral resistance, which remains a major concern of current antiviral therapy. In this chapter, we summarize recent antiviral agents that show promising clinical benefits in various phases of clinical trials and also consider them as potential therapeutic agents in the future. Besides, we highlight and analyze the development of novel inhibitors targeting various stages of the viral life cycle that act by distinct mechanisms against current and emerging viral infections. Many antiviral drugs currently available are based on the concept of traditional chemotherapy. Nevertheless, new developments and advances in molecular biology have opened up possibilities to alternate treatment approaches. Clinical trials to evaluate gene silencing mediated by small interfering RNA (siRNA) and antisense RNAs expression against infection with a respiratory syncytial virus (RSV) have recently been initiated. Moreover, in–vitro studies of antisense RNA or siRNA technology have shown promising results in various virus strains. Despite the recent advancements, the development of targeted delivery of antiviral RNA molecules remains a major challenge since DNA viruses and retroviruses can incorporate their genomes into human genomes. To emphasize, antiviral drugs against particular target proteins have been effective in the treatment of prevalent infectious diseases such as HIV and HCV. Thereupon, broad-spectrum antiviral drugs instead of antivirals against specific virus infections need to be designed. With the rapid development of in-silico tools and gene modification strategies, antiviral drugs with better therapeutic index and safety profile will be developed against infectious diseases in the future. In fact, the effective design of newer antiviral drugs will reduce the possibility of emerging antiviral resistance.

Towards Targeted Therapy: Anticancer Agents Targeting Cell Organelle Mitochondria

Mitochondria are the key source of energy in cells. In a cancer cell, mitochondrial metabolism is deregulated to compensate for the energy requirements of the dividing cells. Mitochondria play a significant role in apoptosis by releasing the pro-apoptotic factors, which are also altered in cancer cells. In this context, the role of mitochondrial bioenergetics in regulating cancer stem cells, chemoresistance, and malignant transformation is just beginning to be unraveled. Additionally, mutations in mitochondrial enzymes can result in oncometabolite production, which acts as signal transducers that help in tumour growth. Mitochondria also play an important role in immune system evasion by altering the tumour microenvironment. All these make mitochondria a key target for cancer therapy. The mitochondrial outer membrane protein BCL2 is an anti-apoptotic protein against which a small-molecule inhibitor, Venetoclax, has been approved to treat leukaemia. Arsenic trioxide, a small-molecule inhibitor that targets complex IV in the inner membrane, has been approved by the US FDA to treat acute promyelocytic leukaemia. Metformin, a complex I inhibitor of the electron-transport chain, has shown a better effect on cancers having a mutation in complex I genes. Several drugs that can modulate the mitochondrial dynamics and functions are being tested for their anticancer property. This chapter discusses the mitochondrial functions in normal cells versus those in cancer cells and cancer stem cells. Anticancer therapy targeting mitochondrial proteins and processes is also elaborated. A catalogue of known mitochondrial mutations involved in cancer is presented. Immunotherapy using mutated mitochondrial proteins or peptides and immunometabolism as a target for cancer therapy is also 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.

Prospects for Therapeutic Targeting of MicroRNAs in Brain Tumors

MicroRNAs (miRNAs) are small non-coding RNAs 18–24 nucleotides long and function as a post-transcriptional regulator of the expression of protein-coding target genes. It has been proven that normally microRNAs play an important role in various biological processes, including proliferation, differentiation, and apoptosis. Importantly, dysregulation of miRNAs is found to be involved in the pathogenesis of various human tumors, including brain tumors. Throughout the world, the problem of morbidity and mortality associated with brain tumors (e.g., glioblastomas multiforme (GBM)) has occupied a leading position for many years. Modern treatment strategies are based on surgery, chemotherapy, and radiation therapy. However, none of these treatments, alone or in combination, is considered effective. The data show that miRNAs can act as both a suppressor and an oncogene of tumor growth, regulating the processes of proliferation, tumor invasion, apoptosis, angiogenesis, immune response, metastasis, and drug resistance. While discussing recent studies targeting miRNAs to treat neuro-oncological conditions, we will discuss the advantages and possible limitations of miRNA-based gene therapy, the feasible methods for miRNA-based gene delivery, and the clinical therapeutic prospects of miRNA-based gene therapy for brain tumors.

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.

Cannabinoid-based Anti-cancer Strategies: Slowly Approaching the Bedside

Modulation of the endocannabinoid system has emerged as a potential therapeutic strategy for the treatment of diverse types of cancer and related pathologies. Thus far, the use of specific cannabinoids has been primarily approved for the management of chemotherapy-induced side effects. Palliative actions of cannabinoids include the control of nausea and vomiting, pain alleviation and appetite stimulation. Moreover, a growing body of research has exposed the anticarcinogenic potential of cannabinoids. In vitro and in vivo studies have shown that endogenous, plant-derived and synthetic cannabinoids can effectively modulate tumor growth in diverse cancer models. Although this has not yet reached the bedside, ongoing clinical trials and research efforts may approach cannabinoid-based antitumor therapies to cancer patients in the near future.

