Hodgkin's Disease

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

Role of GSK-3 in the Regulation of Insulin Release and Glucose Metabolism

Protein kinase (PK) has always been an attractive target for the discovery of

new drugs. However, this year is significant for PK therapeutics since it marks the 20th

anniversary of the FDA’s approval of the first PK drug, imatinib, which was approved

in 2001 as the first protein kinase drug. GSK-3 is a serin protease protein kinase that

plays a key role in glucose homeostasis in our body. It also regulates insulin resistance

and the expression of glucose transporter. In type 2 diabetes mellitus (T2DM), glucose

homeostasis in our body becomes jeopardized due to poor glucose utilization by the

liver, muscle, and adipose tissue. GSK-3 is generally overexpressed among obese

diabetics; therefore, the GSK-3 inhibitor might be a better therapeutic target for the

discovery of new antidiabetic treatment. The lithium salt was experimented with as a

GSK-3 inhibitor using different animal models to evaluate its antidiabetic activity and

prove its action on glucose regulation inside cells. However, owing to the significant

toxicity of lithium salt in the development of colorectal cancer, the WNT signalling

pathway is inhibited. Currently, the major pharmaceutical companies are trying to

design and synthesize some GSK-3 inhibitors that are safe and effective for diabetics.

Some of these molecules are in the initial stages of the clinical trial to assess their

effectiveness. In this chapter, the role of GSK3 in the regulation of insulin release and

glucose metabolism was explained with a number of schematic representations in order

to facilitate biomedical scientists in the drug discovery process.

Free Radical Biology of Diabetes Mellitus

Free radicals play a pivotal role in the etiology of different diseases,

including diabetes mellitus (DM). In the past three decades, the understanding of the

fundamental role of free radicals in the etiology and disease progression of DM was

studied broadly. This chapter aimed to enumerate the recent progress in the areas of

free radical biology for the management of DM. Free radicals, as well as reactive

oxygen species (ROS), having extra electrons in their outer orbitals, react with all

biomolecules, including “protein, lipids, and DNA,” causing oxidative stress and

damage. DM is also associated with oxidative stress induced by the elevated production

of free radicals or reduced antioxidant activity. Recently, the importance of an

antioxidant rich diet, yoga, and exercise has been well documented for the management

of DM. Studies confirmed that exercise-induced ROS is an acute effect, while the

chronic effect of exercise produces endogenous antioxidant defences and promotes a

state of endogenous antioxidant defence mechanism. Therefore, regulating oxidative

stress will lead to a significant future area of research for DM disease management.

Subject Index

Updates on Pediatric Hepatoblastoma

The developing human liver is embryologically central in embryogenesis. It plays a significant role as a hematopoietic and endocrine organ. During the development, hepatocytes change their phenotype. They vary from blueish cells to cells with an eosinophilic nuance and decreased nucleus to cytoplasm ratio. Apart from congenital abnormalities of this organ and inflammatory conditions that can populate medical charts in childhood and youth, the liver's neoplastic transformation in childhood and adolescence is a rare event. In children younger than three years, the liver's most dramatic neoplasm is represented by the occurrence of hepatoblastoma. It is an embryologic tumor. It retains the suffix “blastoma,” similar to neuroblastoma as any other embryologic tumor. Hepatoblastoma originates presumably from the primitive embryo-fetal progenitors. In this chapter, we update our knowledge of this pediatric tumor, specifically the pathology and the treatment

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.

The Actual Role of Nuclear Molecular Imaging in the Follow-up of Chemotherapy-Induced Cardiac Dysfunction

The increase in life expectancy due to the increase in cancer treatment

success has made the follow-up of the acute, short and long-term cardiac side effects of

chemotherapeutic drugs more important today. Although chemotherapy-induced

cardiac dysfunction is one of the major problems, there is still a need for an accurate

and readily available non-invasive monitoring technique. In the present article, we tried

to evaluate past and present nuclear molecular imaging techniques from the perspective

of chemotherapy-induced cardiotoxicity monitoring.

Today neither nuclear imaging methods nor other techniques are sufficiently

accurate/readily available to use in clinical routine to show cardiotoxic effects of

chemotherapeutics at an early stage. However, nuclear molecular imaging can detect

biological processes at the molecular level that precede the structural changes and

pathological consequences of chemotherapy-induced cardiotoxicity.

Until today, many molecules to use with a conventional gamma camera or positron

emission tomography have been tried for this clinic pathology. Many of them have

been shown to have prognostic value in the early stages of the disease, but relatively in

small patient groups. However, sometimes due to difficulty in procuring, the lack of

comparative studies seems to prevent their value from coming to light. There is a need

for additional studies to clarify the role of nuclear imaging of cardiac damage in

chemotherapy-induced carditoxicity.

Theragnostics in Austria

Over the past decades, Professor Kalevi Kairemo has been a well-known and

dear colleague with whom we have excellently cooperated, especially via the

international organisations IAEA (International Atomic Energy Agency) and The

WARMTH (World Association of Radiopharmaceutical and Molecular Therapy). The

work resulted in the construction of radiotracers using different modal systems,

including a variety of radiolabelled peptide analogues such as somatostatin,

cholecystokinin (CCK-2/gastrin), or prostate-specific membrane antigen (PSMA)

ligand for specific tumour targeting. Radiopharmaceuticals are produced at clinical

grade in dedicated laboratories for use in SPECT/CT or PET/CT studies. Patients

evaluated by SPECT/CT dosimetry studies are treated with high dose thera(g)nostics.

Radioiodine ablation therapy of thyroid cancer remnants, peptide receptor radionuclide

therapy (PRRT) of NET patients, and peptide ligand radionuclide therapy (PLRT) of

PC patients are today the most important therapeutic tools.

Radiomolecular Therapy of Neuroendocrine Character, Positive for sst2 Receptor Hepatocellular Malignancies

In 1996, Krenning et al. injected the radiopeptide for the first time

intravenously.111In-Octreotide as a new treatment approach, today, worldwide known as

Peptide Receptor Radionuclide Therapy (PRRT) to confront unresectable

neuroendocrine tumors. We started treating this rare category of neoplasms in our

Institution in 1997, exclusively injecting intra-arterially, initially 111In Octreotide, in

high doses, focused our interest on multiple liver metastases (particularly, less than 20

mm, in diameter) after catheterization of the hepatic artery [“Aretaieion Protocol”]. The

radiopeptide was infused in repeated high activity, ranging per session from 4.070 GBq

(110 mCi) to 5.920 GBq (160 mCi) with a time interval between sessions of 6-8 weeks,

seeking to achieve a tumor absorbed dose according to the dosimetry followed, over 70

Gy (tumor mass 10 gr). When 90Y DOTA-TOC was used (3 folds in total, in bi-monthly

intervals between sessions), the infused activity was 4.1± 0.2 GBq per patient, per

session, whereas when n.c.a. 177Lu-TOTA-TOC was injected (6 folds in total, in bimonthly

intervals between sessions), the activity was 7.0 ± 0.4 GBq per patient, per

session. Follow-up at tri-monthly intervals was performed by means of ultrasonography

(US) and every six months, by contrast, material-enhanced computed tomography (CT)

and / or magnetic resonance tomography (MRI). This therapeutic procedure is

described in detail, based on the experience in more than 800 hundred catheterizations,

analyzing its advantages and limitations as a first-line treatment scheme for the

management of this rare category of tumors.

The Diagnostic Potential of Radiolabelled Neurotensin in PET Imaging of Patients with Pancreatic Cancer: Results from In Vivo, Animal And Human Studies

In nuclear medicine, multiple peptide receptors are recognized as potential

diagnostic and therapeutic targets. 68Ga-NT-20.3 radiopharmaceutical has been

developed for diagnosis of neurotensin receptors. Three neurotensin receptors subtypes

have been cloned: NTR-1, NTR-2 and NTR-3. NTR-1 is the most commonly expressed

neurotensin receptor. High NTR-1 expression has been observed in various tumours

including pancreatic ductal adenocarcinoma. 68Ga-labelled NT ligand was successfully

applied in in vitro, animal model as well as in human. The results on humans

demonstrated that PET radiopharmaceutical 68Ga-NT-20.3 is safe and well tolerated.

Based on the published data, NTR-1 is promising target for the development of

radioactive analogues for both imaging and therapy in patients with primary and

metastatic pancreatic ductal adenocarcinoma.

Subject Index

Future Direction of Nanotherapy in the Management of Hepatocellular Carcinoma

Worldwide, hepatocellular carcinoma (HCC) is one of the leading causes of

cancer-related deaths among humans. Several conventional therapies, including

surgical and non-surgical methods such as liver transplantation, radiation, and

chemotherapy, have been explored to combat this disease and improve the patients'

quality of life. However, due to poor diagnosis of the disease, drug toxicity issues, and

difficulties related to liver transplantation, scientists search for novel techniques to treat

HCC that ensure targeted drug delivery and help in diagnosing the disease.

Nanotherapeutics are a new trend in drug discovery and medicine which deals with

nano-sized formulations loaded with various types of materials such as drugs,

antibodies, aptamers, genes, viruses, etc., and targeted delivery. Moreover, controlled

release of the materials can be achieved through modifying their external and internal

structures as per requirement. Drug delivery through nano theranostics has taken a new

turn as the diagnostic tools tagged with the nano-architectures ensure diagnosis and

treatment simultaneously. Nanotheranostics have significant application in the

identification of cancer progression through continuous monitoring and treatment of

cancer. In this review, we will discuss different beneficial effects and applications of

nanotherapeutics against HCC. Along with that, different upcoming strategies, such as

personalized medicine, layer-by-layer technologies, implant theory, 3D printing

technology, nanorobots, nanocrystals, nano-chips, etc., will be discussed here, which

may pave the path towards successful diagnosis and treatment of HCC to improve the

health of the patients.

Recent Patents and Commercially Available Nanotherapeutics on Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a significant reason for cancerassociated

deaths. The diagnostic methods for early-stage detection are insufficient,

and there are limited treatments available for the late stages. Thus, novel approaches

from nanotechnology have gained much attention to overcome the major hurdles in

designing nanoscale materials that could be used in both diagnosis and treatments.

Recently approved patents showed that progress had been made with nanotechnology

in both diagnosis and therapy. The invention of HCC biomarkers, such as alphafetoprotein,

liver carboxylesterase 1, glypican-3, endoglin, or CD105, has made

significant progress in the area of diagnosis. On the other hand, methods for enhancing

the sensitivity and specificity of imaging in nuclear magnetic resonance using Ga3+ and

nanogold Computed Tomography (CT) contrast agents are noteworthy in the accuracy

of cancer imaging. Nanodrugs have long-circulating times inside the body while

enhancing the bioavailability of these drugs and improving efficacy without higher

doses. Polymer-based nanoparticles, liposomal nanoparticles, and magnetic nano-drug

vehicles are used in therapeutics to transport drugs like paclitaxel, docetaxel,

doxorubicin, and mitomycin. Antisense oligodeoxynucleotides of midkine, phosphoryl

N-fatty acyl nucleosides, siRNAs, and polypeptides have all been used. The long

period between clinical trials and commercialization of nanotherapeutics and key issues

related to clinical development should be addressed by eliminating the regulatory

hurdles limiting nanotherapeutics for HCC in the market.

Potential Nanoformulation Approaches for Delivery of HCC Therapeutic Agents

Hepatocellular carcinoma (HCC) is a major cancer type worldwide. The

major challenge with HCC is that it is usually detected at an advanced stage. After the

launch of the first drug Sorafenib against HCC in 2007, several other small molecules

and monoclonal antibody-based drugs have been launched to fight against HCC.

However, the survival rate in HCC is still very poor. This indicates that there is still a

necessity for more effective therapy or to increase the efficacy of the existing therapy.

