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",isbn:"978-1-83968-924-6",printIsbn:"978-1-83968-923-9",pdfIsbn:"978-1-83968-925-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"ea4ec0d6ee01b88e264178886e3210ed",bookSignature:"Dr. Hiran Wimal Amarasekera",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9500.jpg",keywords:"Bone Tumors, Oncology, Childhood Tumors, Cancer, Risk Factors, Modern Management, Benign Lesions, Tumor-Like Conditions, Immunology, Histochemistry, Cell Oncology, Tumor Markers",numberOfDownloads:473,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfDimensionsCitations:1,numberOfTotalCitations:2,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 28th 2020",dateEndSecondStepPublish:"October 26th 2020",dateEndThirdStepPublish:"December 25th 2020",dateEndFourthStepPublish:"March 15th 2021",dateEndFifthStepPublish:"May 14th 2021",remainingDaysToSecondStep:"6 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Consultant Orthopaedic Surgeon from Sri Lanka currently working in University Hospitals of Coventry and Warwickshire, UK, trained at the National Hospital of Sri Lanka, at the Oldchurch Hospital in Essex UK and The Avenue Hospital Melbourne, Australia and University Hospitals of Coventry and Warwickshire, UK, obtained the FRCS from Royal College of Surgeons of Edinburgh, Scotland.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"67634",title:"Dr.",name:"Hiran",middleName:"Wimal",surname:"Amarasekera",slug:"hiran-amarasekera",fullName:"Hiran Amarasekera",profilePictureURL:"https://mts.intechopen.com/storage/users/67634/images/system/67634.jpg",biography:"Hiran Amarasekera is a Consultant Orthopaedic Surgeon from Sri Lanka currently working in University Hospitals of Coventry and Warwickshire, the UK as a hip preservation fellow. \r\nHis special interests include young adult hip and knee problems, sports injuries, Hip and knee arthroplasty, and complex arthroscopic procedures. \r\nHe completed the MBBS from Kasturba medical college Manipal, India and did his postgraduate in Trauma and Orthopaedics at the Post-graduate Institute of the Medicine University of Colombo obtained the MS. \r\nHe was initially trained at the National Hospital of Sri Lanka and then completed the further training at the Oldchurch Hospital in Essex UK and The Avenue Hospital Melbourne, Australia and University Hospitals of Coventry and Warwickshire, UK.\r\nHe obtained the FRCS from Royal College of Surgeons of Edinburgh in 2003 and was elected a fellow of Sri Lanka College of surgeons (FCSSL) 2012. \r\nHe has a keen interest in academia and research. Working as a clinical research fellow in Warwick Medical School he obtained the MPhil form University of Warwick and was elected for a research fellowship to University of California Los Angeles (UCLA). \r\nHis research interests include blood flow to the hip, failure of hip resurfacing, designing new hip prosthesis, and surgical approaches to the hip. \r\nHe has over 30 international publications and presentations and several book chapter. \r\nHe also works as a reviewer for international orthopedic journals and has reviewed over 35 papers and is a member of the editorial board of Sri Lanka Journal of Surgery.",institutionString:"University of Warwick Science Park",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Warwick Science Park",institutionURL:null,country:{name:"United Kingdom"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:[{id:"73224",title:"Management of Early Osteoarthritis",slug:"management-of-early-osteoarthritis",totalDownloads:112,totalCrossrefCites:0,authors:[null]},{id:"71336",title:"Non-Surgical Regional Therapy for Osteoarthritis: An Update and Review of the Literature",slug:"non-surgical-regional-therapy-for-osteoarthritis-an-update-and-review-of-the-literature",totalDownloads:181,totalCrossrefCites:0,authors:[{id:"77195",title:"Dr.",name:"Charles",surname:"Mackworth-Young",slug:"charles-mackworth-young",fullName:"Charles Mackworth-Young"}]},{id:"72715",title:"Simultaneous Bilateral Joint Arthroplasties in Treatment of Osteoarthritis",slug:"simultaneous-bilateral-joint-arthroplasties-in-treatment-of-osteoarthritis",totalDownloads:121,totalCrossrefCites:1,authors:[null]},{id:"75062",title:"Bone Cancer Pain, Mechanism and Treatment",slug:"bone-cancer-pain-mechanism-and-treatment",totalDownloads:37,totalCrossrefCites:0,authors:[null]},{id:"75735",title:"Osteosarcoma",slug:"osteosarcoma",totalDownloads:22,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247865",firstName:"Jasna",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247865/images/7225_n.jpg",email:"jasna.b@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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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"58623",title:"17β-Estradiol as a Neuroprotective Agent",doi:"10.5772/intechopen.72682",slug:"17-estradiol-as-a-neuroprotective-agent",body:'\nThe steroid hormone 17β-estradiol (E2, Figure 1) is the main human estrogen that is not only involved in sexual maturation and reproduction but also has a myriad of important roles throughout the body affecting, for example, the cardiovascular system, lipid metabolism and brain health [1, 2, 3, 4]. Therefore, E2 cannot only be considered as just a “female hormone.” In humans, the other two endogenously formed estrogens are estrone (E1, Figure 1) and the lesser-known estriol (E3, Figure 1) that is the 16-hydroxy derivate of E2 and formed mostly during gestation by the placenta. E1 becomes the predominant estrogen in women after menopause, when it is synthesized largely in subcutaneous fat from androstenedione. The unique structure of estrogens among steroids arises from the presence of the aromatic A-ring (Figure 1).
