Current and emerging DAI biomarkers.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"1806",leadTitle:null,fullTitle:"Biomimetic Based Applications",title:"Biomimetic Based Applications",subtitle:null,reviewType:"peer-reviewed",abstract:'The interaction between cells, tissues and biomaterial surfaces are the highlights of the book "Biomimetic Based Applications". In this regard the effect of nanostructures and nanotopographies and their effect on the development of a new generation of biomaterials including advanced multifunctional scaffolds for tissue engineering are discussed. The 2 volumes contain articles that cover a wide spectrum of subject matter such as different aspects of the development of scaffolds and coatings with enhanced performance and bioactivity, including investigations of material surface-cell interactions.',isbn:null,printIsbn:"978-953-307-195-4",pdfIsbn:"978-953-51-6007-6",doi:"10.5772/2237",price:159,priceEur:175,priceUsd:205,slug:"biomimetic-based-applications",numberOfPages:574,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"6a088e82c9518ba8fca91ac303d66f9b",bookSignature:"Anne George",publishedDate:"April 26th 2011",coverURL:"https://cdn.intechopen.com/books/images_new/1806.jpg",numberOfDownloads:58889,numberOfWosCitations:90,numberOfCrossrefCitations:17,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:67,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:174,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 4th 2010",dateEndSecondStepPublish:"June 1st 2010",dateEndThirdStepPublish:"October 6th 2010",dateEndFourthStepPublish:"November 5th 2010",dateEndFifthStepPublish:"January 4th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"21288",title:"Prof.",name:"Anne",middleName:null,surname:"George",slug:"anne-george",fullName:"Anne George",profilePictureURL:"https://mts.intechopen.com/storage/users/21288/images/1552_n.jpg",biography:"Anne George received her PhD in Physical Chemistry from Madras University, India in 1983. She then did her Postdoctoral work with Dr. Arthur Veis at Northwestern University on determining the structure of type I collagen in solution using Fourier Transform Infrared Spectroscopy. She joined as an Assistant Professor in 1993 at Northwestern University where she started work on the cloning of the dentin matrix proteins. She was instrumental in identifying the family of dentin matrix proteins from the rat odontoblasts. She was awarded a 'Teaching Excellence Award” from Northwestern University. She then moved to the University of Illinois at Chicago in 1998 as an Associate Professor, became a Full Professor in 2003 , and continued her work on noncollagenous proteins and their role in biomineralization. She is now an Allan G. Brodie Endowed Professor at the University of Illinois at Chicago. Her work was reported in Chicago Tribune 'Calcium Link-Genes may solve mystery of how teeth harden” in 1994 and Scientific Year Book of Encyclopedia Britannica 'Tooth Gene Studied” in 1998. A documentary on her work was produced by Dallas TV. She is the recipient of the IADR Basic Research Award in 'Pulp Biology and Regeneration” in 2008.In 2011 she was conferred with the honor of doctor honoris causa from the University Paris Descartes. Dr. George is the author of over 90 papers in peer-reviewed journals. Her research focuses on biomineralization related proteins and their application as templates in biomimetic mineralization studies and as protein-based templates for bone and dentin regeneration.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Illinois at Chicago",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"690",title:"Biomimetics",slug:"biomimetics"}],chapters:[{id:"15757",title:"Biomimetic Epoxidation of Olefins Catalyzed by Metalloporphyrins with Molecular 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Diseases that it lays down can have systemic scope and significantly affect the quality of life of individuals who suffer them. Periodontal disease is one of the oral health problems that most often affect the global population, lack of treatment leads to loss of tooth organs and consequently alters the digestion and nutrition, without considering other relevant aspects as phonation, aesthetics and social or emotional impact. The importance of periodontal disease has raised possible bidirectional relationships with systemic diseases such as diabetes, metabolic syndrome and cardiovascular disease. We address herein the role of oxidative stress in the etiopathogeny of periodontal disease. In the same context, another disease that has become relevant in our days is the oral cancer. Epidemiological data show that the incidence of this neoplasm has been increasing in several countries. The impact of oral cancer on patients, who suffer it, is devastating. The role of oxidative stress in the development of this disease and some alternatives for its treatment, are topics addressed in this brief review. These two oral diseases are a sample of the plethora of effects that oxidative stress may have at local and systemic level.
\n\t\tPeriodontitis is the second world health problem since it affects between 10 to 15% of the world population [1]. Although the various states in this disease depend on the degree of destruction and inflammation present, the American Dental Association classifies according to a system development based on the severity of the loss of periodontal insertion. The information obtained in clinical and radiographic examination classifies the patient in four typical cases that are:
\n\t\t\tType I: Gingivitis
Type II: Mild Periodontitis
Type III: Moderate Periodontitis
Type IV: Advanced Periodontitis
There are other classifications of the inflammatory process [2]:
\n\t\t\tUlceronecrotic acute gingivitis
Acute gingivitis
Chronic gingivitis
Marginal periodontitis
Superficial marginal periodontitis
Deep marginal periodontitis
Periodontal disease is an inflammatory process involving a set of changes that directly affect tissues that hold the teeth. The etiology plays a role which is essential within the bacterial infection. In fact, within the 300 to 400 species of bacteria located in the oral cavity consider that some of them are exclusive to the periodontal tissues. However in recent years it has been determined that the evolution and spread of the disease will play a decisive role in the host response to bacterial attack. This is reflected in the model of the critical path in the pathogenesis of this disease. Through this one can understand that there are diseases and systemic conditions that have risk factors for periodontal disease, because they are going to modify the host response and favor the development of damage [3].\n\t\t\t
\n\t\t\tWhen it is lost in the inclusion of periodontal fibers, usually after puberty, the cases that are reported before this stage are only 5%. Previously it has reported that there was a ratio of two to one in the frequency of periodontal disease, women being the most affected in this order. Currently known, the presence by gender of this involvement is very similar.
\n\t\t\tIn adults with more than 1 mm of affected dental faces periodontal insertion loss increases with age. An epidemiological report in United States mentions that approximately 80-92% of the population between the ages of 35 and 64 years performed, lost more than 1 mm insertion in 20 to 47% of teeth. From 18 to 22% of the population of 35 to 64 years were more 2 mm deep in the probing of the periodontal bags in 11 to 13% of tooth surfaces. Periodontitis occurs when tissue destruction due to the direct effect of bacterial toxins and removal products, in addition, the effects caused indirectly by the harmful organic defense mechanisms. Microorganisms as
Bacteria causes tissue destruction with its deletion, this is a feature of marginal periodontitis products. Destruction of tissues within a radius of 1.5 to 2.5 mm around the plaque has been observed (the so-called
The human immune system can be classified according to their function within the periodontium, follows:
\n\t\t\tSecretory system
Neutrophils, antibodies and complement system
Leukocytes and macrophages
Immune regulation system.
The system formed by neutrophils, antibodies and complement is crucial to the immune defense against periodontal infections. When functional defects of neutrophils occur, it increases the frequency of serious marginal periodontitis [4].
\n\t\tA phenomenon that occurs within the periodontal disease is called oxidative stress. In order to understand the phenomenon of oxidative stress it is important to know what the free radicals (FR) are, where they come from and how to act. A FR is considered that molecule presented an electron unpaired or odd in the orbital external, in its atomic structure giving it a spatial configuration that generates a high instability. In the molecule of oxygen (O2) know the following FR or also called oxygen reactive species: anion superoxide (O2˙ˉ), hydrogen peroxide (H2O2), hydroxyl radical (OH˙) and singlet oxygen (1O2). The H2O2 is not strictly a FR but by its ability to generate the OH˙ in the presence of metals such as iron, it incorporates it as such. A fundamental characteristic of the reactions of free radicals is that act of chain reactions, where a radical reaction generates another consecutively.
\n\t\t\tOxygen (O2) that this in the air is fundamental to life, many reactions in which participates the O2 generates reactive oxygen species (ROS), of which some have the chemical character of being free radical (FR), whose biochemical entities in its atomic structure presented an odd or unpaired electron in the outer orbital, giving it a spatial configuration that generates a high instability with an enormous capacity for combined with the diversity of molecules members of the cell structure: carbohydrates, lipids, proteins, nucleic acids, and derivatives of each of them, causing important functional alterations. In this sense, the body has an antioxidant system to counteract the generation of ROS, which maintains a homeostatic balance. However there are pro-oxidant factors that favor the generation of FR, causing an imbalance in favor of the latter, generating so-called oxidative stress (OS) [5].
