Summary of production rules.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"2135",leadTitle:null,fullTitle:"Oxidative Stress - Environmental Induction and Dietary Antioxidants",title:"Oxidative Stress",subtitle:"Environmental Induction and Dietary Antioxidants",reviewType:"peer-reviewed",abstract:"This book focuses on the numerous applications of oxidative stress theory in effects of environmental factors on biological systems. 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",isbn:"978-1-83768-481-6",printIsbn:"978-1-83768-480-9",pdfIsbn:"978-1-83768-482-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"5576cda9d50adf4e4256e47427560510",bookSignature:"Associate Prof. Leisheng Zhang",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12387.jpg",keywords:"NK Cell Definition, NK Cell Classification, NK Cell Biofunction, Immune Regulatory Network, Hematologic Malignancies, Metastatic Solid Tumors, Molecule Mechanism, Infectious Diseases, Preclinical Practice, Clinical Trials, Cancer Immunotherapy, Industrial Production",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 24th 2022",dateEndSecondStepPublish:"July 22nd 2022",dateEndThirdStepPublish:"September 20th 2022",dateEndFourthStepPublish:"December 9th 2022",dateEndFifthStepPublish:"February 7th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"21 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Zhang is an associate professor at Gansu Provincial Hospital and the Chinese Academy of Sciences (CAS) Hefei Institutes of Physical Science. 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He received Ph.D degree in Chinese Academy of Medical Sciences & Peking Union Medical College, and received postdoctoral research training in Nankai University and CAS. His research interests mainly focus on the biological function and molecular mechanism of stem cells and immune cells, and in particular, hematopoietic stem cells (HSCs) and natural killer (NK) cells including cellular phenotype and genomic analysis, and applied transformation research. With the aid of small molecule library-based cell programming or gene-editing strategy, they have explored the feasibility for high-efficient of total or specific subpopulation of NK cell generation from hPSCs or peripartum tissues. 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Representative studies of Dr Zhang are available such as Cell Research (2015), Journal of Hematology & Oncology (2017), Stem Cell Reports (2018), Stem Cell Research & Therapy (2018, 2019a, 2019b, 2020, 2021), Stem Cell Reviews and Reports (2020), Cell & Bioscience (2020), Cell Proliferation (2021), Stem Cells International (2020, 2021), American Journal of Cancer Research (2021, 2022), Biomarker Research (2022).",institutionString:"Hefei Institutes of Physical Science",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Hefei Institutes of Physical Science",institutionURL:null,country:{name:"China"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"478200",firstName:"Dominik",lastName:"Samardzija",middleName:null,title:"Mr.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"dominik@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. 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Attention is focused on the one hand on the definition of standards allowing interoperability and reuse (the success of Learning Objects is an example), and on the other hand on the adoption of methodologies and technologies which ensure a controlled fruition of teaching contents (such as Learning Management Systems).
\n\t\t\tOn both these fronts, many advanced solutions have been proposed, and have proven undoubtedly useful and much appreciated. All the same, they are not yet sufficient to guarantee an “optimal training” experience because they do not take into account some significant variables of the learning process (\n\t\t\t\t\tDi Bitonto & Roselli, 2008\n\t\t\t\t). In fact, one of the main problems that has emerged from the e-learning literature is that if different students undertake the same search for a content the LMSs supply the same results without considering the learner profile. Another problem is that these tools often do little more than present the information content, without making any attempt to subject this content to intelligent processing to tailor it to the specific needs of the learner. In fact, they do not allow personalization of the teaching to the true needs and abilities of the individual, nor do they promote adoption of the many different existing teaching strategies (\n\t\t\t\t\tDi Bitonto et al., 2008\n\t\t\t\t).
\n\t\t\tThe architecture proposed in the chapter defines a possible solution to both these problems. It supplies methods and techniques for both recommending the Learning Object (LO) that best fits the learner’s profile and tailoring the navigation of the content of recommended LOs on the basis of the learner\'s knowledge, cognitive styles and metacognitive abilities. In particular, the chapter focuses on methods and techniques for carrying out personalized teaching actions in SCORM (Sharable Content Object Reference Model) (ADL, 2004) compliant Learning Management Systems.
\n\t\t\tIn order to better understand the research work proposed, the fundamental concepts in the technological, pedagogical and methodological context are described. Section 2 presents pedagogical and technological premises of the research work. From the pedagogical point of view, it examines the literature on the different cognitive styles theories used in the adaptive process. Regarding the technological issues the section will focus on the description languages (Roselli & Rossano, 2006) and SCORM specifications (in particular the Sequencing and Navigation rules), that are useful to understand the constraints and potentialities of the available technologies. Section 3 illustrates the methodological context, investigating the state of the art of tailoring approaches in e-learning applications and, in particular, the use of rule-based systems in defining personalised learning paths. Section 4 describes the multi-agent architecture for a SCORM compliant distance learning environment designed using TROPOS methodology. Section five describes the adaptation logic used by the adaptation agent in order to tailor the user navigation within a SCORM package. Finally, some conclusions and future works are discussed.
\n\t\tTo gain a full understanding of the work described, a brief introduction needs to be made to the pedagogical and technological issues faced. In particular, cognitive styles and the Felder model are outlined to help to understand the working logic of the reference scenario. Then the agent-based approach is contextualized to the present work. Finally, a brief introduction to the description languages in e-learning applications is given, as well as an illustration of the essential features of the SCORM standard.
\n\t\t\tEach learner usually shows a tendency or a preference for one or more modalities in the way that teaching actions are received and elaborated. For instance, some students prefer learning by doing, others, learning by images or by example. This implies that different learners approach learning tasks in different ways. Keefe (1985) defines cognitive styles as “characteristic cognitive, affective, and psychological behaviours that serve as relatively stable indicators of how learners perceive, interact with, and respond to the learning environment”. Alonso (1993) defines learning styles as “personal manners to perceive and process information, and how they interact and respond to educational stimuli”.
\n\t\t\t\tIn the last thirty years many researchers (mainly pedagogues and psychologists) have studied how to characterize cognitive styles and how to exploit the different styles during the educational process. A brief description of the most commonly used models in e-learning literature is presented.
\n\t\t\t\tOne of the popular models in e-learning is the Felder and Silverman model (Felder & Silverman, 1988) that defines the appropriate teaching strategy for each user\'s cognitive style. In order to distinguish the different cognitive styles, it considers four dimensions: “source of information”, that can be used to define perceptive or intuitive cognitive styles, “information code”, used to distinguish between visual or verbal styles, “information processing“, to differentiate active or reflective styles, and “summarizing information”, to define sequential or global styles.
\n\t\t\t\tFor each of them, Felder states the typical student’s behaviour and suggests the best way to teach each of them. Perceptive students can easily learn information received from the environment through their five senses, whereas intuitive students prefer information generated by associations drawn from memory, by reflection or by interpretation. Therefore the perceptive student needs detailed examples of concepts and procedures or applications of theoretical concepts, whereas the intuitive student prefers theories or interpretations that associate the facts.
\n\t\t\t\tVisual students prefer a graphic representation of the didactic material: they are better able to acquire information through images, even complex ones, schemes, graphs, and so on. They have some difficulty in memorising information provided during an oral presentation. Verbal students learn best using texts or oral explanations, and have no difficulty in remembering what they hear. Therefore, learning resources with images are the best suited for visual students, whereas text, video or audio resources are the best ones for verbal students.
\n\t\t\t\tActive students memorise the information by applying it in practical situations, whereas reflective students are theorists, modellers, and mathematicians. They prefer to define problems and find possible formal solutions. Therefore, an reflective student needs theory or interpretations that associate the facts, whereas a active student needs simulation or teaching resources built using cooperative learning or learning by doing approaches.
\n\t\t\t\tSequential students learn information by using an ordered approach and building up their knowledge step by step. Global students need to know how the information can be contextualised in the whole domain world. Therefore, a sequential student needs to study concepts step by step, noting their inter-relations, whereas a global student needs to study first of all the general scenario, and then to examine the specific content within it.
\n\t\t\t\tAnother model used in the e-learning literature is the VARK defined by Fleming and Mills in 1992 (Fleming, 2001). The approach used is very similar to the one in the Felder model. It classifies the learner in four different categories (Visual, Aural/auditory, Read/Write, and Kinaesthetic) and describes the main medium used to learn. According to the VARK model visual students usually prefer images (i.e. tables, graphics, flow chart); aural/auditory students learn by listening (i.e. conference, lessons) or discussing; read/write students tend to learn best by reading, taking notes, and kinaesthetic students prefer concrete learning experiences (real or virtual) like simulations or activities that engage them.
\n\t\t\t\tGardner’s multiple intelligences theory offers a different point of view in the field of cognitive styles. He identifies different key aspects through which students think and learn; in (Gardner, 1983), he defines seven kinds of ‘‘intelligences’’ which guide and influence the learning process, namely linguistic, logical-mathematical, spatial, bodily-kinaesthetic, interpersonal, intrapersonal, and musical.
\n\t\t\t\tStudents with a linguistic intelligence display a particular facility for words and languages. Usually they are good at reading and writing, they are able to memorize texts and dates and they tend to learn best by reading, taking notes, listening to lectures, and discussing; usually they are able to manipulate language syntax and structure. Students with a logical-mathematical intelligence are usually good at logical reasoning, abstraction and mathematical computation, so they are good scientists (i.e. mathematicians, computer programmers and so on). A spatial intelligence makes students very good at visualizing and mentally manipulating objects. Spatial students have a strong visual memory and they are often artistically inclined. Students with a bodily-kinaesthetic intelligence learn better if they are physically involved in the learning experience, so they prefer teaching strategies involving learning by doing and simulations. In general, they are good at building and making things. Students with an interpersonal intelligence are extroverts, sensitive, and good at cooperating with their colleagues, discussion and debate, so they learn better if they work in a group. On the contrary, introspective students are typically introverts and prefer to work alone. They learn best when allowed to concentrate on the subject by themselves. Finally, students with a musical intelligence are able to recognize rhythms and tones. They prefer to learn by hearing and reading.
\n\t\t\tThe International Organization for Standardization (ISO) defines a standard as
Already by the end of the ‘90s, various committees and organizations operating in the e-learning field had proposed a number of sets of specifics in the hope that they would be imposed as de facto standards. The most common one in use at the moment is the Dublin Core Metadata Initiative (DCMI). This began in 1995 with an invitational workshop in Dublin, Ohio, that brought together librarians, digital library researchers, content providers, and text mark-up experts aiming to improve discovery standards for information resources. The original Dublin Core emerged as a small set of descriptors, Dublin Core Metadata Element Set that quickly attracted global interest from a wide variety of information providers in the arts, sciences, education, business, and government sectors. Thus, the Dublin Core Metadata Element Set (DCMES) is a standard for cross-domain information resource description. However, the DCMI was the first initiative from which the need to introduce descriptors for online resources emerged, so it acted as the starting point for other organizations (ARIADNE, IMS, IEEE, etc.) that are currently focusing their attention on the definition of LO metadata sets.
