\r\n\tThis book will describe the self-assembly of materials and supramolecular chemistry design principles for a broad spectrum of materials, including bio-inspired amphiphiles, metal oxides, metal nanoparticles, and organic-inorganic hybrid materials. It will provide fundamental concepts of self-assembly design approaches and supramolecular chemistry principles for research ideas in nanotechnology applications. The book will focus on three main themes, which include: the self-assembly and supramolecular chemistry of amphiplies by coordination programming, the supramolecular structures and devices of inorganic materials, and the assembly-disassembly of organic-inorganic hybrid materials. The contributing chapters will be written by leading scientists in their field, with the hope that this book will provide a foundation on supramolecular chemistry principles to students and active researchers who are interested in nanoscience and nanoengineering fields.
",isbn:"978-1-83969-702-9",printIsbn:"978-1-83969-701-2",pdfIsbn:"978-1-83969-703-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"e9cc643ae0a219e91e445a1e61b33a22",bookSignature:"Prof. Hemali Rathnayake and Dr. Gayani Pathiraja",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11908.jpg",keywords:"Amphiphiles, Artificial Siderophores, Coordination Chemistry, Self-Assembly Design, Supramolecular Structures, Metal Oxides, Metal Particles, 2D Inorganic Materials, Supramolecular Devices, Stimuli-Responsive Materials, Assembly-Disassembly Design, Superstructures",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 27th 2022",dateEndSecondStepPublish:"May 25th 2022",dateEndThirdStepPublish:"July 24th 2022",dateEndFourthStepPublish:"October 12th 2022",dateEndFifthStepPublish:"December 11th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"6 hours",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Rathnayake is a pioneering researcher in self-assembly and supramolecular chemistry, with a Ph.D. from the University of Massachusetts Amherst, US. She is an inventor of three innovative technologies, including the Bioinspried Sub-7 nm self-assembled structures for patterning, and holder of multiple registered patents.",coeditorOneBiosketch:"Dr. Gayani Pathiraja is a Postdoctoral Research Scholar at the Joint School of Nanoscience and Nanoengineering (JSNN). She received her Ph.D. in Nanoscience from the University of North Carolina at Greensboro in 2021. Her research interests focus on the crystal growth mechanism and kinetics of metal oxide nanostructure formation via self-assembly.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"323782",title:"Prof.",name:"Hemali",middleName:null,surname:"Rathnayake",slug:"hemali-rathnayake",fullName:"Hemali Rathnayake",profilePictureURL:"https://mts.intechopen.com/storage/users/323782/images/system/323782.jpg",biography:"Dr. Hemali Rathnayake, Associate Professor in the Department of Nanoscience at the Joint School of Nanoscience and Nanoengineering, the University of North Carolina at Greensboro, USA, obtained her B.S. in Chemistry from the University of Peradeniya in Sri Lanka. She obtained her Ph.D. from the University of Massachusetts Amherst (UMass), Department of Chemistry in 2007. She was a Postdoctoral research fellow at Polymer Science & Engineering, UMass Amherst. \r\nDr. Rathnayake is a pioneer scientist and a chemist in the field of Nanomaterials Chemistry, with a focus on the interfacial interaction of nanomaterials, molecules, macromolecules, and polymers in homogeneous and heterogeneous media. Her research on the design, synthesis, self-assembly, and application of well-defined superstructures in nanoelectronics, environmental remediation, and sustainable energy has impacted the scientific community with highly rated peer-reviewed journals publications, and more than 80 invited talks to scientific and non-scientific communities including colleges and high schools.",institutionString:"University of North Carolina at Greensboro",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of North Carolina at Greensboro",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:{id:"427650",title:"Dr.",name:"Gayani",middleName:null,surname:"Pathiraja",slug:"gayani-pathiraja",fullName:"Gayani Pathiraja",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003CCSN2QAP/Profile_Picture_1644217020559",biography:"Dr. Gayani Pathiraja is a Postdoctoral Research Scholar at the Joint School of Nanoscience and Nanoengineering (JSNN). She received her Ph.D. in Nanoscience from the University of North Carolina at Greensboro (UNCG) in 2021. Her expertise area of focus is investigating the crystal growth mechanism and kinetics of metal oxide nanostructure formation via in-situ self-assembly design principles. \r\nDr. Pathiraja earned her master’s degree in electrochemistry/Environmental Engineering from the University of Peradeniya, Sri Lanka, and her Bachelor’s degree in Materials Science and Technology from Uva Wellassa University, Sri Lanka. Dr. Pathiraja started her academic career as a lecturer at the Department of Engineering Technology, University of Ruhuna, Sri Lanka in 2016. She is a co-author of several peer-reviewed journal publications and a book chapter, and she has presented her work at several regional, international, and national conferences.",institutionString:"University of North Carolina at Greensboro",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of North Carolina at Greensboro",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"466998",firstName:"Dragan",lastName:"Miljak",middleName:"Anton",title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/466998/images/21564_n.jpg",email:"dragan@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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1. Introduction
\n
The amygdaloid complex (AC) is a heterogeneous structure described for the first time by Burdach as an “almond‐shaped” mass of grey substance located in the anterior part of the temporal lobe [1]. Since then, the various AC nuclei, which have diverse developmental features and functions, have been considered either as part of a single structural unit [2] or a collection of randomly aggregated structures [3]. There have also been many attempts to consistently demarcate the various AC nuclear components and their subdivisions in the human and other non‐human primates, but there is no consensus as yet [3].
\n
The AC receives highly integrated sensory information of all modalities and is needed for the association between each sensory stimulus and its emotional and motivational significance [4, 5]. The AC also contributes to the visceral and somatic expression of endocrine response to these stimuli. Direct stimulation of the AC produces a subjective perception of fear and anxiety, as well as increased heart rate and blood pressure with pupil dilation [6]. A huge number of studies have related the AC with fear perception and the generation of appropriate affective responses to these types of stimuli [7–14]. Other investigations have, nevertheless, demonstrated that the activity of the AC also increases in response to positive emotional stimuli in humans [15–17] and non‐human primates [5]. The AC is crucial to the acquisition, consolidation and extinction of fear memories, as well as to their retrieval after extinction. Therapies known as “exposition therapies” try to produce the extinction of those fear memories that trigger anxiety behaviors [12].
\n
Bilateral lesion of the medial temporal lobes containing the AC produces a visual‐limbic disconnection [18] or a sensory‐affective dissociation [19]. Both alterations seem to be present in Rhesus monkeys affected by the Klüver‐Bucy syndrome [20]. A variety of symptoms including aphasia, amnesia, or dementia have been observed in human patients with a bilateral temporal lobe lesion, and lesions specifically affecting the AC seem to be related to the difficulty in identifying the emotional significance of facial expressions [21].
\n
The dopaminergic innervation received by the AC is intense in rats [22–26], non‐human primates [27–29], and humans [30]. This particular neurochemical input is required to acquire, consolidate or extinguish fear‐related memories, as well as to generate appropriate affective responses toward aversive stimuli [31–36]. A dysfunction of the dopaminergic system is related to psychiatric diseases such as schizophrenia [37, 38] and/or other stress‐related disorders [39, 40]. In addition, the hyperdopaminergic phenotype of transgenic mice lacking the dopamine transporter (DAT) can show the positive symptoms observed in schizophrenic patients [41]. As discussed below, the dopamine in the AC affects projection neurons either directly or through various types of interneurons.
\n
The present chapter will review data collected in recent years in the human AC related to the amount of neurons, glial and endothelial cells, as well as more specific quantitative data on two main AC interneuron populations, which modulate the activity of the projection neurons. The amount, distribution and specific neuronal targets, of the dopaminergic innervation of the human AC will also be addressed.
\n
\n
2. Anatomical delineation and nomenclature of the human amygdaloid complex
\n
Numerous studies have addressed the anatomical nuclear division in the primate AC [2, 42–50], but the lack of well‐defined anatomical limits between the various AC nuclei has complicated any consensus on the delineation of the AC nuclei and their subdivisions. Table 1 shows the most relevant divisions and nomenclature used in the last years to define the AC nuclei in human and non‐human primates. The correct and detailed division of the AC is important because its various nuclei have distinct developmental origins, specific connections, and codify different aspects of fear [7]. The proper delineation of the AC is also necessary to perform accurate quantitative studies such as stereological estimations of cell numbers or nuclear volumes, and the comparisons of such data collected in different studies. For instance, the basolateral group, especially the lateral nucleus, processes the emotional significance of every stimulus, allowing other structures access to this information, and it is involved in the suppression of fear responses and their retrieval after extinction [7, 8, 11]. The central nucleus is activated by the basolateral group and can initiate key defense mechanisms against species‐specific predators representing a danger to an individual given species [7, 8, 13, 51]. The corticomedial group and the lateral nucleus become activated after the presentation of faces expressing fear [52].
Anatomical delineation of the human amygdaloid complex.
* Subdivisions added to the classification proposed by Price et al. [48]. The abbreviations used in this chapter are indicated in bracket.
1 Classification developed in Saimiri sciureus and in humans.
2 Classification developed in Macaca fascicularis. The other studies are referred to humans.
\n
One of the first descriptions of the architectonic organization of the AC was made by Völsch [2, 42–50] in primates. Later, Brockhaus published a detailed report of the human AC architecture employing Nissl and myelin staining [47]. However, these classifications were rather complex and Crosby and Humphrey proposed a simpler nomenclature, which is still widely used and based on the one suggested by Johnston [53, 54]. Johnston grouped the amygdaloid nuclei into two groups based on developmental origin and age: the first group included the primitive or little‐modified central, medial, cortical, and nucleus of the lateral olfactory tract; the second group included the more recently evolved basal and lateral nuclei formed by infolding or cell immigration. The basal and lateral nuclei together with the accessory basal nucleus conform the basolateral group of the AC, which has undergone a huge increase of volume in humans [2, 49].