\nChemical structure of human estrogens: estrone (E1), 17β-estradiol (E2) and estriol (E3).
E2 is now also considered as one of the neurosteroids, as its regioselective local formation in the brain has been established [5, 6, 7, 8]. Indeed, with today’s modern analytical instrumentations and using validated bioassays that are devoid of the limitations of immunoassays [9], brain E2 level even in ovariectomized animals (i.e., in animals without gonadal E2 source) can be measured [10, 11]. It has been hypothesized that this
Independent of the
Among estrogens and estrogenic compounds, E2 also is the best-known estrogen to be used as a powerful neuroprotective agent in various
Altogether, extensive basic science investigations brought about convincing data on the plethora of mechanisms by which E2 promotes neuronal survival and protects neurons against a wide variety of stressors addressing, thereby, practically all proposed critical contributors to neurodegeneration such as inflammation, oxidative stress, excitotoxicity and collapse of mitochondrial membrane potential. Clinical and epidemiological observations also suggest that in humans the better outcome after neurotrauma (e.g., traumatic brain and spinal cord injuries) in premenopausal females compared with age-matched men, at least in part, is due to the protective role of endogenous estrogens against neuronal injuries [33, 34].
\nThe broad-spectrum protective mechanism of E2 on injured neurons is the end result of well-orchestrated and synergistic combination of genomic and non-genomic actions of the hormone that allows for prevention of both the initiation and progression of neuronal cell death. This implicates a significant translational value for the hormone upon restricting its action to the CNS, as detailed in the following section.
\nEstrogen receptors (ERs) are expressed throughout the brain [35, 36] indicating their role in various CNS functions including neuroprotection. ER density is higher in the hypothalamus than in extrahypothalamic areas with overlapping expression of the two isoforms ERα and ERβ [35, 36]. In some brain regions, ERα or ERβ may also be co-localized in cells [37]. However, ERβ is highly expressed in the cortex [38] and hippocampus [39, 40]. Consequently, estrogen impacts the function of extrahypothalamic areas that are not involved in sex maturation and reproduction [41].
\nThe two ERs have similar affinities to endogenous estrogens [42]. Just like many other members of the nuclear receptor superfamily of proteins, they elicit their genomic effect through gene transcription [43]. The sequence of the classical ligand-dependent genomic mechanism of estrogens’ neuroprotective action is summarized in Figure 2. After E2 (or in general, an estrogen) distributes into the neuron and reaches the nucleus, it is ligated to its cognate receptor. The ligated ERs form homo- (ERα/ERα or ERβ/ERβ) or heterodimers (ERα/ERβ) that bind to the estrogen-response element (ERE) of the nuclear DNA. Transcriptional activation is enabled by a constitutively active and a ligand-dependent function located at the amino-terminus and in the carboxy-terminal ligand-binding domain of ERs, respectively [44]. The DNA-bound dimers recruit co-regulator proteins [45], which can participate in and also recruit many enzymatic and structural proteins permitting the modulation of chromatin structure to facilitate or block gene expression [46]. Additionally, ERE-independent mechanisms have also been shown [47].
\nA simplified model for the ligand-dependent genomic mechanism of E2 neuroprotection. After E2 distributes into the neuron (A) and enters the nucleus, it binds to the cognate receptor followed by dimerization of the ligated ER that binds, together with co-regulators, to the nuclear DNA’s ERE, which results in the transcription of the corresponding gene (B). E2, ER, co-regulator (Co-r) and the nuclear DNA are symbolized by the filled steroid shape, rounded rectangles and elongated rectangle showing an ERE (shaded area), respectively.
Neuroprotective target genes for E2 that directly support vital neuronal functions include neurotrophic factors such as the brain-derived neurotrophic factor [48]. Additional target genes are involved in apoptosis to remove unneeded, damaged or potentially deleterious cells [49] playing thereby a central role in development and homeostasis. Through the apoptosis-associated genomic mechanism, E2 has been shown to rescue neurons through the induction of anti-apoptotic proteins such as Bcl-2 [50] or suppression of apoptotic proteins such as the Bcl-2-associated X protein [50, 51]. Induction of several gene products that maintain cellular architecture such as neurofilament, tau and microtubulin-associated proteins and many additional genomic pathways potentially associated with E2’s neuroprotection have also been described [52].
\nE2 also rapidly induces numerous cellular responses, which cannot be explained by a delayed genomic effect. ERs have been shown to be present in membrane compartments and in the cytoplasm [53, 54]. Specifically, ERα and ERβ are also found as homo or heterodimers at the cell membrane; they are membrane-associated but not actually embedded in the membrane. In addition, a G protein-coupled estrogen receptor (GPER) is localized mainly to intracellular membranes, including the endoplasmic reticulum and Golgi apparatus, under steady-state conditions [55]. G protein-coupled receptors such as GPER can actually signal from intracellular locations [56] and activation results in intracellular Ca2+-mobilization and synthesis of phosphatidylinositol 3,4,5-triphosphate in the nucleus, which could impact gene transcription indirectly. The mitogen-activated protein kinase (MAPK) cascade [57] and the cyclic-AMP-responsive element-binding protein signaling pathway [58, 59] also respond rapidly to E2 and have been implicated in its neuroprotective effects.