\n\t\t\tThe tetravalent reduction of oxygen to produce water through the electron transport chain in mitochondria is relatively safe. However, the univalent reduction of oxygen generates ROS. The human organism also has antioxidant system to counteract the generation of ROS, which maintains a homeostatic balance. However, there are pro-oxidant factors that favor the generation of FR, causing an imbalance in favor of the latter, generating OS. The antioxidant enzyme superoxide dismutase (SOD), Glutathione peroxidase (GP), glutathione reductase (GR) and catalase (CAT), as well as proteins carriers of metals (ceruplasmina, transferrin, lactoferrin, etc.), and another micronutrients as vitamins A, C and E, bilirubin, uric acid and selenium, constitute the most important elements of the antioxidant system. Also, between the most important pro-oxidant factors we can highlight the process of aging, ionizing radiation, ultraviolet rays, environmental pollution, cigarette smoke, excess of exercise, intake of alcoholic beverages and inadequate diet [6].
\n\t\t\tThe role of Coenzyme Q10 is the mitochondrial energy coupling. It is an essential part of the cellular machinery used to produce ATP that provides the energy for muscle contraction and other vital cellular functions. Most of the ATP production occurs in the inner membrane of the mitochondria, where the Coenzyme Q10 is located. The most important function is serving as a suppressor of primary free radicals, located in the membranes in the vicinity of unsaturated lipid chains. There are less established functions that include the oxidation/reduction of the control of the origin and transmission of signals in cells that induce the expression of gender, the control of membrane channels, the structure and solubility in lipids [7].
\n\t\t\tFree radicals cause damage to periodontal tissues by a variety of different mechanisms including:
\n\t\t\tDNA damage
Lipid peroxidation
Protein damage
The oxidation of important enzymes (anti proteases)
Stimulation and release of pro-inflammatory cytokines
ROS covers other reactive species that are not true radicals, but are however capable of react in intra and extracellular environment: peroxide of hydrogen, hypochlorous acid, oxygen, ozone. The living organism has adapted to an existence under a continuous output of radical free flow. Between the different antioxidant defense mechanism adaptation mechanism is of great importance. Antioxidants are "those substances that when they are present in lower concentrations compared to the substrate of an oxidizable, significantly delay or inhibit the oxidation of the substrate". The various possible mechanisms that antioxidants can offer protection against damage from free radicals are:
\n\t\t\tThe prevention of the formation of radical free.
Interception of the radical free to eliminate reactive metabolites and their conversion to less reactive molecules.
Facilitate the repair of the damage caused by free radicals.
Create a favourable environment for the effective functioning of other antioxidants.
Antioxidant defense system is very dynamic and responsive to any disturbance that occurs in the body redox balance. Antioxidants can be regulated and neutralize the formation of radical free that can occur due to oxidative stress, such as the factor transcription factors Activator protein 1 and nuclear-kb are redox sensitive. Redox potential is a measure of the affinity of a substance for electrons [8].
\n\t\t\tThe presence of inflammatory infiltrate is a constant feature in periodontal disease. It is known that these cells release lots of free radicals; it is suspected that these metabolites are involved in the pathogenesis of the disease. The presence of a dense inflammatory infiltrate in periodontal disease leads to the suspicion that the relationship of periodontal leukocyte-tissue has a double aspect. The role of these cells in the containment of the gingival bacteria and their products must be analyzed according to a balance with the destruction of tissue due to the release of the products of its action (FR and proteases). In this way, a defensive mechanism, under the interaction of various factors, can be harmful to periodontal tissues, and they are therefore involved in the pathogenesis of inflammatory periodontal disease.
\n\t\t\tThere is numerous evidence pointing to the involvement of FR in periodontal disease. It has been reported in patients with rapidly progressive periodontitis, that the polymorphonuclear neutrophils (PMN) are functionally activated, produce high levels of O2 and have a high response the luminol-dependent (QL) chemiluminescent. There is an increase of the PMN oxidative response peripherals in patients with localized and generalized juvenile periodontitis, as well as in adult patients with periodontitis (AP). This increase is related to clinical periodontal status and is reversed by therapy.
\n\t\t\tIt has also compared the generation O2 by the activated PMN in the gingival crevicular fluid (GCF) of patients with AP. The PMN activation with phorbolmyristateacetate causes a marked increase in the release of O2 in patients with AP, while the antioxidant activity of the gum is similar to the controls. The effect of the PMN in crevicular fluid of patients is dependent on variations in the rate of formation of O2, relative to the intrinsic antioxidant capacity of the gingival tissue.
\n\t\t\tIn gingival epithelial cells in culture studies have shown the PMN may cause lysis of these through the action of the free myeloperoxidase(MPO), a leukocyte enzyme generating radicals. Its activity has been increased in the crevicular fluid of sites with gingivitis and periodontitis with respect to healthy sites.
\n\t\t\tThere is a close relationship between free radical production by leukocytes and activation of proteases. Altogether these actions could have profound effects on the function and integrity of the gingival epithelium.
\n\t\t\tThe above evidence leads to consider that in the inflammatory periodontal disease, the general etiological factors causing the breakup of physiological systems of inhibition of lipid peroxidation, creates a low level of antioxidant protection of periodontal tissues. In these circumstances, the local factors lead to the migration of neutrophils to the gingiva and gingival fluid. The activation of these leukocytes in phagocytosis, causes the release of ROS, which leads to the outbreak of the lipid peroxidation of the soft tissues of the periodontium and activation of protease. This lipid peroxidation is the mechanism that triggers the development of morphofunctionalchangesin periodontium and their vessels, which results in destruction of collagen and bone resorption.
\n\t\t\tDue to numberless evidences that suggest a participation of the ROS in the pathogenesis of the periodontal disease, it has been raised that the factors that promote a rupture of the antioxidant physiological system, contribute to the development of oxidative mechanisms that initiate the periodontitis. The main cause of lipid peroxidation in the periodontal disease seems to lie in the liberation of ROS by leukocytes in phagocytosis. These concepts emphasize the utility of antioxidants in the prophylaxis and treatment of periodontal disease and therefore justify the search of new antioxidant preparations for this purpose. For example the
The oral cancer occupies 2-5 % of all whole body cancers. This percentage places this neoplasia within the ten most common cancers [10]. Although its magnitude is relatively low, its impact on affected patients and their costs in health systems is high.There is a considerable variation in the incidence and mortality rates around the world. The incidence is greater in south of India, Australia, North of America, many European countries, Brazil, certain countries of Africa and some of central Asia [11]. 90% of oral cancer is of epithelial origin and the rest 10% are distributing in adenocarcinomas, sarcomas, lymphoproliferative disorders, metastasis, melanomas and malignant odontogenic tumors. The intraoral main site of oral squamous cell cancer (OSCC) is the posterior lateral border of tongue (Figure 1) and floor of mouth (Figure 2). If the lips are considered within the oral territory, then this site has the highest frequency (Figure 3).Since oral squamous cell carcinoma (OSCC) is the main malignant neoplasia we focus in it.
\n\t\t\tSquamous cell cancer of the posterior lateral border of the tongue in a 28-year-old woman.She smoked a cigarette per day for 15 years.
Squamous cell cancer of floor of mouth in a 58-year-old woman.She had a history of poorly controlled diabetes type 2 from 42 years. She also has used ill-fitting dentures since age 50. Note the linear lesion with presence of necrosis in the centre of the fissure.
There are premalignant lesions recognized like: leukoplakia, erythroplakia, oralsubmucosal fibrosis, palatal lesions of reverse cigar smoking, oral liken planus, discoid lupus erythematosus, and hereditary disorders likecongenital dyskeratosis and epidermolysisbullosa, but beyond of a clinical standpoint, diverse carcinogenic molecular mechanisms have been postulated.The main target is the DNA, since mutations that occur in it generates a wide range of deleterious effects in the cell. In a very general overview, the balance between tumor suppressor genes and those genes that induce cell cycle is altered.Allowing cells to escape cell cycle control and developing an unpredictable biological behavior. Subsequently, the cells express molecules that allow them to acquire an invasive phenotype, a phenomenon known as epithelial-mesenchymal transition. Why malignant cells colonize distant sites? Is not yet fully understood, but it is the feature that makes it lethal.
\n\t\t\tSquamous cell cancer of the lip in a 74-year-old man. He was a farmer and consumed alcohol chronically.
Free radicals are products of the oxidation-reduction systems of the cell and its participation in cellular metabolic functions is essential for cell survival. A classic example is the electron transport chain in mitochondria. However, in whatpathologicalconditions, free radicals can become deleterious? In fact, what are the results of its harmful effects? The involvement of free radicals in cancer development has been studied for 3 decades, and there is sufficient evidence that implicates theirs in the multistage theory of carcinogenesis. They are proposed to cause diverse DNA alterations like: punctual mutations, DNA base oxidations, strand breaks, mutation of tumor suppressor genes and can induce overexpression of proto-oncogenes [12].It should be added that oxidative protein damage participates in facilitating the development of cancer.