So far, studies on cannabinoids as antitumor agents have been mainly focused on understanding the mechanism of action of well-known phytocannabinoids such as Δ9-THC or CBD. However, novel cannabinoids with antitumor properties are also emerging in the literature. In this chapter, we aim to provide an updated overview of the therapeutic potential of cannabinoids in cancer. We will comprehensively summarize the diverse cannabinoid structures exerting antitumor properties analyzing the molecular basis of these actions. Recent and ongoing clinical trials will be considered to provide a deeper insight into the current scenario of cannabinoids in oncology.

Nigella Sativa (Prophetic Medicine): The Miracle Herb

Nigella sativa Linn. belongs to the family Ranunculaceae and is recognized as a prophetic medicine because of its mention in Prophetic Hadith, as a natural remedy for all diseases except death. It is known as Habat-ul-Barakah/Habat-ul-Sauda in Arabian countries and as Kalonji in India. As per Tibb-e-Nabwi (Prophetic Medicine), its daily consumption has been highly suggested. Considering its potential, ancient herbalists have termed it as ‘the Herb from Heaven.’ Ibni Sina, famous as Avicenna in the West, also referred to N. sativa as the seed “that stimulates the body’s energy and helps recovery from fatigue” in his great book “The Canon of Medicine.” Seeds and oil of N. sativa have a long history of folklore usage in various systems of medicines and food like Unani and Tibb, Ayurveda and Siddha. Numerous studies support that the seed of N. sativa and specifically its main active constituent, thymoquinone, has significant potential and possesses a broad range of biological activities like antihypertensive, diuretics, digestive, hepatoprotective, anti-cancer, appetite stimulant, anti-diarrheal, nephroprotective, neuroprotective, analgesics, anti-bacterial, and in treating skin disorders. In this chapter, we intend to present a comprehensive review of traditional and ethnomedicinal uses of Nigella seeds in different systems of traditional medicines. Then, the present chapter is directed towards highlighting the beneficial contribution of researchers to explore the pharmacological actions with the therapeutic potential of this miraculous herb and its bioactive compounds in modern medicine as in vitro, in vivo, and clinical studies to reveal its potential for the treatment of various diseases.

shRNA-Nanoparticle Conjugate as a Therapeutic Option

The recent trend of gene therapy includes the RNAi therapeutic approach. RNAi therapy comprises the delivery of siRNA, shRNA and miRNA molecules to the cells for gene silencing. Among these types, shRNA is a more stable knockdown method. However, bare shRNA molecules are large and they can not penetrate the cell membrane due to their negative charge and also they are fragile and degradable by RNase enzymes in the body. To overcome these problems, nanoparticles play a vital role. They encapsulate the shRNA within their structure and protect them from degradation. The nanoparticles are sometimes positively charged so they readily penetrate the cell membrane and are internalized by the cell. These features of the nanoconjugate made them a potential therapeutic agent. In this study, we intended to discuss the wide variety of nanoconjugates and their applications in diseases.

Scale-up, Preclinical and Clinical Status of Poly (Lactide-Co-Glycolide) and its Copolymers based Drug Delivery Systems

Poly(lactide-co-glycolide) or PLGA is a kind of a synthetic polymer that has been approved by USFDA for its use in humans. PLGA nano/microparticles have proved to offer controlled as well as the sustained release of several medicinal moieties. PLGA is chemically synthesized by direct polycondensation of glycolic acid (GA) with lactic acid (LA) and different factors like LA: GA ratio, storage temperature, the initial molecular weight of the monomers, and exposure time to water influences the physical properties of PLGA. Similarly, various factors like morphology, crystallinity, molecular weight, shape, size molecular, hydrophobicity, chemical structure, physicochemical properties, glass transition temperature are some of the crucial factors responsible for the biodegradation of PLGA. PLGA based micro/nanoparticles are generally prepared by the oil-in-water emulsification process. On the other hand, spray drying is one of the industrial methods for the production of PLGA particles. In this chapter, we have summarized the extensive applications, laboratory, and industrial-scale methods for the production of PLGA nano/microparticles, preclinical, and clinical status PLGA based drug delivery systems.