\nAn E2-ER complex can also function through cytoplasmic signaling to provide neuroprotection [60]. For example, ERs have been shown to bind in a ligand-dependent manner to the p85 alpha regulatory subunit of phosphatidylinositol 3-kinase (PI3K) [61, 62]. Therefore, stimulation with E2 increases ER-associated PI3K activity, leading to the activation of protein kinase B/Akt and endothelial nitric oxide synthase. However, modulation of intracellular pathways may occur though the binding of E2 to ERs, or independently of ligand binding [63, 64]. A representative of the non-genomic mechanism involving the modulation of intracellular signaling through ERs is summarized schematically in Figure 3.
\nAn example of non-genomic action of E2 involving interaction with intracellular signaling pathways through ERs. As in
E2 has been proposed to influence neurotransmission directly by binding to various transmembrane ion channels [65, 66]. Localization of ERβ to the mitochondria has also been shown [67], implicating E2 in the regulation of mitochondrial structure and function in the brain [68]. In addition to estrogen potentially influencing bioenergetics through long-lasting nuclear-associated processes, rapid mitochondria-intrinsic signaling mechanisms that promote the maintenance of this organelle’s integrity could contribute therefore to the neuroprotective action of E2. Essentially, the hormone could minimize mitochondrial dysfunctions, which accompany neurotrauma, aging and neurodegenerative diseases [69]. However, continued research is needed to fully understand molecular details about the apparently complex interactions between ERs and cellular signaling pathways in the context of neuroprotective mechanisms.
\nThe influence of E2 on neuroinflammation, a process commonly accompanying neurotrauma and neurodegenerative diseases [70, 71, 72], has been well established. Direct action on microglia and astrocytes (the cellular component of the neuroimmune system) and response to peripheral blood cells’ infiltration to the brain have been implicated as major contributors to the observed anti-inflammatory action of the hormone often impacting the cerebral vasculature [73, 74]. For example, E2 can suppress chemokine-mediated induction of the cyclooxygenase-2 (COX-2) pathway in cerebral blood vessels thereby preventing migration of microglia into the brain after an inflammatory challenge [75]. Although inflammatory processes in the brain are usually associated with microglia and astrocytes, expression of the COX-2 gene in neurons and possible mechanisms by which E2 down-regulates this inflammation-associated gene have been shown recently [76]. Specifically, ERβ contributes to neuronal expression of COX-2, and E2 leads to increased recruitment of histone deacetylase 1 (HDAC1), switch-independent 3A (Sin3A) and a concomitant reduction of nuclear factor-κ B (NF-κ B) p65 occupancy and histone 4 acetylation levels. The hormone also prevents the activation of microglia and the recruitment of peripheral monocytes induced by a toxic stimulus. This effect involves ERα activation and reduces the expression of pro-inflammatory mediators and E2 have also shown to prevent morphological changes occurring in microglia during inflammatory response [77]. Decrease of microglial superoxide production and phagocytic activity by both an ER- and MAPK-dependent pathway have also been reported among the anti-inflammatory effects of E2 [78]. In addition, the hormone inhibits pro-inflammatory gene expression by controlling intracellular localization of NF-κ B [79].
\nOxidative stress-induced damage has been linked to brain aging [80], neurodegenerative diseases [81] and neurotrauma [25, 26]. From a long time, therapeutic antioxidant interventions have been proposed to reduce the detrimental impact of oxidative stress [82]. E2’s ER-independent antioxidant effects are mainly due to its ability to attenuate free-radical reactions [83], although indirect mechanisms such as up regulation of antioxidant enzymes [84, 85] and chelation of redox-active metal ions [86] have been reported. The neuroprotective effect of the hormone through direct oxidative stress reduction has been recognized in part by structure-activity relationship studies [87, 88, 89]. Acute E2 neuroprotection in ischemic brain [90] or against damage by ionizing radiation [91] may be largely conferred through antioxidant mechanisms.
\nThe quintessential feature of estrogens as neuroprotective antioxidants is their phenolic A-ring [83, 92, 93]. Because of its lipophilicity, E2 concentrates in lipid-rich regions of the cell such as cellular membranes [94]. Therefore, it is likely that estrogens act in vivo as a highly localized antioxidant [83]. The mechanism of direct oxyradical-scavenging by E2 functioning as a phenolic antioxidant is shown schematically in Figure 4.
\nE2’s effect through the classical phenolic antioxidant mechanism. The solid arrows represent the chain-breaking H-atom transfer, such as lipid peroxidation, while the dashed arrows indicate the conversion of the E2-derived phenoxyl radical back to the phenolic compound by an endogenous reductant (AH) such as ascorbic acid or glutathione.