\n
In a more recent study, García‐Amado and Prensa suggested a detailed nuclear division and nomenclature for the human AC based on the proposal by Sims and Williams [49] and Ledo‐Varela et al. [56], and that also resembled those used by Schumann and Amaral [57] and Sorvari et al. [58] (Table 1; see [55] for further details). The García‐Amado and Prensa study [55] was focused on providing accurate and objective limits of the entire AC and its various nuclear groups, nuclei, and nuclear subdivisions. The establishment of consistent anatomical limits is essential for making comparisons among quantitative data collected in different studies. To this end, the 2012 García‐Amado and Prensa study did not outline as a single whole the structures with rather fuzzy boundaries like the anterior amygdaloid area described by Sims and Williams [49]. Instead, they only outlined the most lateral part of this region, the periamygdalar area, since this area can be objectively identified by its high content in acetylcholinesterase. Other relevant aspects of the study of García‐Amado and Prensa are the consideration of the dorsal subdivision on the lateral nucleus, whose cells are much smaller and more packed than the ones that populate its three other subdivisions, and the inclusion of the paralaminar region within the parvocellular subdivision of the basal nucleus because the former has unclear limits.
\n
\n
3. Volume of the human AC
\n
The volumes of the AC as a whole and some of its nuclei have been estimated in many studies dealing with psychiatric disorders as well as in others on Alzheimer’s disease [59–64]. The range of AC volume for individuals without any neurological or psychiatric disease varied from 630 to 1380 mm3 depending on the study [59–65]. The variability in the delineation of the AC nuclei and/or the different protocols used to process the human tissue could be responsible for the large range of AC volume reported in normal individuals in the different studies. Similar investigations performed in tissue obtained from schizophrenic and bipolar disorder patients report a decrease in the volume of several AC nuclei, such as the basal and lateral ones [63, 64].
\n
The stereological study by García‐Amado and Prensa [55] of the human AC from individuals without any neurological or psychiatric disease showed that the entire complex reached a volume of approximately 950 mm3 with more than 80% of that volume corresponding to the basolateral group, 10% to the corticomedial group, and 6% to the central group (Table 2; [55]). Overall, these volumes fall within the ranges reported by other authors [59–64]. The volume of the total AC as estimated by García‐Amado and Prensa [55] was smaller than the one reported earlier by Schumann and Amaral [62] due to the unclear limits of particular structures such as the nucleus of the lateral olfactory tract, the anterior amygdaloid area, the periamygdaloid cortex and the amygdalohippocampal area, some of which were not included in the AC by the former study. Nevertheless, the volume estimations for individual AC nuclei reported in these two studies were more alike except for certain minor differences in the lateral and basal nuclei. Chance et al. [61] and Berretta et al. [63] reported smaller volume estimations than García‐Amado and Prensa [55], the disparities being most probably due to the difference in the methods used during tissue processing or to the variations in delineation of the nuclei (see [55] for details).
Estimations of the regional volume, and the neuronal number and density of the human AC.
N: number of neurons (× 106 ); V: regional volumen (mm3); Nv: neuronal density (neurons/mm3); –: no estimation reported. For abbreviations see Table 1.
\n
\n
4. Cellular architecture of the human AC
\n
The AC contains three types of cell populations: neurons, glial, and endothelial cells. The morphology, number and density of the first two and the possible changes that they might present in pathologies such as schizophrenia or autism have been discussed in the last years [57, 60, 62–64, 66–68]. There are several morphological neuronal subtypes in the human AC [69]. Some 70% of neurons in the basolateral group show a pyramidal morphology and are thought to be projection neurons; the remaining 30% are interneurons. Cell morphology in the central and medial nuclei is quite variable, but pyramidal cells are not as common as in the basolateral group [70].
\n
Data about the glial cells in the AC are scarce and mostly centered on astrocytes [70, 71]. Certain glial cell populations, such as oligodendrocytes, undergo quantitative changes in major depressive disorder [66, 67]. Further investigations are needed to determine whether other glial cell types (i.e. astrocytes and/or microglia) are involved in this and other psychiatric disorders [72]. The available data on endothelial cells are also very limited and mostly centered on determining the effects on microvasculature that are produced by the antipsychotic treatments or the schizophrenia [73, 74].
\n
4.1. Number and density of neurons, glial, and endothelial cells
\n
The human AC contains approximately 15 million neurons of which 80% are located inside the basolateral group, 10% in the corticomedial group and 5% in the central group [55]. The number of endothelial cells is quite similar to that of neurons, whereas the glial cell number is almost four times higher, and this proportion is maintained in most of the nuclear subdivisions of the AC. This glial/neuron ratio differs from that found in the cerebral cortex, where it ranges from 1.55 to 2.19 depending on the cortical area examined [75], or the one in subcortical structures, which varies from 14 in the mediodorsal thalamic nucleus and ventral pallidum to 3 in the nucleus accumbens [60]. The glial/neuron ratio in the AC increases across species, from rat to human [76], suggesting that the AC is more complex in primates than in rodents.
\n
In terms of neuron number and density in the AC, the estimations of García‐Amado and Prensa [55] (Figure 1) are comparable with, although slightly higher than, those reported in other studies performed in the lateral, basal, accessory basal, and central nuclei [62–64, 66]. Differences in neuron number between studies are due to variations in the delineation of the nuclei whereas differences in neuron density between studies might be the result of different nuclear volume estimations. Particular attention should be given to the work of Dall’Oglio et al. [70], which reported a neuronal and glial cell density in the medial nucleus that was almost 10 times higher than the one reported by García‐Amado and Prensa [55]; this huge difference is probably explained by technical differences in the method used during tissue processing [77] and/or to a different delimitation of the nucleus.
\n
Figure 1.
Density of neurons, glial and endothelial cells (cells/mm3) in the human AC. (A) Mean and standard deviation of the density of neurons (rhombus), glia (squares) and endothelial cells (triangles) in the whole AC and their nuclear groups and nuclei. (B) Mean and standard deviation of the density of neurons (rhombus), glia (squares) and endothelial cells (triangles) in the nuclear subdivisions of the AC. For abbreviations see Table 1.
\n
Regarding neuronal density, the differences among the AC nuclei described in the various studies are consistent [55, 62–64, 66]. The neuronal density in the basal nucleus is considerably higher than that in the rest of the AC nuclei, and this is probably due to the extremely high neuronal density of its parvocellular subdivision [78–80]. The number of neurons in the different AC nuclei and nuclear subdivisions in several non‐human primate species was analyzed by Carlo et al. [81]. Despite the fact that the values reported by these authors are markedly lower than those reported in the human brain by García‐Amado and Prensa [55], the percentages of neurons between nuclei and their subdivisions are roughly similar. Consequently, what Carlo and his colleagues found indicates an increase in the number of neurons in every nucleus of the AC during the evolution of primate species. The percentage of increase in the central nucleus was markedly less than in the rest of AC nuclei.
\n
The reported number and density of glial cells in the AC are consistent in the various studies [65, 66]. The high density of glial cells in the lateral nucleus may be related to the numerous projections from sensory associative cortical structures [82].
\n
The density of neurons and endothelial cells in the AC tends to respectively decrease or increase with age, especially in the basolateral group [55]. In contrast, the number and density of glial cells in the grey matter of AC nuclei tend to increase moderately with age, an observation that could be interpreted as either a compensatory mechanism or a response by the glial cell population to the neuronal loss occurring during aging. Both gliosis and fiber loss have been described as stages of age‐dependent degeneration [83]. The parvocellular subdivision of the basal nucleus is the only AC region that did not show a decrease in the number of neurons over time [55]. The presence of a large number of immature neurons in the paralaminar territory of the basal nucleus in the adult brain might counteract the decrease in neuron number with aging [79, 80]. The increase in the number and density of the AC endothelial cells during aging is considered an adaptation of the brain to maintain the rate of oxygen delivery to this region when the blood flow decreases [84, 85].
\n
\n
4.2. Interneurons in the human AC
\n
Various histochemically and electrophysiologically well‐characterized subsets of interneurons exist in the AC (for review see Ref. [86]). Each of these subsets of AC interneurons is characterized by specific firing patterns, by their targets in discrete subcellular domains of projection neurons, and by their specific modulation by external sensory stimuli [87, 88]. From the functional view point, the AC interneurons exert an important inhibitory effect over the projection neurons of the basolateral nucleus and contribute to generating synchronous theta activity between the amygdala and the hippocampus during the acquisition of emotional memories [87]. The interneurons of the basolateral amygdala are activated by the hippocampal input with theta frequencies that reach the amygdala; this activation causes a transient feedforward inhibition of projection neurons that is followed by the increase of active excitatory synapses and the induction of long‐term potentiation of these synapses during fear memory retrieval [89]. Alterations in the expression of calcium‐binding proteins in some interneuron subsets of the AC [90] or of the cerebral cortex [91–95] have been described in disorders like anxiety in which the extinction of fear memories can be impaired.
\n
As in rodents, four different subsets of interneurons have been determined in primates: (1) parvalbumin (PV) positive (+) interneurons (25% of these also contain calbindin (CB) [86, 96]; (2) CB+ interneurons (30–35% also contain PV) [86, 97, 98]; (3) somatostatin + interneurons [86, 99, 100]; and (4) calretinin (CR) + interneurons [86, 101]. Most of these data were obtained in non‐human primates and the studies performed in humans did not precisely define either the number of AC interneuron subsets or the quantities and percentages of each interneuron population in the various AC nuclei. Nevertheless, PV+ and CR+ interneurons are the most abundant non‐overlapping populations among all the calcium‐binding protein‐containing interneuron populations in the primate AC [86]. Furthermore, these two neurochemically well‐defined interneuron populations are also distinguished by their electrophysiological properties; the PV+ interneurons are associated with “fast” and “burst” firing patterns, whereas the CR+ interneurons show a “regular” firing pattern [102]. PV+ interneurons can innervate the soma, proximal dendrites or the initial axon segment of pyramidal neurons [87, 88], and they receive excitatory inputs from axon collaterals of local pyramidal cells, which form a powerful inhibitory feedback [103].