Nanoformulation approach refers to such formulation approaches where the particle

size of individual particles or vesicles in a formulation range between 1-1000 nm. The

individual particle or vesicle could be either single drug particles or

nanosphere/nanocapsules having drug entrapped in polymer/lipid matrix or drug

connected with metal or metal oxide core. The idea of using nanoformulations for drug

targeting first came around the 1950s. Since then, countless research groups across the

world have advanced the field to the extent that several products based on the

nanoformulation approach have been launched on the market. Besides targeting,

nanoparticles can also help circumvent biopharmaceutical challenges of drugs, such as

dissolution, limited oral bioavailability issue, or formulating “hard to solubilize” types

of molecules for parenteral formulation. This chapter will review different

nanoformulation approaches that can be potentially applied for HCC therapy, their

manufacturing process, and therapeutic benefits. We will review the application of

different nanoformulation approaches for HCC specific therapeutic agents.

Preclinical Findings for Targeted Nanotherapies to Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is considered a major ailment throughout

the world, and conventional therapies including chemo and combinational have suboptimal

responses with toxicity and adverse effects. The use of conventional methods

becomes challenging, especially when the tumor cells adapt resistance rapidly, which

further limits their use. Nanotherapeutics for HCC show their potential with minimal

toxicity and enhanced degree of targeted drug delivery, which has attracted researchers

across the world to explore the various benefits of nanotherapeutics. This chapter has

briefly covered the epidemiology and incidence of HCC, its causes, stages, different

ways to diagnose HCC, its pathology, and conventional treatment options. We have

explained various targeted nanotherapeutic preclinical approaches such as lipidic

nanoparticles, polymeric nanoparticles, and liposomes for HCC. Surface-modified

nanoparticles and liposomes can actively target a wide array of overexpressed receptors

on the tumor surface. It can be seen from the literature that the nanotherapeutic

approach for the management of HCC has a high potential to become the mainstream

treatment platform if explored and tweaked appropriately. In almost all the works,

promising results were seen. Maximum amount of drug was delivered at the tumor site,

drug release at unwanted sites were prevented and selectively caused cell necrosis in

the tumors, while not affecting the normal cells. These remarkable outcomes further

strengthen the nanotherapeutic platform, showcasing its true potential.

Preclinical Studies on Nanocarrier-Mediated Delivery of Radiosensitizing Agents to Brain and Pancreatic Cancer with a Future Projection to Liver Cancer

Radiotherapy is one of the primary treatment modalities in oncology. The

therapeutic effectiveness of irradiation is dependent on the balance between the tumor

control probability (TCP) and the normal tissue complication probability (NTCP), i.e.,

the induction of side effects. Combination treatment of irradiation with chemotherapy

targeted to a tumor or using immune-modulating agents could significantly benefit

from nanotechnology strategies, allowing localized delivery of therapeutic compounds

to the irradiated tumor volume. When used in combination with irradiation, drugs

should be selected on their interaction with the 6 R’s, the six Hallmarks of

Radiobiology, to sensitize the radiation effect on the molecular, cellular, and tissue

level, and in addition to that, positively impact the TCP/NTCP balance. This chapter

presents and discusses preclinical data on the combination of irradiation and

nanocarrier-mediated delivery of drugs in the brain, pancreatic, and liver cancer. Before

implementation into the clinical practice, nanotechnology demands further technical

and biological studies on drug loading efficacy, drug release, cellular and tissue uptake,

biodistribution, tumor-targeting methods, and administration routes to the patient.

Notwithstanding those challenges, the combination of local radiotherapy with tumortargeted

nanocarrier-delivered radiosensitizers, as well as the use of radiosensitizing

nanoparticles, are exciting developments with a great clinical prospect.

Aptamers and Their Potential in Site-Specific Nanotherapy Against Hepatocellular Carcinoma

Globally, hepatocellular carcinoma (HCC) is one of the most devastating

neoplasia and has a remarkably high mortality rate. Furthermore, the long latent period

associated with HCC lends the diagnosis at the intermediate or advanced stages where

the chemotherapy is the solitary therapeutic intervention. The responsiveness of HCC

towards conventional chemotherapeutic agents is notably poor due to multiple factors.

Among them, multiple drug resistance, reduced drug concentration at the tumor site,

quicker clearance, and non-specific distribution are the prime causes leading to

remarkably high off-target toxicity and mortality. More importantly, the approval of

several multikinase inhibitors (MKIs) by the United States Food and Drug

Administration (FDA) for the treatment of HCC as targeted therapeutics has been

found to be inadequate to make a notable impact on survival. Therefore, ligand-based

targeted therapeutics capable of delivering the therapeutic modality specifically into

neoplastic hepatocytes have been explored extensively by researchers worldwide.

Among the plethora of HCC-targeting ligands, aptamer-based targeted therapeutics in

HCC have gained significant momentum compared to others due to some signature

characteristics of aptamer, namely non-immunogenicity, low cost, non-toxicity,

thermostability, simpler manufacturing, and high suitability for chemical modification.

Despite their enormous potential, aptamer-based targeted therapeutics are still in

infancy and require smarter thinking and quick translation from e-clinical to clinical

application. Thus, the fundamental focus of the book chapter is to highlight promising

features of aptamers, their production, chemical modification, mechanism of action,

and finally, detailed emphasis has been given on the overall scenario of aptamer-based

targeted therapeutics in HCC.

A Summarized View of Lipid, Polyplex, Inorganic, and Carbon-Based Nanotherapeutics for Hepatocellular Carcinoma Treatment

Liver cancer is one of the primary causes of global cancer deaths after lung

cancer and colorectal cancer. In 2021, an estimated 42,230 new liver cancer cases will

be diagnosed, and approximately 30 thousand people will die of these cancers in the

United States alone. Hepatocellular carcinoma (HCC) alone accounts for nearly 75% of

all liver cancers. Early detection of HCC enables multiple treatment choices resulting

in improved therapeutic outcomes. Unfortunately, most HCC cases are typically

diagnosed at advanced stages, resulting in poor survival. Among various treatment

modalities, chemotherapy remains the mainstay, particularly for treating advanced

patients. However, the major drawback of conventional chemotherapeutics is the lack

of cancer cell selectivity, leading to significant damage to healthy tissues. These

challenges can be circumvented with the help of targeted nanotherapeutics containing

anticancer drugs. These nanotherapeutics are increasingly favored over their

conventional counterparts due to their specific cancer cell targeting with low off-target

effects. Therefore, in this book chapter, we focus on different types of nanocarriers to

treat hepatocellular carcinoma. Furthermore, current nanotherapeutics in clinical trials

and the future perspective of nanomedicine in liver cancer are discussed.

Nanotherapeutics for the Treatment of Hepatocellular Carcinoma

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

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

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

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

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

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

an impending key for overcoming these challenges. Nanotherapeutics utilizes

nanosized or nanostructured materials to attain particular therapeutic and

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

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

Scientists have developed several nanomaterials like nanoparticles, nanogel, and

liposomes to deliver chemotherapeutic agents specifically to HCC sites with improved

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

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

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

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

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

suitability, and challenges of various nanotherapeutic approaches for HCC

management.

Nanoformulations to Limit Challenges of Conventional Therapy Against Hepatocellular Carcinoma – An Overview

The chapter primarily deals with different nano-drug delivery approaches to

overcome current HCC chemotherapy challenges. The objective of organizing the

various sections in this chapter is to highlight the different nanoformulations that are

currently being explored, benefits of nanoformulations over the free drug, different

approaches and molecular blocks utilized for preparation on different nanoformulations

and their applications in the context of the development of novel drug delivery

approaches in HCC. Conventional chemotherapy and its limitations for HCC, different

targeting approaches for HCC, need for nanoparticulate approach in HCC, different

strategies for delivery of nanoformulations with different targeting approaches,

different nanoformulations (liposomes, micelles, hydrogels, etc.) that are currently

studied in HCC, different molecular blocks under preparation, the current status of

clinical trials of different nanoformulations studied for HCC therapy and perspective

for futuristic role of nanoformulations in HCC have been discussed in the present

chapter.

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.

Hepatocellular Carcinoma and Therapeutic Challenges

Hepatocellular carcinoma (HCC) is the most common primary hepatic

malignancy and accounts for more than 90% of liver cancers. Despite HBV vaccination

programs and targeted therapies, the global burden of HCC is still increasing. Early

diagnosis of HCC has been crucial for selecting the best curative treatment options and

improving overall patient survival. Despite several advancements in surveillance

programs and diagnostic strategies, most HCC cases are still diagnosed at the late

stages when most of the current therapeutics become ineffective, making HCC one of

the main reasons for cancer-related deaths. Enormous heterogeneity in HCC poses the

most prominent challenges for scientists and physicians in designing perfect staging

systems and therapeutic selection for HCC patients. Although several HCC therapeutic

advancements have come up in the past decade, the current status is far from

satisfactory. At present, HCC therapeutics are struggling with several challenges: a

shortage of human donors for transplantation, drug resistance, lack of standard

operating protocol for immunotherapy, etc. Some clinical trials using single or

combination therapies are currently underway, hoping to overcome some of these

challenges. Constant improvement in HCC therapeutic strategies and prevention

measures provides optimism for further advancement in the coming future.

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

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

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

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

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

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

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

the mortality rate persists. Ongoing investigation on exploring molecular pathogenesis

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

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

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

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

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

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

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

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

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

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

the existing conventional treatment approaches.

Subject Index

Current and Future Treatments of Iron Overload in Thalassemia Patients

Iron overload is a major complication among thalassemia patients. In these

patients, ineffective erythropoiesis decreases hepcidin production resulting in iron

dysregulation, which leads to a number of serious complications. Damage to organs

susceptible to iron overload could be prevented by effective iron chelation. Despite the

efficacy of iron chelators, limitations to their use are that they are only used after the

patients have suffered from iron overload, and they have also been associated with a

number of side effects. New therapeutic strategies for the treatment of thalassemia have

focused on addressing the pathophysiology of the disease. Drugs currently being

developed to improve ineffective erythropoiesis are aimed at increasing hemoglobin

levels and subsequently decreasing iron absorption. The new therapeutic drugs in this

class include pegylated erythropoietin, JAK 2 inhibitors, and TGF-β activin receptor

traps (sotatercept and luspatercept). Luspatercept is currently recognized as the most

promising drug in this class and has completed phase III of trials. With the aim of

improving iron dysregulation, these new therapeutic strategies focus on preventing the

absorption of iron in the gastrointestinal tract. These therapies involve hepcidin

agonists and specific derivatives, such as LJPC-401 and Rusfertide (formerly PTG-

300), certain ferroportin inhibitors, such as Vamifeport (formerly VIT-2763) and

transmembrane protease serine 6 (TMPRSS6) antisense oligonucleotides. Although the

therapeutic potential of these new treatments in thalassemia patients is promising,

ongoing clinical trials are needed. Importantly, these new treatment strategies may

provide a new, more effective paradigm of treatment in thalassemia patients.

An Evidence-Based Approach to Treatment with Iron Chelators in Transfusion- Dependent Thalassemia Patients : Present Trends and Future Scenario

Treatment of hemochromatosis is a significant target-based care of

transfusion-dependent thalassemia and non-transfusion dependent thalassemia patients.

In some cases hemochromatosis is a secondary concern to frequent red blood cell

transfusions as in transfusion-dependent thalassemia (TDT) or advances from enhanced

gastrointestinal iron absorption such as in non-transfusion dependent thalassemia

(NTDT), this can cause serious illness and death to the patients. When thalassemia

major patients undergo frequent blood transfusions, hemochromatosis is unavoidable

because the human body lacks a physiological mechanism to evacuate extra iron.

Thalassemia patients with transfusional hemochromatosis regularly need treatment

with iron chelators to decline the iron overload and thereby retard long-term effects

related to iron accumulation in tissues. Deferoxamine, deferiprone, and deferasirox are

the three currently approved iron chelators for the treatment of hemochromatosis in

transfusion-dependent thalassemia patients. Today, iron chelation therapy's goal is to

sustain acceptable levels of iron in the human body at all times. Correct tailoring with

iron chelators and their dose modifications must implement on time.