The process involves H-atom transfer that causes an interruption of free-radical chain reactions, such as lipid peroxidation (R = LOO, where L represents a lipid). Estrogens, indeed, reduce lipid peroxidation in cells and tissues of the CNS [95]. However, the chain-breaking reaction leaves behind a radical product (phenoxyl radical) whose fate has to be explained in consideration of an efficient antioxidant action observed both
Our laboratory pioneered in recognizing a complementary novel neuroprotective antioxidant cycle that involves a
The Prokai antioxidant cycle for E2 through the formation of a
The pathophysiology of neurodegeneration in the central nervous system is complex and multifactorial in nature [102]. Therefore, it is not surprising that an agent like E2 can provide robust protection against a myriad of neuronal insults owing to its broad-spectrum activity resulting from well-orchestrated genomic and non-genomic actions, as detailed in Section 2. The need for clinical therapeutic interventions that can be used to target multiple parallel mechanisms of neuronal injury has been repeatedly expressed [101, 102, 103]. We argue that, despite profound dichotomy between basic science and clinical studies, E2 is ideally suited to be developed as a broad-spectrum neuroprotectant if its action can be restricted to the CNS, that is, to the site of action to avoid undesirable peripheral hormonal burdens. Since neurotrauma triggers a cascade of biochemical events leading to further damages decreasing thereby the chance of appreciable functional recovery [17, 20, 102, 103], chronic pharmacotherapeutic interventions should be considered in the context of translational research. This, on the other hand, brings about critical considerations for safety and efficacy, which highlights the need for brain-selective (or in general CNS-selective) neurotherapy, considering both a preventative and a curative modality.
\nWhen estrogen neurotherapy is considered, however, one cannot ignore the (in)famous Women’s Health Initiative (WHI) study [104]. This was a placebo-controlled, randomized trial of hormone “replacement” therapy in postmenopausal women that indicated detrimental consequences of estrogen and progesterone supplementations, among others, for brain health, propagating thereby a dogma that all estrogens (and progestins) are “created equal.” The fact is that WHI did not use human hormones and, thus, did not study the effect of hormone replacement
Nevertheless, an E2-based neurotherapy cannot be realized in clinical settings until E2’s actions are restricted to the site of action assuring therapeutic safety and efficacy. Currently approved E2 dosage forms expose the entire body to the hormone through the circulation, potentially leading to detrimental side-effects including cardiovascular problems and the development of certain type of cancers upon chronic administration that is required for long-term neuroprotection and functional recovery after neurotrauma. Feminization (e.g., gynecomastia) is also a critical negative aspect of estrogen therapy, especially in case of children and males.
\nEarly attempts to restrict E2’s actions to the brain upon systemic administration included the so-called chemical delivery system, which was conceptually a complex prodrug approach carrying a 1,4-dihydrotrigonellyl promoiety and is capable to usher the hormone through the blood brain barrier (BBB). Once in the brain, the prodrug is oxidized analogously to that of NADP(H) ⇌ NADP+, locking thereby the oxidized prodrug into the brain before it releases E2 [108]. This approach does result in significantly increased brain-enhanced delivery of the hormone compared to that of simple prodrugs of E2; however, it still results in sufficient increase in circulating E2 that can produce unwanted peripheral hormonal burdens [10, 109]. Prodrugs are inert precursors of their corresponding biologically active parent drugs and they traditionally carry auxiliary bioreversible “promoiety(ies)” that are removed enzymatically (rarely
An important development in achieving a true CNS-selective estrogen therapy has been achieved by our laboratory [101] and was derived from our previous discovery of a novel antioxidant cycle for estrogens we call the Prokai antioxidant cycle for simple phenolic antioxidants [98, 99, 100], and detailed in Section 2. We recognized that 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED, Figures 5 and 6), which is chemically a
Schematic illustration of DHED bioprecursor prodrug’s CNS-selective enzymatic metabolism to E2
The transient middle cerebral artery occlusion (tMCAO) model followed by reperfusion is one the most frequently used preclinical animal models for testing an agent for its ability to act as a neuroprotectant, that is, to reduce infarct volume and aid in functional recovery [20, 24, 101, 111]. As Figure 7 shows, a dose-dependent reduction of infarct volumes and neurological deficits was observed in DHED-treated animals. Moreover, about 10-times higher systemic E2 (i.e., the parent drug that is formed in the brain from DHED) dose was needed to achieve the same neuroprotection indicating the profound ability of the bioprecursor prodrug to enter into the brain from the circulation and, then, produce E2 within the brain, and only in the brain. In the context of translational research, it is noteworthy that the capacity to generate E2 from DHED is not lost in an injured brain, as neuroprotection was highly preserved post-stroke and, again, no hormonal exposure to the rest of the body was observed [101].
\nDose-dependent (A) brain infarct volumes and (B) neurological deficit (ND) scores in rats treated with DHED 1 h before tMCAO followed by 24-h reperfusion [
As neurotrauma and neurodegeneration in the CNS are complex and multifactorial in nature requiring therefore broad-spectrum therapeutic interventions, E2 is an attractive lead agent to address unmet medical needs in this field. The powerful antioxidant action of E2 against oxidative stress owing to its phenolic A-ring is unique among neurosteroids with potential neuroprotective roles; therefore, non-genomic mechanisms contribute significantly to the overall neuroprotection. This chapter presented an overview of our current knowledge on the well-orchestrated genomic and non-genomic events by which E2 could beneficially counteract the initiation and/or progression of neuronal cell death. However, there has been incongruency between basic science and clinical studies in terms of estrogen therapy impacting the brain because most researchers ignore the requirement to confine E2’s actions into the CNS upon systemic administration to ensure therapeutic safety and efficacy. We highlighted here a novel and unique bioprecursor prodrug approach our laboratory pioneered for brain-selective delivery of E2 without exposing the rest of the body to unwanted hormonal burden.