\n\t\t\t\tIn 2002 the LOM (Learning Object Metadata) standard was defined by IEEE. Unlike the Dublin Core, it is a set of specifications that serves to specifically describe learning objects and their components. It includes more than 80 descriptive elements subdivided into the following 9 categories: general (includes all the general information that describes the resource as a whole); lifecycle (groups the descriptors of any subsequent versions of the LO); meta-metadata (include the information on the metadata themselves); technical (indicates the technical requisites needed to run the LO and its technical characteristics); educational (contains the pedagogical and educational information about the LO); rights: (indicates the intellectual property rights and any conditions of use); relation: (describes any relations with other Los), annotation (allows insertion of comments) and classification (makes it possible to classify the LO). The main novelty of the LOM is the educational category that contains elements like: Interactivity type, Learning resource type, Semantic density, Typical learning time, that supply indications on how the LO can be inserted in the teaching program. Another strong point of the LOM is that it can be used to describe many closed vocabulary items. These facilitate automatic processing of the information.
\n\t\t\t\tAs stated in (Roselli & Rossano, 2006) as regards the LOM definition, the e-learning community has concentrated hard on the task of defining standards that can guarantee the interoperability and reusability (from the informatics standpoint) of materials, but has tended rather to neglect their reusability (from the pedagogical standpoint) and the personalization of learning paths. In the LOM the quality, as well as the quantity, of the pedagogical information is somewhat lacking and it is not sufficiently detailed to provide a full description of the educational context where the teaching resource to which it refers should preferably be used. To overcome this problem, in 2003 the IMS Global Learning Consortium developed the IMS Learning Design. It consists of a set of specifications aiming to provide a detailed description of a learning scenario by means of a special language denominated Educational Modelling Language (EML). The specifics can describe a wide range of pedagogical models or learning approaches, including work groups, and collaborative learning. The ultimate aim is to define new learning models to describe how the actors in a given scenario interact among themselves, using the teaching resources (in terms of both teaching materials and support services), and how the whole procedure can be coordinated and channelled to create a learning path.
\n\t\t\tThe Sharable Content Object Reference Model (SCORM) provides a set of technical specifications serving to create content that will run on any conforming LMS. SCORM is not a standard but it is one of the best and most recent examples of the application and integration of current e-learning standards. It was defined in early 2000 in the Advanced Distributed Learning (ADL) initiative of the US Federal Government. The ultimate aim of the ADL initiative was to supply a comprehensive set of guidelines that enable interoperability, accessibility and reusability of e-learning content within the Department of Defence. The US military, therefore, can all use, exchange, manage, track and reuse all of the learning content and data no matter what its source or application.
\n\t\t\t\tThe ongoing work of the ADL has produced different versions of the SCORM specifications. The latest was released in 2004. It is organized in the form of four books: Overview, Content Aggregation Model (CAM), Run Time Environment (RTE), Sequencing and Navigation (SN).
\n\t\t\t\tAs stated in (ADL, 2004) the Content Aggregation Model (CAM) book describes
Run-Time Environment (RTE) book describes
Adaptivity in distance learning environments is one of the main problems faced by researchers (Ruiz et al., 2008; Chun-Hsiung et al.; 2008; Popescu, 2008). Their primary goal is to meet the individual user’s learning needs. In the literature, two different solutions are proposed: to tailor the content of a single learning resource by modifying the navigational path within the LO, that can be named the
The intra-adaptivity approach allows the development of very complex learning resources for simple LMS. The single LOs should implement different learning paths for different cognitive styles, background knowledge, goals, etc. On the contrary, in the inter-adaptivity approach the learning resources are very simple and the LMS should be able to build personalized learning paths by assembling different LOs using the best teaching strategies according to the learner profile. In both approaches (intra-adaptive and inter-adaptive) the key points are the description of the student and of the LOs, as well as the logic used to associate the learner’s profile to the teaching strategy. The trend in adaptive system research is to face this issue using the cognitive styles theories. The state of the art analysis reported below illustrates different applications of the two approaches in e-learning environments and the use of different cognitive styles to personalize learning paths in distance learning environments.
\n\t\t\tThe Intra-adaptivity approach is supported by many researchers (Arapi et al, 2003; Brusilovsky, 2004; Friesen, 2005) and by the SCORM standard (starting from version 1.3).
\n\t\t\t\t\tA lot of works on Learning Objects are contributing to identify patterns for developing instructional contents characterized by an adaptive, generic, portable nature and sufficiently scalable to improve their potential for reusability (Alvino et al, 2008; Bodendorf et al, 2005; Earle, 2002). In addition, a wide range of virtual learning environments has been proposed to support the use of learning objects, their properties and characteristics (Fischer, 2001; Pollyana & Silveira, 2006; Brady et al, 2008).
\n\t\t\t\t\tWhen using an Intra-adaptivity approach, highly complex LOs need to be built, owing to the numerous variables that need to be considered in the adaptivity process, as stated in (Ruiz et al. 2008). In (Monacis et al, 2009) the authors built an adaptive learning object using the standard SCORM, which dynamically related different learning contents to students’ cognitive styles. In order to define the personalized learning paths for each student, the authors defined a set of navigation rules and a questionnaire to acquire the cognitive style.
\n\t\t\t\t\tIn Pollyana and Silveira (Pollyana & Silveira, 2006) a six-tiered architecture for adaptive learning objects is presented, that organizes the information in a macrostructure in order to standardize learners’ profiles, learning objectives, structure of courses and so on. The “Course tier” allows learning objectives to be defined so that for each course the expected skills and abilities are stated; the “Reusable LOs tier” allows the characteristics related to each learning objective to be defined; the “Apprentice Model Tier” keeps track of students\' historical information; the “Learning Styles Tier” keeps track of the student’s learning style in all its dimensions; the “Presentation tier” is responsible for the dynamic generation of a suitable display of learning objects according to the learner’s profile, taking into account his/her inferred learning styles for a certain learning context. The Presentation tier is composed of two parts: a “Learning Objects Model”, which describes all the learning objects that are to be used in the learning context, and an “Apprentice Profile”, formed by the learner’s historical profile and by learning styles that are detected according to the specific learning context.
\n\t\t\t\t\tSuch an approach, although extremely interesting, is difficult to apply on a large scale because it has many constraints and is expensive in terms of the creation and description of learning contents. Moreover, the countless descriptions that have to be considered make the process of seeking the most suitable LO for the user too slow.
\n\t\t\t\tThe inter-adaptivity approach allows us to think of the LO as “any digital entity which can be used, reused or referenced during a technology-mediated learning process”, according to Wiley\'s definition (Wiley, 2000). Moreover, this makes it possible to create simpler LOs that can then be dynamically assembled according to the student\'s learning needs. The problem arising in this case is how best to combine these LOs.
\n\t\t\t\t\tDifferent methods and approaches have been proposed for determining the learning paths that can best support the learning experience of navigation through the set of LOs. It is possible to distinguish three kinds of techniques: rule-based, ontology based and planning based.
\n\t\t\t\t\tThe rule-based techniques use an explicit knowledge representation to describe characteristics, constraints and relations in the domain knowledge. They consider, for each LO, a set of skills that describes it. In this way it is possible to add to the LMS some adaptation components that use the knowledge about the LO skills, together with the student description (learning goal, prior knowledge and mental aptitude), to produce sequences that fit the user\'s requirements and characteristics, within the limits of the available learning objects. Working at the skills level makes it easier to consider the relations among LOs, and this makes reuse of the learning objects easier, as well as their application in goal-directed reasoning processes. Primitive forms of adapting systems were presented in (Seal & Przasnyski, 2001), where the authors propose a system that can collect students’ feedback during interaction with the course in order to suggest to the teacher how to adapt the course itself to the classroom needs. No adaptation was conducted automatically. A more complete solution is presented by (Trigano & Pacurar-Giacomini, 2004). They propose CEPIAH, a system that can help teachers to develop pedagogical web sites and on-line courses. Using CEPIAH, the teacher (starting from two questionnaires) can automatically generate educational Web site structures, add pedagogical contents, and finally visualize, manage and participate in the courses. The questionnaires are related to pedagogical issues (i.e. teaching scenario, pedagogical approach …) and interaction issues (i.e. colours, shape of menus, buttons…). In short, the automatically generated course structure is based on teaching scenarios which integrate the features of different pedagogical theories. The system’s inference mechanism is based on rules that specify how the pedagogical models are assembled.
\n\t\t\t\t\tAnother example of a rule-based system for automatic content creation is the ECSAIWeb presented in (Sanrach & Grandbastien, 2000). The system describes each LO as a learning unit composed of “content”, what the student has to learn, any “pre-condition”, what the student has to know before starting to study the LO, and “post-condition”, what the student has to know after studying the LO. Using combination rules that fit together LOs on the base of content, pre-condition, post-condition and student’s profile, the system builds the personalized learning path.
\n\t\t\t\t\tIn general, using rule-based systems yields interesting results in small and static domains where it is possible to build a set of rules to manage the entire possible situation that can develop. In more complex cases, it could be necessary to consider different domain knowledge. In these cases it is necessary to use a more flexible knowledge representation: the ontology.
\n\t\t\t\t\tThe ontology-based techniques, like the rule-based techniques, use an explicit knowledge representation to describe characteristics, constraints and relation of the domain knowledge. Unlike rule-based, ontology-based techniques allow the domain to be described in great detail, so it is possible not only to define rules to associate learning resources to the student, but also to browse the knowledge domain.
\n\t\t\t\t\t(Ronchetti & Saini, 2003) present an e-learning environment able to manage a course on data base, organized as a set of LOs. Each LO is associated by metadata to its topic, and each topic is organized by ontology where a set of relations is defined (membership, subclass, pre-requisite, conceptual similarity …). The defined ontology is used not only to assembly the best learning path for the student, but can also be browsed in order to allow the student to find topics which are related to a given LO and then find other similar topics whose study is correlated.
\n\t\t\t\t\t(Benayache & Abel 2005) present an e-learning environment for automatic course generation. The knowledge about resources, domain and users is organized in two ontologies: the first, “application ontology”, describes the specific didactic domain; the second, “domain ontology”, describes teaching resources like teachers, competences, didactic material and so on. Using pedagogical relations, like pre-condition and post-condition, the system defines topic maps that contextualize each LO. The ontologies are used by teachers and learners to find the learning resources.
\n\t\t\t\t\tThe planning based techniques are able to construct different learning paths considering the domain constraints and they are able to choose the best learning path according to the user’s needs. Planning based techniques do not exclude rule-based or ontology-based approaches to describe the domain knowledge. For instance, (Peachy & McCalla, 1986) use planning techniques to summarize the educational resources that achieve the learning goals and rule-based techniques to define the domain constraints. Likewise, in (Karampiperis and Sampson) use ontologies and metadata in order to calculate the best learning path through the didactic resources automatically generated using a planning system.
\n\t\t\t\t\tIn the WLog system (Baldoni et al, 2004a) the learning objects are represented as actions, each of which has a set of prerequisites (skills needed to be able to use the learning object) and a set of effects (skills supplied). The skills can be linked by different relationships, causal or requirement, for instance, (Baldoni et al, 2004b). Using planning algorithms, the adaptation components can infer the best way to combine LOs.