We first describe the pathophysiology of hemochromatosis in thalassemia patients in

this chapter. We then cover iron chelation therapy's general goals, the features of the

permitted iron chelators, and the evidence-based practice behind the usage of iron

chelators as a single drug, or as part of combination therapy, and the mechanisms by

which chelators work. The guiding principles for monitoring treatment with iron

chelators to reduce the toxicity risks from iron chelation are later explained. Finally, the

importance of deferasirox twice-daily dose instead of a once-daily dose in transfusiondependent

thalassemia patients with inadequate response to high doses and the future

directions in treating iron overload in thalassemia patients is discussed.

Recent Advances in the Diagnosis and Management of Pulmonary Embolism

Acute pulmonary embolism (PE) is a form of venous thromboembolism

(VTE) and has varied clinical manifestations with significant morbidity and mortality.

The general population's overall incidence is on the rise due to the increasing

availability of D-dimer and computed tomographic pulmonary angiography. The

incidence is higher in males than females (58 versus 48 per 100,000, respectively),

increasing with age. In the United States, PE accounts for approximately 100,000

deaths annually. Specific populations, including patients with malignancy, pregnant

females, hospitalized medical and surgical patients, or patients with total joint

replacement, or arthroplasty, are at a higher risk for PE. Patients presenting with

hemodynamic compromise due to PE need to be treated with intravenous thrombolytic

therapy unless contraindicated, followed by anticoagulation. For over six decades,

traditional anticoagulants like unfractionated heparin (UFH) are used for short-term

anticoagulation. For patients who require long-term anticoagulation, low molecular

weight heparin (LMWH) like enoxaparin and a vitamin K antagonist like warfarin are

used to achieve therapeutic anticoagulation. Options for anticoagulation have been

expanding steadily over the last decade with the introduction of the first direct oral

anticoagulant (DOAC). Since their introduction, DOACs have changed the landscape

of anticoagulation. This narrative review aims to summarize for clinicians managing

pulmonary embolism (PE) the main recent advances in patient care, including risk

stratification, current data regarding the use of thrombolytic treatment, and direct oral

anticoagulants.

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.

Qualitative and Quantitative Investigation of Bio Tissues using Microscopy and Data Mining

The effects of glucose and salt on white blood cells, red blood cells, and

platelets (PLTs) in the blood of a leukemic patient by using a white light microscope

have been investigated for different concentrations (0 mM to 500 mM) of glucose and

salt. It has been revealed that the shape of erythrocytes, leukocytes, and platelets

changes and forms aggregates. Increasing the concentration of sodium chloride causes

an increase in the rouleaux formation and aggregation of platelets. The comparison of

CBC reports of these samples with and without analytes shows that total leukocyte

count (TLC) decreases gradually towards normal ranges of leukocytes, which is

favorable in the treatment of leukemia; at the same time, decreased level of hemoglobin

HGB, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin

concentration (MCHC) and increased level of red blood cell (RBCs) causes a reduction

in the oxygen supply, which is in favor of cancer growth and anemia.

In the second set of work, a computer-aided system was planned for automatic

classification of ultrasound kidney diseases and ultrasound liver (i.e., cirrhosis). Two

types of images were considered normal and chronic. By using the data mining

technique, the statistical features were extracted to differentiate between normal and

abnormal ultrasonic kidney images. By using feature extraction software (FES), a set of

statistical features were extracted from the region of interest of each image at different

frame rates. The data sets which were obtained using FES at different frame rates were

then classified by using Weka. These extracted feature results were classified by using

Weka and a 96.5% correct classification rate was obtained. The difference between the

values of these features was useful to identify between normal and abnormal images.

Desmocollin-3 and Cancer

Desmocollin-3 (DSC3), a desmosomal adhesion molecule, is expressed in basal and suprabasal layers of the normal epithelium as a membranous protein. The development of cancer is associated with cytoplasmic expression or the absence of DSC3. It is present in a variety of cancers, such as ovarian cancer, skin, colorectal cancer, bladder cancer, cervical cancer, oral squamous cell carcinoma, head and neck cancer, non-small cell lung cancer (NSCLC), meningioma, chondrosarcoma, pancreatic cancer, liver cancer and melanoma. It is used as a diagnostic biomarker for the identification of squamous NSCLC amongst undifferentiated and poorly differentiated NSCLC. It is a promising prognostic biomarker for NSCLC, Oral squamous cell carcinoma, colorectal cancer and prostate cancer. It has a reciprocal relationship with infiltrating immune cells in squamous NSCLC, ovarian cancer and melanoma. Chemotherapeutic agents alter DSC3 expression in therapeutic as well as subtherapeutic doses. It may be helpful in the selection of appropriate therapy in patients with cancers.

Bioactive Steroids from Marine Organisms

Natural products have played a key role in cancer drug discovery, as well in other therapeutic fields. In the past decades, marine organisms have proven to be a primary source of new potentially bioactive natural products for drug discovery. By reviewing the literature describing marine organisms and isolated metabolites, we can notice a large increase in the number of studies today compared to the end of the 20th century. The number of structures isolated each year has almost doubled over the past 20 years. Because of their topicality, we have focused on natural bioactive steroids isolated from marine organisms. In the chapter ‘Bioactive Steroids from Marine Organisms’, an overview of the new steroid compounds isolated from marine sponges, macroalgae and cucumbers, described in the relevant literature in the period from 2011 to 2020, is given. To provide a comprehensive introduction in the field of marine bioactive steroids, we highlighted typical molecules grouped according to their structural characteristics with additional reference to their biological activity. The structures of the new compounds, their natural origin (species of the organism) and their rich biological activities are presented and described in detail. In addition, biological tests performed on known compounds during this time period are also described. Some of the compounds possess multiple activities and have been tested only in a limited number of biological assays, which means that the full potential and significance of these compounds may only be discovered in the future.

The Chemical Compositions of Bixa orellana and their Pharmacological Activities

For many years, natural products have been exploited to obtain extracts and pure substances, especially to treat various diseases and conditions. Bixa orellana, the seasoning and colouring known as “Achiote”, is used in several countries in traditional medicine to treat a variety of health needs, mainly using the dried pulp of the fruit, the seeds, the leaves and the roots. The objective of this review is to provide information regarding the numerous pharmacological activities of the different parts and extracts of B. orellana, such as the anti-inflammatory, anti-bacterial and anti-parasitic activity, as well as the hypoglycaemic, cytotoxic, antioxidant, bronchodilator, diuretic and hepatoprotective effects. This information will promote the development of further research regarding this plant and its various benefits, either in the form of an extract or pure substance, such as bixin and norbixin. Similarly, it will allow the discovery of its various mechanisms of action for each disease, which will promote the development of new active compounds.

Emerging Nanomaterials for Cancer Therapy

Nanotechnology has gained much interest over the past few years due to its ability to efficiently detect and treat different types of cancers. To overcome the limitations associated with traditional cancer treatment strategies such as lack of specificity, toxic effects, the pre-mature release of the drug, and multidrug resistance, nanomaterials have been widely utilized. Nanomaterials not only enhance the drug accumulation at a specific site but also improve the therapeutic efficacy of anti-cancer drugs. Some other advantages of nanocarriers include targeted and controlled drug delivery, less toxic effects, enhanced solubility and stability, and greater availability of chemotherapeutic agents to the cancer cells due to enhanced permeability and retention effect. The physicochemical properties of nanocarriers can be modified by varying their shapes, sizes, and surface characteristics (PEGylation, ligand, or functional group attachment). Various types of nanomaterials have been utilized for pharmaceutical and medical purposes, most importantly for cancer therapy, depending upon their nature and composition, such as lipid-based, polymeric-based, protein-based, carbon-based, and hybrid nanomaterials. Many of these nanocarrier drug delivery systems have been developed, among which only a few have been clinically approved for anti-cancer drug delivery. The rationale of using nanotechnology for anticancer drugs is to achieve targeted delivery via active or passive targeting and diminish the damages to healthy tissues. So, the ultimate objective of these nanocarriers is to effectively treat the diseases with fewer side effects.

Role of Biochemistry in Tumor Detection

Learning objectives:

1. Enlist Specific Tumor markers for particular cancer.

2. Illustrate different oncogenes and their products.

3. Describe in detail Ectopic production of hormones.

Immunotherapy for the Treatment of Hepatocellular Carcinoma

This chapter will present the most recent advances in the management of hepatocellular carcinoma (HCC) with immune checkpoint inhibitors (ICIs). Immunotherapy is a rapidly developing and promising field of cancer treatment with many applications, including HCC. In this chapter, we will explain the rationale behind the use of ICIs in the management of HCC by highlighting their molecular mechanisms of action and interactions with the tumor microenvironment. We will also present the most recent data for their safety and efficacy in the resectable, unresectable and posttransplantation setting. Furthermore, we will assess their current status according to the most recent HCC management guidelines and how they compare with other available treatments. The proposed synergy of ICIs with other molecular targeted agents, such as vascular endothelial growth factor inhibitors, will also be analyzed. Finally, we will discuss the current limitations and challenges of ICIs and explore future research perspectives that may solidify their role as a standard HCC therapeutic option, in an era of personalized cancer treatment.

Postbiotics: A Solution to Leave Problems of the Production and Consumption of Probiotics

The process of producing and distributing probiotics in the matrices of a wide variety of foods in the form of living cells has often been associate with difficulties. Several investigations have been doing to develop or optimize various approaches to maintain the viability of probiotic microbes. On the other hand, in recent years (mainly since 2010), a great deal of attention has been paid to using non-viable forms (postbiotics) bacteria as substitutes for probiotics. The term “postbiotic” refers to modified inactivated microbial cells, cell fractions, or cell metabolites that are naturally or synthetically generated by live probiotic cells and exert biological health-promoting effects to the host when administered in sufficient amounts. This chapter provides an overview of key concepts and main constituents of postbiotics, with emphasis on their biological activities.

Clinical Milestones in Nanotherapeutics: Current Status and Future Prospects

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

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

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

Applications and Implementations of 6G Internet of Things

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

Subject Index

Pathophysiology and Risk Factors for CancerAssociated Thrombosis

Virchow’s triad of venous stasis, vascular damage, and blood hypercoagulability is the hallmark of VTE formation. Despite many studies done in recent times, the exact pathophysiology of cancer and VTE is still unknown. Various Tumor related, treatment-related and patient-related risk factors (RF) have been identified. Tissue-factor (TF), microparticles (MPs), inflammatory cytokines, and cancer procoagulants (CP) are some of the tumor-related risk factors. Tumor cellderived TNFa, IL-1b, and VEGF also contribute to cancer-induced hypercoagulability by other mechanisms, firstly they induce TF expression on monocytes. Several tumorrelated characteristics such as tumor site, type, stage (especially metastasis), histological variance and duration, are considered risk factors for the development of cancer-associated VTE. Surgery is the most important treatment-related risk factor in VTE in cancer patients along with other risk factors like hospital admission, chemotherapy, hormonal therapy, radiation therapy. patient-related factors such as age, gender, race, performance status, comorbidities, prior thrombosis, and prothrombotic mutations, are associated with an increased VTE risk in cancer patients. Several biomarkers have been investigated to quantitate and to predict the risk of VTE in cancer patients most important being D dimer, RF. Elevated levels of Ddimers are predictive of a higher risk of recurrent VTE in patients with cancer. Prechemotherapy platelet count has been shown associated with increased VTE risks in at least one study.

Subject Index

How Can a Country Defeat COVID-19? Value of R0, Rt and Re

Eradication of a disease is a very difficult and multi-factorial, multi-faceted question. The prevalence of COVID-19 in the regions around the country, the intensity of the population’s relationship with other countries, age distribution, and other demographic factors affect the magnitude of the impact of the disease on a population. In addition, the virulence of the virus, the immunity level of the population, measures taken for immunization, availability of necessary drugs, the capacity of the health sector to mitigate the pandemic will affect the damage on the society as a whole. The tests applied to identify the cases, filing, and surveillance are effective factors in the response of the state's health organization to this disease.