\n\t\t\tSeveral works explore the levels of oxidative stress in patients with oral cancer [13-15] most of them quantified the products of lipid-peroxidation(mainly malonilaldehyde) and contrast them with the activity of antioxidant enzymes or exogenous antioxidants levels in blood or even saliva. The results agree that there is an imbalance between the high amount of free radicals and insufficient antioxidant system activity.Added to this, some researchers have observed that high levels of lipid-peroxidation combined with low levels of thiols and antioxidant status, correlate with poor survival rate in patients with oral cancer [16].
\n\t\t\tThe OSCC is a multifactorial disease, however, a factor strongly associated, is smoking. 90% of individuals with oral cancer are smokers. It is considered that the smoke from cigarettes have 4000 chemicals, 40 of which have carcinogenic potential. It has been shown that cigarette smoke contains pro-oxidants that are capable of initiating the process of lipid-peroxidation and deplete levels of antioxidants from the diet [17,18].
\n\t\t\tIn contrast, there is epidemiological evidence that demonstrates the protective effect of diet on some populations [19-21].For example in Greece, which has the lowest rates of oral cancer among European countries,its population is exposed to latent risk factors such as alcohol intake and smoking; micronutrients consume such as riboflavin, magnesium and iron correlated inversely with oral cancer [19].
\n\t\t\tConsequently, several authors have proposed the ingestion of diverse exogenous antioxidants; supporting in those epidemiological studies, where the diet offers protection for the development of cancer, and taking into account that the endogenous antioxidant systems have been overwhelmed by oxidative stress.
\n\t\t\tFor example, vitamin C is one of the most extensively evaluated antioxidants in oral cancer alternative co-therapies. Low or even undetectable levels of vitamin C correlate with the presence of oral cancer [17, 22]; in contrast, is one of the micronutrients that have a consistent inverse correlation in different studies [23].Vitamin C acts as a scavenger of free radicals and impedes the detrimental chain reactions triggered by the free radicals.The l-glutamine is another antioxidant that has shown a beneficial modulating effect in patients with oral cancer in stages III and IV. The l-glutamine is administered in the diet as a complementary therapy; the proposal is that restores glutathione cascade system [15].In addition, other antioxidants such as carotene, vitamin E, thiamine, vitamin B6, folic acid, niacin and potassium have shown a convincing protective effect [24]. Even more,when them are administered together during the cycles of radiotherapy [25].
\n\t\tCentral nervous system (CNS) trauma including traumatic brain injury (TBI) is a major cause of long-term injury, disability and death among young adults worldwide [1, 2]. Around 1.6 million individuals suffer from TBI every year in India with 200,000 deaths [3]. In the USA, there were more than 223,000 TBI-related hospitalizations in 2018 and about 166 Americans died from TBI-related injury each day in 2019 [4]. These estimates do not include the many TBIs that are only treated in the emergency department, primary care, urgent care, or those that go untreated [5]. Since the affected individuals are disabled and out of work during the most productive period of their life, these devastating conditions have an enormous physical, mental and economic burden to the country.
TBI is a heterogeneous neurological condition, ranging from single or repetitive concussion /mild TBI to penetrating head injury, focal contusion, different forms of hematoma (subdural and epidural) and diffuse injury. Depending on the motor, verbal, and eye-opening responses of the affected individuals, the Glasgow coma scale (GCS) was designed to access the disability. The GCS measures the following three functions: Motor response (scores: 6-normal, 5-localized to pain, 4-withdraws to pain, 3-flexion response to pain, 2-extension response to pain, 1-no motor response), Verbal response (scores: 5-normal conversation, 4-oriented conversation, 3-words, but not coherent, 2-no words, only sounds, 1-none), and Eye-opening response (scores: 4-spontaneous, 3-to voice, 2-to pain, 1-none). Based on the GCS score, TBI is classified as mild, moderate, or severe. TBI patients with GCS of 13 to 15 are classified to be mild, which includes the majority of these patients. Patients with a GCS of 9 to 12 are considered to have a moderate TBI, while patients with a GCS below eight are classified as having a severe TBI [6].
The heterogeneous nature of TBI with respect to severity of the injury and comorbidities make patient outcome difficult to predict. While mild TBI or concussion may affect neural cells temporarily, severe TBI is associated with substantial axonal injury and physical damage to the brain, which can result in blood-brain barrier disruption and neuroinflammatory changes [7]. Moderate to severe TBI can usually be visible as structural abnormalities using radiological examinations such as computed tomography (CT) or magnetic resonance imaging (MRI). However, more subtle neural alterations characteristic of mild TBI are not easily detected by these imaging techniques.
Although TBI is an extremely complex condition, there have been many advances in recent years in relation to the diagnosis, monitoring and treatment of the affected patients. Shortcomings in our knowledge of the physiopathology of TBI and the development of reliable predictive models capable of offering an early orientation as to the patient outcome, will improve the diagnostic and therapeutic strategies on an individualized basis. Likewise, we need valid predictive models in severe TBI in order to define efficacy endpoints in the evaluation of new drugs or treatment strategies–since the usual primary endpoints (death and disability) are widely recognized as being inadequate and could explain the discouraging results obtained with certain promising drugs.
Diffuse axonal injury (DAI) is a type of TBI that results from a blunt injury to the brain, which happens when the brain rapidly shifts inside the skull as an injury is occurring. It is one of the most common but devastating types of TBI. Neuronal injuries associated with DAI fall into two categories: (i) primary injury, which is directly caused by mechanical forces during the initial insult; and (ii) secondary injury, which is caused as a consequence of primary injury to further tissue and cellular damages.
Primary brain injuries refer to the sudden and profound injury to the brain that occurs at the time of the motor vehicle accident, gunshot wound, or accidental fall. The immediate impact of different mechanical insults to the brain can cause two types of primary TBI: focal and diffuse brain injuries. Focal TBI generally results from a blow to the head that produces cerebral contusions or hematomas. Epidural hematomas, subdural hematomas, and cerebral contusions are the results of focal brain injuries [8]. In contrast, diffuse lesions (also known as DAI) are seen more commonly in lesions that involve rapid acceleration, deceleration, or rotational forces. DAI accounts for about 70% of TBI cases. The sites that are most prone to DAI are the reticular formation, basal ganglia, superior cerebellar peduncles, limbic fornices, hypothalamus and corpus callosum [8]. Interestingly, both types of injuries may co-exist in patients who suffered from moderate to severe TBI [9].
Brain injuries may occur in one of two ways: closed brain TBI and penetrating TBI. Closed brain TBIs occur when there is a non-penetrating injury to the brain with no break in the skull. A closed brain injury is caused by a rapid forward or backward movement and shaking of the brain inside the bony skull that result in bruising and tearing of brain tissue and blood vessels. In contrast, Penetrating, or open head injuries occur when there is a break in the skull, caused by hitting with a sharp object such as a bullet. These injuries exhibit focal brain damage due to lacerations, compression and concussion forces with evidence of skull fracture and localized contusion (Figure 1) at the core of injury site, known as the ‘coup’ area [10, 11]. Compromised blood supply at the coup area due to epidural, subdural and intracerebral hemorrhages and hematomas might result in necrosis of neuronal and glial cells at confined layers of the brain. Secondary contusion may develop in brain tissues opposite to or surrounding the coup area due to secondary impact when the brain rebounds and strikes the skull [11].
Schematic representation of the pathogenesis of TBI. TBI may be divided into primary injury and secondary injury. Primary TBI results from mechanical injury at the time of insult, while secondary injury is caused by the physiologic responses to the initial injury. Primary brain injury comprises the direct physical injury to the brain such as compression, deformation, displacement, stretching, shearing, tearing, and crushing of brain which results in damage to vasculature, neural, and glial tissues. Most of the neurological damage from TBI is due to the secondary injury which evolves over the ensuing hours and days after the initial injury or impact. The mechanisms by which TBI trigger neurodegeneration are areas of active research. Previous investigations found roles of excitotoxicity, loss of cerebral autoregulation, blood-brain barrier compromise, mitochondrial dysfunction, oxidative stress, lipid peroxidation, neuroinflammation, axon degeneration, impaired autophagy and apoptotic cell death in the development of neurodegeneration following brain injury. TBI produces both acute and chronic consequences that lead to permanent disabilities that increase long-term mortality and reduced life expectancy. The direct consequences of a single or repetitive TBI can result in various secondary pathological conditions, including seizures, sleep disorders, neurodegenerative diseases, neuroendocrine dysregulation, and psychiatric problems. Changes initiated by TBI can persist for weeks to months or even years after injury and significantly affect quality-of-life of the affected victims.