\n\t\t\t\t\tOther adaptive and dynamic courseware generation systems based on planning approach are Tangram (Jovanovic et al 2005), OntAware (Holohan, et al, 2005), and Paser (Kontopoulos et al, 2008). These systems provide guidance and direction towards the most appropriate learning path that the student could follow each time. The principal limits of the approaches based on the planning algorithm are the computational costs, that are usually very high (Kontopoulos et al, 2008; Morales et al, 2008) and the inability to decompose didactic resources into smaller units which can be reassembled in different learning paths. A primitive solution to this problem is presented in (Jovanovic et al 2005).
\n\t\t\t\tCognitive styles are used in intra-adaptivity and inter-adaptivity approaches, as shown in (Pollyana & Ismar, 2006). As reported in (Popescu, 2008), one of the first adaptive educational systems to consider cognitive styles is shown in (Carver et al, 1999) where an adaptive hypermedia interface is developed. It provides dynamic tailoring of the presentation of course material based on the individual student\'s cognitive style. In particular, it is based on three cognitive dimensions of the Felder-Silverman model (Felder & Silverman, 1988): perception, input, understanding. Each of them is evaluated by applying Felder-Soloman’s questionnaire. The adaptation is based on suitability for each particular learning style. Another example of an adaptive hypermedia system that uses the Felder-Solomon Learning Style Questionnaire to measure the cognitive style of students is described in (Bajraktarevic et al 2003). The system uses global and sequential learning styles to adapt the learning path, to cater for individual learner preferences. The work shows the importance of cognitive styles adaptation in e-learning settings, comparing the “matched session” (global student interacts with global approach) with the “mismatched session” (global student interacts with sequential approach and vice versa). In (Monacis et al, 2009) the Italian Cognitive Styles Questionnaire defined by De Beni, Moè, and Cornoldi (De Beni et al, 2003) it is used to decide how to tailor the learning content to the students’ profiles.
\n\t\t\t\tOther models of cognitive styles used in literature are the VARK (Auditory, Visual, Read/Write, Kinaesthetic) proposed by Kolb in 1995 and Gardner’s theory of multiple intelligences (Gardner, 1993). The VARK model is used in Arthur\'s system (Gilbert & Han, 1999) and in the SACS (Style-based Ant Colony System) (Wang et al, 2008); Gardner’s theory is used in EDUCE (Kelly & Tangney, 2006). Other systems consider different cognitive styles at the same time, as reported in (Pollyana & Ismar, 2006) or are independent of any particular learning style model, like the AHA! system (Stash, 2007).
\n\t\t\tThe technologies, methods and techniques presented in the previous sections are able to furnish a personalized educational process in a distance education environment. The main problem is the low level of integration of such solutions, in particular between the inter-adaptive and intra-adaptive type. This section presents a multi-agent architecture proposal that integrates both approaches. This idea was presented for the first time in (\n\t\t\t\t\tDi Bitonto & Roselli, 2008\n\t\t\t\t), where a rule-based technique to adapt SCORM compliant learning objects was proposed.
\n\t\t\tThe basic idea (showed in Figure 2) is that the student interacts with a SCORM compliant learning environment that suggests, by means of a Search Engine, the resources best suited to the learner\'s characteristics (inter-adaptive approach). Each recommended resource is then adapted to the student’s cognitive styles by means of an Adaptation Engine that modifies the navigation within the resources (intra-adaptive approach) using the sequencing and navigation rules of the manifest file. A first implemented prototype is presented in (Di Bitonto, 2009) where a multi-agent system was presented to support the learning process in an open community.
\n\t\t\tConceptual framework of adaptive learning environments.
\n\t\t\t\tFigure 1, shows the conceptual framework of an e-learning environment. When the student searches for teaching material, the Search Engine selects the LOs best suited to the student\'s needs using the LOM metadata collected in the LOR (Learning Object Repository), and the student profile (inter-adaptivity). For intra-adaptivity, the adaptation engine defines how to modify the file manifest according to the student\'s cognitive styles, other data tracked and memorized in the student profile and the teaching strategies implemented in the Knowledge Base (KB). The problem at this point is that on account of its internal features, the LO may be more or less adaptable to the student\'s needs. Thus, the adapting agent must calculate the level of changes possible and select the most adaptable option. After doing this, it transfers the file manifest to the LMS so that it can be presented to the student.
\n\t\t\tThis section presents the multi-agent architecture design used to develop the conceptual framework. In particular, it highlights how the adaptive agent builds a personalized learning path within a LO.
\n\t\t\tAccording to Russell and Norvig (Russell & Norvig, 2003) an agent is any software entity that can perceive its surrounding environment by means of sensors and modify it using actuators. One of the most common techniques used to define an agent is the PEAS (Performance Environment Actuator Sensor) description. It is important to define the agent’s performance so as to provide it with heuristics on which to choose the strategy to be actuated from among those available. The environment supplies the context of use, characterizing the problem that the agent is designed to solve. The actuators are the tools that allow the agent to carry out actions on the environment. Finally, the sensors are the sources from which the agent acquires the information on the environment that it needs to work on.
\n\t\t\t\tAgents are structured in two distinct parts: the architecture and the agent program. The architecture makes the perceptions available to the program, carries out the program and passes on the actions it has chosen to the actuators, as they are generated. Instead, the agent program relates the perceptions to the actions. The agent has goals to satisfy, it is autonomous and it collaborates with the other agents to satisfy the common goals. A group of agents that communicate with each other is defined as a Multi-Agent System (MAS).
\n\t\t\t\tThe complexity of MAS has required an ad hoc methodology to be defined for the MAS analysis and design: GAIA (Wooldridge et al 2000), MASE (Wood & DeLoach, 2001)) and TROPOS (Giorgini et al 2006) are some examples reported in literature. The methodology used in this work is TROPOS. It covers the entire software development process, from requirement analysis to system implementation. It consists of five phases: early requirements, late requirements, architectural design, detailed design, and implementation.
\n\t\t\t\tIn the Early Requirements phase the environment and its organization are studied. The outputs of this phase (goal diagram, and actor diagram) are organizational models that include the relevant actors and the goals that need to be satisfied for each of them, the plans to be carried out and the resources necessary. In the Late Requirements phase a new actor is included, named the “system-to-be”, that represents the software architecture to be implemented. Its goals are individuated, as well as the dependencies on the otehr actors in the environment. The output of this phase is the extended actor diagram.
\n\t\t\t\tIn the Architectural Design phase the overall structure of the system is defined as a series of subsystems that are interlinked by control data and flows that are modeled to cater for dependencies. Instead, the agents, their dependencies and interactions are detailed in the Detailed Design phase. Finally, what has been defined in the previous phases is coded in the final “Implementation” phase.
\n\t\t\tIn the early and late requirements phase the MAS actors are defined. Starting from the conceptual framework of an adaptive learning system the following actors were defined: student, Teaching Manager, Student Assistant, Learning Path Builder, Content Manager, and User Profiler.
\n\t\t\t\tThe students are the main users of the learning environment. They interact with the learning environment through the e-learning platform in order to communicate with other users, to search the LOs and to navigate into personalized learning paths.
\n\t\t\t\tThe Teaching Manager (TM) manages the monitoring and tracking of students’ navigation and the administrative activities. The Student Assistant (SA) evaluates the student’s needs. The Learning Path Builder (LPB), represents the adaptation engine, it decides if the LO must be modified and builds a personalized learning path according to the student’s cognitive styles. It also manages information on the cognitive styles in the student model. The LPB is the main actor, in the sense that it coordinates the main communication between the other actors. The Content Manager (CM), represents the search engine of the adaptive learning environment; it seeks the best suited learning resources to the learner. Finally, the User Profiler (UP) manages the student information that serves to personalize the teaching strategies. The interactions among the actors are depicted in Figure 2.
\n\t\t\t\tInteractions among the actors.
Some examples of interaction among actors are presented. Let us suppose that a student logs on to the system for the first time. The UP actor checks on the student information and points out the lack of knowledge about the student’s cognitive styles. So it alerts the LPB actor to produce and submit to the student (though the SA actor) a questionnaire that helps to make for the cognitive styles evaluation. The questionnaire is evaluated by the SA that indicates the student\'s cognitive style to the LPB.
\n\t\t\t\tLet us envisage another interaction scenario: the adaptation of the learning path within the LO according to the student’s cognitive style. Let us suppose that the LPB knows the student\'s cognitive styles. The SA actor, interacting with the CM, seeks for the LO that will be submitted to the student according to her/his cognitive styles. When the LO has been selected, it is passed to the LPB, that evaluates the student’s cognitive style and decides how to personalize the learning path. If the LO is modified the file manifest will change, and the new SCORM content package is then passed to the SA for use by the student.
\n\t\t\tIn the architectural and detailed design phase, the LPB is decomposed into sub-actors, each of which has specific sub-capabilities. The sub-actors are: the Cognitive Styles Manager (CSM), the Learning Path Manager (LPM), the Selection Path Manager (SPM) that decides how to change the learning paths.
\n\t\t\t\tLPB decomposition.
After the LPB decomposition has been defined the agents that must be implemented in the MAS and their capabilities are defined (according to the actor\'s capabilities).
\n\t\t\t\tThe agents are the CM, CSM, LPM, SPM, UP, and SA. The CM (Content Manager) agent is able to search, insert, modify, and delete the LO; the LPM (Learning path manager) agent that is able to extract, modify and re-zip the SCORM package; the SPM (selection path manager) agent that is able to decide how to change the learning paths; the CSM (cognitive styles manager) agent that evaluates and updates the student\'s cognitive style; the UP (user profiler) agent that authenticates the student, manages and updates her/his profile; the SA (Student assistant) agent, that alerts the system if new LOs are added or if a user profile is changed. It is also able to check the learner’s knowledge and seek for knowledge gaps.
\n\t\t\tSome of the agent capabilities, defined in the architectural and detailed design phases, are supported by the e-learning platform [rif]. The UP agent, for instance, manages the system registration and authentication procedures. Since those capabilities are partially supported by e-learning platform, the UP agent manages the data exchanged between E-learning platform and the MAS system. For instance in the log-in process the UP agent checks the user-id and password in the E-learning platform DB. Figure 4(a) shows the login page. Finally, the UP agent evaluates the user\'s cognitive style by implementing the Felder/Soloman questionnaire. The resulting cognitive styles are memorized in the e-learning platform DB.
\n\t\t\t\tSystem screenshot.
The CM agent is implemented using the repository functions offered by e-learning platform. Figure 4(b) shows the page for the selection of LOs that are memorized in the repository. If new LOs are added in the repository they will automatically appear in the list of available LOs.
\n\t\t\t\tUnlike the UP and CM agents, the CSM, LPM, SPM agents are not supported by E-learning platform services. They work in the background and are not visible to the student. The CSM agent examines the student’s activity tracking to infer any change in her/his cognitive styles. If some change has occurred, it modifies the user’s profile.
\n\t\t\t\tThe LPM and SPM agents work together to modify the learning path within the LO. First of all the LPM extracts the manifest file from the LO zip package and parses the manifest file starting from the root node. For each node, if the name of the tag is <imsss:sequencing>, it selects the set of tags that can be adapted to the learner’s characteristics and passes them to the SPM. The SPM agent implements a rule-based technique that, according to the student’s cognitive style, determines how to modify the <imsss:sequencing> tags and attributes. The changes are passed to the LPM that modifies the manifest, creates a new content package and passes the LO to the e-learning platform for the use by the student.