\n
In terms of their topographic distribution within the AC, the PV+ interneurons are restricted to the basolateral group, whereas CR+, as well as CB+, interneurons are homogeneously distributed through the AC. This means that PV+, CR+ and the CB+ subsets of interneurons exist in the basolateral group, but only CR+ and CB+ subsets of interneurons are present in the corticomedial and the central nuclear groups. CR+ interneurons are especially abundant in the accessory basal nucleus, whereas the PV+ cells abound in the lateral nucleus and gradually diminish toward the more medial regions of the basolateral group [58, 96, 101, 104, 105].
\n
Quantitative data regarding the relative proportion of the PV+ and the CR+ interneuron subtypes with respect to both the total interneuron population and the total neurons in the AC in rodents, primates and humans are already available in the literature. In the basolateral group, the PV+ interneurons represent 19–43% and the CR+ interneurons 17–20% of the total of all interneurons in rodents [106]. In the non‐human primate basolateral group, the PV+ interneurons represent 28–37% of the GABAergic interneurons, while CR+ interneurons represent 23–27% [86]. In rats, PV+ interneurons make up 6% of the total AC neuron population whereas CR+ interneurons are 4% [26]. In the human AC, however, the proportion of PV+ interneurons is lower than that of CR+ interneurons with respect to total AC neurons; PV+ interneurons do not reach 1% in any AC territory whereas CR+ interneurons range from 4 to 23% depending on the AC area studied [105]. Taken together, these data show that the amount of PV+ and CR+ interneurons in the AC decreases and increases, respectively, over the phylogenetic scale, a finding that is in agreement with previous reports made in the striatum, in comparisons of humans with the squirrel monkey and the rat [107].
\n
\n
\n
5. The dopaminergic innervation of the human AC
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The AC receives a substantial dopaminergic innervation originating mainly from the A8, A9 and A10 ventral mesencephalic groups [29] and dopamine is a key neurotransmitter in the AC that modulates the entry of information through the basolateral group. Furthermore, this dopaminergic innervation is required for the acquisition, consolidation and extinction of fear memories as well as for generating appropriate affective responses [31–36] and, as mentioned earlier, dysfunctions of this dopaminergic system have been proposed as pathogenic mechanisms in psychiatric diseases such as schizophrenia [37, 38] and stress‐related disorders [39, 40]. Accurate quantitative data regarding the amount of dopaminergic axons and their distribution in the AC from human donors who had not been diagnosed with neurological or psychiatric diseases before their death was collected by García‐Amado and Prensa [108] using DAT immunoreactivity as a marker for the dopaminergic fibers and stereological approaches. Since intrinsic dopamine instability prevents its immunodetection in brain tissue that has not been rapidly fixed by perfusion after the donor’s death, previous studies that were focused on analyzing the dopaminergic innervation of the human AC had used the TH protein to detect dopaminergic profiles. However, TH protein also labels noradrenergic and adrenergic fibers in the AC [109, 110]. Since the AC consists of several nuclear groups with a vast array of interconnections with the cerebral cortex, hippocampal formation, basal ganglia, thalamus, hypothalamus, and brainstem (for review see Refs. [48, 50]), information on the content of dopaminergic axons in each of the nuclear groups is needed to better understand the internal functional organization of this complex.
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The human AC is targeted by widespread DAT‐positive fibers, which are dense and unevenly distributed in every subdivision of this nuclear complex [108] (Figures 2 and 3). Furthermore, their study has yielded accurate information regarding the quantity of DAT‐ir fibers per neuron in each amygdaloid territory. As shown by these authors, the amount of DAT‐ir axons in the human AC varies among the several nuclei of the AC and also varies considerably in the various subdivisions of a given AC nucleus (Figure 2), indicating functional variations among these territories.
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Figure 2.
Distribution of DAT‐positive fibers in the human AC. Series of two adjacent coronal sections stained for acetylcholinesterase (AChE) (A, C, E) and DAT (B, D, F) at three anteroposterior levels of the AC, with the corresponding plates from Ref. [119]. The stippling in B, D and F represents the DAT‐positive axons drawn with camera lucida at 20× and superimposed over the same micrographs stained for DAT. Arrowheads in C and D indicate patches with either AChE or DAT enriched staining, respectively. For abbreviations see Table 1. Scale bar: 1 mm.
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Figure 3.
Length density of DAT‐positive fibers in the human AC. Mean DAT‐positive fiber length density for every nuclear group, nucleus and nuclear subdivision of the AC. The error bars represent standard deviation. For abbreviations see Table 1. Modified from García‐Amado and Prensa [108].
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One of the most striking gradients in the amount of the DAT‐ir fibers occurred along the mediolateral axis of the lateral nucleus: the total length of DAT‐ir axons range from nearly 300 mm/mm3 in its medial subdivision to nearly 800 mm/mm3 at its external (most lateral) subdivision (Figures 2 and 3). This large variation in the amount of DAT‐ir fibers between the medial and lateral sectors of the lateral nucleus might be related to their differentiated extrinsic and intrinsic connections. Thus, the lateral nucleus would be the main target of sensory information from the external world, and it sends heavy projections to the other amygdaloid nuclei [111]. The external subdivision of the lateral nucleus receives most of these sensory projections (Figures 2 and 3), and the information flows toward the medial side of the nucleus [111, 112]; in addition, this AC region has the shortest latency of conditioned responses elicited by sensory stimuli associated with adverse events in emotional learning tasks [113]. On the other hand, the medial subdivision of the lateral nucleus receives information from higher‐order cortical processing areas [114–117]. In the hippocampus, DAT‐positive axons were present only in the outer two‐thirds of the molecular layer of the dentate gyrus, where the perforant pathway ends [118], indicating that dopamine may potently and selectively regulate the input from the entorhinal cortex and thus the early stages of hippocampus processing, as might be the case for the sensory information entering the AC lateral nucleus.
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The central nucleus receives information from the rest of the AC nuclei and is one of the main output nuclei of the AC [111]. Descending projections from the central nucleus terminate in a wide mediolateral region of mesencephalic dopamine cells [120]. In turn, this nucleus receives the heaviest DAT‐positive dopaminergic innervation of all the AC nuclei, however its innervation is not uniformly distributed and markedly decreases along a mediolateral gradient, a finding that agrees with the distribution pattern of TH‐ir fibers [27]. In the basal and accessory basal nuclei of the AC, the content in DAT‐ir fibers decreases from dorsal to ventral sectors, though this gradient is much less marked in the latter than in the former nucleus (see Figure 2A and B) [27–29, 49, 58, 121].
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The regulation of extracellular dopamine levels is controlled by distinct mechanisms in different brain areas and is probably related to DAT content. Thus, whereas the dorsal striatum and the nucleus accumbens show an “uptake‐dominated” regulation (i.e. one in which dopamine is quickly recaptured from the extracellular space to end its action), the medial prefrontal cortex and the AC show a “release‐dominated” regulation (i.e. dopamine is maintained in the extracellular space more time) [122]; these findings agree with the observation that there is more DAT in the striatum than in the other two structures [27–29, 49, 58, 121].
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The AC is a main target for mesencephalon projections made up of cells from the substantia nigra pars compacta (A9 dopaminergic group), the ventral tegmental area (A10 dopaminergic group) and the retrorubral field (A8 dopaminergic group) [4, 123–125]. In the human mesencephalon, DAT abounds in neurons located in the lateral ventral tegmental area and in the substantia nigra pars compacta and is largely absent from the medial ventral tegmental area [30]. DAT mRNA is more abundant in the A9 ventral tier than in the dorsal tier [125]. The human AC nuclei that contain the most DAT‐ir fibers correspond to those that receive strong projections from the ventral mesencephalon, as also observed in primates [29]. There are, nevertheless, other AC regions showing a high density of DAT‐positive fibers, such as the lateral subdivision of the central nucleus, that do not seem to receive innervation from any part of the ventral midbrain [29]. There are other possible sources of AC dopamine that lie outside the ventral midbrain, but whether they contribute to the DAT‐ir fibers encountered in the AC or not, is not yet clear. The parabrachial nucleus projects to the central and medial nuclei of the AC [29, 123, 124] and it contains putatively dopaminergic neurons that do not carry DAT [126]. Moreover, the neurons of the parabrachial nucleus that project to the AC also lack tyrosine hydroxylase (TH) [29, 123, 124]. The periaqueductal gray substance is another source of input to the AC and it contains dopaminergic neurons (i.e. A11 group) that contain DAT [126] and project to the central and medial AC nuclei [4, 123, 124, 127–129]. This dopaminergic connection is relevant as it specifically targets the lateral subdivision of the central nucleus, a region that sends efferent projections to the medial subdivision of the central nucleus, which in turn projects back to the periaqueductal gray substance handling “freezing” behavior in animals exposed to a potentially dangerous stimulus [12]. There are also TH+ cells in the dorsal raphe nucleus that project to the central AC nucleus [129], but the DAT content of these cells has not been yet determined.
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The ultrastructural localization of DAT in the primate AC is unknown at present. In the cerebral cortex, most of the DAT‐labeled profiles correspond to thin unmyelinated axons that rarely form synapses, whereas TH‐labeled profiles vary more in their diameter and TH‐ir varicosities contain abundant vesicles and frequently form synapses [118]. Consequently, Lewis et al. believe that DAT is likely to be restricted to the intervaricose segments [118]. The specific postsynaptic targets of the dopaminergic fibers that reach the human AC are not known. Several studies in rodents have demonstrated that these fibers make synapses with both projection neurons [23, 24, 130] and interneurons [25, 26, 130]. Although projection neurons receive the majority of dopaminergic synapses [130], the CR+ and PV+ interneuron subsets are also innervated by these fibers, especially the ones containing PV [26]. The CR+ interneurons receive only 6% of the dopaminergic synapses, whereas the PV+ cells receive 40% [26]. In the central and basal nuclei, as well as in the paracapsular intercalated groups, the dopaminergic terminals form symmetric synapses more frequently than asymmetric ones [23, 24, 26, 130].