Secondary brain injuries refer to the changes that evolve over a period of time after the primary brain injury. The biochemical, cellular and physiological events that occur during primary injury often progress into delayed and prolonged secondary damaging cascade of cellular, chemical, tissue, or blood vessel changes in the brain that contribute to further destruction of brain tissue. Secondary brain injuries can last from hours to days and even weeks and may be caused by impairment or local declines in cerebral blood flow resulting in local edema, hemorrhage, or increased intracranial pressure and even brain herniation. Other types of secondary injury due to TBI include hypercapnia, acidosis, meningitis and brain abscess [12]. Mechanistically, a number of factors contribute to these changes, which include excitotoxicity, loss of cerebral autoregulation, blood-brain barrier compromise, mitochondrial dysfunction, oxidative stress, lipid peroxidation, neuroinflammation, axon degeneration, impaired autophagy and apoptotic cell death (Figure 1) [10, 13].
The hallmark feature of DAI is extensive damage of axons predominantly in subcortical and deep white matter tissue, which leads to impairment of axonal transport and degradation of axonal cytoskeleton. The strong tensile forces generated during primary injury by rapid deceleration and acceleration of the brain due to multiple non-contact forces causing shearing and stretching injury in cerebral brain tissues damage neuronal axons, oligodendrocytes and blood vasculature, leading to brain edema and ischemic brain damage [14]. These axonal damages can persist for months after DAI.
The degree of axonal injury and neuronal degeneration determines the severity of TBI. While explosive blast TBI is a result of shock waves instead of inertial forces, it displays the characteristics of a typical DAI. Depending on the severity of the injury, patients may later develop cognitive deficits, behavioral changes and hemiparesis (Figure 1).
While mild TBI or concussion may affect neural cells temporarily, severe TBI is associated with substantial axonal injury and physical damage to the brain, which can result in blood-brain barrier disruption and neuroinflammatory changes [7]. Although, moderate to extensive brain injury may be visible as structural abnormalities using CT scan or MRI, more subtle neural alterations characteristic of mild TBI are not easily detected by these imaging techniques. Moreover, changes due to DAI in the brain are often microscopic and may not be visualized on CT scan or MRI scans.
Mild TBI is highly prevalent in military populations, with many service members suffering from long-term symptoms [15]. It is also very common among road accident victims. The condition results from etiologies of neural contusion and axonal injury, which subsequently results in biochemical, metabolic, and cellular changes that may be responsible for some of the long-term problems observed in patients who develop post-concussion syndrome [16]. Moreover, moderate to severe TBI remains another important public health problem, due to the large percentage of unfavorable outcomes involved such as death and disabling sequelae. The huge treatment costs, associated compensations, disability pensions and years of income from work lost in affected individuals are the major financially devastating turns in the affected families. Therefore, identifying critical markers of neural injury in biofluids of these patients would be crucial for predicting long-term functional outcome and for taking rehabilitation decisions. Encouragingly, significant scientific advances on the TBI biomarker research in the last decade have increased our understanding of the complex and heterogeneous pathophysiological processes associated with this condition. Emerging evidence from multiple research teams suggests that biofluid-based TBI biomarkers may have the potential to diagnose the presence of TBI of different severities, and to predict outcome.
A biomarker is defined as a quantifiable biological indicator specific for a given physiological or pathological condition. Based on clinical utility, biomarkers may be categorized as: 1) diagnostic biomarkers, which identify the presence or absence of TBI, 2) prognostic biomarkers, which inform the clinicians about expected outcomes in injured individuals, and 3) predictive biomarkers, which predict response to a specific intervention and can be used to monitor response to therapy. Identification of biological markers of TBI could offer a more precise indication of the extent and severity of TBI, independently of the prior biological substrate and of other circumstances that accompany severe TBI–thereby contributing to homogeneously define different patient categories and risk stratify the head injury. These can also serve to screen and identify patients who may expect an altered or complicated recovery or might develop neurobehavioral deficits during the latter part of their life. Such markers would facilitate
individualization of the intensity of TBI/DAI
improve knowledge of the physiopathology of brain damage
afford essential complementary information for the diagnosis
predict the outcome of these patients
timing of patient management
development of strategies for preventing or minimizing secondary damage
evaluation of neuroprotective effects of novel biomolecules.
An ideal TBI/DAI biomarker should have
high specificity and sensitivity for the brain tissue
rapid appearance in accessible biofluids such as cerebrospinal fluid (CSF), plasma and/or whole blood immediately after irreversible brain tissue damage.
must be elevated in various forms and/or severities of brain damage in the acute phase (3 h to 24 h post-injury).
must reflect the extent and severity of the damage, as defined by GCS, CT abnormality, in due course of time.
variations between age and gender groups must be minimal.
must have low basal biofluid levels in non-injured healthy control population
should be responsive to therapeutic treatments
the tools for analysis and immediate detection of the marker must be available and reproducible.
determination of the marker must be clinically relevant.
The literature given below is a concise description of the principal investigational brain damage biomarkers with a description of the tissues in which they originate, the compartment from which samples were collected, their pathological serum concentrations, and the main prognostic features (Table 1).
Biomarker | Localization | Role in prognosis | Drawbacks | References |
---|---|---|---|---|
Tau/c-tau | Neuronal axons and astrocytes | May predict outcomes after severe TBI | Not fully characterized | [17, 18, 19] |
Aβ | Extracellular space | Altered levels in CSF | Contradictory findings | [20, 21, 22] |
MBP | Axonal myelin sheath, oligodendroglial cells | Elevated levels in serum and predict severity and outcome | Limited sensitivity | [23, 24] |
CK-BB | astrocytes | May predict outcomes after severe TBI | Low sensitivity and specificity in polytrauma | [25, 26, 27] |
NSE | Neuron | Elevated serum levels and specific to neuronal tissue than glial cell | Long half-life and are expressed in red blood cells | [28, 29, 30, 31, 32] |
S100B | Astrocytes | Predict severity and act as adjuvant marker | Reduced specificity; not suitable for children under 2 years | [33, 34] |
GFAP | Astrocytes | May predict neurological outcomes | Also expressed by the Leydig cells of the testes | [35, 36, 37] |
UCH-L1 | Neuronal cell body | Increased serum levels in brain damage | Not fully characterized | [38, 39, 40] |
SBDPs | Axons and presynaptic neuronal endings | May predict neurological outcomes | Not brain specific and difficult to quantify | [41, 42, 43, 44] |
NfL | Neuronal cytoplasm | Released in response to CNS neuronal damage | Released in response to neurodegeneration and neuroinflammation | [45] |
Current and emerging DAI biomarkers.
Tau protein is an axonal cytoskeleton-stabilizing protein (Figure 2) of molecular weight of 30–50 kDa that provides structural elements of the cytoskeleton that are crucial for neuronal protein flow [46, 47]. There are 6 different tau protein isomers, which is phosphorylated at many sites by kinases such as casein kinase II, tau tubulin kinases, glycogen synthase kinase 3β, and cyclin dependent kinase 5 [48, 49, 50]. While these are present in a stable, unfolded and monomeric morphology in a healthy brain, tau proteins exist in hyperphosphorylated state in several neurodegenerative diseases including Alzheimer’s disease (AD) [46, 51]. Interestingly, TBI has been indicated as a risk factor for later development of AD and other neurodegenerative conditions [52, 53, 54, 55, 56] .
Origin of biomarkers of DAI. In normal brain, NSE and UCH-L1 are localized in neuronal cytoplasm, while tau/c-tau are restricted mainly to axons and its terminals. Although tau is abundant in the neurons of the CNS, astrocytes express very low levels of this protein and it can be secreted into the brain interstitial fluid. APP is a type I transmembrane protein expressed in many cell types, including neurons. Aβ is derived from APP by enzymatic cleavage and is released to extracellular space. MBP is a constituent of neuronal myelin sheath, which is produced by oligodendrocytes. Spectrins (precursors of SBDPs), specifically βIV-spectrin is concentrated at axon initial segments and nodes of Ranvier. GFAP, CK-BB and S100B are normally present in astrocytes. DAI not only injures pre- and post-synaptic neurons but also damages their synapses, axons, myelin sheaths and neighboring astrocytes, oligodendrocytes, blood microvasculature and even the extracellular matrix network. Damages to specific cells and cellular components during DAI enable release of various molecules contained in those cells into the extracellular space. The released molecules, including those present in extracellular space like Aβ enter the damaged blood vessels and may be detected in the circulation.