Current Status and Future Outlook of Deep Learning Techniques For Nodule Detection

This chapter reports that Artificial Intelligence (AI) in clinical oncology includes deep learning for detecting the lung nodules and other algorithms for analyzing the nodules to acquire an early diagnosis of nodules and tumors. Therefore, the early diagnosis is of great significance in the treatment of lung cancer or precancerous disease. Also, the early detection of nodules can improve the treatment effects and reduce the chance of misdiagnosis.

Cloud/edge Computing and Big Data System with 6G

This chapter gives a systematic introduction to cloud/edge computing and big data system. Cloud computing provides the ability to use flexible and telescopic services for cloud users and could implement through various hosted services provided by the Internet. Edge computing refers to the open platform which uses the network, computing, storage, and application core capabilities on the side of the object or data source and provides the nearest end service to avoid the relatively long delay to reach the data cloud center. Big data technology refers to the analysis of potentially useful information from a large number of data. Analysis of big data can get hidden patterns, unknown relevance, customer trends, and other messages to ensure comprehensive data management. In addition, the speed of 6G is faster, and its service field becomes more extensive compared with the previous generation communication technologies, which makes 6G play a more important or extensive role in the future of the technology field and society. In this regard, the authors also analyze the effect of 6G on cloud/edge computing and big data system. According to the future users' demand for 6G and the characteristics of 6G itself, cloud/edge computing and big data system will play an irreplaceable role in achieving high efficiency and benefits.

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.

Inhibition of Key Protein-Protein Interactions by Small Molecules for Cancer Drug Design

Human genome sequencing has revealed the complex nature of the human proteome. Researchers have been focused on mapping the proteome to find the right target for drug design. Inhibition of target proteins may be complemented by redundant forms of the proteins in the pathogenesis of diseases. Therefore, it is important to determine key proteins and their coordinating and/or cooperating partner proteins in protein pathways to design innovative chemotherapeutics. Computational and experimental studies indicated that approximately 200.000 protein-protein interactions (PPIs) have been predicted, with only about 8% identified in humans. PPIs play key roles in many important cellular processes, and especially their up-regulation is closely associated with each step of the tumurogenesis in cancer cells. Therefore, the identification of protein interactions helps researchers to design drugs for target specific cancer treatment. To understand the relations between tumorigenesis and p53- MDM2, c-MYC-MAX, Bcl-2/Bcl-xL, Hsp90-Hsp70, β-catenin-TCF4, and Menin- MLL interactions are an important approach to design specific chemotherapeutics for the treatment of individuals with cancer. This work focuses on key protein interactions on protein signaling pathways and designed inhibitors at these specific junctions in the literature.

Molecular Biology

Melatonin as an Anti-cancer Agent

Cancer is a disease that causes a huge health burden for communities. Despite the great progress made in diagnostic tools for cancer and the advancement of treatment strategies, cancer is still one of the commonest causes of death in the world. Melatonin, a hormone produced mainly by the pineal gland, possesses an anti-cancer property. The discovery of this effect of melatonin on cancer cells was a breakthrough in the field of cancer research. Several lines of evidence support this property of melatonin, including in vitro and in vivo studies and clinical trials. This effect of melatonin was examined in various types of cancer, and a consensus has been reached with regard to its oncostatic/anti-cancer effect. Multiple mechanisms have been proposed for this effect of melatonin, among which are the anti-oxidant, antiinflammatory, anti-estrogen/androgen, anti-angiogenic, and pro-apoptotic actions of melatonin. This chapter presents an account on the anti-cancer effect of melatonin, focusing on mechanisms of action by presenting examples of cancer types, including the most common types of cancer in the world: cancers of the lung, prostate, breast, and colon, as well as ovarian cancer.

Recent Patents on Exosome-Derived Therapeutic Agents

Exosomes are extracellular vesicles that are 30-150 nm in diameter. Exosomes have recently emerged as critical mediators of cell-cell communication by the transfer of DNA, RNA, and protein structured macromolecules between cells and tissues. With the advantage of the distant endocrine signalling, cancer cells use exosomes to suppress the immune system, next contribute to the formation of premetastatic niches and angiogenesis. On the other hand, researchers have been benefited from the immunosuppressive, natural carrier, and tissue regenerating roles of exosomes and disclosed patents that are claiming the utilities of exosomes for treating chronic inflammation, autoimmunity related diseases, targeted drug delivery vehicles, and tissue regenerating agents. Moreover, the use of exosomes as vaccine components to prevent cancer, therapeutic molecules for cancer treatment, and the host of biomarkers for the diagnosis and prognosis of cancer are among the issues that are protected by recent patents. The most inspiring one among them could be the incorporation of a therapeutic siRNA that is complementary to oncogenic KRASG12D into CD47+ exosomes for the treatment of pancreatic cancer. The other one could be the demonstration of the utility of exosomes secreted from dendritic as a cancer vaccine component in phase II clinical trial. It is clear that we have started to understand the fundamentals of exosomes. However, more studies are needed to develop exosomebased cancer vaccines, drug delivery vehicles, immune-stimulating agents that evoke immune cells to kill the cancer cells, and diagnostic and prognostic markers for monitoring cancer in the next years.