\n\t\t\tIn order to understand how an adaptive learning environment based on the multi-agent architecture presented works, it is important to briefly illustrate the SPM adaptation logic. The basic element is the IMS SS Sequencing Definition Model. It defines a set of elements that can be used to describe and affect various sequencing behaviours within the LO. There are four main sections for the technique presented here:
The six elements in the Sequencing Control Modes section are:
The
There are two elements in the
The
The two elements in the Limit Condition section are:
Let us suppose that the SPM agent receives the <imsss:sequencing> elements for the purpose of modifying the LO navigation according to the student\'s cognitive styles. For each cognitive style and <imsss:sequencing> element a production rule changes the manifest settings. Table 1 shows some of the production rules defined, when components of the LO are text and images. In the case of simulation, collaborative or practical activities the production rules defined will be different.
\n\t\t\t\n\t\t\t\t\t\t | Information summarizing | \n\t\t\t\t\t\tInformation processing | \n\t\t\t\t\t||
\n\t\t\t\t\t\t | sequential | \n\t\t\t\t\t\tglobal | \n\t\t\t\t\t\treflective | \n\t\t\t\t\t\tactive | \n\t\t\t\t\t
S.C. Choice | \n\t\t\t\t\t\tnot relevant | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\tfalse | \n\t\t\t\t\t
S.C.Choice Exit | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\tfalse | \n\t\t\t\t\t
S.C.Flow | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\tfalse | \n\t\t\t\t\t
S.C.Forward Only | \n\t\t\t\t\t\tfalse | \n\t\t\t\t\t\tfalse | \n\t\t\t\t\t\tfalse | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t
Att. Abs. Dur. Limit | \n\t\t\t\t\t\tnot relevant | \n\t\t\t\t\t\tnot relevant | \n\t\t\t\t\t\tincreased | \n\t\t\t\t\t\tnot relevant | \n\t\t\t\t\t
Attempt Limit | \n\t\t\t\t\t\tnot relevant | \n\t\t\t\t\t\tnot relevant | \n\t\t\t\t\t\tincreased | \n\t\t\t\t\t\tincreased | \n\t\t\t\t\t
Prevent Activation | \n\t\t\t\t\t\tfalse | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\tfalse | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t
Constrain Choice | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t\tfalse | \n\t\t\t\t\t\ttrue | \n\t\t\t\t\t
Summary of production rules.
The sequential cognitive style implies that the student tends to study step by step without jumping from one concept to another. So, for the sequential student the
Global students need to know how the information can be contextualised in the whole domain world. Therefore, they need to study first of all the general scenario, and then to examine the specific content within it. So, for the global student the
The Reflective student tends to examine the concepts very carefully before answering; moreover she/he proceeds with care using a step by step approach and reflects deeply before answering. Usually the reflective student is very responsible. For those reasons the Sequencing Control Choice,
Finally, active students prefer simulation and practical activities. Sometimes they are superficial, so they should be guided during their navigation. So, Sequencing Control Choice,
Each student can have a different cognitive style and the different cognitive style can activate different changes in the manifest. Conflicts among the different rules can arise. In order to solve this problem, salience values (from 1 to 3) are defined according to empirical evidence, that serve to choose the best rule to apply. In (Di Bitonto, 2009) other kinds of production rules are presented to select the teaching strategies. The other two dimensions of the cognitive styles “source of information” and “information code” are not yet considered because they are not related to navigation of the LO. To consider them, it is necessary to use the
Let us suppose that a new user is registered in the system. When she/he makes the first login, she/he chooses a LO. The system recognizes the absence of a cognitive style evaluation and proposes the questionnaire. Let us now suppose that the student is active and global. The saliencies of the rules and the result of conflict resolution are shown in Table 2.
\n\t\t\t\t\n\t\t\t\t\t\t\t | global | \n\t\t\t\t\t\t\tsalience | \n\t\t\t\t\t\t\tactive | \n\t\t\t\t\t\t\tsalience | \n\t\t\t\t\t\t\tresult | \n\t\t\t\t\t\t
S.C. Choice | \n\t\t\t\t\t\t\ttrue | \n\t\t\t\t\t\t\t1 | \n\t\t\t\t\t\t\tfalse | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\tfalse | \n\t\t\t\t\t\t
S.C.Choice Exit | \n\t\t\t\t\t\t\ttrue | \n\t\t\t\t\t\t\t3 | \n\t\t\t\t\t\t\tfalse | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\ttrue | \n\t\t\t\t\t\t
S.C.Flow | \n\t\t\t\t\t\t\ttrue | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\tfalse | \n\t\t\t\t\t\t\t3 | \n\t\t\t\t\t\t\tfalse | \n\t\t\t\t\t\t
S.C.Forward Only | \n\t\t\t\t\t\t\tfalse | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\ttrue | \n\t\t\t\t\t\t\t3 | \n\t\t\t\t\t\t\ttrue | \n\t\t\t\t\t\t
Att. Abs. Dur. Limit | \n\t\t\t\t\t\t\tn.r | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | n.r. | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | n.r. | \n\t\t\t\t\t\t
Attempt Limit | \n\t\t\t\t\t\t\tn.r | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | incr. | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\tincr. | \n\t\t\t\t\t\t
Prevent Activation | \n\t\t\t\t\t\t\ttrue | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | true | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | true | \n\t\t\t\t\t\t
Constrain Choice | \n\t\t\t\t\t\t\ttrue | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\ttrue | \n\t\t\t\t\t\t\t1 | \n\t\t\t\t\t\t\ttrue | \n\t\t\t\t\t\t
Conflict resolution among production rules.
In Figure 5 some results of the adaptation process are shown. Figure 5 (a) shows the LO before the modification: the activity tree and “previous” button are on the left and the top of the page, respectively. After the adaptation those tools are removed.
\n\t\t\t\tAn example of LO adaptation.
One of the main advantages of distance education is that it offers the possibility of personalizing the learning path. The challenge for researchers is to define methods, techniques and tools to support intelligent searches and tailoring of the retrieved contents. Nevertheless, the main problem of the technological solutions defined so far is that they are often ad hoc solutions.
\n\t\t\tThe present chapter faces both these problems, presenting a multiagent architecture that is able to search for LOs and personalize educational processes in a SCORM compliant distance learning environment.
\n\t\t\tFirst of all, unlike other systems reported in literature, where the solutions use only one of the two approaches (intra-adaptive and inter-adaptive), the presented framework uses a combined approach. Thus, it merges searching techniques, developed in an intra-adaptive area, with learning path personalization techniques developed in an inter-adaptive area.
\n\t\t\tMoreover, the multi-agent architecture was defined starting from the conceptual framework of an adaptive learning environment. In order to retrieve and tailor the resource best suited to the user, it adopts the Felder and Silverman cognitive styles theory. The difference from other systems presented in literature is that the proposed MAS modifies the SCORM package in accordance with users\' cognitive styles using sequencing and navigation rules. The use of the SCORM standard makes the adaptive technique very general and adaptable in any context. The prerequisite is that the LO should have been designed to be adapted.
\n\t\t\tOne of the probable weak points of the adaptation technique is that it may develop problems when it is applied in a context where many students are using the system at the same time. Simultaneous access can slow the system performance, reducing the efficiency of the presented solution. In order to measure the performance of the system in such contexts, an experiment is being designed to cope with a large number of students.
\n\t\t\tFuture work will involve the completion of the adaptation rules in order to integrate the Sequencing rule description section of the imsss Definition Model.
\n\t\tHuman malignant pleural mesothelioma (MPM) is an invariably fatal tumor due to its heterogeneity, growing from the serous surfaces of the pleura. Many factors are involved in its occurrence, such as exposure to asbestos fibers and simian virus 40; these factors being those that are strongly associated with the tumorigenesis of this disease. The annual incidence of MPM is relatively low, estimated in a range of 0.6–30/10,00,000, but the global occurrence is expected to increase continuously in future years [1]. MPM is extremely heterogeneous in its morphology and molecular phenotypes. The latency period for MPM development is 10–50 years after asbestos exposure. The prognosis for MPM is generally poor, with a median survival time of 12 months from diagnosis [1].
Intratumor heterogeneity refers to a mixture of phenotypic, functional, and genetic differences within cancer cells with various differentiation or hierarchical statuses within the tumor. It is a common feature in most tumors. This heterogeneity has been considered the greatest obstacle to the effectiveness of most cancer therapies, manifesting itself in its sensitivity to different therapies. Several studies have been focused on genetic alterations as part of the mechanism of tumoral cells for the generation and maintenance of this heterogeneity. In addition, some other studies show the role of epigenetic modifications involved in its heterogeneity. Despite this, there is scarce information about epigenetic modifications that could explain this process [1, 2].
Epigenetic modifications are heritable and stable alterations of genes that do not change the DNA sequence, including DNA methylation, histone modification, and non-coding RNA interference modifications. DNA methylation has been extensively studied in the development of cancer. On the one hand, hypermethylation in cancer-related promoter genes induces the silencing or downregulation of tumor suppressor genes and repair genes. On the other hand, hypomethylation of DNA leads to activation of oncogenes and genomic instability. Several authors suggest that aberration in DNA methylation may play an important role on tumor cells heterogeneity [3, 4, 5].
The exact mechanisms by which asbestos fibers promote the development of cancer are unknown, however, the most accepted theory is the induction of chronic inflammation and signaling pathways in the transformation of reactive oxygen species generated by asbestos fibers. Therefore, this chapter will address an overview of the epigenetic profile of MPM and the mechanisms that promote epigenetic modifications where asbestos fibers might play an important role.
As previously mentioned, asbestos exposure is a primary cause of the development of pleural mesothelioma. Molecular analyses show that asbestos-related carcinogenesis is caused by chronic inflammation that both promote the release of oxygen free radicals that alter intracellular components, and DNA mutation and its consequent transformation. Asbestos fibers also contain iron ions and can induce hemolysis by sequestering iron from hemoglobin. This is particularly important since free iron disproportionately releases H2O2, which consequently releases hydroxyl radicals (OH) that oxidize DNA, and release nucleic acids, proteins, and lipids. This process is exacerbated by the release of cytokines including tumor necrosis factor-alpha from macrophages and high mobility of box group 1 (HMGB1) proteins from necrotic cells, leading to an amplification of the inflammatory response and an increase in cells that are driven to oxidative damage. Damaged oxidized DNA, if not properly repaired, is highly mutagenic and can lead to genomic instability. A multitude of oxidative DNA lesions includes oxidation of DNA bases, baseless sites, single-strand breaking, double-strand breaking, and interchain breaking, all of which require different pathways for proper repair. These last two chain-breaking types are particularly toxic, since they cause replication collapse, as well as allow chromosome rearrangements, chromosome gains, losses, or fragmentation [2].
There are other mechanisms involved in how asbestos fibers cause MPM (Figure 1). Four proposed models related to asbestos fibers induce genetic and cellular damage to cells, in addition to the previously mentioned chronic inflammation. The different molecular models involved in asbestos exposure are explained below:
Reactive oxygen species generated by asbestos fibers with their surface exposed leads to DNA damage and cell membrane rupture. Macrophages that engulf asbestos fibers but cannot digest them also produce abundant reactive oxygen species.