Subject Index

Modifications of the mean value inequality for quasinearly subharmonic functions

We find necessary and sufficient conditions under which subsets of balls are big enough for the characterization of nonnegative, quasinearly subharmonic functions by mean value inequalities. A similar result is obtained also for generalized mean value inequalities where, instead of balls, we consider arbitrary bounded sets which have nonvoid interiors and instead of the volume of ball we use functions depending on the radius of this ball.

Subject Index

Characterization of Nanostructured Systems for Bioactive Compound Delivery

Characterization of nanostructured systems is an important aspect to support the choice of the better formulation composition and the best production conditions throughout a development process. Several methods can be used alone or combined for the determination of physical (e.g., mechanical, electrical, electronic, magnetic, thermal and optical), chemical or biological properties of a nanomaterial. This chapter is an overview of the most employed techniques, including dynamic light scattering and laser diffraction for the determination of size distribution; zeta potential and its relationship with stability and the surface charge of the particles; microscopies (optical microscopy, SEM, TEM, AFM) utilized in morphological analyses; spectroscopies in the infrared or ultraviolet-visible regions, and X-rays diffraction, which help to elucidate the crystalline state, polymorphism and drug-nanosystem interaction; and thermal analyses, which can provide information about the physical state, crystallinity, and stability. Further complementary information can be obtained from many other methods, such as nuclear magnetic resonance or Raman spectroscopy, but they are beyond the scope of this chapter. The careful choice of the characterization techniques to be used is certainly a decisive step in the successful and rational development of a nanocarrier formulation.

Strategies and Mechanisms for Plant Resistance Protein Function

Given the current constraints to sustainable agricultural production, with increasing crop losses due to plant pests and diseases and climate change, considerable advances are required in crop improvement approaches for enabling durable disease resistance. Interestingly, advances in fundamental understanding of the plant immune system will have far reaching implications for genetic resistance development, appropriate for effective and durable disease control and global sustainable agriculture. In particular, a deeper understanding of the molecular and functional mechanisms of resistance (R) genes would make it possible to engineer new resistances for future agriculture. In general, there are currently two main strategies, which include nine recognized molecular mechanisms for R genes, most of them (all but one, mechanism 6: executor genes) have been used against various types of biotic stress and tend to be widely applicable among plants.

Overview of Iron Products in Gastroenterological Anemia

The gastrointestinal tract is the site of iron absorption and also the most common localization of hemorrhage. The cause of iron deficiency anemia (IDA) is often chronic blood loss. One liter of blood contains approximately 500 mg of iron. Despite the representative increase in the absorption rate, the loss in this case cannot be compensated and the body's iron reserves decrease. Iron deficiency leads to disruption of hemoglobin synthesis: iron deficiency anemia. The etiology of iron deficiency anemia can be widely categorized into: decreased iron uptake (malabsorption due to gastrointestinal disease or surgery, inadequate diet) and increased iron use/loss (blood donation, pregnancy, acute/chronic blood loss, rapid growth during childhood, menses). IDA can be the first sign of celiac disease, gastritis and occult GI malignancy. The first choice treatment (after finding and disposal of the cause of the bleeding) consists of the oral administration of Fe II compounds. It can take several months to replenish iron reserves. Oral administration, however, has the major advantage that it is difficult, even impossible to overload the body with iron, because the absorption is regulated through an intact mucosa (enteral blockage). Only when adequate oral replacement is not possible, parenteral administration of iron compounds is indicated. There are potential side effects: administration of persistent pain at the injection site (i.m. administration) and facial flushing, hypotension, anaphylactic shock (i.v. administration).

Latest Data on the Epidemiology, Pathological Classification, and Staging of the Combined Hepatocellular Carcinoma-Intrahepatic Cholangiocarcinoma

Combined hepatocellular carcinoma–intrahepatic cholangiocarcinoma (cHCC–CCA) is a primary liver cancer with features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). This combined tumor represents 1% of all primary liver cancers, but recent studies have shown its increasing incidence and incidence-based mortality. The risk factors (identifiable in about 30% of the cases) are similar to those of HCC and CCA: cholestatic liver diseases, hepatobiliary flukes, toxins, liver cirrhosis of any etiology, and metabolic diseases such as obesity and diabetes mellitus. The first pathological classifications of cHCC-CCA described three types of tumors: collision, transition and intermediate tumors. Intermediate tumors develop from a cell intermediate between the hepatocyte and biliary epithelial cell. The 4th WHO classification of digestive system tumors (2010) was the first one to report cHCC-CCA as a distinct entity, with two main subtypes: classical type and cHCC-CCA with stem-cell features. The collision type was no longer accepted. In the 5th WHO classification (2019), the tumors of the subtype with stem cell features were recategorized as either HCC or iCCA. Due to the cHCC-CCA mixture of phenotype characteristics, the staging criteria have been also controversial. Presently, the cHCCCCA tumors are staged by a similar algorithm as for iCCA: the TNM staging of HCC is used for clinical applications and prognosis, and the SEER staging is used for epidemiological studies. The growing interest in molecular research, genetic biomarkers identification, diagnosis and staging of these combined tumors will eventually lead to the development of effective therapeutical approaches.

Treatment of Intermediate Stage Hepatocellular Carcinoma – from Guidelines and Beyond

Hepatocellular carcinoma (HCC) BCLC-B class is characterized by an extensive heterogeneity due to the wide range of liver function (Child Pugh A or B cirrhosis) and variable lesion number and size. With this regard, hepatologists must develop a better stratification of this HCC stage for patients to benefit from a better treatment allocation. Trans-arterial chemo-embolization (TACE) procedure is the most widely used therapeutic option for intermediate stage HCC. One therapy is not beneficial unless clinicians might predict its outcome. Along these lines, several predictive factors for the TACE success have emerged such as mRECIST criteria, HAP and mHAP, Munich and CHIP score. The overall survival (OS) after the TACE procedure is around 16 months and in rigorous selected candidates, might increase the survival up to 3 years. Nevertheless, in some BCLC B patients, other therapies have proved their benefit compared to TACE. Resection and liver transplantation when technically possible is associated with an increased OS versus TACE. Moreover, astounding results have arisen from the combination of TACE with radiofrequency ablation. However, the literature fails to support the use of multi-kinase inhibitors in combination with TACE. Selective internal radiation therapy (SIRT) also known as radioembolization (TARE) induces fewer side effects and maintains a better tumoral control than TACE, but it is less available worldwide and is less cost-efficient. In conclusion, navigating through all these treatment options, we believe that intermediate stage HCC has to be managed in a personalized way for each patient in order to have the best outcome.

Advances in Imaging Diagnosis of Hepatocellular Carcinoma - the Place of Contrast Enhanced Ultrasound (CEUS)

Hepatocellular carcinoma (HCC) is a primary malignant liver tumor that complicates advanced chronic liver disease, especially liver cirrhosis. Surveillance of this category of patients is mandatory for early detection of HCC and improved prognosis. Screening should be carried out by the abdominal US every 6 months with or without alpha-fetoprotein. The diagnosis of HCC is confirmed by imaging methods that highlight the typical behavior of HCC: hyper-enhancement in the arterial phase and washout in the late phase. Imaging methods used for HCC diagnosis are Multi-detector computer tomography (MDCT), multi-phase nuclear magnetic resonance imaging (MRI), or contrast-enhanced ultrasound (CEUS). LI-RADS algorithm is now one of the most used widely systems for the imaging diagnosis of HCC. It is a standardized system for technique, interpretation, reporting, and data collection for imaging (CT, MRI, and CEUS). The algorithm includes 8 categories with an increasing probability of HCC and malignancy with higher categories. Studies that have attempted to validate this LI-RADS scheme for the diagnosis of HCC shown that LR-5 is highly predictive for HCC.

The Role of Cytokines and Inflammatory Mediators in Alcoholic Liver Disease

Cytokines are low molecular weight substances, mediating intra and intercellular communications. They are produced by several cell types, including the liver with a special focus on Kupffer cells. In the liver, pathological stimuli induce cytokines release and are responsible for cell lesions, destruction, necrosis, apoptosis and regeneration. In alcoholic liver disease (ALD) inflammatory cytokines such as interleukin-8 (IL-8) tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) as an acute phase-cytokine are involved in the liver injury. Another proinflammatory interleukin is interleukin-12 (IL-12), which seems to be related to chronic alcoholism. Transforming growth factor β (TGF-β) has the most important fibrogenic properties in the liver and it is also involved in regulating apoptosis along with tumor necrosis factor. Several types of cytokines are described to induce antiinflammatory effects on the liver with chronic alcoholic exposure: Kupffer cells produce the hepatoprotective cytokine IL-6 and the anti-inflammatory cytokine interleukin- 10 (IL-10) during liver injury induced by alcohol. IL-6 acts in a protective manner via the activation of transcription 3 and induction of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver damage in Kupffer cells/macrophages. Interleukin-22 (IL-22) is another important hepatoprotective cytokine against acute and chronic alcoholic liver injury. Adipocytokine adiponectin decreases hepatic insulin resistance and attenuates liver inflammation and fibrosis. Thus findings in the complex “puzzle” of ALD could launch the research for new therapeutic perspectives.

Emerging Techniques for Assessment of Chronic Liver Diseases: The “Omics” Cascade

Chronic liver diseases are carrying an important social and economic burden, as they are having a high prevalence and are accompanied by many comorbidities. Furthermore, their progression ends frequently in a cirrhotic stage with its complications, the most fearful of these being the hepatocellular carcinoma. Therefore, diagnosing the disease at an early stage, then classifying the severity of the disease properly is mandatory. In addition, identifying the forms of liver diseases that are prone to progression towards severe fibrosis and cirrhosis is also very important. The invasive methods of diagnosis are almost completely replaced by noninvasive techniques, some of them failing to prove a high diagnostic accuracy, others being very expensive or not applicable or reliable. Consequently, the researchers are diving lately into a new domain of noninvasive diagnosis, namely OMICS cascade, which is very complex and through its multiple faces, addresses the different pathogenetic pathways of liver disease, increasing the probability of diagnosis, staging and prognosis to a higher level. The aim of this review is to present the data we have gathered until now from the field of genomics, proteomics, transcriptomics and metabolomics in the assessment of liver diseases.

Gallbladder Tumors

Conventional ultrasound (US) is the most important and fundamental

imaging method for gallbladder diseases.

Biliary disorders are still very common nowadays, especially the ones affecting the

gallbladder. Either benign (in most cases), or malignant, their diagnosis still relies on

the abdominal ultrasound. Gallstones and their complications represent a major public

health issue in Europe and other developed countries, and affect > 20% of the

population.

According to GLOBOCAN 2020 data, gallbladder cancer is the 23rd most incident, but

the 20th most deadly cancer worldwide, which could be explained by the late discovery

of gallbladder cancer. Worldwide, gallbladder cancers represented 0.6% of the total

cancer cases in 2020, with a mortality of 0.85% among all cancers.

US becomes more appropriate than computed tomography (CT) and magnetic

resonance imaging (MRI) for the detection of gallbladder diseases, having the

advantages of safety (without radiation), real-time imaging, considerable cost

effectiveness and high spatial resolution.

Regardless of the previously mentioned advantages, the accuracy and sensitivity of US

are not satisfactory, particularly when gallstones or other gallbladder lesions occupy

the entire gallbladder lumen. Contrast-enhanced ultrasound (CEUS) is considered to

increase the diagnostic precision of US.