\nThe project was supported in part by the National Institutes of Health for the authors, in particular grant numbers NS044765, AG031535, MH100700, HD078077 & CA215550 to L.P. and AG031421 & EY027005 to K.P.-T. and by the Robert A. Welch Foundation (endowment BK-0031 to L.P.).
\nThe authors are inventors in the patents covering the use of 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) as a CNS-selective bioprecursor prodrug of 17β-estradiol and are co-founders of AgyPharma LLC with equity in the company that licensed the patents.
In 1994, when computers had just begun to be accessible to regular classrooms, an article titled “Why Use Technology?” was published [1]. The authors, Kyle Peck and Denise Dorricott, began the article by asking the question “If we removed all of the computers from schools tomorrow, would it make a big difference in the knowledge and skills students demonstrated upon graduation?” They answered, “Probably not.” In the minds of Peck and Dorricott, the introduction of computers in K-12 schools did not create an electronic highway of accelerated learning but rather a dirt road without clear expectations or purpose. More than two decades have passed, and in that time, technological progress has surpassed anyone’s imagination. Technologies are more capable, diverse, and accessible than ever. However, if we ask the same question again, we believe the answer is still no. This is probably because the pace of school reform is far behind the pace of digital progress. The techniques and tools that are used by today’s teachers to achieve learning goals are not fundamentally different from the ones used in previous decades [2]. Teachers use
Percentage of K-12 teachers engaged in the use of technologies in the USA. Note: Data source from Project Tomorrow’s 2017 Report [
Digital technologies are very diverse—different technologies have unique functions and features that are distinct from one another, and hence, generalization should be avoided when studying the use of technology in any field. Unfortunately, most current studies on technology in the field of education regard them as a singular concept without making any distinctions among different kinds of technologies—as if all technologies are homogeneous. To correct this widespread and long-lasting oversight, we will attempt to categorize technologies that have been employed in educational settings.
\nEducational technologies can be categorized into two groups:
The process and resources needed for teachers to adopt technologies are qualitatively different across different kinds of technologies [4]. Countless individual technologies can be employed in pedagogical practices, and pedagogical technologies can be further categorized into two large groups:
Tool-based technologies are the ones not specifically designed for education. They are merely tools that have been widely used in various fields, such as the Internet,
Program-based technologies, on the other hand, are the ones that are specifically designed for pedagogical purposes with premade learning content delivered through algorithm-enabled instruction, such as learning games and online personalized learning programs that use artificial intelligence to give each student individualized academic exercises. They are often developed by companies and large not-for-profit organizations. They give classroom teachers less control over the design and content. They are designed to replace considerable portions of teachers’ traditional work, such as delivery of instruction. Teachers and schools tend to focus on managing the logistics for the implementation of such technologies to fit into their learning goals. Program-based technologies are relatively new, emerging with the advancement of artificial intelligence. These technologies have received tremendous attention, largely due to Silicon Valley’s increasing interest in this field. For example,
Digitalized contents, such as e-books, slide shows,
Categorization of educational technologies.
Most studies on teachers’ use of technology refer to the use of tool-based technologies. Teachers’ successful adoption of this kind of technology, for themselves to either motivate students or deliver instructions more efficiently or for students to engage in learning activities using technology, depends on three crucial factors: professional support, teachers’ attitude, and learning goals.
\nThe use of tool-based technologies in educational settings highly depends on teachers’ competency to innovate and design. A misconception is that the introduction of technological tools to schools is equivalent to the introduction of educational technologies. On the contrary, teachers tend not to innovate when technologies are provided [6]. Teachers need to develop knowledge and skills to employ technological tools for educational purposes. Therefore, adequate professional support is needed, so teachers will be able to master the effective use of technologies specifically within a classroom setting. Teachers who have received professional development are more proficient in using technologies and are more likely to use them, whereas without professional development, teachers are not only less proficient but also likely to resist integration of technologies [4, 7]. Unfortunately, educational technology training is lacking in teacher preparation programs in universities [8]. Thereafter, in the teaching field, the majority of teachers only receive <8 h of professional development on educational technology annually [9].
\nA successful professional development program needs to pay attention to both its content and its format. It should contain content knowledge in three areas [10]:
Knowledge about technological tools: technical knowledge that helps teachers to become equipped with skills to use hardware and software
Technology-supported pedagogical knowledge: specific knowledge and skills that teachers need to learn that help them to use technology to design materials, deliver instructions, or engage students to achieve the learning goals in specific academic domains
Knowledge about technology-related classroom management: knowledge giving teachers insight into students’ reaction in a tech-infused learning environment, for example, how to prevent students from using the devices and the Internet to do inappropriate activities in disguise.
The effectiveness of such a program is closely tied to a school’s ability to develop a supportive learning community [7, 11, 12]. Professional development programs on educational technologies work less efficiently when they are only content- and knowledge-based; communication and interaction are of high significance [10]. A successful professional development program should be a place where:
Teachers can discuss their tangible and immediate needs related to the use of technologies [7, 13].
Teachers can share successful examples of the use of technologies in real educational settings [14, 15].
Teachers can have opportunities to work with knowledgeable peers [11].
Teachers have adequate time to explore the technologies on their own [4, 16].