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Dopaminergic fibers in the AC form perineuronal nets around the soma of the projection neurons and the PV+ interneurons, and 72% of the contacts that these nets establish with the PV+ interneurons are synaptic [25, 26, 130]. These nets are abundant in some 10–15% of all PV+ interneurons and they appear to avoid other interneuron subsets. These nets are functionally related with the strong inhibition observed in the activity of the projection neurons of the basolateral group after dopamine release [131, 132]. The dopaminergic innervation of the various interneuron populations of the AC could contribute to the induction of long‐term potentiation mechanisms involved in conditioned fear acquisition, which requires suppression of GABAergic interneuron inhibition of projection neurons [35]. Dopamine inhibits the “fast firing” interneurons, which coincide with the PV+ interneurons [102], and reduces the inhibition of projection neurons in the lateral amygdaloid nucleus. More recently, Chu et al. have demonstrated that dopamine blocks GABA release from PV+ interneurons to projection neurons acting on type D2 presynaptic receptors but it does not affect the release of GABA to other interneuron types from this interneuron population [133]. The blockade of both D1 and D2 receptors in the basolateral group prevents fear conditioned acquisition [134–136].
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\n
6. Concluding remarks
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The AC is a heterogeneous structure formed by numerous nuclei with diverse morphological and functional features. Numerous neurological or psychiatric diseases are linked to alterations in specific cell populations, as well as neurotransmission systems in the human AC. Understanding how AC dysfunction may be related to the pathogenesis of human disorders or accompany behavioral impairments requires a profound knowledge of the normal anatomy of the human AC. In this sense, several studies performed in the last 5 years have provided accurate quantitative data related to the cellular composition and dopaminergic innervation of the various nuclear complexes and their subdivisions that make up the human amygdala. Data from these studies have revealed, for instance, that the human AC contains approximately 15 million neurons with nearly 80% residing in the basolateral group, 10% in the corticomedial group and 5% in the central group. The number of endothelial cells is similar to the number of neurons whereas the number of glia is approximately four times that of neurons. Most amygdaloid neurons are glutamatergic or GABAergic neurons that project their axons outside the AC. The activity of the AC principal neurons is tightly modulated by local circuit interneurons and this modulation is required for the acquisition of fear memories. The AC interneurons are cataloged into different subsets based on their firing properties, their synaptic inputs and their expression in proteins such as calcium‐binding proteins. Among all the interneurons containing calcium‐binding proteins in the primate AC, the PV+ and the CR+ interneurons are the most abundant, representing 1% and 6–24% of the total neuron population of the human AC, respectively. PV+ interneurons exert robust perisomatic inhibition of principal neurons, but their activity is likely to be mostly concentrated in the basolateral complex, since almost none of these neurons populate other AC territories. In contrast, the CR+ interneurons are, basically, homogeneously distributed through the entire AC. The human AC receives a heterogeneous dopaminergic innervation that mostly originates in the midbrain areas and regulates the activity of the various subsets of AC neurons. Dysfunctions of this dopaminergic system have been described in schizophrenia and stress‐related disorders. Stressful events enhance dopamine release in the AC and this facilitates the formation of fear memories as well as appropriate affective responses. A recent study has demonstrated that the dopaminergic innervation of the human AC is heterogeneous and that the main output nucleus of the AC (i.e. the central nucleus) receives the highest density of dopaminergic axons containing the dopamine transporter, with almost double the density of these fibers compared to the density in the main entrance nucleus of the AC (the basolateral group). The postsynaptic targets of the dopaminergic fibers in the human AC remain unknown, but these fibers make synapses with both projection neurons and interneurons in rodents. The CR+ and the PV+ interneurons of the AC are important targets of the dopaminergic synapses in rodents, but further studies are needed to determine what the main neuronal targets of this neurotransmitter are in the human AC and the role that this innervation has in emotional learning.
\n
Acknowledgments
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The project was supported by grants from the Fundación Eugenio Rodríguez Pascual.
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\n',keywords:"amygdala, human, dopamine, stereology, dopamine transporter, neurons, glia, endothelial cells",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/54963.pdf",chapterXML:"https://mts.intechopen.com/source/xml/54963.xml",downloadPdfUrl:"/chapter/pdf-download/54963",previewPdfUrl:"/chapter/pdf-preview/54963",totalDownloads:1453,totalViews:307,totalCrossrefCites:1,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:65,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"May 13th 2016",dateReviewed:"March 8th 2017",datePrePublished:null,datePublished:"July 5th 2017",dateFinished:"April 23rd 2017",readingETA:"0",abstract:"The human amygdaloid complex (AC) is associated with the perception of fear and consequent anxiety‐related behaviors, apart from other functions ranging from attention to memory and emotion. The AC is composed of several regions with specific cytoarchitectures, chemistry, and connections that encode different aspects of fear. Detailed understanding of AC cell composition is basic to determining whether cell number alterations coincide with neurological and psychiatric pathologies associated to anxiety imbalances, as well as with changes in brain functionality during aging. Here, we describe quantitative data gathered applying stereological methods to human AC tissue; the amounts of neurons, glial and endothelial cells, as well as of various interneuron subsets that populate the AC regions were noted and compared with those collected in the AC of non‐human primates and rodents. This chapter also addresses the dopaminergic innervation of the AC, which exerts a modulatory effect over the intrinsic AC network and is critical for reward‐related learning and fear conditioning. This innervation is twice as abundant in the main output nuclei as in the principal entry nuclei of the human AC, and this irregularity may indicate functional variations between these entry and output amygdaloid territories.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/54963",risUrl:"/chapter/ris/54963",book:{id:"5485",slug:"the-amygdala-where-emotions-shape-perception-learning-and-memories"},signatures:"María García‐Amado and Lucía Prensa",authors:[{id:"191571",title:"Ph.D.",name:"Maria",middleName:null,surname:"Garcia-Amado",fullName:"Maria Garcia-Amado",slug:"maria-garcia-amado",email:"maria.garciaamado@uam.es",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Autonomous University of Madrid",institutionURL:null,country:{name:"Spain"}}},{id:"195253",title:"Dr.",name:"Lucia",middleName:null,surname:"Prensa",fullName:"Lucia Prensa",slug:"lucia-prensa",email:"lucia.prensa@uam.es",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Anatomical delineation and nomenclature of the human amygdaloid complex",level:"1"},{id:"sec_3",title:"3. Volume of the human AC",level:"1"},{id:"sec_4",title:"4. Cellular architecture of the human AC",level:"1"},{id:"sec_4_2",title:"4.1. Number and density of neurons, glial, and endothelial cells",level:"2"},{id:"sec_5_2",title:"4.2. Interneurons in the human AC",level:"2"},{id:"sec_7",title:"5. The dopaminergic innervation of the human AC",level:"1"},{id:"sec_8",title:"6. Concluding remarks",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Burdach KF. Vom Baue und Leben des Gehirns Leipzig. pp. 1819-1822\ufeff\ufeff\ufeff\ufeff\ufeff\ufeff'},{id:"B2",body:'Johnston JB. Further contributions to the study of the evolution of the forebrain. Journal of Comparative Neurology. 1923;35(5):337-481\ufeff\ufeff\ufeff\ufeff\ufeff\ufeff'},{id:"B3",body:'Swanson LW, Petrovich GD. What is the amygdala? 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Department of Anatomy, Histology and Neuroscience, School of Medicine, Autónoma de Madrid University, Madrid, Spain
Department of Anatomy, Histology and Neuroscience, School of Medicine, Autónoma de Madrid University, Madrid, Spain
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1. Introduction
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Breast cancer is the most frequently diagnosed cancer among women worldwide, affecting over 1.5 million women each year. In 2015, it is estimated that worldwide 500,000 women have died from this malignancy, which represents 15% of all cancer-related deaths among women [1].
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It is now well recognized that breast cancer comprises a heterogeneous group of diseases in term of differentiation and proliferation, prognosis and treatment. Over the past decades, microarray-based gene expression studies have allowed the identification of breast cancer intrinsic subtypes [2, 3, 4]. One of these subtypes is the so-called human epidermal growth factor receptor 2 (HER2)-enriched subtype. HER2 is a transmembrane tyrosine kinase receptor [5]. This protein is encoded by the HER2 gene, which is located on the long arm of chromosome 17 (17q12–21.32) [6]. The HER2-enriched subtype is characterized by high expression of HER2 and other genes of the 17q amplicon, including growth factor receptor bound protein 7 (GRB7), and low to intermediate expression of luminal genes such as Estrogen Receptor 1 (ESR1) and Progesterone Receptor (PGR) [7]. Clinically, HER2-positive breast cancer occurs in 15–20% of breast cancer patients and is characterized by the overexpression of the HER2 receptor and/or HER2 gene amplification [8]. HER2-positive breast cancer patients have a particular worse prognosis. Importantly, HER2-positive breast cancer patients are eligible to receive targeted treatment with trastuzumab, a monoclonal antibody specifically directed against the HER2 receptor [9]. Trastuzumab treatment, in combination with chemotherapy, improves the outcome of early [10, 11] and metastatic [12, 13] HER2-positive breast cancer patients. The US Food and Drug Administration (FDA) approved trastuzumab for the treatment of metastatic HER2-positive breast cancer patients in 1998 and for the treatment of early HER2-positive breast cancer patients in 2006. Lapatinib is a small-molecule inhibitor of the intracellular tyrosine kinase domain of both HER2 and EGFR receptors [14]. Lapatinib has received FDA approval in 2007 as combination therapy with capecitabine for the treatment of patients with HER2-positive advanced breast cancer patients who had progressed on trastuzumab-based regimens [15]. Although anti-HER2 agents are generally well tolerated, trastuzumab administration has been associated with cardiac side effects, especially when used in combination with anthracyclines [16].