Osteosarcoma Cell Culture and Maintenance to Detect the Apoptotic Effect of Some Promising Compounds by Potent Markers viz. DNA

Osteosarcoma is the most common type of malignancy of bone and generally occurs among adolescent and young adults. Like the osteoblast cells of normal bone, osteosarcoma also forms the bone matrix, but the osteoid is not as strong as that of normal bones. Osteosarcoma is characterized by the production of weak or immature bones by the malignant cells. As the diagnosis of osteosarcoma is extremely poor, it suggests a critical need to develop some promising anti-osteosarcoma drugs to improve disease outcome. Many anti-cancer compounds induce apoptotic cell suicide via some potent cellular, molecular and biochemical markers. The cancer cell lines provide a valuable model system to study an extensive variety of cancer characteristics in the cell biology, genetics and chemotherapy or the impact of therapeutic molecules. The methods presented in this chapter describe the experimental technique used to culture the osteosarcoma cells for the documentation of DNA fragmentation and Caspase-3 activation associated with apoptosis.

Cancer Stem Cell Targeting For Anticancer Therapy: Strategies and Challenges

Cancer Stem Cells (CSCs) are those tumour cells, which possess the ability to self-renew, form a new tumour, produce progeny of multiple phenotypes and are responsible for maintaining the growth of the tumour. CSCs have different gene expressions and signalling pathways compared to other tumour cells. The mutation in the CSC gene is the main reason for cancer initiation, progression, metastasis, recurrence and drug resistance. Hence, targeting the CSCs selectively can cure the disease without much damage to the healthy tissues caused by traditional chemotherapy and radiotherapy. Previous works have shown various therapeutic strategies for cancer using new drugs molecules, nanomedicines, specific surface markers of CSCs, modulators of signalling pathways, agents for adjustment of the microenvironment signals, drug-efflux pump inhibitors, manipulators of miRNA expression, inducers of CSCs apoptosis and differentiation. A few selective novel compounds and therapeutic strategies targeting CSCs are presently in preclinical and clinical trials. This chapter highlights the novel strategies targeting CSCs for the successful treatment of cancer. The challenges in the development of new strategies leading to the eradication of cancer and recent patents issued in the area of CSCs targeting are also discussed.

Anticancer Agents: Plants Used in Ayurveda

Cancer is one of the deadliest diseases of the century. Though a lot is known about its pathogenesis, a cure for the disease is not yet available. The present therapies for cancer lack specificity and show various toxicities. Ayurveda is one of the oldest traditional systems of medicine along with the Chinese system of medicine, Siddha, and Unani. Cancer has been described as clinical entities arbuda and granthi in the famous ayurvedic text Sushrutha samhita centuries before the detection of cancer by modern medicine. In this chapter, we discuss the phytoconstituents of medicinal plants with anticancer properties as described in Ayurveda from ethnopharmacology and experimental pharmacology perspective. The chapter summarizes and emphasizes the importance of Ayurveda, a traditional system of medicine in the treatment of cancer.

Alternative Approaches to Antimicrobials

Historically, infectious diseases has been a major threat to human and other animals health and an important cause of morbidity and mortality. The introduction of antimicrobials in the first half of the twentieth century revolutionized medicine by substantially reducing morbidity and mortality rates from infectious diseases. Nevertheless, it was soon observed that bacteria could become resistant to antimicrobials, and resistant strains emerged shortly after the introduction of every new antimicrobial drug. Unfortunately, resistance is a natural and unavoidable consequence of antimicrobial use. For this reason, new antimicrobials are urgently needed, but so are additional approaches to protect the value of available antimicrobials. The discovery of a new antimicrobial is not an easy task where the scene is further complicated by a variety of interacting factors. In order to eliminate the spread of antimicrobial resistance, firstly, the inappropriate use should be reduced both in human and veterinary applications and alternative approaches should be considered. Until now, many alternatives, including plant-derived compounds, bacteriophages and phage lysins, probiotics, and into antimicrobial peptides from a variety of sources have been tested especially against resistant strains. These approaches are currently lacking in antimicrobial management, meanwhile, they have demonstrated considerable potential for application in other diseases. The review presents an insight into antimicrobials, particularly direct-food microbial, as well as other alternative products such as plant-derived compounds, bacteriophages and phage lysins, and antimicrobial peptides along with other alternative products, including novel approaches applicable to the field.