Asbestos fibers are also engulfed by mesothelial cells. Asbestos fibers collected in cells can physically interfere with the mitotic process of the cell. The cycle is cut by the interruption of the mitotic spindles. Another important aspect is the entanglement of asbestos fibers with the chromosomes or mitotic spindles that can give rise to structurally damaged chromosomes such as aneuploidies of normal mesothelial cells.
Asbestos fibers can absorb a variety of proteins and chemicals on the wide surface of asbestos, which can result in the accumulation of dangerous molecules including carcinogens. The asbestos fibers also bind to important cellular proteins and a deficiency of these proteins can also be detrimental to normal mesothelial cells.
Finally, mesothelial cells and macrophages exposed to asbestos release a variety of cytokines and growth factors that induce inflammation and tumor promotion. These include tumor necrosis factor α, interleukin 1β, transforming growth factor β, and platelet-derived growth factor. Tumor necrosis factor-α has been shown to activate nuclear factor-κB, leading to mesothelial cell survival and inhibiting asbestos-induced cytotoxicity. The high mobility group protein box 1 (GAMB1) is released from mesothelial cells, which are exposed to asbestos and then undergo necrotic cell death, promoting an inflammatory response. Thus, aberrantly activated signaling between mesothelial cells, inflammatory cells, fibroblasts, and other stromal cells can create a set of mesothelial cells, which harbor aneuploidy and DNA damage, potentially developing cancer cells and together all these phenomena form a tumoral microenvironment that supports and nurtures them [6, 7, 8].
Possible oncogenic mechanisms induced by asbestos. Abbreviations: HMGB1 = high-mobility group box 1. ROS = reactive oxygen species. TGF-B = transforming growth factor beta. VEGF = vascular endothelial growth factor.
Methylated DNA studied through immunoprecipitation grounded on next-generation sequencing makes it possible to analyze the DNA methylome, which constitutes a useful and efficient tool in the approach of cancer epigenomics [5, 9, 10].
An important and widely described phenomenon in the development of MPM is the epigenetic dysregulation that promotes changes in gene expression [11]. DNA methylation modifications play an important role in the malignant transformation of mesothelioma. Survival in MPM has been attributed to promoter methylation and silencing of genes such as SFRP4, SFRP5, FHIT, and SLCA20.
The methylated CpG islands have been shown to affect different process, such as uncontrolled cell proliferation & differentiation and dysregulations in apoptosis, in the oncogenic process of MPM. It is important to mention that asbestos fibers have been related with increased prevalence of aberrant promoter methylation by controlling the APC and RASSF1 genes, directly affecting the cell cycle [1, 2, 3, 4].
Epigenetic modifications require active maintenance and are potentially reversible, characteristics that make them targets for therapeutic strategies. Multiple DNA methyltransferases and histone deacetylases (HDACs) participate on the regulation of some tumor suppressor genes by gene silencing and chromatin compaction. Therefore, changes in these two enzymes promote disturbances in gene expression and allow deflections in cell proliferation, differentiation, and apoptosis. When HDACs are inhibited, there is a massive production of superoxide radicals and the caspase system is activated, leading to cell death. Additionally, hyperacetylation of non-histone proteins takes place, promoting angiogenesis and tumor cells motility and invasion [12].
DNA modifications are not the only mechanisms involved in tumorogenesis. Epigenetic changes also play an important role in oncogenesis through changes in DNA-associated proteins, modifying their expression. In this regard, the most important changes are DNA methylation and histone deacetylation. These changes lead to important modifications in DNA activity and expression. As a result of this process, some proteins involved in tumorogenesis can be induced and modulated, for example, epidermal growth receptor factor, tumor necrosis factor-alpha protein fusion peptide, transforming growth factor-beta and others. As mentioned above, these changes are induced by epigenetic mechanisms that are potentially reversible [12, 13].
In recent years, inhibiting tyrosinase-like receptors (RTKs) has been used as a therapeutic target because MPM cells have been shown to express high levels of receptors that can bind to key molecules, such as epidermal growth receptor factor (EGFR) and platelet-derived growth factor (PDGF), fibroblast growth receptor factor (FGFR-1y3), transforming growth factor-beta (TGF-B), insulin-like growth factor (IGF-1R), and tumor necrosis factor-alpha protein fusion peptide (NGR-hTNF-alpha). All these molecules undergo through epigenetic changes and play a dead serious role in tumor invasion and angiogenesis [12, 13].
Numerous genes have been shown to be epigenetically downregulated, as the DNA methylation of transcriptional promoters. These changes deregulate several signaling pathways, including the WNT pathway, in which several negative regulators are hypermethylated and silenced [14, 15]. The global epigenetic profile determined by high-throughput analysis differs between MPM and normal pleura, showing that MPM has aberrant methylation in the CpG islands, as has been mentioned [16, 17]. These data support the hypothesis that a specific DNA methylation pathway is induced during mesothelial carcinogenesis.
Kim et al. [1] carried out a study in a patient with MPM, 122 differently regulated genes were found, 118 genes were down-regulated and four were up-regulated by hypomethylation. Therefore, MPM cells may be epigenetically regulated, and DNA methylation plays a main role in intratumorally heterogeneity, characteristic that boost MPM more aggressiveness.
There are sundry important factors that have been related with DNA methylation of gene loci in MPM such as age-related changes, ethnicity, histological subtype, and asbestos exposure. These factors could explain discrepancies between DNA methylation frequencies in published studies, as well as the experimental method used to detect it. In patients diagnosed with MPM, an increased DNA methylation associated with increased age has been reported. Some studies have shown that methylation status of the IGFBP2 (insulin growth factor binding protein) locus and GDF10 (bone morphogenetic protein) locus is significantly higher in MPM in Japanese patients compared with US patients [18, 19].
There are some concrete characteristics that are related to specific genes, for example; RASSF1 suppressor gene has been reported to have a significantly higher frequency of aberrant methylation in epithelioid MPM than in the sarcomatoid subtype [20, 21]. Methylation of MT2A gene, is shown to differ between these two histological subtypes. Epithelioid and sarcomatoid mesotheliomas also have different methylation changes at 87 CpG islands [22, 23]. MT1A and MT2A gene loci associated with DNA methylation have also been described in MPM.
CpG island methylation in the CCND2, CDKN2A, CDKN2B, HPPBP1, and RASSF1 genes has been studied in correlation with asbestos exposure. The RASSF1 DNA methylation locus is related with a higher number of asbestos bodies in the lung. There are different methylation profiles in MPM according with its exposure to asbestos and a positive association between asbestos fiber load and CDKN2A, CDKN2B, RASSF1 methylation status, and MT1A at another 100 loci.
Some differences have been described in DNA methylation for sundry genes between MPM, lung adenocarcinoma, and in non-malignant lung tissues. That’s why, at these days, DNA methylation is an important tool in the diagnosis of MPM [20, 24]. Thus, the DNA methylation profile has potential helpfulness in the diagnostic of MPM and reject of other differential diagnoses. It has been demonstrated by high-throughput analyses for methylation, spanning several thousand CpG islands. It was recently suggested that DNA methylation at three specific loci: TMEM30B, KAZALD1, and MAPK13, could be useful in the differential diagnosis of MPM. In the near future, MPM diagnosis may be based on the methylation profile, but by now, further studies in larger populations are necessary before using a limited number of hypermethylated loci [19, 20, 21].
Other studies have shown alterations in the methylation status of individual genes, such as those HIC1, PYCARD, LZTS1, and SLC6A20. All of these genes have been associated with a good or bad prognosis [22, 23]. Besides, patients with MPM and a low frequency of DNA methylation had longer survival [22, 23, 24].
In view of the aberrant epigenetic events observed in MPM and the clinical value of histone deacetylase inhibitors (HDACis), the latter is currently being studied as a potential diagnostic method. However, insufficient data is yet available on the regulation of histone modifications, despite their crucial role in maintaining chromatin stability. These data are needed to support clinical trials based on HDACis [6, 7, 25, 26].
Each nucleosome is made up of 147 base pairs (bp) of DNA wrapped twice around a histone octamer. Epigenetic regulation of gene expression occurs in the context of chromatin, the basic unit of the nucleosome. Lysine-rich histone tails extend from the nucleosome and provide sites for covalent and reversible binding, promoting processes such as acetylation, methylation, ubiquitination, phosphorylation and SUMOylation, which produce the activation or inhibition of gene expression [8, 27].
DNA methylations represent the most important mechanism regulating major changes in gene expression during normal cell cycle and tissue differentiation, as well as long-term repression of imprinted alleles, germ cell-restricted genes, repetitive DNA, and sequences. Endogenous retrovirals [27, 28, 29]. Normal somatic cells have three major DNA methyltransferases: DNMT1, DNMT3A, and DNMT3B. All these enzymes mediate the transfer of a methyl group from S-adenosyl-methionine to the 5′ position of cytosine in the context of CpG. CpG dinucleotide groups are found in the promoters of approximately 60% of genes. Furthermore, most of these islands are unmethylated, allowing for a relaxed structure (euchromatin) and active transcription [30]. Some other CpG dinucleotides and CpG islands, which are often hypermethylated in normal cells, are scattered throughout the genome [31]. Although there is considerable overlap, DNMT1 preferentially binds hypermethylated DNA and works primarily as a housekeeping methyltransferase, restoring DNA methylation patterns during the process of DNA repair or replication. On the other hand, DNMT3A and 3B mediate de novo DNA methylation after recognition of unmethylated or hypermethylated DNA [30, 31].
It is important to recapitulate that methylation-sensitive transcription factor binding is inhibited by DNA methylation, and these changes promote the recruitment of the CpG methyl-binding domain (MBD) and relevant proteins such as UHRF1, syn3a-containing repressor complexes, NCoRs and histone deacetylases (HDACs), resulting in silent transcriptional heterochromatin output [32, 33, 34].
During the process of malignant transformation, the aberrant orientation and overexpression of some factors involved in DNA methylation promote the epigenetic silencing of genes related to differentiation, many of which are tumor suppressors. On the other hand, tumor suppressor genes can be inactivated by DNA methylation through transitional mutations resulting from deamination of 5-methylcytosine (5-MC) or adduct formation with environmental carcinogens such as benzopyrene [35].
DNA demethylation occurs passively during DNA replication [36, 37]. In addition, DNA can be actively demethylated by oxidation of 5-MC to 5-hydroxymethylcytosine, a ten-eleven translocation (TET) enzyme-mediated reaction [20].
The total amount of methylated CpGs, during malignant transformation, is up to 50%, excluding CpG promoter islands. The genome-wide DNA demethylation is importantly related to a deficient DNA repair process [38, 39, 40, 41]. Besides, it can promote unrepression of imprinted alleles, endogenous retroviruses, and transposable elements, inducing genomic instability [42, 43]. On the other hand, the mechanisms that mediate this phenomenon, such as decreased expression of methyltransferase 1 [44, 45, 46] glycosylase-mediated cleavage of 5-MC and aberrant expression/orientation of TET proteins, have not been fully elucidated [38].