Efficacy of Hepatic Arterial Infusion Chemotherapy (HAIC) for Advanced Hepatocellular Carcinoma

As per the latest data of the International Agency for Research on Cancer, more than 8 million individuals die annually owing to the exacerbation of a given neoplasm, and the total number of annual deaths due to hepatocellular carcinoma (HCC) is 0.78 million, the second-highest of all cancer-related deaths. HCC has a very poor prognosis, reflected by the fact that the incidence-to-mortality ratio of HCC has been estimated to be more than 90%. Liver cancer is generally diagnosed only in the advanced clinical stage because HCC tends to be clinically silent during the early stages. With regard to HCC management, transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC), as well as molecularly targeted agents such as sorafenib and lenvatinib, have shown promising benefits for advanced HCC. However, even though the Barcelona Clinic Liver Cancer staging system has been widely accepted, controversies still exist regarding the best choice for the management of HCC in individual cases. In this chapter, we infer that HAIC treatment is not inferior to molecularly targeted therapies for the treatment of advanced HCC—particularly in case of intravascular invasion in both compensated and decompensated cirrhotic patients. Furthermore, the rate of adverse events leading to discontinuation of antitumor treatment appears relatively low. Given the hepatic function reserve preservation afforded by HAIC chemotherapy, we suggest that HAIC should be considered as an alternative strategy even for advanced-HCC patients with decompensated cirrhosis, who do not respond to TACE.

Beneficial Impacts of Essential Oils on Poultry Health and Production

With the rapid growth of the poultry sector, a major human health concern is noticed relating to the excessive and uncontrolled abuse of antibiotics, which leads to the development of antibiotic-resistant bacteria. Antibiotics are used in sub-therapeutic doses as antimicrobial agents for rapid growth performance in poultry and for prevention of diseases. For this reason, there is a need to develop alternatives to antibiotics. The beneficial effects of plants and plant extracts that have traditional use are evaluated in many studies. The most common beneficial effects of these plants and their extracts are stimulating endogenous digestive enzymes and antioxidants. Essential oils (EOs) have a wide variety of effects, including antimicrobial, antioxidants, and digestive stimulant activities. Essential oils have been demonstrated to positively affect growth performance, gut health, and meat quality, but the responses are inconsistent. The inconsistencies have been related to the species/subspecies of the plant, harvest time, geographical location, and plant part used that can affect the EOs structure. The oils undergo a patented micro fusion process that creates a surface area of oil droplets that is 20 times greater than other commercially available oilsthus increasing the stability and effectiveness of the oils. The EOs exhibit high antioxidant activity, which is attributed to its two main phenols, carvacrol, and thymol. Conclusively, essential oils can be used in poultry nutrition, but still need more studies, especially metabolism, and the optimum dose in various poultry species.

Cassia Fistula: Potential Health-Promoting Candidate for Livestock and Poultry

The beneficial uses of natural herbal plants in medical sciences have achieved great attention due to promising health benefits in comparison with synthetic pharmaceutics. Cassia fistula (CF) is one of the most famous medicinal plants due to its broad range of incredible biological functions, such as laxative or purgative, antidiabetic, hypolipidemic, hepatoprotective, antioxidant, anti-inflammatory, antipyretic, antitussive, antimicrobial, anticancer, antiparasitic and wound healing as well. Moreover, flavonoids derived from CF, such as tannins and glycosides, exhibit a broad spectrum of therapeutic activities and low toxic effects. Previously most studies discussed in vitro-based models, humans, and rodents. The aim of this review is to highlight the medicinal importance of CF on the production performance of animals. Up to now, there are still many research areas waiting to be explored, such as finding out the metabolic pathway of flavonoids of CF in different animal models, mainly focus on poultry. Therefore, the present chapter aimed to attract attention to health-promoting and medicinal uses of this plant in poultry and animals. The above-mentioned research will provide further medicinal development of this genus.

Turmeric (Curcuma longa) as a Useful Feed Supplement in Poultry

In the last decade, poultry nutritionists were particularly interested in inspecting relevant natural antibiotic alternatives to be used in poultry feeding to reduce the competitive efficacy of bacterial resistance and its residuals in poultry products. Using antibiotics and hormones in feed not only raises production costs but they also get incorporated into the processing of meat and eggs and increase microbial resistance. Several synthetic medicine and growth promoters are fortified into broilers diets for fast growth. However, their use still shows some drawbacks, such as high costs, adverse side effects on bird health, and extended residual properties. Thus, the primary aim of poultry production is to obtain higher performance through increasing the feed efficiency besides getting safety products for consumption. Due to their nutritional and immunological effects, such as improved feed efficiency, regulation of endogenous digestive enzymes, immune response stimulation, antiviral, antibacterial, and antioxidant properties, medicinal plants seem to be of great importance. Turmeric (Curcuma longa) is a useful medicinal herb belonging to the ginger family, Zingiberaceae which is inherent to the Asian subcontinent. It has numerous medicinal properties, such as antimicrobial, anti-inflammatory, antimutagenic activities, and other beneficial health applications. Furthermore, turmeric contains several biologically active compounds such as curcumin, bisdemethoxy curcumin, demethoxy-curcumin, and tetrahydrocurcuminoids, which may be responsible for these beneficial effects. Besides, turmeric is safe due to its low toxicity index and could be effective against aflatoxin-induced mutagenicity and hepatocarcinogenicity. In this chapter, we will discuss the valuable effects of turmeric in terms of the production, carcass traits, and ameliorative role in bird .

Beneficial Impacts of Licorice (Glycyrrhiza glabra) Herb to Promote Poultry Health and Production

Supplementations of livestock diets with herbs that have many active constituents revealed favourable effects as natural feed additives. These compounds could stimulate nutrient digestion, growth performance, food utilization, enhance immunological sides and antioxidant status and decrease health disorders. Various previous reports have employed mixture formulas of herbal with partial enclosure of licorice. However, the data about using licorice independently is very scared. The poultry industry faces many epidemiological syndromes; principally, those are confined to digestive, respiratory and immune system syndromes. Flavonoids and glycyrrhizin are the main bioactive components in Licorice. The roots of this herb contain 1-9% glycyrrhizin, which has several pharmacological actions such as antioxidant, antimicrobial, anti-heat stress, and anti-infective antiviral and antiinflammatory activities. Licorice extracts (LE) have affirmative impacts on the management of high incidence ailments, such as the immune system, lung, and liver disease. Licochalcone A (2-8μg/mL) inhibits cancer cell proliferation by reducing DNA synthesis in these cells . Moreover, the hepatoprotective effect of LE (100-300 mg) against CCI4-induced hepatic injury in rats has been observed. Studies suggested the potential role of LE (0.1, 0.2, or 0.3 g/L of drinking water) in reducing serum total cholesterol of broiler chicken significantly. Also, the presence of licorice root extract (0.1 g/d) in the patient diet for 1 mo led to a decrease in plasma triglyceride (by about 14%) and cholesterol (by about 5%) levels. Moreover, dietary supplementation of LE plays a substantial role in the productive performance of poultry owing to the improvement of organ development and stimulating influence on digestion and appetite. Along with its growth promoting properties, licorice has antioxidant, detoxifying, anti-inflammatory, antimicrobial, and many more health benefits as enclosed in the current chapter. This chapter highlights the favourable applications and modern features of Glycyrrhiza glabra (licorice) herb, including its chemical composition and maintenance of the health status of poultry. Hence, it will be highly useful for nutritionists, physiologists, pharmacists, veterinarians, and poultry producers.

Clinical Application of Liquid Biopsy in Solid Tumor HCC: Prognostic, Diagnostic and Therapy Monitoring Tool

The idea of using liquid biopsy in the field of oncology is relatively new. Its significant advancement and revolutionized diagnosis and therapy monitoring in cancer research is strengthening the field of precision medicine. Liquid biopsy is a noninvasive method of isolation and detection of circulating tumor cells, circulating tumor DNA and exosome depict the exact picture of early stage cancer genomics and proteomics. The techniques like digital PCR, CAPPSEQ, BEAMing and next generation sequencing contributed to utilize liquid biopsy in clinical settings. It can facilitate cancer prognosis and early stage detection before metastasis. Importantly, it can help in finding responders and non-responders, devising treatement plan and screening of new drugs. In this chapter, the clinical application of liquid biopsy in solid tumor management with focus on Hepatocellular Carcinoma (HCC) is discussed. Besides the advancement in diagnostics and treatment of HCC, the prognosis is still poor with a high rate of mortality. Liquid biopsy has the potential for better diagnosis and monitoring of HCC in patients. We have also summarized different advanced diagnostic techniques for the isolation and enrichment of circulating tumor cells, circulating tumor DNA and exosome. Moreover, the limitation of the use of liquid biopsy in the healthcare system is also the point of discussion.

Biobank for Personalized Immunotherapy

A biobank is a resource for keeping blood and tissue samples, which is going to play an increasing role for personalized immunotherapy, called precision immunotherapy. Moreover, large profits from biobanks are their futures of patients' personalized immunotherapy. A new generation of immunotherapy often relies on a person's tissues/cells/molecules/data so that personalized immunotherapy starts to deposit the patient's specimens and clinical information with genomics data. If tumor patients can save their specimens such as tumor tissues or blood before treatment, furthermore, if patients can achieve some genomic data for future treatment, the specimens saved in biobanks and the genomics data observed from their tissues can contribute clinical physicians and clinical scientists to develop a new generation of treatment, for example, patients respond to immunotherapy predicted by individualized measurement and undergoing personalized T-cell immunotherapy. This chapter introduces biobank, one of the most up-to-date personalized immunotherapies, which enable conducting research and development (R&D) for professional collection of clinical specimens and clinical data. The chapter aims at describing the concept of biobank and future potential to treat patients. It also includes sample preservation protocols and data management as well as online service of samples and clinical data. Thus, some standard operating procedures apply for personalized immunotherapy of diagnostic and treatment procedures. Finally, ethics for sampling, clinical information, and genomics data are mentioned to support the biobank chapter.

System Modeling of T-cell Function-Development of Adoptive T-cell Immunotherapy

When primary-cells, including non-genetically modified and genetically modified T-cells to produce a special substance, are infused into patients, these performances would be defined as cell therapy. An excellent cell performance with its optimal proliferation for cell therapy should maintain its functional feature and efficacy in vivo with ethical acceptance and safe application. Because the efficacy of cell therapy maybe will be decreased in vivo special microenvironment after infusion, moreover, because cell therapy with these genetically modified T-cells would be faced by a safe challenge in clinics, a functional induction/inhibition of some genes’ expressions used in T-cell growth without genetic modification has been increasingly studied. Here, T-cell therapy based on system biology for an induction/inhibition of special function and maintaining a special function in vivo microenvironment is called as functional cell therapy. Nowadays, following research and development (R&D) of T-cell proliferatively engineering techniques and system modeling by this computational simulation performance, the novel techniques of T-cell culture based on genomic analysis and supported by system biology will be increasingly studied for adoptive T-cell therapy so that oncologists can safely and effectively utilize the new strategy for personalized immunotherapy.

Genetically Modified T-cells Affinity to Tumor Cells-Development of Adoptive T-cell Immunotherapy

T-cells play an essential role in the cell-mediated immune response to tumor cells, while tumor cells in tumor sites take many strategies to evade the host immune response, including creating many immune-suppressive factors from tumor microenvironment (TME) or decreasing expression of immunogenicity of target antigens. To resolve the evasion of tumor cells from T-cells attacking, some strategies such as genetically modified T-cells altering the specificity of the T-cell receptor (TCR) or introducing antibody-like recognition of chimeric antigen receptors (CARs) have made significant advances. The modified TCR T-cells or CAR T-cells have been administered to cure B-cell lymphoma or B-lymphocyte leukemia in clinical trials successfully. We have been going to study the specificity and safety of T-cell adoptive immunotherapy for more than 30 years so that our experiences to apply for genetically modified T-cell more focus on the specificity and safety of these therapies. Moreover, the strategies using genetically modified T-cell immunotherapy need face challenges for immunogenicity from different types of tumors. The chapter will introduce T-cell specific affinity between T-cell and tumor cells such as TCR and CAR T-cells, discuss challenges from the selection of antigen targets, and address safety issues to clinical development. All in all, T-cell adoptive immunology regarding TCR and CAR T-cell improves the clinical application.