Physical trauma causes activation of a number of proteases, which cause release of tau protein fragments in cleaved tau (c-tau) into the blood and CSF [57, 58]. Studies showed that the c-tau levels in CSF increase in the first 24 h after severe TBI [17, 59, 60]. Plasma phosphorylated tau (p-tau) and p-tau/t-tau ratios have been demonstrated to distinguish patients with acute and chronic TBI from healthy controls [18]. Smith and colleagues (1999) have shown deposition of p-tau following TBI [61]. C-tau in CSF is shown to be a predictor of clinical outcomes in severe TBI subjects [60, 62]. Moreover, elevated c-tau could be a chronic manifestation in DAI, since tau is localized to the axons [59]. However, the practical role of this molecule in DAI has not been fully established.
Amyloid-β (Aβ) is a 4 kDa extracellular protein derived from amyloid precursor protein (APP), which is cleaved by secretase enzymes [63]. APP is a membrane protein expressed in both CNS (APP 695) and peripheral organs and tissues (APP 751 and APP 770) [64]. APP with 695 amino acids is present as glycosylated receptors on cell surface and is hydrolysed by α-secretase followed by γ-secretase under normal conditions to produce soluble Aβ through non-amyloidogenic pathway [63, 65]. In amyloidogenic pathway, the mutations in APP and components of α-secretase, presinillin 1 (PSEN1) and presinillin 2 (PSEN2) leads to the cleavage by β amyloid cleaving enzyme-1 (BACE1) and γ-secretase to form insoluble Aβ, Aβ1–40 and Aβ1–42. This amyloidogenic cleavage leads to extracellular accumulation of Aβ plaques, a pathological hallmark in AD [20, 65, 66].APP plays an important role in cell adhesion processes and thus high concentrations are found at neuronal synaptic junction. Certain type of caspase breaks it down into a series of products which accumulate in cell bodies and axons. There are discordant evidence on the use of this protein as biomarker of TBI. One study of 29 patients with severe TBI revealed low levels of this protein in CSF probably due to reabsorption of the protein in the form of amyloid plaques [21]. As a contradiction to the above, Emmerling et al. (2020) found increasing levels in CSF after trauma and suggested that this could be a result of secondary axonal damage or loss of integrity of the BBB [22]. These contradictory findings, have caused Aβ-protein to be regarded as a non-reproducible biomarker and its potential role remains unclear requiring further research.
MBP (molecular weight of 18.5 kDa), found in oligodendroglial cells, is a key structural component of the multi-layered myelin sheath covering nerve fibers. The myelin sheath on neuronal axons serves as an insulator to increase the velocity of axonal impulse conduction. Due to the extended length of axonal fiber tracks, axons are particularly vulnerable to physical trauma to the brain. Thus, axonal injury is a common occurrence in both focal as well as diffuse brain trauma and can be found in TBI of all severities [14, 67]. As MBP maintains myelin structure by interacting with the lipids in the myelin membrane [68], axonal injury causes breakdown of the myelin sheath and release of MBP. This myelin-specific protein is also released into the bloodstream in cases of demyelinating diseases such as multiple sclerosis, or degradation by proteases, such as calpain [69, 70].
MBP is found to be elevated in serum after severe TBI in children [23, 24] and after mild TBI in adults [24]. Even though, it takes around 1–2 days to appear in the serum after TBI, the peak levels of MBP can persist for up to 2 weeks and can be a specific indicator for future intracranial hemorrhage [71]. However, as per present literature there is contradicting evidence for its role in TBI/DAI [72, 73, 74]. There was no difference in initial levels of serum MBP in a pediatric population with mild TBI when compared with controls, but there was a significant difference in the peak MBP levels between patients and controls [72]. MBP is also expressed on the myelin of peripheral nerves and its transcripts are present in the bone marrow and immune system and therefore it is not specific to the CNS. Even though serum levels are correlated with patient severity and outcome [71, 75] it has limited sensitivity as a marker for predicting severity of TBI [76].
CK isoenzymes are of three types: CK-1 (also known as CK-BB) is predominantly expressed in brain, lung, thyroid and prostate glands, gastrointestinal tract, urinary bladder, uterus and placenta. CK-2 (CK-MB) and CK-3 (CK-MM) are expressed in cardiac and skeletal muscles [77]. Brain tissue-specific CK-1 (CK-BB), with a molecular weight of 40–53 kDa, is found in astrocytes [25, 26]. A peak in serum cerebral CK concentration is observed in the first few hours after severe TBI and then gradually decrease and the marker remains high for days [78, 79, 80, 81]. In polytrauma, it remains persistently high without an initial dip [82, 83] . Its levels have been shown to rise significantly in CSF following hypoxic brain injury in cardiac arrest, which suggests that CK-BB release may be secondary to cerebral hypoperfusion due to systemic trauma [84]. The major limiting factor is that it has low sensitivity and specificity especially in cases of polytrauma [27, 85].
NSE, also known as γ -enolase or enolase 2, is a glycolytic enzyme with a molecular weight of 78 kDa and a half-life of 48 h. It exists as a homodimer (γ–γ) in mature neurons and neuroendocrine cells. The normal concentration of NSE in blood is <10 ng/ml. NSE elevations in blood compartment has been documented in severe as well as mild TBI [28, 29, 30, 31, 86]. Experimental models of trauma have correlated serum NSE to the severity of damage in TBI [87]. Major limitation of using NSE as specific biomarker for TBI is that it is also abundantly expressed in red blood cells [88]. Moreover, increased levels of NSE was also recorded previously in the serum of patients following non-traumatic brain damage such as ischemic events, intracerebral hemorrhage, cardiopulmonary resuscitation, secondary cerebral hypoxia etc. [89]. Some studies had correlated the biomarker to the development of DAI, though its behavior has not been clearly established in prospective trials.
NSE was initially suggested to be a very promising TBI severity marker due to its specificity to neuronal tissue than of glial cells. However, the results published till date has been contradictory on its role in predicting prognosis of patients with severe TBI. Long half-life is a major limiting factor for its use in trauma setting. Also, extracranial origin of NSE was demonstrated in hemorrhagic shock, long bone fracture, hemolysis, heart surgery, ischemia–reperfusion injury and malignant lung tumors making it a poor marker for TBI [90, 91, 92, 93, 94].
GFAP is a monomeric intermediate filament protein (molecular weight 52 kDa), present in the cytoskeleton of astrocytes in the brain. An increase in blood level of this biomarker suggests injury to the astrocytes and the BBB. Plasma concentrations >0.033 μg/l are regarded as pathological. Missler et al. (2002) were the first to propose the possible use of GFAP as an identifier of brain damage in serial serum measurements [95]. Later studies also confirmed that the serum concentration of this protein is not affected by extracranial injuries thus making it an effective biomarker for predicting poor outcome in the acute phase of severe TBI as well as for advocating the need for urgent neurosurgical procedures [41, 96]. GFAP (52 kDa) or its breakdown products (44–38 kDa) are released from injured brain tissue into biofluids such as CSF and enter the bloodstream after crossing the BBB with an early plasma peak (within 3 to 34 h) following brain injury [97, 98]. The blood levels then decrease gradually over the first week, starting from third day of injury.
Previous studies demonstrated that GFAP levels show an unfavorable outcome in patients with moderate or severe TBI [41, 96, 99, 100]. However, this may not be the case in patients with mild TBI due to the contamination from other sources [101, 102, 103]. However, Serum GFAP levels were also significantly higher in patients who died or had an unfavorable outcome [104]. Moreover, GFAP levels have correctly predicted neurological outcome at 6 months [35, 36, 104]. Furthermore, serum GFAP measured on day 1 of injury in pediatric TBI cases significantly correlated with functional outcomes at 6 months [105]. Thus, GFAP can be considered as an ideal biomarker of brain damage when combined with clinical variables though multicenter studies are needed for further validation.
S100B, the most widely studied brain damage biomarker, is a low molecular weight (11 kDa) calcium binding protein of astroglial origin [33]. The homodimeric beta-subtype of S100 proteins (S100B) is synthesized in astrocytes of the CNS and in Schwann cells of the peripheral nerves, where it regulates intracellular calcium levels [106, 107, 108]. S100B localizes to the nucleus and cytoplasm associating with endomembranes, the centrosomes, microtubules and type III intermediate filaments [109]. The protein is naturally secreted by astrocytes into the extracellular space. Low amounts of S100B can cross the BBB and enter the microvasculature. Elevated levels of S100B in the serum were observed in TBI patients as well as in patients suffering from neurodegenerative diseases [110]. The serum levels of the protein have been associated with clinical severity, radiological severity, and an unfavorable outcome [111, 112, 113, 114] .