The most widely characterized histone modifications in normal cells and malignant cells have been the acetylation-deacetylation and the methylation-demethylation [1, 2, 43, 47]. Histone acetylation is mediated by a variety of histone acetyltransferases (HAT), increasing the net negative charge leading to DNA repulsion, chromatin relaxation, and gene expression. Some non-histone proteins, including Hsp90, SP1, p53, and HDAC1, are targets for HAT and HDAC. In the other hand, histone deacetylation is regulated by HDAC [48].
Histone lysine methylation is mediated by a variety of histone methyltransferases (KMTs), lysine mediating monomethylation/dimethylation/trimethylation of specific residues, whereas histone demethylation is mediated by histone demethylases [47, 49, 50]. Histone modifications are highly dynamic in response to environmental signals [51, 52]. Unlike histone acetylation, histone lysine methylation does not modify the charge of core histones. Furthermore, histone lysine methylation can promote or inhibit gene expression.
ATP-dependent chromatin remodeling complexes have emerged, in recent years, as critical mediators of the epigenetic regulation of gene expression in normal and malignant cells [53, 54]. To date, four gene families have been described including switch/non-fermentable sucrose (SWI/SNF), SWI mimetic (ISWI), DNA-binding helicase chromodomain (CHD), and INO80, named for their ability to regulate inositol-responsive gene expression. All these complexes have multiple subunits with diverse isoforms and exhibit pleiotropic functions including regulation of gene expression, maintenance of chromatin structure, replication of pericentromeric heterochromatin, repression of ribosomal RNA, and repair of cell damage. DNA [55]. There are several mechanisms by which different families remodel chromatin. For example, the SWI/SNF complexes expose DNA by disassembling the nucleosome, while members of the ISWI, INO80, and CDH families reposition (slide) the nucleosomes and extend the intervening DNA, promoting access to transcriptional factors. These complexes also have an important role in maintaining chromatin structure and genome stability, through mechanisms that reassemble the nucleosome [53, 55].
Studies in transcriptome analysis have revealed that almost 90% of the genome is transcribed as non-coding RNAs (IncRNAs), which are critical mediators of chromatin structure and gene expression in normal cells and malignant transformation [56, 57, 58]. Besides, lncRNAs participate in the recruitment of DNMTs and histone methyltransferases to chromatin [59], adding another layer of epigenetic regulation in normal cells which is altered in malignant tumors.
There are several studies that have shown a relationship between silencing suppressor gene by methylation process and the development of MPL. For example, Christensen et al. [23] examined the DNA methylation status of the promoter of six genes that regulate cell cycle progression at 70 MPM. The extent of methylation of these genes was correlated with lung asbestos burden and overall survival. Goto et al. [60] studied methylation process in more than 6000 GpC islands, comparing twenty MPM versus twenty lung adenocarcinomas, using microarray PCR technique. Their results are interesting because they found out that 387 genes (6.3%) were hypermethylated in mesotheliomas, while the number of hypermethylated gene in lung adenocarcinoma were higher with a total amount of 544 genes (8.8%).
MPL patients’ survival is related with DNA methylation levels. In this way, higher levels of DNA methylation correlate with lower patient survival. Three genes; TMEM30B, KAZALD1 and MAPK13, are specifically hypermethylated in MPM. Several reports have documented tumor suppressor gene silencing related to DNA methylation process in MPM (Table 1) and there is evidence of hypermethylation of some of these genes affecting overall survival.
APC1A | P151NK4B |
APC1B | P16 |
BMP3b | RARB |
CDH1 | RASSF1A |
DAPK | SFRPs |
ESR1 | SLC6A20 |
FHIT | SYK |
IGFBP3 | TMEM30B |
KAZALD1 | THBD |
MAPK13 | TMEM30B |
MGMT | TYMP |
P14ARF | WIF-1 |
Hypermethylated genes related to MPM.
MPM: malignant pleural mesothelioma.
Currently, scientific evidence has shown that recurrent hypermethylation is highly related to tumor suppressor genes in MPM, however, the mechanisms behind this process have been poorly studied. Novel studies have identified TC2N gene as a tumorigenesis promoter by silencing p53. Cytokine signaling participate in modulation process of DNMT expression and mediate hypermethylation of target genes enrolled in some types of cancer such as colorectal carcinoma and erythroleukemia cells [61, 62]. Exposure to asbestos fibers leads to a cytokine cascade induced by high mobility group 1 (HMGB1) or the NLRP3 inflammasome. These cytokines use to change the regulation of the expression of DNMT and other components of the methylation machinery during the process of MPM evolution.
A study of a panel of genes encoding epigenetic regulators in a panel of cultured cell lines derived from asbestos-associated MPM relative to LP-9 (a commercially available normal mesothelial cell line) was recently carried out. Consistent with the study results, TCGA data demonstrate a spectrum of DNMT expression in MPM and suggest that overexpression of DNMT1, DNMT3A, and DNMT3B correlates with decreased survival of pleural mesothelioma patients (Figure 2).
Association between intratumoral DNMT expression levels and surveillance in patients with MPM. The Kaplan Meier waves show that DNMT1, DNMT3A, and DNMT3B expression, measured by RNA-seq technique, has negative impact in patients’ surveillance.
Kim et al. [1] studied gene expression and methylation profiles in pluripotent populations (SP) and non-SP fractions in human MPM samples, using RNA-seq and methylated DNA immunoprecipitation techniques. They found 6400 hypermethylated genes and 3400 hypomethylated genes in SP. Seven hundred and ninety-five genes were upregulated, while three hundred and thirty-five were significantly repressed in SP compared to non-SP fractions. They looked at changes in DNA methylation and expression levels of 122 genes; 118 genes were hypermethylated and downregulated, while 4 were hypomethylated and upregulated. Ten other genes showed hypermethylation and low expression of CpG promoter islands.
The loss of the imprinting process is largely due to DNA hypomethylation. Repression of endogenous retroviral sequences and activation of GC genes can promote malignant transformation by increasing proliferation, genomic instability, and resistance to apoptosis [63, 64].
A fascinating phenomenon can occur during the malignant transformation of somatic cells. The development of highly limited tumor antigens that induce serological and cell-mediated immune responses in cancer patients can be caused by abnormal activation of GC genes [also known as testicular cancer (TC) genes]. As a result, testicular cancer antigens (ATCs) have become popular targets for cancer immunotherapy in recent years [65]. More than 270 GC genes have been registered in the international TC database thus far. Seventy-five percent of these genes are only expressed in normal testes and malignant neoplasms, while the rest have high levels of expression in testes and varying levels of expression in other normal tissues and malignancies. On the X chromosome, around half of the GC genes are encoded. Families of cancer-testis-X (CT-X) chromosomal genes with inverted DNA repeats are common. On the other hand, inverted repetitive DNA sequences or extended families or are not linked to non-X CT genes [66, 67]. Furthermore, CT-X genes are frequently active in malignancies, and genes from families are increased in a tumor-specific manner, implying that the CT-X genes have a transcriptional coregulation and functional link.
In human malignancies, the stage at which the disease is discovered at a specific time corresponds to the degree of CG gene repression. Malignant and aggressive phenotype of cancer cells is promoted activations of this genes. BORIS/CTCFL, for example, upregulates h-TERT and suppresses apoptosis in cancer cells via processes that are still unknown [68, 69]. MAGE-A11 regulates the activity of the tumor suppressor gene RBL1/p107 [63]. MAGE-A11 inhibits the tumor suppressor gene RBL1/p107, while MAGE-B2 promotes cell cycle advancement by increasing E2F activity. MAGE-A2 and MAGE-C2 prevent p53 from binding to target promoters, changing its activities and leading to p53 deacetylation (inactivation) or enhanced ubiquitin-mediated degradation. The absence of CG gene regulation does not appear to be just a symptom of pluripotency, as it is accompanied with chromosomal hypomethylation. In human ESC, mesenchymal stem cells, and adipose-derived stem cells, Loriot et al. [70] found no overexpression of 18 different CG genes. In induced pluripotent stem cells (iPSCs) produced from normal small airway epithelial cells, transcriptional repression of CG genes such as NY-ESO-1, MAGE-A1, and MAGE-A3, which are generally located upward in thoracic malignant tumors, has been detected, which is consistent with these findings. Although these findings imply that iPSC reprogramming is partial, induction of CG genes in cancer cells may necessitate more extensive DNA hypomethylation as well as activation of tissue-specific transcription factors.
There is currently such little information on the expression of CG genes in MPM. MAGE1--4, NY-ESO-1, GAGE1-2, GAGE1-6, SSX2, SSX1-6, and RAGE-1 expression in five MPM lines was compared to normal mesothelial cells employing RT-PCR techniques, according to Sigalotti et al. [71]. In these MPM lines, diverse expressions of the CG gene were identified, with each line exhibiting a unique profile, as previously reported for lung malignancies [72]. None of these genes were found in normal mesothelial cells [71, 73].
Polycomb group proteins (PcG) play an important role as regulators of stem cell pluripotency and differentiation [74], as well as inappropriate gene expression during cancer transformation [75, 76]. In mammals, two main Polycomb repressor complexes (PRCs) have been discovered. PRC-2 is an initiating complex that causes trimethylation of histone 3 lysine and contains the subunits EZH1/EZH2, SUZ12, EED, and RBAP46/48 (H3K27Me3).
PCAF, PHC, RING1, CBX, and BMI1 are components of the housekeeping complex PRC-1, which mediates the ubiquitination of H2AK119 (H2AK119Ub). CRC recruitment and heterochromatin growth are aided by these histone marks, which are frequently detected in the context of DNA hypermethylation and gene suppression [75, 76]. Several proteins, such as including JARID2 and members of the sex comb-like family (ASXL), interact with EZH2 and SUZ12 to lead PRC-2 to polykyl response elements (PRE) throughout the genome [77, 78]. Goto et al. [79] investigated gene repression in MPM and observed that a subset of genes repressed in MPM had H3K27Me3 without DNA hypermethylation, implying that disruptions in polycomb gene expression may play a role in MPM etiology [80, 81].
Several immunoblotting investigations studies revealed that MPM cells overexpress EZH2 with associated increases in H3K27Me3 levels when compared to normal mesothelial cells. Another set of tests, which included QRT-PCR, immunoblotting, and IHC, revealed that EZH2 was overexpressed in almost 80% of primary MPMs (most of which were epithelioid histology). As a result of these findings, it was identified that EZH2 is overexpressed in MPM and that PRC-2 could be considered as a potential therapeutic target in these cancers. The overexpression of EZH2 in MPM was verified by TCGA analysis, as was a strong link between EZH2 upregulation and lower MPM patient survival (Figure 2A). Further TCGA analysis reveals that SUZ12 overexpression is associated with poor survival in MPM patients (Figure 2B). On the other hand, there is no evidence about MPM patients’ survival related to EED expression (Figure 2C).
The foregoing findings are especially important in light of recent findings that inactivating mutations in BRCA-associated protein 1 (BAP1), which encodes a nuclear ubiquitin hydrolase with several functions, are found in uncommon familial MPMs as well as almost 60% of sporadic MPMs. H2AK119Ub is ubiquitinated, for example.