Learning with real examples in the field created by peers has been proven to be essential in professional development. This is also true of teacher preparation programs. Preservice teachers who have real in-school experience learning about technologies in real educational practices are more likely to succeed [8, 14, 15, 17, 18]. To leverage the power of tool-based technologies in teaching and learning, educational technology training should be very content-specific—for example, how to use the visual features of
Teachers’ attitude toward the effectiveness of technology affects the adoption of tool-based technologies as well. Such effects can be played out on both personal and interpersonal levels. Teachers who individually believe technologies will help them conduct better education are more likely to succeed at using them [15, 16, 19, 20]. Many of these teachers believe that technologies can help to better engage students, introduce project-based learning, help students access more information, and enhance communication and collaborative learning [21, 22, 23]. However, it is common for teachers to hold negative impressions toward the use of certain technologies, which makes it harder for them to integrate those technologies [19, 24, 25]. This situation often happens when teachers are not given sufficient information and training to learn the specific benefits of technologies, which leads them to worry about risking educational resources and teaching time to integrate unnecessary or potentially detrimental technologies [26, 27]. Additional common negative attitudes among teachers include fear of losing control over technologies, technological misfunction and lack of IT support, and concerns about the lack of time to adjust to new pedagogical practices, risking student test scores [26, 27, 28].
\nOn the interpersonal level, experienced teachers’ attitude toward technology significantly influences young professionals’ impressions about technology. When experienced teachers exhibit a more positive and welcoming attitude toward technology, that often translates into a school culture that embraces technology and encourages teachers to support one another in terms of developing and designing learning programs that take specific advantage of technology [24, 25]. Moreover, a positive attitude among teachers also translates into positive attitudes toward education among students and better learning engagement [29].
\nResearch also shows that teachers who believe technologies can help them transform from lecture-based learning to student-centered learning are more likely to welcome technologies [21, 23]. Therefore, the foundation provided by a school’s learning goals, often reflected in institutional policy as well as practice, also significantly affects teachers’ adoption of technologies [7, 16, 30]. Teachers tend to avoid technologies if they believe technologies, even if helpful, deviate from the school’s learning goals [31]. For example, teachers may believe certain technologies can help students to do collaborative projects, but given the limited time and pressure from standardized testing, teachers may choose to teach to tests instead of integrating the technologies for new learning tasks.
\nOur current education model was largely invented for and defined by the Industrial Revolution, designed to meet the need of massive labor demand with standardized skill sets [32]. The advantage of technology has been restricted by the nature of our traditional education paradigm, where teaching and learning occur in a mechanical way with learning goals aimed at the mastery of knowledge. This learning goal can be very often achieved by traditional pedagogical techniques that do not require technological integration, such as direct instruction. Therefore, teachers often do not see the need to use technologies to conduct education in an efficient way to help students to achieve learning outcomes set by graduation standards and measured by standardized testing [1]. On the other hand, teachers are likely to have a positive impression of technology if they believe in constructivist learning [33, 34]. From a constructivist perspective, technology can serve as a powerful tool for both teachers and students to conduct research, assist in self-directed learning, and design and produce media-infused projects. Indeed, teachers tend to increase the use of technology if the learning goals are set up to be student-centered and project-based, focused on high-level skills such as creativity, research, and critical thinking [7, 21].
\nFundamentally, technologies should be offered as a way to achieve schools’ learning goals, and the question we should ask is: What can we do now with technology that was not possible before? [1]. However, very often, we do not have an identified problem in education that we hope technologies can help us solve, and we do not have a clear goal or expectation about how technology should be positioned in education to help with our learning goals [35]. We realize that technologies are something good to have, and it seems irresponsible if we fail to harness this power for education. Therefore, we have introduced technologies into schools, without changing any of our traditional practices, in an effort to enact their great potential. Instead, what we have largely done is carve out some tiny spaces for technology to fit into the traditional learning paradigm. If we go into a classroom, we will find out that the most popular technologies in schools are projectors, document cameras, and smartboards. Those technologies are helpful, but not necessary; the functions they perform could be done adequately before we had technology. Teachers who see technologies merely as supplemental tools for instruction are less likely to successfully adopt them [7]. Technology in today’s school setting gives teachers a third hand. It is something good to have, as it allows teachers to accomplish some tasks in a more convenient and efficient way [36]. However, its existence only brings quantitative difference without qualitative difference to the advancement of pedagogical practices [35]. Teachers who are experienced in teaching without technologies often do not see the necessity of having them [24, 25, 30]. Therefore, a true, successful adoption of tool-based technologies in education should start at the institutional level by redefining the learning goals that cannot be accomplished without technologies. For example, if our learning goals go beyond mastering of testable knowledge that can be obtained through direct instruction to creative and collaborative skills in project-based learning, we would arrange our class in such a way that students, under teachers’ guidance, could conduct research on the Internet and produce digital media such as videos and
Tool-based technologies are only as good as the way in which they are used by teachers. These technologies are not educational in nature but rather require teachers, through design and proper implementation, to transform technological tools into tool-based technologies that enhance teaching and learning. In the case of tool-based technologies, this adoption process is more important than the technologies themselves. Therefore, teachers are the key instead of machines, and teachers need to have the incentive and adequate skills to realize the process. Unfortunately, schools tend to spend tremendous resources to purchase and maintain equipment but often neglect to invest in helping teachers to adopt them [37]. The adoption process starts with redefining learning goals. Learning goals that demand less mechanical learning of content knowledge and value high-level skills—aligned with student-centered, constructivist learning and creative instruction—motivate teachers to see the unique value of technologies and develop a positive attitude toward their use. Suitable learning goals set direction for professional development for both preservice teachers in universities and in-service teachers in the field. Positive attitudes create a solid foundation for a collaborative learning community to take place, which helps teachers to be equipped with sufficient content knowledge and skills for adopting technologies to assist pedagogical practices. An efficient and thorough change starts with redefining learning goals, which are hopefully initiated top-down. The role of school leaders and experienced teachers is of the utmost importance (Figure 3).