The biological function of this protein has not been fully established till date, though it is known to participate in neurogenesis, astrocytosis and axonal elongation. However, the molecule can also be produced and found outside the CNS, e.g., in kidney epithelial cells, ependymocytes, chondrocytes, adipocytes, melanocytes, Langerhans cells, dendritic cells, certain lymphocyte subpopulations, skeletal myofibers, myoblasts and muscle satellite cells [109]. Metabolism takes place in the kidneys, followed by excretion in urine, with an approximate half-life of 30–113 min, and is not affected by hemolytic phenomena [115]. Its role in urine level also needs further validated study. Since S100B can also be released from adipose tissue and cardiac/skeletal muscles, its levels are also elevated in orthopedic trauma without head injury [116]. Despite these confounders, S100B is actually a sensitive TBI biomarker for predicting CT abnormality and post-concussive syndrome development [117, 118, 119]. A number of previous studies have shown that S100B can actually differentiate between mild and severe TBI [120, 121].
The maximum serum concentration of S100B is reached 20 min after brain damage. The normal upper limit for this protein in relation to the detection of intracranial damage was defined as 0.1 μg/l based on a multicenter study in patients with mild TBI [122]. The measurement of S100B-protein can be influenced by patient age and gender in CSF samples but not in serum samples thus making it a practically feasible biomarker.
Some studies have determined its usefulness as a predictor of mortality, establishing orientative serum cut-off points for predicting a course leading to death or an unfavorable outcome [123, 124, 125]. On the other hand, S100B level has been correlated to the presence of secondary lesions, the extent of diffuse brain damage, and to modifications in intracranial pressure following different release patterns [126, 127]. S100B levels can also detect brain death development or mortality after severe TBI [128, 129]. Interestingly, serum levels of S100B > 0.7 ng/mL were reported to correlate with 100% mortality [130].
Another possible application of this protein refers to its time course according to the severity of the patient condition. A number of studies have documented persistently elevated serum levels in patients in those with poor GCS, while the plasma levels have been seen to decrease after 36 h among survivors [82, 131, 132, 133]. On the other hand, S100B protein has been suggested as a tool for monitoring management efficacy [134, 135], since it has been seen that the blood concentrations of the protein decrease after effective neurosurgical treatment thus making its role more relevant. A high level of S100B during the initial TBI can predict a poor outcome, especially if it is accompanied by a second increase in levels of serum S100B that occurs during the subacute phase [131, 136]. This second peak during the subacute phase may be due to secondary injury to the astroglial cells exhibiting excitotoxicity and neuroinflammation. In addition, elevation in serum levels of S100B and GFAP in TBI patients has been correlated with unfavorable neurological outcomes [137, 138, 139]. On the other hand, an initial lower level of S100B and the lack of second peak might suggest the occurrence of a mild TBI and a good functional recovery [140, 141].
A previous study demonstrated the sensitivity of S100B to predict significant intracranial pathology up to 100% but with specificity of only 28%.Moreover, in pediatric population (specifically for children under the age of 2 years), S100B is not a useful marker due to high normal levels in this group [32, 142]. Thus, S100B may be suggested to be used as an adjuvant marker in patients with TBI, but its diagnostic value is still controversial [76].
Doctors in the acute hospital settings primarily rely on the patient’s neurological examinations and radiologic imaging to characterize TBI/DAI diagnosis. Depending on the severity of the initial insult, different imaging modalities such as CT scan and MRI are used to obtain the necessary information for patient care and prognosis. However, CT scans, used for assessing cerebrovascular integrity or for determining gross anatomical changes induced to the brain, have low sensitivity to diffuse brain damage, and confers exposure to radiation [143]. In contrast, while MRI can provide information on the extent of diffuse injuries, yet its widespread application is restricted by prohibitive cost, limited availability of MRI in many hospitals, and practical difficulty of performing it in physiologically unstable TBI patients [143]. Thus, diagnostic and prognostic tools for risk stratification of TBI patients are very limited in the early stages after injury.
To fill this gap, research in the field of biofluid-based TBI biomarkers has increased exponentially over the last three decades [116]. Extensive research on fluid biomarkers have demonstrated that a number of brain-specific proteins, as illustrated above, have potential for acting as biomarkers of TBI. These biomolecules are released into the CSF and/or blood, after brain injury due to damage of neural cells [28, 144, 145, 146]. Additionally, neuroimmune activation might have the potential to be novel diagnostic and/or prognostic marker of TBI. A few of these molecules, like S100B have shown promise to be clinically used as biomarkers of TBI [145]. However, this has been disputed in recent studies [147] and till now, there are no rapid, definitive diagnostic blood tests for TBI.
Despite its high sensitivity and negative predictive value, S100B protein is not a specific marker of the CNS damage. Polytraumatized patients without TBI can present S100B protein elevations in blood, though the concentrations return to normal within 6 h after trauma. Patients with brain damage and associated extracranial injuries (hypotension, hypothermia, coagulopathy, inotropic drugs, sedatives, corticosteroids, etc.) can alter the early assessment of S100B protein. Therefore, early determination of this protein is to be avoided in patients with extracranial injuries associated with TBI making it’s role dismal probably in trauma care even though the above features of an ideal biomarker are met.
CNS is very complex and can present a range of different lesions, which in turn can affect different target cells with variable degrees of severity. Brain damage markers must establish differentiations with respect to other alterations. Furthermore, the existence of the blood–brain barrier conditions the structural characteristics of these biomarkers, which must be able to cross the mentioned barrier in order to reach the bloodstream. Biomarkers are dynamic elements that experience changes in response to different inflammatory states, tissue necrosis etc. So serial measurements rather than isolated or point determinations are thus required.
As direct sampling of the damaged brain tissue is not practically feasible there is some controversy regarding the type of biological fluid that should be analyzed. CSF compartment is located closer to the damage site, but frequent collection of CSF samples is unethical. As a result, most biomarkers are studied in peripheral blood as the process is simple, accessible and reproducible. Thus, estimation of blood biomarkers will be the most appropriate option for performing simple and minimally invasive serial measurements. Still more easy will be to estimate biomarkers in fluids that serve as vehicles for their clearance, for example urine.
UCH-L1 mainly resides in the cytoplasm of neuronal cell body representing approximately 5% of all the soluble brain proteins. It is implicated in the elimination of degraded and denatured proteins following oxidative phenomena [148]. Proteomics data first implicate UCH-L1 as promising TBI biomarker candidate [149, 150]. Later studies point to it as a promising brain damage biomarker, since there are data indicating that it can predict the presence of lesions on the CT scan, the need for neurosurgery, and the outcome of patients with TBI [151, 152, 153].
UCH-L1 can be detected in blood, with early increases in its serum concentration following brain injury [151]. The protein level in the blood is shown to be elevated both in mild and severe cases of TBI [100, 154]. Mondello et al. (2012) have obtained interesting results regarding its possible capacity to distinguish between focal and diffuse brain damage [155]. Additionally, it has been suggested that UCH-L1 together with GFAP form the foundation of a biomarker panel representing the two dominant cell types (neuron and astrocytes) in the brain [38]. Interestingly, serum levels of both of these proteins are elevated in professional breacher trainees who were exposed to repeated explosive discharges as well as athletes who experienced concussions [39, 40]. Further investigations are needed to evaluate the properties of this protein as a promising biomarker of DAI.
Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane forming a scaffold, which maintains plasma membrane integrity and cytoskeletal structure [156]. It is a heterodimeric protein, composed of two α and two β chains, and contains 106 contiguous amino acid sequence motifs called “spectrin repeats”, which are essential to diverse cell functions such as cell adhesion, cell spreading, and the cell cycle [156].
Necrotic and apoptotic cell death during primary and secondary brain injury respectively, cause overactivation of cysteine proteases, such as calpain and caspase-3. These proteases cleave components of the axonal cytoskeleton [157] including spectrin resulting in generation of SBDPs with characteristic molecular weights [26, 158]. The presence of degradation products of spectrin has been described in the CNS in axons and presynaptic neuronal endings [23, 44, 159, 160]. However, SBDPs are not brain specific and its increased serum levels may reflect multiorgan damage in trauma [42, 161]. Moreover, accurate quantification of brain-derived SBDPs in blood is difficult since some proteins found in erythrocytes are similar to those found in the neuronal cytoskeleton [162], thus reducing the diagnostic value of SBDPs.