LaFave et al. [82] discovered that BAP1 mutations, which are linked to protein expression loss, enhanced the expression of EZH2 and SUZ12 in MPM cells in a series of experiments. Likewise, overexpression of EZH2 was related to lower levels of H4K2Me1 and less occupancy of L3MBTL2 (an unusual polycomb protein that identifies this repressive histone mark) inside the EZH2 promoter in BAP1 mutant cells. Despite the strong connection between BAP1 mutations and repression of Polycomb stem cell targets, no specific clinical manifestation of BAP1 mutant MPM has been identified. Somatic mutations in BAP1 appear to be more common in current or past smokers with MPM [83].
SWI/SNF are mammalian homologs of yeast trithorax complexes. Their major purpose is to antagonize PRC-2’s repressive effects by destroying DNA-nucleosome connections allowing movement and ejection, or by switching nucleosomes to increase factor accessibility transcription to DNA [84, 85]. In human malignancies, the genes encoding the SWI/SNF complexes are commonly altered, with various subunit mutations related to specific cancer histologies.
Yoshikawa et al. [86] used whole exome sequencing to identify a substantial number of mutations in genes involved in the SWI/SNF pathways, including homozygous SMARCA4, ARID2, and PBRM1 mutations in short-term established MPM lines [86, 87]. They also evaluated at the loss of somatic copies in the 3p21 region (which is roughly 10.7 Mb in size and contains 251 genes) in 33 MPM samples, using techniques including comparative genomic matrix high-density hybridization (a-CGH) and next-generation targeted sequencing (NGS). Bi-allelic deletions (3 Kb) were observed in 46 genes, four of which have been associated to malignant tumors, including two SWI/SNF-related genes [PBRM1 (15%) and SMARCC1 (6%)], BAP1 (48%) and SETD2 (27%). More than 200 MPM were studied in a recent thorough genomic investigation.
Bueno et al. [88] described mutations in genes encoding SWI/SNF components in 8% of the samples, as well as mutations in two histone methyltransferases (SETDB1 and SETD5) in about 3% of the samples. The discrepancies between the results reported by Yoshikawa et al. [87] and Bueno et al. [88] may be attributable to the identification of minuscule deletions by high-density, a-CGH, and specific NGS that are not detectable by conventional NGS techniques. To establish final conclusions, more studies are needed to determine the frequency and clinical significance of SWI/SNF mutations in mesothelioma.
MPM inhibits tumor suppressor genes by promoting LOI and repression of CG genes by site-specific hypermethylation of DNA and/or polycomb repressor complexes in the context of hypomethylation of the genome. This “DNA methylation paradox” mimics epigenomic conditions in normal germ cells and lays the groundwork for epigenetic regimens that restore tumor suppressor gene expression and trigger growth arrest/apoptosis. Upregulation of CTAs, development of viral mimicry by derepression of endogenous retroviruses, and control of the tumor microenvironment all help to boost antitumor immunity [89, 90].
DNMTs are potential targets for MPM treatment because of their direct functions in suppressing tumor suppressor genes and maintaining pluripotency [91, 92]. Previous clinical attempts to inhibit DNMT activity in MPM, however, have failed miserably. Yogelzang et al. [93] showed a 17% objective response rate in 41 MPM patients who received 120 h of continuous dihydro-5-azacytidine infusions. Amazingly, 6 years following treatment, the single responder was disease-free. The lack of efficacy of DNA hypomethylating drugs in solid tumors could be due to their usage at maximum tolerated doses, resulting in myelosuppression, rather than prolonged use at lower doses to obtain pharmacodynamic effects without systemic toxicity. The Phase I decitabine trial (DAC) clearly demonstrates that chronic exposures are required to achieve maximum gene induction effects in cancer tissues [94].
Furthermore, 5-AZA and DAC administered IV, SQ , or PO have short half-lives (less than 5 min) and poor biodistribution, limiting their potential utility in patients with solid tumors. Cytidine deaminase (CDA), which is found in practically all organs but mainly the gastrointestinal system, quickly inactivates these molecules [95, 96]. Documented toxicity increases Cmax and t1/2 (>50 nM and 4 h, respectively) as well as biodistribution of oral decitabine, decreasing inter-patient variability in drug levels significantly [95, 96, 97, 98]. Significant increases in fetal hemoglobin, without neutropenia, thrombocytopenia, or lymphopenia, are indicative of hypomethylation of systemic DNA caused by oral DAC-THU. A phase II trial (NCT02664181) is currently underway at the Cleveland Clinic and NCI to examine whether DAC/THU can improve responses to nivolumab when given as second-line therapy to patients with non-small cell lung cancer. Despite encouraging preclinical data [26], efforts to target HDAC on MPM have also been disappointing.
As second- or third-line therapy, Krug et al. [99] randomized 661 MPM patients to receive the HDAC inhibitor vorinostat or placebo. Overall survival, as well as the drug’s safety and tolerability, were the key outcomes. Vorinostat-treated patients had a median OS of 30.7 weeks (95% CI 26.7–36.1) compared to 27 weeks (95% CI 23.1–31.9) for placebo-treated patients. Given the absence of evidence for HDAC upregulation in MPM and the limited antitumor effects of HDAC inhibitors alone in preclinical tests, the lack of efficacy of the single-agent vorinostat in patients with MPM is not surprising. Combinated techniques, such as using HDAC inhibitors to sensitize cells to TRAIL-mediated apoptosis or flavopiridol to boost romidepsin-mediated growth arrest and death, might be helpful for future clinical trials. Hypomethylating drugs, on the other hand, do not appear to lessen the incidence of mesothelioma after asbestos exposure. In fact, non-solid cancers such leukemias, lymphomas, and other myelodysplastic syndromes show the best benefits with this medicine.
It is feasible that BAP1 mutations could be used for MPM therapy in the future. BAP1 promotes the recruitment of the polychial deubiquitinase PR-DUB complex to DNA damage sites by stabilizing BRCA-1 and promoting poly (ADP-Ribose) dependent recruitment of the polychial deubiquitinase PR-DUB complex to DNA damage sites. This activity is dependent on deubiquitinase activity and BAP1 phosphorylation. BAP1 mutations, which invariably show as a loss of function, cause BRCA-1 levels to drop and double-stranded DNA repair to be inhibited [100, 101, 102]. A BAP1 isoform including part of the catalytic domain sensitized MPM cells to the PARP1 inhibitor, according to Parotta et al. [102]. (Olaparib). Concomitant treatment with GDC0980, a dual PI3K-mTOR inhibitor that is downregulated by BRCA-1, could improve this sensitivity. These strategies could improve responses to cisplatin/pemetrexed in patients with BAP1 mutant MPM and should be evaluated in future clinical trials.
There is considerable interest in chromatographic remodeling agents with adoptive cell transfer or immune checkpoint inhibitors for cancer therapy, given the extensive preclinical studies showing DNA demethylating agents, HDAC inhibitors, and KMT inhibitors in the immunomodulatory effects of potentials [103]. In a syngeneic mouse tumor model, cytolytic T lymphocytes target testicular cancer antigen in vivo using decitabine to destroy metastatic cancer. The preclinical basis for combining gene induction regimens with cancer adoptive immunotherapy was established in these studies. Furthermore, novel microenvironmental data are likely to have a substantial impact on the outcomes of clinical trials for epigenetic treatments and immunotherapies [89].
While malignant pleural mesothelioma is a disease with a low incidence worldwide, with aggressive behavior, its survival does not go beyond 12 months once the diagnosis is made [1, 2]. Its origin has been related to the chronic exposure of asbestos as the main factor. Also, asbestos fibers have been an essential component in structural changes at the molecular level, with much evidence about its genetic behavior and to a lesser extent, its epigenetic behavior. All of this gives it a fairly heterogeneous behavior [13, 14, 15]. New molecular techniques allow a broader understanding of the carcinogenesis of this tumor and an approach to new diagnostic tools. Epigenetic dysregulations require active maintenance and are potentially reversible, making them a therapeutic target [7, 23, 30].
The study of methylome has made it possible to carry out differential diagnoses thanks to the methylation of some specific loci, such as TMEM30B, KAZAZD1, MAPK13 and to demonstrate greater survival rates in patients with low frequencies of methylations [16, 17, 28].
It is important to mention the exposure to asbestos fibers as the main resistance factor associated with the methylation of tumor suppressor genes seen in pleural mesothelial cells such as APC and RASSF1. Additionally, there are direct cellular effects such as chronic inflammation measured by free radicals leading to DNA oxidation, hemolysis with the release of hydroxyl ions, intrachain breakdown plus subsequent chromosomal fragmentation, and production of pro-inflammatory cytokines with higher expression of angiogenic growth factors, another aspect that can be considered a potential therapeutic objective. Genomic responses related to methylation conclude in a gene silencing, most likely in tumor suppressor genes such as SFRP4, FHIT, SLCA20 [69, 71, 80]. Another diagnostic approach that can be observed by methylation is the overexpression of DNMT in patients with MPM and consequently could be an attractive therapeutic target, however, clinical efforts for its inhibition have been disappointing and future studies should focus on the therapeutic approach to the inhibition of DNMT.
A greater association of methylation has been seen in advanced ages and ethnic groups such as the Japanese population. However, the greater association related to histological changes in proliferation, differentiation, invasion, and reduction of apoptosis has been seen with the increased methylation of CpG islands in genes such as CCND2, CDKN2A, and associated with asbestos bodies with RASSF1.
Although methylation is the most studied epigenetic mechanism, there are other modifications that lead to the silencing of tumor suppressor genes, such as the activation of the Polycomb complex and the mutation of the SWI/SNF pathway [82, 83]. Deacetylation mediated by HDAC has been seen in the p53 gene and other aspects such as HAT-mediated acetylation or demethylation by KDMs.
The modification in histone features such as stability in chromatin has a great relationship with HDCAs, thus making them a potential therapeutic target. There are few studies with inhibitors such as vorinostat, however, where there are no positive results due to the low expression in MPM.
Finally, it is clear that there is much to know about the modifications and/or epigenetic changes in MPM. The current evidence of the molecular mechanisms opens up another panorama for us to adjust personalized therapeutic strategies aimed at reversing normal changes and thus be able to identify in a timely manner those patients who are susceptible to such treatments. Therefore, clinical trials should focus on those epigenetic markers that at some point in their disease are overexpressed or silenced.