\nTeachers’ adoption of tool-based educational technologies.
With recent advances in technology, we have entered the Information Era, especially after the invention of the Internet. Technology made digitalized content become the main resource from which we gain information and knowledge [38]. If we think of learning as a broad, lifelong process, most knowledge we learn today is not in classrooms. With technology, we expand the learning environment, which means that learning is no longer restricted to formal classroom instruction. Some believe that if we focus solely on the work of passing information and knowledge, technology is probably able to replace some components of traditional teaching. Others predict that mobile learning will partially take the place of teachers [39]. Mobile learning has several advantages. First, technology makes information and knowledge more accessible, and students can access more enriched resources of information through mobile learning. Second, learning environments can be expanded, and as long as students can access technology, they can learn anything, anytime, and anywhere. Third, mobile learning allows students to customize learning [40]. Among all the expected benefits, personalization of education has stirred up the most hope—traditionally, dozens of students receive the same information from one teacher in a classroom. However, with technology, every student has the opportunity to learn topics that have been individually tailored. Using technologies to fulfill personalized education has recently attracted tremendous attention from Silicon Valley, fueled with hundreds of millions of dollars from the Chan Zuckerberg Initiative [5, 41]. A program developed out of this initiative is called Summit Learning, which has been collaborating with hundreds of US schools to implement its personalized learning programs. These programs deliver individualized learning content of core academic subjects of grades 4–12, from a computer to a student, with the hope that students will study better with technologies than teachers [5]. These personalized learning programs are given to individual students based on an analysis of their learning attributes using an artificial intelligence algorithm. In such programs, technologies and learning contents included have been predeveloped by technology companies that give teachers little autonomy over the balance of teaching between teachers and machines. Also, many aspects of how the algorithm works often reside in a black box, remaining largely unknown to teachers or researchers. Learning through these technological programs, or, in other words, program-based technologies, is a fundamentally different pedagogical practice and learning experience than the use of tool-based technologies, which are still largely driven by teachers. However, program-based technologies are primarily driven by digital programs.
\nAlthough in the technology industry such distinction has been seldom made, the field of educational research has classified personalized education into two categories: outcome personalization and process personalization [42]. Outcome personalization gives students autonomy in the learning process. Many student-centered, project-based learning programs are designed in such a way that students may design a project of their choice, while the education process helps students to master necessary skills and knowledge to achieve the project. Outcome personalization is often filled by tool-based technologies, which give both teachers and students more creative power. However, most program-based technologies are used to fulfill process personalization, which gives students little choice over the learning process. Students are merely given customized learning materials selected based on computer algorithms, and the end goal of the process is to help students achieve standardized learning goals. In essence, program-based technologies could sufficiently fit into the demand of the traditional educational paradigm that emphasizes mastering standardized knowledge and skills. If implemented well, program-based technologies are expected to replace a considerable portion of teachers’ functionality.
\nAdvocates for the use of program-based technologies in personalized education believe that technologies can do a better job than traditional teachers because these technologies can unremittingly monitor individual students’ learning progress and simultaneously provide learning contents that are most suitable to individual students’ habits and learning attributes [43]. With a highly sophisticated algorithm, big data, and a large pool of well-tailored contents, technologies are expected to have certain advantages over human teachers in terms of delivering more effective instruction to each student. Additionally, advocates believe that technologies are more economically efficient and more accessible than human teachers, which can help to scale up good education and improve equity and equalization in education [40, 43]. Finally, teachers could be liberated from the mechanical work of teaching students basic knowledge and skills so they could be more focused on helping students with additional higher-level learning.
\nBefore using artificial intelligence for personalized learning, program-based technologies were largely made of learning games, with the hope that learning could be delivered in an attractive format. However, the downfall came when it became more and more clear that most educational games were not as attractive to students as regular computer games, and students easily lost interest over time [44, 45]. As a consequence, the interest in learning games has been gradually disappearing in the industry. Unfortunately, personalized learning technologies seem to share the fate of learning games—not only the fate of failure but also the specific inability to engage and motivate students in the learning process.