Development of Adoptive T-cell Immunotherapy- Future of Personalized Immunotherapy

Lymphocytes play vital roles in surveillance of the formation and development of tumors as well as control of tumor disease. Employing the immune cells to recognize and destroy tumor cells is a central task of anticancer immunotherapy. Since 1987 cultured tumor-infiltrating lymphocytes (TIL) from the site of tumor tissue have been discovered more than 100-fold to kill tumor cells to compare cultured T-cell from peripheral blood, we have been studying TIL anti-tumor mechanism and clinical feasibility of immune-cell immunotherapy, especially functionally inducing TILs for immunotherapy purpose for more than two decades. At present, to make it a clinically feasible treatment, there have been increased reports in optimizing those procedures. Several standard protocols of laboratory performance and clinical treatments have been quickly developed in cancer immunotherapy. With using this standard protocol, cytotoxic T-cells are infused into cancer patients with cytokine help in recognizing, targeting, and destroying tumor cells. In the chapter, we review some of the significant successes of adoptive T-cell immunotherapy (AIT or ACT) and the significant obstacles that have been overcome to optimize ACT. Here, we also more focus on the study of research and development of T-cell inducing, culture and proliferation for adoptive immunotherapy, and eventually introduce clinical knowledge of lymphocytes application including feasible and affordable to treat patients.

Bioinformatics of T-cell and Primary Tumor Cells- Fundamental of Adoptive T-cell Immunotherapy

Epitope discovery of tumor antigen and mutant proteins has enabled a better application of T-cell immunotherapy. Genomic profiles analyzed by genomic expression and single nucleotide polymorphisms (SNP) by genome-wide association studies (GWAS) are an essential fundamental to screen and define T-cell therapeutic targets. To determine tumor antigens or mutant proteins related to T-cell targets with their TCR or CAR reconstruction, we will introduce the SNP technique related to primary tumor cells for personalized T-cell immunotherapy, including global and local SNP detection of the therapeutic targets. Moreover, the use of mRNA genomic expression can discover gene expression signature and further uncover tumorassociated antigen (TAA) or tumor-specific antigen (TSA) for T-cell immunotherapy. Accompany with the ongoing development of next-generation sequencing, epitope discovery of tumor neoantigen and mutant proteins will be irreplaceable for a novel generation of T-cell adoptive immunotherapy. System biology, which is a mathematical modeling of complex biological systems,can integrate data of SNP signature and genomic expression signature. Thus, a new bioinformatics platform with the analysis of GWAS and genomic expression profile along with system modeling is an essential fundamental for T-cell adoptive immunotherapy.

Primary Cell Culture and T-cell Cloning - Fundamental of Adoptive T-cell Immunotherapy

Tumor-associated antigen (TAA) or tumor-specific antigen (TSA) is essential for the target of tumor-specific T-cells such as tumor-infiltrating T cells (TIL), specific T-cells, TCR T-cells and CAR-T-cells for adoptive T-cell immunotherapy. The tumor cells often accumulate hundreds of mutations and harbor several immunogenic neoantigens, and thus, the repertoire of mutation or neoantigen from patient tumor cells might need the screen to uncover for engineering these T-cells. To understand the Tcell screening and determining tumor antigen-based on primary tumor cells from an individual patient, this chapter, we focus on streamlining the process of ex vivo T-cell culture and primary tumor cell culture, T-cell cloning for tumor neoantigen-specific T cells, allowing the patient to the benefit of downstream T-cell targets. Because T-cell engineering cultures are very important methods for TIL, TCR and CAR T-cells, moreover, because using primary tumor cells isolation and cultures is very important for screening and identifying tumor antigen of patients, we first introduce primary cell culture techniques, including those developed from two-dimensional (2-D) tumor cell cultures, three-dimensional (3-D) tumor cell culture and multiple dimensional tumor cell culture (4-D cultures). These methodologies are increasingly supporting clinical oncologists to apply to tumor therapeutic agents and Ag targets for patients in the clinical laboratory. Besides, we also conclude some growth factors for T-cell cloning cultures. The chapter aims to present a foundation to adoptive T cell immunotherapy of clinical patients.

Molecular Targeting Checkpoint in Cancer- Foundation of Personalized Immunotherapy

Currently, in the study of new anti-tumor therapies, the suppression of tumor growth through target checkpoints is a breakthrough in this treatment method. Now, this has gradually become the focus of in-depth research. By acting on specific molecular targets, tumor cells can be inhibited through information transmission in the human immune pathway, thereby inhibiting their growth and proliferation. Molecularly targeted checkpoint inhibitors can specifically kill tumors within the tumor microenvironment (TME), inhibiting the occurrence and development of tumors. On the other hand, they can target and inhibit other molecules, so that they can restore immune cell activity, and improve the body's anti-tumor immune function, namely the tumor immune microenvironment (TIME). At present, molecular target checkpoints that have been increasingly studied within TIME include PD-1, PD-L1, CTLA-4, TIM- 3, LAG-3, and Siglec-15. Corresponding molecular target inhibitors have been prepared for these molecular targets, and thus they have been increasingly applied to the clinic. Although these inhibitors have unavoidable adverse reactions and limitations in their scope of application in certain types of tumors, they still offer hope for the successful elimination of tumors.

MHC and Cancer Immunotherapy

Major Histocompatibility Complex (MHC) is a gene region, which is named human leucocyte antigen (HLA) in humans. The human leukocyte antigen (HLA) system is a highly polymorphic family of genes involved in immunity and responsible for identifying self-cells versus no self-cells. Although HLA typing is essential for solid organ and bone marrow transplantation, at present, MHC is going to study on cancer immunotherapy increasingly. In order to introduce MHC related to cancer immunotherapy, the chapter aims at focusing on several MHC issues related to cancer immunotherapy. For example, MHC research and development (R&D) in MHC class I molecular loss related to cancer immunotherapy; tumor immune escape related to nonclassical MHC I; T-cell epitope vaccines; as well as MHC issues in adoptive immune cell therapy and personalized immunotherapy. In each part for MHC related to immune responses for tumor disease, we also introduce clinical uses in a study on MHC issues for T-cell immunotherapy, MHC for T-cell vaccines, and MHC TCR reconstructions for tumor shared/specific antigen related TCR T-cell personalized immunotherapy.

Subject Index

Preface

Targeting the PI3K/AKT/mTOR Signaling Pathway in Hepatocellular Carcinoma: Current State and Future Trends

Hepatocellular carcinoma (HCC) is the most common liver cancer and the leading cause of cancer-related deaths. Advanced HCC has a poor prognosis with limited treatment option. Chronic liver diseases and cirrhosis are the main risk factors for the development of HCC. Phosphoinositide 3-kinase PI3K/AKT/mTOR, intracellular mediators play a very important role in the development and progression of HCC. This signaling pathway is frequently activated in HCC patients. Therefore, signaling pathways have become the main source of targets for new treatments in HCC patients.

In our chapter, we will discuss the role of PI3K/AKT/mTOR signaling pathway in the pathology of HCC and provide an update on the preclinical and clinical approaches for the development of various molecular agents targeting this proliferation/survival pathway, which include various PI3K/Akt/mTOR inhibitors and other agents for the treatment of HCC.

Subject Index

Exploration of Dill Seeds (Anethum Graveolens): An Ayurpharmacomic Approach

Since time immemorial, traditional medicine, largely Ayurveda, has established the usability and proficiency of many natural herbs and their formulations in curing ailments. However, the Asian continent or to be specific, India, could be considered as the “Land of Spices”. The saga of food-spice-medicine recipes has been passed down to several generations with a motto to “Make Food as Medicine”. One such exotic and the extensively used herb is Anethum Graveolens (Dill). This herb has the potential for various bioactivities. The whole plant, used as vrushya (a natural aphrodisiac), vataghna (balance vata) quenching excess free radicals, against vrana (non-healing wounds), shoola (abdominal colic pain), cure disorders and ulcers in eyes, plays a vital role in enema during panchakarma (bastikarma), functions as a galactagogue, inhibits uterine fibroids, increases milk secretion during lactation and above all enhances the taste of the food. With this background, a major lacuna is with an understanding of the functionality and mechanism of action at a molecular level. Hence, this chapter highlights the therapeutic potential of Dill seeds and their probable targets with modern knowledge and implications using ayurpharmacomic approach (understanding classical herbal formulation and exploring their pharmacological attributes with advanced -omic studies as tools). Further, virtual screening was performed to evaluate the structure-activity relationship (SAR) between lead phytobioactives and their pathological biomarkers/targets. These studies will enable a better understanding of potential pathways in developing newer therapeutic targets for future drug design and development, which would facilitate prime phytobioactive candidates to be subjected to clinical trials and drug approval.

Coriander Seeds: Ethno-medicinal, Phytochemical and Pharmacological Profile

Coriander (Coriandrum sativum L.; family Apiaceae/Umbelliferae), locally known as dhanya, is a popular culinary herb, well recognized for its therapeutic properties in Indo-Pak subcontinent. The plant is native to North Africa, Southern Europe, and southwestern Asia and is also one of the widely cultivated herbs. The aerial plant parts including seeds of coriander are being excessively used in traditional cuisines due to its pleasant color and flavor. Coriander seeds are commonly used spices and ingredients of curry and traditional recipes in the Mediterranean and South Asian regions.

The leaves (hara dhanya) are also used to garnish meals before serving. Besides, essential oils of coriander leaves and seeds are also used in several foods including fish and meat products, beverages, pickles, and sweets due to its pleasant aroma and health benefits owing to high free radical scavenging activity. Apart from culinary applications, coriander seeds and leaves are also well recognized for their therapeutic potential in traditional medicine since ages. Coriander is known to have significant hypoglycemic, hypo-cholesterolemic, anti-inflammatory, hepato-protective, and antioncogenic potential. It is also effective in mitigating gastrointestinal complications.

Deregulation of Enzymatic Post-Translational Modifications in Breast Cancer

Post-translational modifications (PTMs) regulate vital cellular processes such as signaling, proteasomal mediated degradation of proteins, and transcription. Deregulation of post-translational modifications (PTMs) has been proven to have a strong association with breast cancer development. Aberrant PTMs can promote carcinogenesis by perturbing normal cellular homeostasis. The current literature review showed that breast cancer cells displayed abnormal ubiquitination, glycosylation, phosphorylation, and SUMOylation patterns. Breast cancer cells also exhibited stable modifications in histone proteins and DNA. These epigenetic modifications can directly affect the expression of cell cycle regulators by disrupting the transcriptional state of the genome. The current chapter summarizes the involvement of PTMs in carcinogenesis and the mechanism by which PTMs promote abnormal cell growth. Enzymes responsible for aberrant PTMs could be targeted to reduce the severity of the disease and may improve the prognosis of breast cancer.

Metabolic Inflammation at the Crossroads of Obesity Phenotypes

The idea that there is heterogeneity among obese individuals in their risk for disease is not new, and may have begun with the acknowledgement that the distinct cardiovascular disease risk between males and females was influenced by their body pattern of adipose tissue accumulation (i.e. predominantly in the upper body versus in the lower body, respectively). Later came the debate on the pathophysiological meaning of adipose tissue accumulation in visceral as opposed to subcutaneous depots and even of distinct patterns of adipose tissue growth (hyperplasia versus hypertrophy). More recently, epidemiological evidence has shown that individuals with similar degrees of obesity may be at different ranges of metabolic abnormality and cardiometabolic risk spectrum. In addition, many subjects not fulfilling the criteria for obesity diagnosis share the same metabolic disturbances of some obese individuals. Although, it has been discussed that healthy obese people will sooner or later become unhealthy, the question on why some subjects attain a status of metabolic chaos earlier than others (for the same obesity levels or adipose tissue amount) is still matter of debate. In this chapter, we propose to discuss the contribution of obesity-related inflammation – metabolic inflammation – as cause or consequence of different obesity phenotypes, overviewing the main possible adipose tissue inflammation triggers.