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HER2 plays a significant role in breast cancer pathogenesis. It is therefore essential to understand the biology of this receptor in order to better treat HER2-positive breast cancer patients. Evaluation of HER2 status in breast cancer specimens raises several technical considerations. In the last decades, several methods have been developed for HER2 assessment. In this article, we will review important aspects of the HER2 biology and its relevance in breast cancer and present the techniques that are used in clinical practice for the determination of HER2 status in breast cancer specimens.
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2. HER2 biology and methods of assessment of HER2 status
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2.1. HER2 receptor
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The HER2 receptor is a 185 kDa transmembrane protein that is encoded by the HER2 (also known as erb-b2 receptor tyrosine kinase 2 [ERBB2]) gene, which is located on the long arm of chromosome 17 (17q12–21.32) [6]. HER2 is normally expressed on cell membranes of epithelial cells of several organs like the breast and the skin, as well as gastrointestinal, respiratory, reproductive, and urinary tract [17]. In normal breast epithelial cells, HER2 is expressed at low levels (two copies of the HER2 gene and up to 20,000 HER2 receptors) [18], whereas in HER2-positive breast cancer cells, there is an increase in the number of HER2 gene copies (up to 25–50, termed gene amplification) and HER2 receptors (up to 40 to 100 fold increase, termed protein overexpression), resulting in up to 2 million receptors expressed at the tumor cell surface [19]. Besides breast cancer, HER2 overexpression has also been reported in other types of tumors, including stomach, ovary, colon, bladder, lung, uterine cervix, head and neck, and esophageal cancer as well as uterine serous endometrial carcinoma [20].
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2.1.1. HER2 structure and function
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HER2 belongs to the epidermal growth factor receptor (EGFR) family. This family is composed of four HER receptors: human epidermal growth factor receptor 1 (HER1) (also termed EGFR), HER2, human epidermal growth factor receptor 3 (HER3), and human epidermal growth factor receptor 4 (HER4) [5].
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HER family members are transmembrane receptor tyrosine kinases. Tyrosine kinases are enzymes that carry out tyrosine phosphorylation, namely the transfer of the γ phosphate of adenosine triphosphate (ATP) to tyrosine residues on protein substrate [21].
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HER receptors share a similar structure. They are composed of an extracellular domain (ECD), a transmembrane segment and an intracellular region [22]. The ECD domain is divided into four parts: domains I and III, which play a role in ligand binding, and domains II and IV, which contain several cysteine residues that are important for disulfide bond formation [23]. The transmembrane segment is composed of 19–25 amino acid residues. The intracellular region is composed of a juxtamembrane segment, a functional protein kinase domain (with the exception of HER3 that lacks tyrosine kinase activity [24] and must partner with another family member to be activated [25]), and a C-terminal tail containing multiple phosphorylation sites required for propagation of downstream signaling [23]. The catalytic domain contains the ATP binding pocket, a conserved site essential to ATP binding [26].
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HER receptors are activated by both homo- and heterodimerization, generally induced by ligand binding [27]. This suggests that HER receptor family has evolved to provide a high degree of signal diversity [28]. The cellular outcome produced by HER receptors activation depends on the signaling pathways that are induced, as well as their magnitude and duration, which are influenced by the composition of the dimer and the identity of the ligand [28].
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Several growth factor ligands interact with the HER receptors [29]. HER1 receptor is activated by six ligands: epidermal growth factor (EGF), epigen (EPG), transforming growth factor α (TGFα), amphiregulin, heparin-binding EGF-like growth factor, betacellulin and epiregulin. HER3 and HER4 receptors bind neuregulins (neuregulin-1, neuregulin-2, neuregulin-3, and neuregulin-4). HER2 is a co-receptor for many ligands and is often transactivated by EGF-like ligands, inducing the formation of HER1-HER2 heterodimers. Neuregulins induces the formation of HER2-HER3 and HER2-HER4 heterodimers [29]. However, no known ligand can promote HER2 homodimer formation, implying that no ligand can bind directly to HER2 [30].
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The structural basis for receptor dimerization has been elucidated in recent years through crystallographic studies [31, 32]. Dimerization is mediated by the dimerization arm, a region of the extracellular region of HER receptors. While in its inactivated state the dimerization arm of EGFR, HER3 and HER4 is hidden, ligand binding induces a receptor conformational change leading to exposure of the dimerization arm [31]. In contrast to the other three HER receptors, the dimerization arm of the HER2 receptor is permanently partially exposed, thus permitting its dimerization even if the HER2 receptor lacks ligand-binding activity [32].
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Interaction between the dimerization arms of two HER receptors promotes the formation of a stable receptor dimer in which the kinase regions of both receptors are closed enough to permit transphosphorylation of tyrosine residues, i.e. the transfer of a phosphate group by a protein kinase to a tyrosine residue in a different kinase molecule [33, 34]. The first member of the dimer mediates the phosphorylation of the second, and the second dimer mediates the phosphorylation of the first [23].
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The phosphorylation of specific tyrosine residues following HER receptor activation and the subsequent recruitment and activation of downstream signaling proteins leads to activation of downstream signaling pathways promoting cell proliferation, survival, migration, adhesion, angiogenesis and differentiation [35]. The Phosphatidylinositol 3′-kinase (PI3K)-Akt pathway and the Ras/Raf/MEK/ERK pathway (also known as extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway) are the two most important and most extensively studied downstream signaling pathways that are activated by the HER receptors [5, 36]. These downstream signaling cascades control cell cycle, cell growth and survival, apoptosis, metabolism and angiogenesis [37, 38]. Signaling from HER receptors is then terminated through the internalization of the activated receptors from the cell surface by endocytosis. Internalized receptors are then either recycled back to the plasma membrane (HER2, HER3, HER4) or degraded in lysosomes (HER1) [39, 40].
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HER heterodimers produce more potent signal transduction than homodimers. This can be explained by the fact that heterodimerization provides additional phosphotyrosine residues necessary for the recruitment of effector proteins [28]. Heterodimerization follows a strict hierarchical principle with HER2 representing the preferred dimerization and signaling partner for all other members of the HER family [41]. HER2 seems to function mainly as a co-receptor, increasing the affinity of ligand binding to dimerized receptor complexes [42, 43]. HER2 has the strongest catalytic kinase activity [41] and HER2-containing heterodimers produce intracellular signals that are significantly stronger than signals generated from other HER heterodimers [44]. The HER2-HER3 heterodimer in particular exhibits extremely potent mitogenic activity through the stimulation of the PI3K/Akt pathway, a master regulator of cell growth and survival [45]. Furthermore, HER2 containing heterodimers have a slow rate of receptor internalization, which results in prolonged stimulation of downstream signaling pathways [28]. HER2 can also be activated by complexing with other membrane receptors, such as Insulin-like growth factor I receptor (IGF-1R) [46].
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2.1.2. Consequences of constitutive HER2 receptor activation
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Whereas in normal cells the activity of tyrosine kinases is a tightly controlled mechanism, in cancer cells, alterations in tyrosine kinases—overexpression of receptor tyrosine kinase proteins, amplification or mutation in the corresponding gene, abnormal stimulation by autocrine growth factors loop or delayed degradation of activated receptor tyrosine kinase—lead to constitutive kinase activation and therefore to aberrant cellular growth and proliferation [34, 47]. Constitutive activation of HER1, HER2, HER3, IGF-1R, Fibroblast growth factor receptor (FGFR), c-Met, Insulin Receptor (IR), Vascular Endothelial Growth Factor Receptor (VEGFR), Jak kinases and Src have been associated with human cancer [34, 48, 49, 50, 51, 52].
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Several ways of aberrant activation of HER receptors have been described, including ligand binding, molecular structural alterations, lack of the phosphatase activity, or overexpression of the HER receptor [53].
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In HER2-positive tumors, receptor overexpression has been identified as the mechanism of HER2 activation. The increased amount of cell surface HER2 receptors associated with HER2 overexpression leads to increased receptor-receptor interactions, provoking a sustained tyrosine phosphorylation of the kinase domain and therefore constant activation of the signaling pathways. HER2 overexpression also enhances HER2 heterodimerization with HER1 and HER3 [54] resulting in an increased activation of the downstream signaling pathways. It has also been shown that HER2 overexpression leads to enhanced HER1 membrane expression and HER1 signaling activity through interference with the endocytic regulation of HER1 [54, 55, 56]. While HER1 undergoes endocytic degradation after ligand-mediated activation and homodimerization, HER1-HER2 heterodimers evade endocytic degradation in favor of the recycling pathway [57, 58], resulting in increased HER1 membrane expression and activity [55, 56, 59].
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It has also been reported that HER2 overexpression enhances cell proliferation through the rapid degradation of the cyclin-dependent kinase (Cdk) inhibitor p27 and the upregulation of factors that promote cell cycle progression, including Cdk6 and cyclins D1 and E [60].
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Several methods have been developed for the assessment of HER2 status in breast cancer specimens, at the protein level, DNA level, and RNA level. Here below, we present some of the existing techniques that are used for the HER2 determination in clinical practice.