Neurofilaments, consisting of three chains, light (L), medium (M) and heavy (H), make up part of the axonal cytoskeleton. NfL is 68 kDa subunit of the neurofilaments located on the neuronal cytoplasm which is released in response to CNS neuronal damage due to neuroinflammation, neurodegeneration, and/or traumatic or vascular injury [163, 164]. Following axon damage, the influx of calcium alters the phosphorylation state of NfL and subsequent proteolysis. As a result, there is loss of cytoskeletal structure and NfL is released into both CSF and the bloodstream [165]. A number of investigational studies have underscored the role of NfL as biomarker of axon damage [45, 166, 167]. Serum NfL has been shown to distinguish patients with mild, moderate or severe TBI for months and even years after injury [168]. However, serum detection of NfH is considered a better biomarker candidate [169].
Since all brain damage biomarkers have some limitation precluding their universal application in the management of severe TBI/DAI, they do not yet form part of routine clinical practice. Some markers, such as NSE and S100B protein, have shown good correlations to clinical severity, the extent of brain damage, response to treatment, and patient outcome. However, the limitations associated with the clinical yield of the molecule or invasiveness of the technique required to obtain the sample have not allowed their generalized use in this patient population.
On the other hand, further studies are needed to understand the role of these proteins in the physiology of the CNS and in the physiopathology of severe TBI/DAI, as well as to clarify the usefulness of those biomarkers that appear to be promising in this field. In this respect, mention must be made of nervous tissue-specific GFAP, as well as of other biomarkers that are currently the focus of interest, such as ubiquitin carboxy-terminal hydrolase L1, the light neurofilaments and spectrin degradation products.
Since these molecules offer isolated information on some of the many elements implicated in the physiopathology of TBI/DAI, we believe that the best strategy is to analyze them in combination. Rather than seeking a biomarker exclusive for brain damage, this approach would allow us to define a panel of biomarkers which jointly – and considering the characteristics inherent to each of them–could offer information referred to severity, the potential benefits of management, and the evolutive course of patients following severe TBI. Only in this way can we hope to complement the traditional methods with a tool that is simple, non-invasive, reproducible and extraordinarily useful for addressing and managing severe TBI/DAI. Moreover, since TBI/DAI is quite complex heterogeneous conditions, it might be clinically justified to use multi-modal biomarkers to evaluate the status of full clinical endophenotypes by combining a panel of biofluid-based and physiologic biomarkers coupled with advanced neuroimaging that are appropriately obtained at multiple time points during the time course of TBI/DAI.
The authors declare that they have no conflicts of interest.
RRM is a senior research fellow of Indian Council of Medical Research (ICMR), Government of India. GC is supported by The Ramalingaswami fellowship from the Department of Biotechnology, and grants from the Department of Health Research and ICMR, Government of India.
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Lack of knowledge and awareness on earthquake as well as its comeback is conspicuous and results in disaster; leading to bitter memories. Therefore, earthquake forecast has been a polemical study theme that has defied even the most intelligent of minds. In this chapter, an attempt was made to do an extensive overview in the area of the earthquake prediction as well as classifying them into the main strategies comprising short‐, immediate‐, and long‐term prediction. An example of each strategy was carried out by mentioning their corresponding approaches/algorithms, such as ΔCFS, CN, MSc, M8, ANN, FFBPANN, KNN, GRNN, RBF, and LMBP; depending on the importance of each strategy. Based on these, it was concluded that, after the Tohoku‐Oki earthquake with M9.0, the current orientation of the Headquarters for earthquake Research Promotion of MEXT in Japan declare that, their mission would be long‐term statistical forecast of seismicity. Even, it is claimed that they do not emphasize on short‐term forecasting. Besides, intermediate‐term estimations are not capable to be used for prevention of all damages and protect all human life, but they may be utilized to undertake certain affordable activities to decrease damage, losses, and modify postdisaster relief. And, despite the long‐term prediction is more concerned by researchers, there is no certain satisfactory level to content them. De facto, the made covenant of 1970 that investigators will be capable to forecast/predict ground excitations within a decade, still remains unmet.",book:{id:"5499",slug:"earthquakes-tectonics-hazard-and-risk-mitigation",title:"Earthquakes",fullTitle:"Earthquakes - Tectonics, Hazard and Risk Mitigation"},signatures:"Khaled Ghaedi and Zainah Ibrahim",authors:[{id:"190572",title:"Dr.",name:"Khaled",middleName:null,surname:"Ghaedi",slug:"khaled-ghaedi",fullName:"Khaled Ghaedi"},{id:"196228",title:"Prof.",name:"Zainah",middleName:null,surname:"Ibrahim",slug:"zainah-ibrahim",fullName:"Zainah Ibrahim"}]},{id:"52524",doi:"10.5772/65425",title:"Earthquakes and Structural Damages",slug:"earthquakes-and-structural-damages",totalDownloads:3352,totalCrossrefCites:13,totalDimensionsCites:20,abstract:"Earthquakes are the most destructive natural hazards throughout human history. Hundreds of thousand people lost their lives and loss of billions of dollars’ properties occurred in these disasters. Occurred medium or high-intensity magnitude earthquakes in last twenty years showed that these loses continue. For reinforced concrete (R/C) buildings, inappropriate design such as soft and weak stories, strong beam–weak column, short column, hammering, unconfined gable wall and in-plane/out-of-plane movement of the walls causes damages. These are the main reasons. In addition to this, low quality of structural materials, poor workmanship, lack of engineering services, and construction with insufficient detailing of the structural elements are the another reasons of damages. Main reasons of masonry building damages in terms of design faults can be shown as heavy earthen roofs, inappropriate detailing of wall to wall connection and wall to roof connection, absence of bond beams, large openings. However, construction of buildings by using local materials with poor workmanship on the base of traditional rules is the other reason of failures for these buildings. In this book chapter, earthquakes and reasons of damages arose from earthquakes for reinforced concrete and masonry structures were presented. In addition to this, appropriate solutions are suggested.",book:{id:"5499",slug:"earthquakes-tectonics-hazard-and-risk-mitigation",title:"Earthquakes",fullTitle:"Earthquakes - Tectonics, Hazard and Risk Mitigation"},signatures:"Burak Yön, Erkut Sayın and Onur Onat",authors:[{id:"192483",title:"Dr.",name:"Burak",middleName:null,surname:"Yön",slug:"burak-yon",fullName:"Burak Yön"},{id:"192486",title:"Dr.",name:"Erkut",middleName:null,surname:"Sayın",slug:"erkut-sayin",fullName:"Erkut Sayın"},{id:"192487",title:"Dr.",name:"Onur",middleName:null,surname:"Onat",slug:"onur-onat",fullName:"Onur Onat"}]}],mostDownloadedChaptersLast30Days:[{id:"41664",title:"Volcanic Natural Resources and Volcanic Landscape Protection: An Overview",slug:"volcanic-natural-resources-and-volcanic-landscape-protection-an-overview",totalDownloads:3724,totalCrossrefCites:2,totalDimensionsCites:3,abstract:null,book:{id:"3088",slug:"updates-in-volcanology-new-advances-in-understanding-volcanic-systems",title:"Updates in Volcanology",fullTitle:"Updates in Volcanology - New Advances in Understanding Volcanic Systems"},signatures:"Jiaqi Liu, Jiali Liu, Xiaoyu Chen and Wenfeng Guo",authors:[{id:"60000",title:"Prof.",name:"Jiaqi",middleName:null,surname:"Liu",slug:"jiaqi-liu",fullName:"Jiaqi Liu"}]},{id:"31815",title:"Disaster Management Based on Business Process Model Through the Plant Lifecycle",slug:"disaster-management-based-on-business-process-model-through-the-plant-lifecycle",totalDownloads:2690,totalCrossrefCites:6,totalDimensionsCites:10,abstract:null,book:{id:"600",slug:"approaches-to-managing-disaster-assessing-hazards-emergencies-and-disaster-impacts",title:"Approaches to Managing Disaster",fullTitle:"Approaches to Managing Disaster - Assessing Hazards, Emergencies and Disaster Impacts"},signatures:"Yukiyasu Shimada, Teiji Kitajima, Tetsuo Fuchino and Kazuhiro Takeda",authors:[{id:"70197",title:"Dr.",name:"Yukiyasu",middleName:null,surname:"Shimada",slug:"yukiyasu-shimada",fullName:"Yukiyasu Shimada"},{id:"82055",title:"Dr.",name:"Tetsuo",middleName:null,surname:"Fuchino",slug:"tetsuo-fuchino",fullName:"Tetsuo Fuchino"},{id:"82056",title:"Prof.",name:"Teiji",middleName:null,surname:"Kitajima",slug:"teiji-kitajima",fullName:"Teiji Kitajima"},{id:"121284",title:"Dr.",name:"Kazuhiro",middleName:null,surname:"Takeda",slug:"kazuhiro-takeda",fullName:"Kazuhiro Takeda"}]},{id:"52524",title:"Earthquakes and Structural Damages",slug:"earthquakes-and-structural-damages",totalDownloads:3345,totalCrossrefCites:13,totalDimensionsCites:20,abstract:"Earthquakes are the most