\nVery little research has been conducted on the effectiveness of Summit Learning’s personalized learning technologies; nor has there been much research on other program-based technologies on personalized learning [45]. Besides questionable learning outcomes, these technologies face tremendous challenges due to students’ negative reaction toward the learning experience under such programs. A study shows that students significantly feel less engaged in and experience less enjoyment in school due to lack of human interaction [46, 47]. Also, there have been news reports showing that personalized learning technologies face backlash among students and parents. Some students claim they feel they were like zombies sitting in front of computers all day long [41]. The intangible “joy” of learning, so often derived from human discussion and interaction, seems to be compromised by such programs. Overall, concerns about these technologies are as follows: they reduce students’ reported joy of learning; jeopardize students’ bond with teachers, while a healthy relationship between children and adults is essential in their development; isolate students; encourage unhealthy competition by exposing the difference in students’ learning progress; and are prone to misuse of student data by big corporations [48]. With all these perceived negative images in the public arena, it is not hard to assert that current efforts of using program-based technologies to conduct personalized education to replace teachers, represented by Summit Learning, will be far from successful. However, there is not much rigorous evaluation of such programs through imperial research, nor does it seem that the developers of these programs have any immediate intention to grant access to scholars to conduct any evaluation.
\nGiven that program-based technologies in education are largely developed by the technology industry instead of educators or educational researchers, as well as a special commercial interest in the industry, those technologies have seldom been well-examined in an empirical way, nor have their developers been given the incentive to conduct considerable research or comprehensive program evaluation. Chan Zuckerberg’s Initiative originally planned to work with the Harvard Graduate School of Education to examine the effectiveness of its Summit Learning Program, but it was called off by the initiative before the research started [41]. By the time this paper was written, we still did not know, despite students’ negative emotional reaction toward the program, whether the program could deliver its academic promises. Many factors may determine the success of program-based technologies, such as the content of learning materials, the artificial intelligence or other algorithms to assess students’ learning progress, and the implementation in school settings in relation to teachers’ assistance and other school activities. Many of the promises of technology-enabled personalized learning do not lose their attraction because of the failure of a first attempt. Future research is urgently needed to comprehensively examine these new technologies.
\nThe significance and advantage of human teachers cannot be easily replaced. Although knowledge can be easily accessed through program-based technologies, a lack of human interaction and motivation results in reduced knowledge acquisition among students. As learning is not a mechanical cognitive activity, students’ negative emotions could lead to
It has been a long-held misconception that educational technologies are homogeneous and they behave in a similar way in relation to teachers’ adoption and school implementation, among other factors. It is an oversight in the field of educational research that we have seldom made any distinction in the kinds of technologies that have been used in schooling, instead often studying them in a singular set. This was not an influential mistake when most technologies used in pedagogical practices were tool-based technologies and indeed shared many similarities. However, with the recent introduction of artificial intelligence into personalized education, new categories of technologies have emerged that are drastically distinct from the ones before. Therefore, a careful categorization of educational technologies should be made to help us study issues on educational technology in a well-structured way. Educational technologies are composed of pedagogical technologies (used in direct participation of teaching and learning activities) and operational technologies (used in the operative and administrative work of teachers).
\nPedagogical technologies can be further split into two groups: tool-based technologies and program-based technologies. Tool-based technologies are the most common, have a longer history, and have been well-researched. They refer to technologies that are not specifically designed for educational purposes and are versatile tools in nature. Teachers’ adoption of these technologies through a process of design and implementation transforms these technological tools into pedagogical technologies that assist in teaching and learning. Teachers are less inclined to use tool-based technologies if they are considered supplemental instructional tools for efficient lectures. On the other hand, teachers are more likely to use such technologies for student-centered constructivism learning because of technologies’ power to hone creative and critical thinking skills. Therefore, efficient adoption needs to be top-down, starting by setting learning goals that demand high-level creative skills instead of the mechanical acquisition of content knowledge. Suitable learning goals motivate teachers to see the value of developing positive attitudes toward technologies, which should fuel professional development programs, which should not only deliver adequate content knowledge but also create supportive and collaborative learning communities among preservice and in-service teachers. As such, teachers could be equipped with the skills, knowledge, and emotional drive to adopt tool-based technologies.
\nProgram-based technologies are predeveloped with learning contents that are delivered to students in a preprogrammed way. They leave less control to teachers and instead drive learning by their own artificial intelligence or other program algorithms. Although there has been high hope that they could replace teachers’ instruction to provide students with a personalized learning experience, the lack of human interaction often makes students feel less engaged in schooling and results in learning resistance. More research should be conducted in this field to study these technologies and the possibility of teachers working with algorithms in a more collaborative way instead of a either teacher or computer modal.
\nTechnologies bring the Information Era to schools. As the economy has shifted from labor-demanding to innovation-demanding, learning of basic skills and content knowledge is far from enough. A new competence set of creativity, collaborative learning, and research is more valuable than ever, which translates into new learning goals that demand students to be innovative and proactive learners. Technologies can help with that, but, without question, the role of teachers is still critical. Technologies cannot exclude teachers but should rather work with teachers to transform education from instruction-centered to student-centered. Tool-based technologies give teachers the means to be innovative and achieve that goal. Program-based technologies should be developed in a way that work seamlessly with teachers through research-based practices, instead of repeating the failure of pursuing student-centered learning by replacing teachers. After all, information can be digitalized, but learning itself is still a very human business.
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\\n\\n-eHealthcare Solutions EHS is a unique marketing platform that specializes in connecting niche audiences with healthcare brands. You may view their privacy policy here: https://ehealthcaresolutions.com/privacy-policy/ “This ensures we are also compliant with our various partners such as DMD, we pass the privacy review of pharma when they require it.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). 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Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. 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