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2.2. Methods for the evaluation of HER2 status in breast cancer specimens
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2.2.1. HER2 status evaluation at the protein level
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2.2.1.1. Immunohistochemistry (IHC)
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IHC allows the evaluation of the HER2 protein expression in formalin-fixed, paraffin-embedded (FFPE) tissues using specific antibodies directed against the HER2 receptor protein [61]. HER2 receptor is then visualized with the chromogen 3,3′-diaminobenzidine tetrahydrochloride (DAB) resulting in a brownish membranous staining. Several commercially available diagnostic tests for the determination of HER2 expression have been approved by the FDA: the HercepTest™ kit (DAKO, Glostrup, Denmark), the InSite™ HER2/neu kit (clone CB11; BioGenex Laboratories, San Ramon, CA), the Pathway™ kit (clone 4B5; Ventana Medical Systems, Tucson, AZ), and the Bond Oracle HER2 IHC System (Leica Biosystems, Newcastle, UK).
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By this method, it is possible to estimate the number of cells showing membranous staining in the tissue section as well as the intensity of the staining [62]. Membranous staining in the invasive component of specimen is scored on a semi-quantitative scale. According to the American Society of Clinical oncology (ASCO) and the College of American Pathologists (CAP) recommendations for HER2 testing in breast cancer published in 2013, HER2 expression is scored as 0 (no staining or weak/incomplete membrane staining in ≤10% of tumor cells), 1+ (weak, incomplete membrane staining in >10% of tumor cells), 2+ (strong, complete membrane staining in ≤10% of tumor cells or weak/moderate and/or incomplete membrane staining in >10% of tumors cells) or 3+ (strong, complete, homogeneous membrane staining in >10% of tumor cells) [61]. In clinical practice, HER2 immunohistochemical status is evaluated as negative if the immunohistochemical score is 0 or 1+, equivocal is the score is 2+, and positive if the score is 3+. Patients with a positive HER2 status at the IHC are eligible for targeted therapy with HER2 inhibitors. The IHC 2+ category is considered borderline and confirmatory testing using an alternative assay (fluorescence in situ hybridization (FISH) or other in situ hybridization (ISH) methods, see Section 2.2.2) is required for final determination.
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IHC is an easy and relatively inexpensive method [63]. However, this technique can be affected by numerous factors, including warm/cold ischemic time [64], delay and duration of fixation [65], and antibody used [66, 67]. Moreover, since the interpretation of results is based on semiquantitative scoring, this technique is prone to interobserver variability and therefore to substantial discrepancies in the IHC results, particularly for cases scoring 2+ [68].
As mentioned before, HER2 receptor is composed of an extracellular domain (ECD), a transmembrane domain, and an intracellular domain with tyrosine kinase activity. The HER2 ECD can be cleaved from the HER2 full-length receptor through matrix metalloproteases and released into the serum [69]. HER2 ECD levels present in serum can be measured using an enzyme-linked immunosorbent assay (ELISA). HER2 ECD is detected using two antibodies that recognize two specific epitopes of the antigen. Several commercially available ELISA assays received FDA approval: the automated ELISA assay Immuno-1 (Siemens Healthcare Diagnostics, Tarrytown, NY), the manual ELISA assay (Siemens Healthcare Diagnostics) in 2000, and the automated ELISA assay ADVIA Centaur (Siemens Healthcare Diagnostics) in 2003 [70].
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Although some studies suggest that HER2 ECD levels measured in patient’s serum could be used as a biomarker for the monitoring of the disease course and the response of the patient to therapy, the clinical use of the ELISA assay for the evaluation of the HER2 ECD has not yet been widely implemented [71, 72]. This is mainly due to the fact that studies that analyzed the association between HER2 ECD levels and prognostic and predictive factors in breast cancer patients reported conflicting results, depending on which cutoff value was considered or which assay was used [71].
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ELISA is an easy and fast method. In addition, given that HER2 ECD can be measured directly in serum, ELISA can be used to monitor the dynamic changes of HER2 status following treatment or over the course of the disease progression [71]. Results obtained by ELISA, however, might not be reliable if the serum samples are from patients under treatment, as trastuzumab present in the patient’s serum might compete with the two antibodies used in the assay.
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2.2.2. HER2 status evaluation at the DNA level
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2.2.2.1. Fluorescence in situ hybridization (FISH)
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The FISH technique is a cytogenetic technique that uses fluorescent probes to target specific DNA sequences in FFPE tissue samples [73]. FISH is effectuated either as a single-color assay (HER2 probe only) to evaluate HER2 gene copies per nucleus or as a dual-color assay using differentially labeled HER2 and chromosome 17 centromere (chromosome enumeration probe 17, CEP17) probes simultaneously. The dual-color assay allows the determination of the HER2/CEP17 ratio [74]. The HER2/CEP17 ratio is often regarded as a better reflection of the HER2 amplification status, as the latter may be influenced by abnormal chromosome 17 copy number (mainly polysomy) [75].
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The HER2 gene locus on chromosome 17 is recognized by the HER2 probe, which is labeled with a fluorophore (orange as example). The α satellite DNA sequence located at the centromeric region of chromosome 17 is recognized by a fluorophore-labeled chromosome 17 centromere probe (green as example). Nuclei are then counterstained with 4,6′-diamino-2-phenylindole (DAPI). Fluorescent hybridization signals can be visualized using a fluorescence microscope equipped with appropriate filters (for example Spectrum Orange for locus-specific probe HER2, Spectrum Green for centromeric probe 17, and the UV filter for the DAPI nuclear counterstain) [76].
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Three FISH assay kits have been approved by the FDA for the determination of the HER2 gene amplification in breast cancer specimens: the single-probe INFORM HER2 FISH DNA kit (Ventana Medical Systems), the dual-probe PathVysion HER-2 DNA probe kit (Abbott Molecular, Des Plaines, IL), and the dual-probe HER2 FISH PharmDx kit (DAKO).
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According to the 2013 ASCO/CAP guidelines, a case is evaluated as amplified when the mean HER2 gene copy number is ≥6 signals/nucleus or HER2/CEP17 ratio is ≥2.0, else as equivocal if mean HER2 gene copy number is ≥4 and <6 signals/nucleus, and else as non-amplified when the mean HER2 gene copy number is <4 signals/nucleus. In order to adequately evaluate HER2 status, a minimum of 20 tumor cell nuclei are counted in at least two invasive tumor areas. For equivocal FISH specimens, results are confirmed by counting 20 additional cells [61]. Moreover, the equivocal category requires reflex testing with the alternative assay (IHC) on the same specimen for final determination. Reflex testing can also be performed using IHC or ISH methods on an alternative specimen. If specimen is evaluated as equivocal, even after reflex testing, the oncologist may consider targeted treatment.
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Although still matter of debate, several researchers consider FISH as being more accurate and reliable than IHC in the assessment of HER2 status in breast cancer specimens [77, 78, 79, 80]. In addition, given that DNA is more stable than protein, preanalytical factors have less impact on assay results compared with IHC [81]. Although the FISH technique yields results that are considered more objective and quantitative than immunohistochemical scoring [73, 82], this method is nine times more time-consuming [83] and three times more expensive compared with IHC [84]. In addition, costly equipment is required for signal detection [67]. The FISH assay can be interpreted only by well-trained personnel, as distinguishing invasive breast cancer from breast carcinoma in situ under fluorescence is arduous [85].
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Moreover, fluorescence signal counting is time consuming. To overcome this limitation, image analysis software for the automated assessment of fluorescence signals has been developed. Several investigators have reported an excellent concordance between HER2/CEP17 ratios calculated through manual counting and those obtained with automated image analysis system [86, 87, 88]. Some image analysis systems has been approved by the FDA for the automated determination of HER2 gene amplification: the Metafer (MetaSystems, Altlussheim, Germany) and the Ariol HER2/neu FISH (Applied Imaging, San Jose, CA). Furthermore, this software allows the storing of captured images [86].
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2.2.2.2. Bright-field in situ hybridization (ISH) methods
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Given that FISH technology have some limitations, alternative ISH methods have been developed for the assessment of HER2 gene amplification in breast cancer specimens. Similar to FISH, these methods allow the quantification of HER2 gene copy number within tumor cell nuclei in FFPE tissues using a DNA probe that specifically recognizes specific DNA sequences. However, whereas the FISH assay is performed with DNA probes that are coupled to a fluorescent detection system, these alternative ISH methods are performed with probes that are coupled to chromogenic (chromogenic ISH [CISH]), or silver detection system (silver-enhanced ISH [ISH]), or a combination of CISH and SISH (bright-field double ISH [BDISH]) [89]. Similar to FISH, ISH methods are performed either as single-color assay or as a dual-color assay.
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Since visualization is achieved using other reactions than fluorescence-labeled probe, signals can be evaluated using a standard bright-field microscope, allowing the simultaneous analysis of HER2 gene amplification and morphologic features of tissues. Moreover, contrary to fluorescent signals that fade over time, bright-field ISH signals are permanent [90]. Here after, we will briefly describe the bright-field ISH methods that are used in clinics.
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2.2.2.3. Chromogenic in situ hybridization (CISH)
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CISH allows the visualization of target genes in breast cancer tissue sections through peroxidase enzyme-labeled probes [90]. The single-color CISH assay (SPOT-Light HER2 CISH kit; Life Technologies, Carlsbad, CA), and the dual-color CISH assay (HER2 CISH PharmDx kit; Dako) received FDA approval in 2008 and 2011, respectively [61].
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With the single-color CISH assay, only the absolute HER2 gene copy number is evaluated. The hybridized HER2 probe is visualized by DAB as chromogen. HER2 gene copies are recognizable as brown chromogenic reaction product signals within nuclei. Slides are then counterstained with hematoxylin [82, 91, 92]. HER2 signals are recognizable either as large brownish signal clusters or as numerous individual brownish small signals [92]. Cases with low-level amplification show six to 10 signals per nucleus in more than 50% of breast cancer cells, whereas high-level amplification cases are characterized by a mean HER2 gene copy number of more than 10 or by large gene copy clusters in more than 50% of breast cancer cell nuclei [92, 93].
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The dual-color CISH assay allows the simultaneous visualization of the HER2 and CEP17 probes on the same slide [94]. HER2 probes are visualized using a chromogen (green as example), whereas CEP17 probes are visualized using another chromogen (red as example). Slides are then counterstained with hematoxylin. Results obtained by dual-color CISH are reported as dual-color FISH [61].