Geometric Properties: Dimensions and Social Status

This chapter presents the integrated elements of headstone geometric properties (e.g. height, width, and thickness), and has the potential to incorporate a newly developed scale for capturing social status. In this case, an aspect of the physical record (e.g. headstone dimensions) has social implications and so contributes to a physicocultural approach. This study illustrates the known trend of headstone size increase across time, particularly in the late 19th century. However, the results show a different pattern in England and Scotland, with the latter having two groups of headstone size. One ranging from 9000 cm3 up to 100,000 cm3 and another ranging from 200,000 cm3 to beyond 900,000 cm3.

Cancer as an Occupational Hazard

Cancer is one of the most dreaded diseases of mankind that causes alarming mortality and morbidity in humans. According to International Labour Office (ILO), Occupational cancer is the most common work-related cause of death, leaving accidents and account for 32% of all work-related deaths worldwide leaving accidents and other occupational diseases well behind. It has long been evident that cancer has a multi-factorial etiology and is a multi-stepped process involving initiation, promotion and tumor progression. Studying occupational cancer is very challenging because of the long latency of cancer and the involvement of many factors in the development of cancer including family history, personal characteristics, dietary and personal habits besides exposure to cancer-causing agents in the workplace and environment. Occupational factors continue to be highly prevalent in new or upgraded IARC (International Agency for Research on Cancer) classifications in last decade. Inhalation, skin exposure and ingestion are significant modes of exposure of chemicals resulting in Cancer.Prevention of occupational cancer is a multistep strategy which involves eradication/minimization of carcinogenic process or agent coupled with good work /hygiene practices, employee education /counselling and workplace monitoring.

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.

Cytotoxicity Through Molecular Targets Involved in Apoptosis. Where Should We Further Search for Mushrooms Functionalities in Future Cancer Treatment?

Apoptosis is considered as a classical way of programmed cell death and important control mechanism of cell homeostasis. Cancer cells acquire different instruments to circumvent programmed cell death. This promotes uncontrolled growth and frequently confers chemoresistance to tumor cells. Activation of apoptotic signaling pathway has been a target of anti-cancer drugs in an induction of cytotoxicity. The mechanism of apoptosis is complex and includes many pathways. This chapter will focus on the current knowledge of apoptosis-triggering approaches in cancer therapy, as well as on mushroom extracts and isolated compounds acting as initiators of apoptosis through regulation of genes expression involved in cancer cell death. Furthermore, we pointed out directions for novel search for mushroom functionalities in this experimental field and discuss the possible further steps for exploration on the in vitro and in vivo levels.

Plant Based Bioactive Compounds as an Alternative for Cancer Therapy

Medicinal Plants have been known to be one of the oldest and most consistent sources for the production of novel drugs. Utilization of plant extracts as drugs can be attributed to their chemical and structural diversity along with their ability to interact with different biological targets in the cell. Moreover, they act as huge reservoirs for the phytochemicals which provide defense against a number of diseases. Cost effectiveness along with lesser adverse effects, allowed natural plants to be used as an alternative to conventional strategies for cancer treatment. Extracts from different natural plants have also been explored in the treatment of infectious diseases. The present chapter emphasizes on the use of plant extracts and their purified compound as cancer therapeutics. Cancer is one of the major causes of mortality worldwide. Owing to several limitations of current treatment regimens of cancer, the attention of researchers has been drawn towards exploration of natural sources. Herein, we will focus majorly on bioactive compounds as therapeutic agents for cancer treatment with emphasis on their other possible beneficiary roles.

Encapsulated Plant-Derived Polyphenols as Potential Cancer Treatment Agents

Cancer is one of the leading causes of death worldwide. There are many problems in cancer therapy due to the side-effects which limit its usage. Products derived from natural substances, particularly polyphenolic compounds which have very little toxic effects on normal cells, have gained a crucial interest as therapeutic weapon in clinical oncology due to their chemopreventive, antitumoral, radiosensibilizing and chemosensibilizing activities against different types of aggressive, recurrent and drugresistant cancers.

Especially now, polyphenols and their applications are one of the most studied topics in the literature due to their promising results against cancer cells. In many studies, it has been reported that, polyphenols inhibited the development of tumors through variety of mechanisms and reduce the tumor cell mass. However, with all the advantages of polyphenols, in the literature it is stated that, issues like poor solubility, high degradation rate and high dose requirement restrict the applications of polyphenols. Still, these obstacles can be overcome by using encapsulation and nano-drug delivery systems for plant-derived polyphenols. With the encapsulation techniques it is possible to increase their bioavailability, stability of the polyphenols and their uptake in the targeted cells. Encapsulated polyphenols have been used against cancer in various scientific studies. And the obtained results were promising. With the encapsulation methods, greater accumulation of polyphenols has been observed on the cell membrane and cytoplasm due to smaller size.

In this chapter, plant-derived polyphenols, their stabilities and encapsulation of polyphenols in order to increase their stability and their potential as cancer treatment agents will be explained.

Herbal Extracts from Carica papaya and Azadirachta indica: What Role for ROS in Cancer Cell Lines?

The use of plant-derived medications in the treatment and prevention of diseases, i.e., phytotherapy, comprises the traditional knowledge of therapeutic advantages deriving from the use of herbal parts to prevent, protect against and cure several pathologic conditions, such as cancerous, metabolic and inflammatory diseases. Herbal medications are prevalent in countries with limited resources, but, recently, increasing attention is devoted to their exploitation in cancer management on the basis of their low cost and side effects absence compared to conventional radiation or chemotherapic cancer approach. Currently, about 114,000 herbal extracts have screened for anticancer activity and 60% of the commercially available and clinically used cancer drugs, such as vinblastine and vincristine, paclitaxel, campothecin and its derivatives, are from natural sources. These compounds are active against a number of cancer types (ovarian, breast, lung, colon, liver, blood, prostate cancer). There are many types of cancer elicited by several factors that still render this disease a major public health problem, almost everywhere in the world.

The human body is constantly exposed to free radicals arising from exogenous and endogenous origins, which cause oxidative stress. Oxidative stress is closely related to various diseases, including cancer. There are many evidences that ROS are pivotal in cancer progression (via damage of DNA leading to genomic instability) and regression (via cell death induction through oxidative stress burst). Antioxidants stabilize free radicals and, in turn, prevent the oxidative stress, playing a key role in protection of the body, In this context, natural plants-derived antioxidants are universally considered very important for the prevention and treatment of oxidative stress and cancer. However, a dual role of plants in ROS generation or scavenging is recognized as plants extracts can also increase ROS production in the cells. Consequently, the role of plant extracts in ROS balancing inside cancer cells is a very fascinating feature in phytotherapy.

Among the plants reported in traditional medicine as a very panacea in active compounds, Carica papaya and Azadiracta indica (also known as Neem) extracts from different parts (leaves, seeds, fruits, etc.) are scientifically validated in the treatment of several diseases, including cancer. In this context, the two plants have different impact on cancer cell lines. In particular hydro-alcoolic extract of Neem leaves shows a pro-oxidant activity in hepatoma HepG2 cells, whereas water extract of C. papaya seeds exerts an anti-oxidant activity in leukemia HL-60 cells. Neem extract is unable to quench oxidative stress induced on HepG2 and synergizes with hydrogen peroxide (H2O2) in inducing cell death. Conversely, C. papaya extract quenches ROS induced by H2O2 in HL-60 cells but at the same time negatively affects cell viability.

These evidences corroborate the idea that the extracts from plants could act in patients with cancer to modulate oxidative homeostasis and obtain benefit during cancer therapy.

Herbal Products in Hypertension: Paradox or, Paragon

Hypertension is one of the most common diseases in the current health scenario as per the report of World Health Organization. It is a chronic medical condition in which the blood pressure remains elevated and thus leads to a plethora of pathological conditions including renal, pulmonary and cardiovascular disorders. The root cause of this disease lies in the changing lifestyle that includes food habits and stress. A number of conventional drugs are available for hypertension and its comorbidities viz. thiazide-diuretics, angiotensin converting enzyme inhibitors and calcium channel blockers. Use of these drugs is limited by side effects like hypokalaemia, precipitation of diabetes, hyperuricaemia, diarrhoea, rash, abdominal pain, chest pain, dizziness, impotence, bleeding, etc. In last few decades, researchers have focused on drug discovery from herbal medicines. Moreover, we have a long history of usage of herbal drugs for the clinical management of hypertension. The pharmacological activity of these drugs is mainly attributed to phytoconstituents such as flavonoids, phenols and alkaloids, which synergistically act against hypertensive disease and significantly diminish the co-morbidities of this disease. In this chapter, we discuss about the anti-hypertensive activity of plants selected among the most reported in literature, with a focus on their possible mode of action.

Cancer as an Occupational Hazard

Environmental Pollutants and Risk of Cancer

Cancer is characterized by cell proliferation, prevention or bypass of programmed cell death, genomic instability, angiogenesis, invasion and metastasis which are influenced by environmental pollutants. It is the major cause of death in world wide. Lifestyle factors such as diet, smoking and use of alcohol are responsible for the development of cancer in a large part of the population of developed countries. Existence of carcinogens or co-carcinogens in polluted air and drinking water, as well as in food, played a significant contribution in our country. Endocrine disrupters modify the risk of breast, endometrial and prostate cancer. Laryngeal, oropharyngeal, hypopharyngeal, sinonasal, nasopharyngeal, oral and lung cancer are positively associated with smoking and air pollutants. Tobacco smoking induces DNA adducts formation which is responsible for mutations at K-RAS and TP53 gene in the lung and pancreatic adenocarcinomas. Tobacco smoking induces promoter hypermethylation of p16 and DAPK genes in Non-Small Cell Lung Cancer (NSCLCs). Aflatoxin B1 (AFB1) causes promoter hypermethylation of tumour-suppressor genes RASSF1, MGMT, and p16 in human hepatocellular carcinoma (HCC) patients. Down-regulation of p15, p16, PRKG1, PARD3, and EPHA8 genes at mRNA level due to hypermethylation and increased expression of STAT3, IFNGR1 at mRNA level due to hypomethylation were reported in patients having benzene exposure. Methylationinduced transcriptional inactivation of tumor suppressor genes, including p53, CDKN2A (p16INK4A), Ras association domain family member 1 (RASSF1A), and death-associated protein kinase (DAPK) were reported in arsenic exposed individuals. The genetic and epigenetic alterations respond to environmental carcinogens have significant contribution for biomarker development in assessment of health risk.

Subject Index

Cutting Edge Targeting Strategies Utilizing Nanotechnology in Breast Cancer Therapy

Breast cancer is one of the major reasons for mortality and trauma amongst women. Therapy for breast cancer has various options such as, chemotherapy, hormone therapy, gene therapy, immunotherapy, and radiation therapy. Chemotherapy is the choice in most cases but is often associated with side/adverse effects. These side/adverse effects can be eliminated by delivering the drug to the target site. With the help of nanotechnology and drug delivery through a suitable carrier, targeting has become achievable. Targeting includes both, the active as well as the passive approach. Passive targeting is based on the accumulation of the drug over tumor tissues whereas active targeting is done by means of an interaction with the receptor/antigen and the targeting moiety. Nowadays, the focus is on the active targeting of drugs in which an approach to target the drug directly to the diseased cells is taken. The approaches can be broadly classified mainly into antigen-antibody, aptamers, ligand-receptors and lectin-carbohydrate based, respectively. Every targeting strategy is based on one basic concept, i.e. an overexpression of a biomarker on a specific diseased cell type. Hence, a suitable moiety is utilized to carry out the active targeting of drugs. Apart from chemotherapeutic agents, hormonal drugs, gene silencing molecules can also be successfully delivered through nanotechnology. Some of the nano based medicines are already in the market and there is a constant enhancement in the success of the systems. Some are in the trial phase and some approaches have been patented. However, the translational challenge yet exists and there is a need to overcome it. Thus, this chapter discusses the various delivery systems, different materials and various approaches for the active targeting of the drug, recent clinical trials, challenges and some recent patents.