destructive natural hazards throughout human history. Hundreds of thousand people lost their lives and loss of billions of dollars’ properties occurred in these disasters. Occurred medium or high-intensity magnitude earthquakes in last twenty years showed that these loses continue. For reinforced concrete (R/C) buildings, inappropriate design such as soft and weak stories, strong beam–weak column, short column, hammering, unconfined gable wall and in-plane/out-of-plane movement of the walls causes damages. These are the main reasons. In addition to this, low quality of structural materials, poor workmanship, lack of engineering services, and construction with insufficient detailing of the structural elements are the another reasons of damages. Main reasons of masonry building damages in terms of design faults can be shown as heavy earthen roofs, inappropriate detailing of wall to wall connection and wall to roof connection, absence of bond beams, large openings. However, construction of buildings by using local materials with poor workmanship on the base of traditional rules is the other reason of failures for these buildings. In this book chapter, earthquakes and reasons of damages arose from earthquakes for reinforced concrete and masonry structures were presented. In addition to this, appropriate solutions are suggested.",book:{id:"5499",slug:"earthquakes-tectonics-hazard-and-risk-mitigation",title:"Earthquakes",fullTitle:"Earthquakes - Tectonics, Hazard and Risk Mitigation"},signatures:"Burak Yön, Erkut Sayın and Onur Onat",authors:[{id:"192483",title:"Dr.",name:"Burak",middleName:null,surname:"Yön",slug:"burak-yon",fullName:"Burak Yön"},{id:"192486",title:"Dr.",name:"Erkut",middleName:null,surname:"Sayın",slug:"erkut-sayin",fullName:"Erkut Sayın"},{id:"192487",title:"Dr.",name:"Onur",middleName:null,surname:"Onat",slug:"onur-onat",fullName:"Onur Onat"}]},{id:"41478",title:"Monogenetic Basaltic Volcanoes: Genetic Classification, Growth, Geomorphology and Degradation",slug:"monogenetic-basaltic-volcanoes-genetic-classification-growth-geomorphology-and-degradation",totalDownloads:6142,totalCrossrefCites:72,totalDimensionsCites:141,abstract:null,book:{id:"3088",slug:"updates-in-volcanology-new-advances-in-understanding-volcanic-systems",title:"Updates in Volcanology",fullTitle:"Updates in Volcanology - New Advances in Understanding Volcanic Systems"},signatures:"Gábor Kereszturi and Károly Németh",authors:[{id:"51162",title:"Dr.",name:"Károly",middleName:null,surname:"Németh",slug:"karoly-nemeth",fullName:"Károly Németh"},{id:"62029",title:"Dr.",name:"Gabor",middleName:null,surname:"Kereszturi",slug:"gabor-kereszturi",fullName:"Gabor Kereszturi"}]},{id:"62769",title:"Disaster Mitigation Model of Eruption Based on Local Wisdom in Indonesia",slug:"disaster-mitigation-model-of-eruption-based-on-local-wisdom-in-indonesia",totalDownloads:1424,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Kelud is one of the most active volcanoes in Indonesia and suffered a major eruption in 2014. Although they are not part of the super volcano, the impact of the eruption is extraordinary. However, the eruption is not too worrying for the surrounding community. The lack of disaster victims caused by the eruption in 2014 became a successful representation of disaster mitigation models owned by local communities in answering the eruption problem. The easy evacuation process and quickly post-eruption rehabilitation illustrate a pattern of environmental adaptation around the volcano. This discussion focuses on how the people behavior around the volcano in responding to the challenge of eruption? How the role of local government in preparing the community in the face of an eruption, and what actions are done so that the rehabilitation process can take place quickly? To answer all these questions, the researchers collected relevant data through observation, documentation, and interviews with the local communities and local government representatives directly involved in disaster mitigation measures. In addition, the researchers also revealed local traditions that are considered capable of supporting the process of preparing the community in answering the eruption challenges and becoming part of disaster mitigation in the volcanic region.",book:{id:"6821",slug:"natural-hazards-risk-assessment-and-vulnerability-reduction",title:"Natural Hazards",fullTitle:"Natural Hazards - Risk Assessment and Vulnerability Reduction"},signatures:"Eko Hariyono and Solaiman Liliasari",authors:[{id:"214360",title:"Dr.",name:"Eko",middleName:null,surname:"Hariyono",slug:"eko-hariyono",fullName:"Eko Hariyono"},{id:"219699",title:"Prof.",name:"Liliasari",middleName:null,surname:"S",slug:"liliasari-s",fullName:"Liliasari S"}]}],onlineFirstChaptersFilter:{topicId:"106",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. 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Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. from Integral University, Lucknow, India, with his work titled ‘Development and evaluation of silymarin nanoformulation for hepatic carcinoma’. Currently, he is an Assistant Professor of Pharmaceutics, at the Faculty of Pharmacy, Integral University. He has been teaching PharmD, BPharm, and MPharm students and conducting research in the novel drug delivery domain. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than twenty-four original journal articles, two edited books, four book chapters, and several scientific articles to his credit. He is a member of the American Association for Cancer Research, the International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"333824",title:"Dr.",name:"Ahmad Farouk",middleName:null,surname:"Musa",slug:"ahmad-farouk-musa",fullName:"Ahmad Farouk Musa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333824/images/22684_n.jpg",biography:"Dato’ Dr Ahmad Farouk Musa\nMD, MMED (Surgery) (Mal), Fellowship in Cardiothoracic Surgery (Monash Health, Aust), Graduate Certificate in Higher Education (Aust), Academy of Medicine (Mal)\n\n\n\nDato’ Dr Ahmad Farouk Musa obtained his Doctor of Medicine from USM in 1992. He then obtained his Master of Medicine in Surgery from the same university in the year 2000 before subspecialising in Cardiothoracic Surgery at Institut Jantung Negara (IJN), Kuala Lumpur from 2002 until 2005. He then completed his Fellowship in Cardiothoracic Surgery at Monash Health, Melbourne, Australia in 2008. He has served in the Malaysian army as a Medical Officer with the rank of Captain upon completing his Internship before joining USM as a trainee lecturer. He is now serving as an academic and researcher at Monash University Malaysia. He is a life-member of the Malaysian Association of Thoracic & Cardiovascular Surgery (MATCVS) and a committee member of the MATCVS Database. He is also a life-member of the College of Surgeons, Academy of Medicine of Malaysia; a life-member of Malaysian Medical Association (MMA), and a life-member of Islamic Medical Association of Malaysia (IMAM). Recently he was appointed as an Interim Chairperson of Examination & Assessment Subcommittee of the UiTM-IJN Cardiothoracic Surgery Postgraduate Program. As an academic, he has published numerous research papers and book chapters. He has also been appointed to review many scientific manuscripts by established journals such as the British Medical Journal (BMJ). He has presented his research works at numerous local and international conferences such as the European Association for Cardiothoracic Surgery (EACTS) and the European Society of Cardiovascular Surgery (ESCVS), to name a few. He has also won many awards for his research presentations at meetings and conferences like the prestigious International Invention, Innovation & Technology Exhibition (ITEX); Design, Research and Innovation Exhibition, the National Conference on Medical Sciences and the Annual Scientific Meetings of the Malaysian Association for Thoracic and Cardiovascular Surgery. He was awarded the Darjah Setia Pangkuan Negeri (DSPN) by the Governor of Penang in July, 2015.",institutionString:null,institution:{name:"Monash University Malaysia",country:{name:"Malaysia"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}}]}},subseries:{item:{id:"10",type:"subseries",title:"Animal Physiology",keywords:"Physiology, Comparative, Evolution, Biomolecules, Organ, Homeostasis, Anatomy, Pathology, Medical, Cell Division, Cell Signaling, Cell Growth, Cell Metabolism, Endocrine, Neuroscience, Cardiovascular, Development, Aging, Development",scope:"Physiology, the scientific study of functions and mechanisms of living systems, is an essential area of research in its own right, but also in relation to medicine and health sciences. The scope of this topic will range from molecular, biochemical, cellular, and physiological processes in all animal species. Work pertaining to the whole organism, organ systems, individual organs and tissues, cells, and biomolecules will be included. Medical, animal, cell, and comparative physiology and allied fields such as anatomy, histology, and pathology with physiology links will be covered in this topic. Physiology research may be linked to development, aging, environment, regular and pathological processes, adaptation and evolution, exercise, or several other factors affecting, or involved with, animal physiology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11406,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. 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