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The CISH assay is twice cheaper [72] and 1.2 times faster [82] comparatively to FISH. Furthermore, since the CISH assay allows an easier identification of the invasive component compared with FISH, evaluation of CISH signals is less time-consuming than FISH [82, 94]. In addition, tumor heterogeneity is promptly recognizable, even at low magnification [95]. Moreover, the dual-color assay can be performed on an automated slide stainer, improving the reproducibility of the assay [96]. However, the assessment of HER2 gene copy number can be arduous in tumor regions showing high-level amplification, since overlapping dots lead to formation of signal clusters that are difficult to evaluate [94]. In addition, technical problems, including under- or overfixation, over- or underdigestion of tissue samples can lead to inaccurate results or loss of signals [91, 93].
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2.2.2.4. Silver-enhanced in situ hybridization (SISH)
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SISH is an automated enzyme metallography assay, in which an enzyme reaction is used to selectively deposit metallic silver from solution at the reaction site to produce a black staining [97]. All steps of the assay are performed on the Ventana BenchMark XT automated slide stainer [98, 99]. HER2 and chromosome 17 analysis is performed on sequential slides [98, 99]. As previously mentioned, HER2 and CEP17 probes are visualized through the process of enzyme metallography. During the process, silver precipitation is deposited in the nucleus, and HER2 or CEP17 signals are visualized as black dots within cell nuclei [99]. Similar to the FISH assay, HER2 gene amplification status assessed by SISH is reported as a HER2/CEP17 ratio, according to the ASCO/CAP guidelines [61].
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Given that the SISH assay is fully automated, this technique is six times faster to perform than the FISH assay [99]. In addition, black SISH signals are easier to evaluate compared with other bright-field ISH techniques [100, 101]. However, to correct for chromosome 17 aneusomy, the hybridization of a further section is required for separate assessment of CEP17 copy number [100].
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2.2.2.5. Bright-field double ISH (BDISH)
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Bright-field double ISH (BDISH) or dual-color in situ hybridization (dual ISH) is a fully automated bright-field ISH assay for the simultaneous determination of HER2 and CEP17 signals on the same FFPE breast cancer tissue sections [100]. This assay combines the visualization of HER2 gene copies through the deposition of metallic silver particles, similar to the mono-color SISH procedure, with the detection of CEP17 copies with a red chromogen, similar to the CISH assay [102]. HER2 signals are visualized as discrete black spots and the CEP17 signals as red spots in the nuclei. Slides are then counterstained with hematoxylin [100]. HER2 gene amplification status assessed by BDISH is reported as a HER2/CEP17 ratio, according to the ASCO/CAP guidelines.
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This technique is very pertinent especially for cases displaying chromosome 17 aneusomy or intratumoral heterogeneity, as it allows the simultaneous visualization of both HER2 and CEP17 probes on the same slide [100]. Furthermore, as the HER2 signals and CEP17 signals differ in color and size (HER2 black spots are smaller than CEP17 red spots), both signals can be distinguished from each other, even though they colocalize within cell nuclei [100]. Moreover, since this assay is completely automated, results are available within 6 h, in addition of being more reproducible, as risk of human errors are diminished [101]. The BDISH assay presents the same disadvantages as CISH and SISH.
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2.2.2.6. Instant-quality FISH (IQFISH) and automated HER2 FISH
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Recently, new FISH assays have been developed for the evaluation of HER2 gene amplification in breast cancer specimens, including instant-quality FISH (IQFISH), which received FDA approval, and automated HER2 FISH. In analogy to conventional FISH, these new assays allow the quantitative determination of HER2 gene amplification. The IQFISH assay is performed in the same way as manual FISH, with the exception of the hybridization buffer (IQFISH buffer), which considerably reduces the time required for the hybridization step (16 times faster) and therefore the total assay time [103, 104]. Moreover, while hybridization buffer provided in conventional FISH assay contain the toxic formamide, the IQFISH buffer is nontoxic [103]. Compared to conventional FISH, automated FISH is less expensive, since the full automation of the assay requires less human intervention [105]. Furthermore, automated FISH enables faster processing of samples and recording [105].
Polymerase chain reaction (PCR) is a technique used for the detection of DNA samples through the exponential amplification of target DNA sequences.
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Reverse transcription PCR (RT-PCR) assay allows the quantification of mRNA and can be used for the evaluation of HER2 expression in breast cancer specimens in both FFPE and frozen tissues [106, 107]. Extracted mRNA is at first reverse transcribed into complementary DNA (cDNA). cDNA is then measured by quantitative PCR (qPCR). The relative quantitation of HER2 gene expression is evaluated comparing the target gene expression with that of housekeeping genes. The relative HER2 gene expression measured in samples is then normalized to a calibrator obtained by mixing RNA from several normal breast tissue specimens. Of note, the Oncotype Dx (Genomic Health, Redwood City, CA) assay is a test based on RT-PCR technology and is used to analyze the expression of 21 genes involved in breast cancer biology, such as HER2, ER, and PR. This assay is used to predict the likelihood of breast cancer recurrence in patients with early-stage, node-negative, ER-positive breast cancer [106].
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RT-PCR has a large dynamic range, in addition of being a quantitative method. PCR results, however, are often associated with false-negative results due to dilution of amplified tumor cells with surrounding nonamplified stromal cells [108, 109]. In addition, the evaluation of HER2 status at the mRNA level by RT-PCR using FFPE tissues can be problematic, as mRNA integrity can be damaged by several factors, including tissue fixation and storage time [110].
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3. Conclusion(s)
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HER2 is a prognostic marker in breast cancer. HER2 overexpression and HER2 gene amplification, which occur in 15–20% of breast cancer patients, cause aberrant constitutive activation of the signaling pathway. This leads to uncontrolled and unregulated cell growth and correlates with poor outcome of HER2-positive breast cancer patients.
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In addition, HER2-positive status is considered a predictive marker of response to HER2-targeted drugs, including trastuzumab and lapatinib [111]. Considering the clinical and economic implications of targeted anti-HER2 treatments, reliable HER2 test results are essential. False negative results would deny the patients access to the potential benefits of trastuzumab, whereas false positive results would expose patients to the potential cardiotoxic side effects of this expensive agent without experiencing any therapeutic advantages [89].
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Although several techniques have obtained FDA approval for the HER2 assessment in breast cancer specimens, the ASCO/CAP guidelines recommend performing IHC or ISH methods to determine HER2 status in breast cancer. The optimal method for evaluating HER2 status in breast cancer specimens, however, is still matter of debate, since each method is characterized by its own advantages and disadvantages. Therefore, emphasis must be put on standardization of procedures and quality control assessment of already existing methods. Also, development of new accurate assays should be promoted. Moreover, large clinical trials are needed to identify the technique that most reliably predicts a positive response to HER2 inhibitors.
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Acknowledgments
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DF received doctoral fellowships from the Fonds de recherche du Québec—Santé (FRQS) and the Laval University Cancer Research. CD is a recipient of the Canadian Breast Cancer Foundation-Canadian Cancer Society Capacity Development award (award #703003) and the FRQS Research Scholar.
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Conflict of interest
The authors have no conflicts of interests to declare.
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Notes/thanks/other declarations
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The authors have no other declarations.