In-vitro Anti-Proliferative Assays and Techniques Used in Pre-Clinical Anti-Cancer Drug Discovery

The hallmark features of cancer emphasize essential biological characteristics associated with malignant transformation. Anti-cancer drug discovery is a strenuous task, requiring a number of pre-clinical and clinical investigations. Preclinical investigations offer a foundation for anti-cancer drug discovery. A number of cell based in-vitro assays have been introduced to investigate each major hallmark feature of cancer. Selection of the most suitable in-vitro assay for pre-clinical investigations mainly depends on the researcher’s objective(s) to be investigated. A wide range of cell based in-vitro anti-proliferative assays/techniques have been developed based on different assay principles and chemistries to evaluate the effects of testing agent (s) on cancer cell proliferation. In this chapter, we have outlined commonly utilized cell based anti-proliferative assays in pre-clinical anti-cancer drug discovery approaches.

Challenges in the Management of Hepatoblastoma

Hepatoblastoma is the third most common pediatric tumor of the abdomen with an incidence of about 1.2-1.5 cases/million population/year. It has been associated with various genetic conditions, such as familial adenomatous polyposis, Beckwith- Wiedemann syndrome and Edwards syndrome, while genetic mutations of the Wnt signaling pathway are also frequently seen. The different staging systems and treatment approaches of the four hepatoblastoma study groups, International childhood liver tumors strategy group, Children’s Oncology Group, German Society for Pediatric Oncology, and Japanese Study Group for Pediatric Liver Tumors, led to different outcomes among the various trials published over the years. Some groups tended to follow a protocol of an upfront surgical resection, while others suggested neoadjuvant chemotherapy to all patients. Now these groups try to come on the same page by initiating an international collaborative attempt to pool previously published data, as well as to classify future patients into risk-stratified groups that would determine treatment options and facilitate improved survival outcomes. The aim of this chapter is to review the general characteristics of hepatoblastoma, the various treatments implemented over the last years, as well as the challenges in management that its rarity and discrepancies among the study groups pose.

The Regulation and the Function of Autophagy in the Development and Behavior of Esophageal Cancers

Autophagy (AP) is a cell recovery programme that plays a critical role by degrading dysfunctional organelles and misfolded proteins. Besides its position to maintain homeostasis, the contribution of AP to the development and progression of several pathological conditions, including cancer has been denoted. A significant number of findings indicate the involvement of AP-mediated cell survival in the progression of many tumors. However, the data in esophageal cancer (EC) appears to be less initiated. In this chapter, first definition, types and mechanisms of AP are described, and the following sections are focused on giving a clear view of the findings that communicate AP with oncogenesis and tumor progression in EC. Moreover, the use of several drugs, which are known to modulate AP (inhibitors [3-MA, Bafilomycin etc.] and inducers [Nimotuzumab etc.]) in the treatment of EC, is discussed.

The current data indicated that although the role of AP in carcinogenesis, tumor behavior and response to treatment in EC is non-negligible, the first problem to be resolved is to determine whether AP should be stimulated or inhibited because it seems that both strategies are encouraging. Another problem is the identification of the patient who will benefit from the manipulation of AP. Finally; the use of existing drugs that may have off-target effects warrants the development of specific AP modulating compounds suitable for use in patients with EC. The potential role of AP in EC chemoresistance necessitates further investigations not only with AP related proteins but also their related pathways into open up new corners for therapeutic intervention.

The Role of ncRNAs in Human Cancer and its Related Patents

The development of the new sequencing technologies has unveiled a new world of regulatory non-coding RNAs (ncRNAs) that is revolutionizing our understanding of the RNA world. New transcripts with non-coding functions are being identified from most of the human genome. Although we have just started to study these ncRNAs, the broad list of regulatory functions assigned to them has assured a prominent role in the regulation of the molecular processes involved in human cancer. This chapter presents a review of the state of the art in the study of ncRNAs and their relationship with human cancer, summarizing the origin, structure and function of the most relevant new classes of ncRNAs. In addition, a selection of recent patents related to ncRNAs and human cancer is included here, analyzing their promising potential in the diagnosis and treatment of human cancer.

Impact on Health of Artichoke and Cardoon Bioactive Compounds: Content, Bioaccessibility, Bioavailability, and Bioactivity

Artichoke, cultivated cardoon, and their common relative, the wild cardoon are botanical varieties of the species Cynara cardunculus L., a perennial plant native to the Mediterranean Basin and belonging to the Asteraceae family. While commonly used as food, leaf extracts of this plants have been traditionally used as a natural remedy in folk medicine. These plants are in fact a rich source of bioactive compounds such as polyphenols, inulin, and sesquiterpene lactones. Many studies demonstrated that these compounds and their metabolites are responsible for several beneficial properties attributed to the extracts of artichoke and cardoon. As we gain knowledge on the effects and mode of action of these compounds, artichoke and cardoon are considered ‘functional food’ and are increasingly used to extract bioactive compounds and for numerous pharmaceutical applications. In this chapter, after a brief introduction on the origin and the importance of these crops, each class of bioactive compounds is presented summarizing the specific chemical properties, the biosynthesis, and the concentration range in plant tissues. The third section discusses the main factors (plant portion, physiological stage, plant genotype, environment, pre-harvest agronomic practices, post-harvest handling and processing) influencing the concentration of bioactive compounds in artichoke and cardoon. The following section is focused on the physiological fate of the bioactive compounds, reviewing the results of the most recent in vitro and in vivo studies conducted to assess their bioaccessibility, bioavailability, and pharmacokinetics. Finally, in the last section the main health-promoting effects attributed to artichoke and cardoon polyphenols are reviewed.

Solanaceae: A Family Well-known and Still Surprising

The family Solanaceae features many popular vegetable crops, mainly belonging to its three major genera Solanum, Capsicum, and Physalis. They have played an important role in human nutrition and health since ancient times, most of them being native to South and Central America, but nowadays domesticated worldwide. Edible fruit, leaves, tubers as well as non-edible plant parts are a valuable source of often unique compounds with multiple biological activities. Despite numerous studies and intensive research, there are still novel compounds being discovered from both cultivated and wild species, that could bring more benefits into treatment of civilisation diseases not only as part of pharmaceutical products, but also as functional foods important in everyday prevention of health problems, especially those related to oxidative stress. Apart from the edible parts, the organic waste from production of these vegetables is a useful source of bioactive substances and extracts that can be used both in the food and pharmaceutical industry. In this chapter, the most important species from three genera are described in detail with emphasis being given on the research studies published within the last two decades. Major bioactive constituents representing each genus and biological activity of extracts and individual compounds, with special attention to the most interesting findings regarding antioxidant, anti-inflammatory and anticancer activity, are also discussed in the corresponding subsections.

Anticancer Properties of Apiaceae

The aim of this book chapter was to highlight the great importance of plants from Apiaceae family as functional food products, focusing on its anticancer properties. The plants that will be discussed for their anticancer properties include: caraway (Carum carvi L.), dill (Anethum graveolens L.), anise (Pimpinella anisum L.), fennel (Foeniculum vulgare Mill.), coriander (Coriandrum sativum L.), celery and celeriac (Apium graveolens L.), lovage (Levisticum officinale Koch.), carrot (Daucus carota L.), parsley (Petroselinum crispum L.), parsnip (Pastinaca sativa L.), angelica (Angelica archangelica L.), cumin (Cuminum cyminum L.), chervil (Anthriscus sp.) and eryngo (Eryngium campestre L.). Leaves, roots and seeds of these plants are widely used as spices, flavoring agents and dietary supplements in the folk medicine and pharmaceutical industry. Furthermore, roots and leaves of these plants are valuable sources of phytochemicals used on a daily basis as food with nutraceutical potential. Their essential oils have characteristic aroma and have potent antioxidant and antimicrobial properties, which contribute to their ability to serve as natural food conservatives. Additionally, due to their anticancer, hypoglycemic, hypolipidemic, hepatoprotective and other activities these plants are widely used as alternative and healthy food for the prevention and treatment of many disorders.

Headspace Analysis of Volatile Compounds From Fruits of Selected Vegetable Species of Apiaceae Family

Parsley (Petroselinum crispum L.), celery (Apium graveolens L.), celeriac (Apium graveolens var. rapaceum), carrot (Daucus carota L.), parsnip (Pastinaca sativa L.), lovage (Levisticum officinale Koch.) and angelica (Angelica archangelica L.) are vegetable plants belonging to the Apiaceae family. They are often used as spices due to their characteristic aroma, originating from the volatile compounds present in the plant tissues. Mainly, all parts of the plant i.e. roots, leaves and fruit are used in nutrition. However, the focus of this chapter is plant fruit (i.e. seed), which is mostly used as spice. The contemporary method used for the analysis of volatiles compounds is called headspace and it is widely applied in flavor chemistry. The dominant compounds in P. crispum are α-pinene (46.2-49.0%) and β-pinene (33.5- 35.4%), while in A. graveolens, it is limonene (84.1-94.4%). In D. carota, the main components are sabinene (28.3%) and α-pinene (25.0%), while in P. sativa fruit, it is octyl ester of butanoic acid (53.8%) and 1-octanol (27.6%). In L. officinale and A. archangelica, the dominant component in fruit is β-phellandrene (77.1% and 84.7%, respectively).

Phytochemicals Content and Health Effects of Cultivated and Underutilized Species of the Cucurbitaceae Family

Cucurbitaceae represents a large plant family with more than 120 genera and 800 species, among which many significant cultivated vegetable species are included, such as watermelon, melon, cucumber and cucurbits (squash, pumpkin and zucchini). These species are usually consumed for their edible fruits, however several other uses have been reported for the various plant parts, including medicinal and therapeutic ones among others. The present chapter will demonstrate the most common vegetable species in terms of their chemical composition and health effects, as well as their edible, medicinal and industrial uses, based on the phytochemical content of the various plant parts. Special focus will be given on cucurbitacins which are an important group of phytochemicals present in the Cucurbitaceae family, since several studies have confirmed its bioactive properties and multiple health effects. Finally, selected less known species of this family (gourds) will be presented, considering their important health effects and their use in vegetable grafting. In conclusion, future perspectives for further valorization of these species will be highlighted, especially for the ones that are less commonly used.

Designing Bioactive Nanoparticles: The Era of Nutraceuticals

Two thousand and five hundred years ago, Hippocrates stated ‘let food be the medicine and medicine be the food’, but only in 1989, Stephen DeFelice coined the term nutraceutical to describe the hybrid between ‘nutrition’ and ‘pharmaceutical’. A ‘nutraceutical’ is defined as a supplement to the diet that is composed of bioactive compounds found in foods and botanicals, vitamins, and minerals. It is formulated and taken under the form of capsules, tablets, etc., resulting in beneficial health impacts. Owing to their biological properties, phenolic compounds are considered nutraceuticals with great potential; however, their effects are limited due to their low bioavailability. The rationale for developing an efficient drug/nutraceutical delivery system is to increase the bioavailability and half-time of the drug in the vicinity of the target cells, reducing at the same time, its exposure to non-target cells. Nutraceutical delivery to the brain is a major challenge imposed by physical barriers, such as the blood-brain barrier (BBB). In the last decade, nanotechnology has become a powerful strategy to enable nutraceuticals’ target-delivery to tissues and organs, including the brain. This chapter will present the latest results obtained with phenolic-based nanoparticles, showing the failures, achievements, and most promising routes for future works.