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Acronyms and abbreviations
HER2
Human epidermal growth factor receptor 2
GRB7
Growth factor receptor bound protein 7
ESR1
Estrogen Receptor 1
PGR
Progesterone Receptor
FDA
Food and Drug Administration
EGFR
Epidermal growth factor receptor
IHC
Immunohistochemistry
FISH
Fluorescence in situ hybridization
ERBB2
erb-b2 receptor tyrosine kinase 2
HER3
Human epidermal growth factor receptor 3
HER4
Human epidermal growth factor receptor 4
ATP
Adenosine triphosphate
ECD
extracellular domain
EGF
Epidermal growth factor
EPG
Epigen
TGFα
Transforming growth factor α
PI3K
Phosphatidylinositol 3′-kinase
ERK
Extracellular signal-regulated kinase
MAPK
Mitogen-activated protein kinase
FGFR
Fibroblast growth factor receptor
IR
Insulin Receptor
VEGFR
Vascular Endothelial Growth Factor Receptor
Cdk
Cyclin-dependent kinase
FFPE
Formalin-fixed, paraffin-embedded
DAB
3,3′-diaminobenzidine tetrahydrochloride
ASCO
American Society of Clinical Oncology
CAP
College of American Pathologists
ELISA
Enzyme-linked immunosorbent assay
CEP17
Chromosome enumeration probe 17
DAPI
4,6′-diamino-2-phenylindole
ISH
in situ hybridization
CISH
Chromogenic in situ hybridization
SISH
Silver-enhanced in situ hybridization
BDISH
Bright-field double ISH
PCR
polymerase chain reaction
RT-PCR
Reverse transcription PCR
cDNA
Complementary DNA
qPCR
Quantitative PCR
\n',keywords:"breast neoplasm, oncogene, tyrosine kinase receptor, molecular oncology, HER2 status, HER2 inhibitors",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/61662.pdf",chapterXML:"https://mts.intechopen.com/source/xml/61662.xml",downloadPdfUrl:"/chapter/pdf-download/61662",previewPdfUrl:"/chapter/pdf-preview/61662",totalDownloads:1672,totalViews:549,totalCrossrefCites:5,dateSubmitted:"February 6th 2018",dateReviewed:"May 2nd 2018",datePrePublished:"November 5th 2018",datePublished:"December 5th 2018",dateFinished:"May 24th 2018",readingETA:"0",abstract:"The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor protein. HER2 gene amplification and receptor overexpression, which occur in 15–20% of breast cancer patients, are important markers for poor prognosis. Moreover, HER2-positive status is considered a predictive marker of response to HER2 inhibitors including trastuzumab and lapatinib. Therefore, reliable HER2 determination is essential to determine the eligibility of breast cancer patients to targeted anti-HER2 therapies. In this chapter, we aim to illustrate important aspects of the HER2 receptor as well as the molecular consequences of its aberrant constitutive activation in breast cancer. In addition, we will present the methods that can be used for the evaluation of HER2 status at different levels (protein, RNA, and DNA level) in clinical practice.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/61662",risUrl:"/chapter/ris/61662",signatures:"Daniela Furrer, Claudie Paquet, Simon Jacob and Caroline Diorio",book:{id:"6813",type:"book",title:"Cancer Prognosis",subtitle:null,fullTitle:"Cancer Prognosis",slug:"cancer-prognosis",publishedDate:"December 5th 2018",bookSignature:"Guy-Joseph Lemamy",coverURL:"https://cdn.intechopen.com/books/images_new/6813.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78984-775-8",printIsbn:"978-1-78984-774-1",pdfIsbn:"978-1-83881-722-0",isAvailableForWebshopOrdering:!0,editors:[{id:"182568",title:"Dr.",name:"Guy-Joseph",middleName:null,surname:"Lemamy",slug:"guy-joseph-lemamy",fullName:"Guy-Joseph Lemamy"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. HER2 biology and methods of assessment of HER2 status",level:"1"},{id:"sec_2_2",title:"2.1. HER2 receptor",level:"2"},{id:"sec_2_3",title:"2.1.1. HER2 structure and function",level:"3"},{id:"sec_3_3",title:"2.1.2. Consequences of constitutive HER2 receptor activation",level:"3"},{id:"sec_5_2",title:"2.2. Methods for the evaluation of HER2 status in breast cancer specimens",level:"2"},{id:"sec_5_3",title:"2.2.1. HER2 status evaluation at the protein level",level:"3"},{id:"sec_5_4",title:"2.2.1.1. Immunohistochemistry (IHC)",level:"4"},{id:"sec_6_4",title:"2.2.1.2. Enzyme-linked immunosorbent assay (ELISA)",level:"4"},{id:"sec_8_3",title:"2.2.2. HER2 status evaluation at the DNA level",level:"3"},{id:"sec_8_4",title:"2.2.2.1. Fluorescence in situ hybridization (FISH)",level:"4"},{id:"sec_9_4",title:"2.2.2.2. Bright-field in situ hybridization (ISH) methods",level:"4"},{id:"sec_10_4",title:"2.2.2.3. Chromogenic in situ hybridization (CISH)",level:"4"},{id:"sec_11_4",title:"2.2.2.4. Silver-enhanced in situ hybridization (SISH)",level:"4"},{id:"sec_12_4",title:"2.2.2.5. Bright-field double ISH (BDISH)",level:"4"},{id:"sec_13_4",title:"2.2.2.6. Instant-quality FISH (IQFISH) and automated HER2 FISH",level:"4"},{id:"sec_15_3",title:"2.2.3. HER2 status evaluation at the RNA level",level:"3"},{id:"sec_15_4",title:"2.2.3.1. Polymerase chain reaction (PCR)-based assays",level:"4"},{id:"sec_19",title:"3. Conclusion(s)",level:"1"},{id:"sec_20",title:"Acknowledgments",level:"1"},{id:"sec_23",title:"Conflict of interest",level:"1"},{id:"sec_20",title:"Notes/thanks/other declarations",level:"1"},{id:"sec_23",title:"Acronyms and abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'WHO. 2017. 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Diagnostic Molecular Pathology: The American Journal of Surgical Pathology, Part B. 2009;18(2):88-95\n'},{id:"B100",body:'Nitta H, Hauss-Wegrzyniak B, Lehrkamp M, Murillo AE, Gaire F, Farrell M, et al. Development of automated brightfield double in situ hybridization (BDISH) application for HER2 gene and chromosome 17 centromere (CEN 17) for breast carcinomas and an assay performance comparison to manual dual color HER2 fluorescence in situ hybridization (FISH). Diagnostic Pathology. 2008;3:41\n'},{id:"B101",body:'Schiavon BN, Jasani B, de Brot L, Vassallo J, Damascena A, Cirullo-Neto J, et al. Evaluation of reliability of FISH versus brightfield dual-probe in situ hybridization (BDISH) for frontline assessment of HER2 status in breast cancer samples in a community setting: Influence of poor tissue preservation. The American Journal of Surgical Pathology. 2012;36(10):1489-1496\n'},{id:"B102",body:'Bartlett JM, Campbell FM, Ibrahim M, O’Grady A, Kay E, Faulkes C, et al. A UK NEQAS ISH multicenter ring study using the Ventana HER2 dual-color ISH assay. American Journal of Clinical Pathology. 2011;135(1):157-162\n'},{id:"B103",body:'Franchet C, Filleron T, Cayre A, Mounie E, Penault-Llorca F, Jacquemier J, et al. Instant-quality fluorescence in-situ hybridization as a new tool for HER2 testing in breast cancer: A comparative study. Histopathology. 2014;64(2):274-283\n'},{id:"B104",body:'Matthiesen SH, Hansen CM. Fast and non-toxic in situ hybridization without blocking of repetitive sequences. PLoS One. 2012;7(7):e40675\n'},{id:"B105",body:'Ohlschlegel C, Kradolfer D, Hell M, Jochum W. Comparison of automated and manual FISH for evaluation of HER2 gene status on breast carcinoma core biopsies. BMC Clinical Pathology. 2013;13:13\n'},{id:"B106",body:'Cronin M, Pho M, Dutta D, Stephans JC, Shak S, Kiefer MC, et al. Measurement of gene expression in archival paraffin-embedded tissues: Development and performance of a 92-gene reverse transcriptase-polymerase chain reaction assay. The American Journal of Pathology. 2004;164(1):35-42\n'},{id:"B107",body:'Noske A, Loibl S, Darb-Esfahani S, Roller M, Kronenwett R, Muller BM, et al. Comparison of different approaches for assessment of HER2 expression on protein and mRNA level: Prediction of chemotherapy response in the neoadjuvant GeparTrio trial (NCT00544765). Breast Cancer Research and Treatment. 2011;126(1):109-117\n'},{id:"B108",body:'Jacquemier J, Spyratos F, Esterni B, Mozziconacci MJ, Antoine M, Arnould L, et al. SISH/CISH or qPCR as alternative techniques to FISH for determination of HER2 amplification status on breast tumors core needle biopsies: A multicenter experience based on 840 cases. BMC Cancer. 2013;13:351\n'},{id:"B109",body:'Merkelbach-Bruse S, Wardelmann E, Behrens P, Losen I, Buettner R, Friedrichs N. Current diagnostic methods of HER-2/neu detection in breast cancer with special regard to real-time PCR. The American Journal of Surgical Pathology. 2003;27(12):1565-1570\n'},{id:"B110",body:'Nistor A, Watson PH, Pettigrew N, Tabiti K, Dawson A, Myal Y. Real-time PCR complements immunohistochemistry in the determination of HER-2/neu status in breast cancer. BMC Clinical Pathology. 2006;6:2\n'},{id:"B111",body:'Esteva FJ, Yu D, Hung MC, Hortobagyi GN. Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nature Reviews Clinical Oncology. 2010;7(2):98-107\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Daniela Furrer",address:null,affiliation:'
Cancer Research Center at Laval University, Canada
Oncology Axis, CHU of Quebec Research Center, Canada
Department of Social and Preventive Medicine, Laval University, Canada
Cancer Research Center at Laval University, Canada
Oncology Axis, CHU of Quebec Research Center, Canada
Department of Social and Preventive Medicine, Laval University, Canada
Deschênes-Fabia Center for Breast Diseases, Canada
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His main topic of research is dependability assessment of NAND flash memories and of embedded systems for mission-critical applications.\n\nFor this scope he is also exploiting Yet Another Flash File System (YAFFS), a particular flash-based file-system currently used also in embedded systems like Google Android.\n\nIn particular he is developing a powerful YAFFS-based core kernel FLash Architecture Evaluation (FLARE) tool. It is able to emulate a flash-memory device, to implement different algorithms (e.g., Wear Leveling, ECC, etc.) and to evaluate them, by generating the desired statistics.\n\nIn addition he is working with ECCs for flash-memory devices, like binary\nBose-Chaudhuri-Hocquenghen (BCH) codes. 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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). 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conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. 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:"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. 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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:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. 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://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.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.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",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:"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/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",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. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. 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 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, 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 that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{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"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"28",type:"subseries",title:"Animal Reproductive Biology and Technology",keywords:"Animal Reproduction, Artificial Insemination, Embryos, Cryopreservation, Conservation, Breeding, Epigenetics",scope:"The advances of knowledge on animal reproductive biology and technologies revolutionized livestock production. Artificial insemination, for example, was the first technology applied on a large scale, initially in dairy cattle and afterward applied to other species. Nowadays, embryo production and transfer are used commercially along with other technologies to modulate epigenetic regulation. Gene editing is also emerging as an innovative tool. This topic will discuss the potential use of these techniques, novel strategies, and lines of research in progress in the fields mentioned above.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/28.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11417,editor:{id:"177225",title:"Prof.",name:"Rosa Maria Lino Neto",middleName:null,surname:"Pereira",slug:"rosa-maria-lino-neto-pereira",fullName:"Rosa Maria Lino Neto Pereira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9wkQAC/Profile_Picture_1624519982291",biography:"Rosa Maria Lino Neto Pereira (DVM, MsC, PhD and) is currently a researcher at the Genetic Resources and Biotechnology Unit of the National Institute of Agrarian and Veterinarian Research (INIAV, Portugal). She is the head of the Reproduction and Embryology Laboratories and was lecturer of Reproduction and Reproductive Biotechnologies at Veterinary Medicine Faculty. 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