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Its first known use in rehabilitation published by Max North named as “Virtual Environments and Psychological Disorders” (1994). Virtual reality uses special programmed computers, visual devices and artificial environments for the clients’ rehabilitation. Throughout technological improvements, virtual reality devices changed from therapeutic gloves to augmented reality environments. Virtual reality was being used in different rehabilitation professions such as occupational therapy, physical therapy, psychology and so on. In spite of common virtual reality approach of different professions, each profession aims different outcomes in rehabilitation. Virtual reality in occupational therapy generally focuses on hand and upper extremity functioning, cognitive rehabilitation, mental disorders, etc. Positive effects of virtual reality were mentioned in different studies, which are higher motivation than non‐simulated environments, active participation of the participants, supporting motor learning, fun environment and risk‐free environment. Additionally, virtual reality was told to be used as assessment. This chapter will focus on usage of virtual reality in occupational therapy, history and recent developments, types of virtual reality technologic equipment, pros and cons, usage for pediatric, adult and geriatric people and recent research and articles.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Orkun Tahir Aran, Sedef Şahin, Berkan Torpil, Tarık Demirok and\nHülya Kayıhan",authors:[{id:"172938",title:"Prof.",name:"Hulya",middleName:null,surname:"Kayihan",slug:"hulya-kayihan",fullName:"Hulya Kayihan"},{id:"183079",title:"Ph.D.",name:"Sedef",middleName:null,surname:"Şahin",slug:"sedef-sahin",fullName:"Sedef Şahin"},{id:"196848",title:"M.Sc.",name:"Orkun Tahir",middleName:null,surname:"Aran",slug:"orkun-tahir-aran",fullName:"Orkun Tahir Aran"},{id:"197159",title:"Mr.",name:"Tarık",middleName:null,surname:"Demirok",slug:"tarik-demirok",fullName:"Tarık Demirok"},{id:"197312",title:"M.Sc.",name:"Berkan",middleName:null,surname:"Torpil",slug:"berkan-torpil",fullName:"Berkan Torpil"}]},{id:"61806",doi:"10.5772/intechopen.78312",title:"Executive Functions and Neurology in Children and Adolescents",slug:"executive-functions-and-neurology-in-children-and-adolescents",totalDownloads:1731,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"This chapter discusses the theoretical and methodological issues of creating a developmental perspective on executive function (EF) in childhood and adolescence. Focusing on school periods, this section outlines the development of the basic components of EF—inhibition, working memory, and attention. Cognitive and neurophysiological evaluations show that despite the emergence of EF in the first few years of life, it continues to grow significantly in childhood and adolescence. The components vary slightly according to their developmental sequence. The chapter links findings to long-standing developmental issues (i.e. developmental sequences and processes) and suggests the necessary research to establish a developmental framework covering early childhood throughout adolescence.",book:{id:"6772",slug:"occupational-therapy-therapeutic-and-creative-use-of-activity",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Therapeutic and Creative Use of Activity"},signatures:"Gokcen Akyurek",authors:[{id:"197265",title:"Dr.",name:"Gokcen",middleName:null,surname:"Akyurek",slug:"gokcen-akyurek",fullName:"Gokcen Akyurek"}]},{id:"56049",doi:"10.5772/intechopen.69101",title:"Measurement of Participation: The Role Checklist Version 3: Satisfaction and Performance",slug:"measurement-of-participation-the-role-checklist-version-3-satisfaction-and-performance",totalDownloads:2800,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Participation in society is an area of interest to both clinicians and population researchers. Measurement of participation is therefore important, yet differences in definition, in terms of both content and scope, have made general agreement on one instrument tool elusive. What is recognized is the need for a theoretically based tool that captures both the insider and the outsider perspective. The outsider perspective, inclusive of the generally held views of a society, supports the utility for aggregating population data, whereas the insider perspective provides the internally held views of an individual needed for client-centered treatment planning. The Role Checklist Version 3 modifies one of the most commonly used assessment tools in occupational therapy practice, has good preliminary psychometric properties, and is theoretically consistent with both the ICF and the Model of Human Occupation. The Model of Human Occupation is the most widely used theoretical model in occupational therapy. This chapter provides an overview of the theoretical development, empirical testing, and implications for use of this participation measure by occupational therapists along with implications for population researchers.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Patricia J. Scott, Kelsey McKinney, Jeff Perron, Emily Ruff and Jessica\nSmiley",authors:[{id:"195495",title:"Dr.",name:"Patricia J",middleName:null,surname:"Scott",slug:"patricia-j-scott",fullName:"Patricia J Scott"},{id:"208801",title:"Dr.",name:"Kelsey G.",middleName:null,surname:"McKinney",slug:"kelsey-g.-mckinney",fullName:"Kelsey G. McKinney"},{id:"208802",title:"Mr.",name:"Jeffrey M.",middleName:null,surname:"Perron",slug:"jeffrey-m.-perron",fullName:"Jeffrey M. Perron"},{id:"208803",title:"Dr.",name:"Emily G.",middleName:null,surname:"Ruff",slug:"emily-g.-ruff",fullName:"Emily G. Ruff"},{id:"208804",title:"Dr.",name:"Jessica L.",middleName:null,surname:"Smiley",slug:"jessica-l.-smiley",fullName:"Jessica L. Smiley"}]},{id:"55024",doi:"10.5772/intechopen.68463",title:"Occupational Therapy in Oncology and Palliative Care",slug:"occupational-therapy-in-oncology-and-palliative-care",totalDownloads:2664,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Cancer is a chronic disease that may occur in both children and adults. Occupational therapy focuses on the activity limitations and participation problems in their life. Oncology rehabilitation involves in helping an individual with cancer to regain maximum physical, psychological, cognitive, social, and vocational functioning with the limits up to disease and its treatments in an interdisciplinary team concept. These treatment options are associated with the risk of some side effects, including fatigue, pain, cognitive problems, decrease in bone density and muscle endurance, weight loss, and stress- or anxiety-related psychosocial problems. Occupational therapy approaches are a holistic view in a client center and use training in activities of daily living, assistive technology, education of energy conservation techniques, and management of treatment-related problems, such as pain, fatigue, and nausea. In palliative and hospice care, occupational therapists support clients with cancer by minimizing the secondary symptoms related to cancer and its treatments. At the end of life, occupational therapy offers to identify the roles and activities that are meaningful and purposeful to the client with cancer and try to determine the barriers that limit their performance. Clients with cancer who have childhood cancer or adult cancer can face problems about body structure and functions, activity, and participation, which may limit their participation to their daily life.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Sedef Şahin, Semin Akel and Meral Zarif",authors:[{id:"183079",title:"Ph.D.",name:"Sedef",middleName:null,surname:"Şahin",slug:"sedef-sahin",fullName:"Sedef Şahin"},{id:"183078",title:"Dr.",name:"Burcu Semin",middleName:null,surname:"Akel",slug:"burcu-semin-akel",fullName:"Burcu Semin Akel"},{id:"198859",title:"Dr.",name:"Meral",middleName:null,surname:"Zarif",slug:"meral-zarif",fullName:"Meral Zarif"}]},{id:"69611",doi:"10.5772/intechopen.89596",title:"What to Expect: Medical Quality Outcomes and Achievements of a Multidisciplinary Inpatient Musculoskeletal System Rehabilitation",slug:"what-to-expect-medical-quality-outcomes-and-achievements-of-a-multidisciplinary-inpatient-musculoske",totalDownloads:753,totalCrossrefCites:0,totalDimensionsCites:3,abstract:"The incidence of chronic diseases is rising. Rehabilitation plays a vital role in preventing and minimizing the functional limitations associated with chronic conditions and aging. Routine outcome measures include disease-specific and unspecific general health parameters. This study evaluates indicators for medical quality outcomes from 10,373 patients (61.00 ± 13.65 years, 51.7% women) who have undergone orthopedic rehabilitation for three weeks. Inpatient rehabilitation reduces lifestyle-related risk factors, optimizes organ functioning and improves the well-being in the majority of patients (81.3%; SMD = 0.52 ± 0.38). Improvements of unspecific and indication specific outcome parameters can be observed in a comparable magnitude. However, disease specific and unspecific health factors are not directly related to each other (r = 0.19). Age, gender, ICD-classification and time of rehabilitation have an influence on initial values and on indication-specific medical outcomes but are insignificant with regards to improvements in unspecific medical outcome parameters. Inpatient rehabilitation includes two main pathways of medical practice, which can be clearly distinguished in terms of their therapeutic outcome. There are general health interventions, such as lifestyle modifications, diet and physical exercise, and symptom-specific treatments. So multidisciplinary medical rehabilitation improves general well-being and physical functioning as well as reduces risk factors in the majority of patients.",book:{id:"7543",slug:"physical-therapy-effectiveness",title:"Physical Therapy Effectiveness",fullTitle:"Physical Therapy Effectiveness"},signatures:"Vincent Grote, Alexandra Unger, Henry Puff and Elke Böttcher",authors:[{id:"308501",title:"M.D.",name:"Henry",middleName:null,surname:"Puff",slug:"henry-puff",fullName:"Henry Puff"},{id:"308502",title:"Dr.",name:"Vincent",middleName:null,surname:"Grote",slug:"vincent-grote",fullName:"Vincent Grote"},{id:"309934",title:"Dr.",name:"Elke",middleName:null,surname:"Böttcher",slug:"elke-bottcher",fullName:"Elke Böttcher"},{id:"310535",title:"Dr.",name:"Alexandra",middleName:null,surname:"Unger",slug:"alexandra-unger",fullName:"Alexandra Unger"}]}],mostDownloadedChaptersLast30Days:[{id:"55080",title:"Life Skills in Occupational Therapy",slug:"life-skills-in-occupational-therapy",totalDownloads:6021,totalCrossrefCites:3,totalDimensionsCites:0,abstract:"Occupational therapy is a health profession that uses the purposeful activities to achieve multiple and complex rehabilitation aims. The main goals of the occupational therapy are to support the reintegration of individuals in daily living skills as well as to increase their independence and autonomy. Interventions of occupational therapists have primarily focused on self-care, productivity, and leisure time activities. Since the life skills includes a wide range of abilities that enable a person to perform personal care and more complicated tasks such as traveling, shopping, community participation etc., occupational therapists provide life skills training programs to meet the needs of the clients. This chapter aims to contribute to the current understanding and practices of life skills from an occupational therapy perspective. The chapter starts with a brief discussion of the importance of life skills in occupational therapy. After this introduction, the first part takes a look at the definition of life skills and identifies core components of life skills. The second part describes assessment and interventions of life skills. The third one gives an overview about school life skills programs for children and adolescents. Finally, the last part explains some life skills programs in people with disadvantages.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Hatice Abaoğlu, Özge Buket Cesim, Sinem Kars and Zeynep Çelik",authors:[{id:"197551",title:"Dr.",name:"Hatice",middleName:null,surname:"Abaoğlu",slug:"hatice-abaoglu",fullName:"Hatice Abaoğlu"},{id:"205199",title:"Dr.",name:"Sinem",middleName:null,surname:"Kars",slug:"sinem-kars",fullName:"Sinem Kars"},{id:"205200",title:"Dr.",name:"Zeynep",middleName:null,surname:"Celik",slug:"zeynep-celik",fullName:"Zeynep Celik"},{id:"205203",title:"Ms.",name:"Özge Buket",middleName:null,surname:"Cesim",slug:"ozge-buket-cesim",fullName:"Özge Buket Cesim"}]},{id:"62493",title:"Occupational Therapy in Forensic Settings",slug:"occupational-therapy-in-forensic-settings",totalDownloads:2515,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"It is necessary for a person to comply with the expectations of society and the rules of law to which these expectations are secured. Offenders turn back to the community after the penalty was executed by isolating from society and some occupations. An occupational imbalance is seen in the individuals, during this penalty period and afterward, because of limited occupational participation. As an occupational being, this affects their physical, mental and psychological well-being. Imprisonment is an important practice in criminal law to punish criminals. This may be necessary for the protection of society from criminals, but successful integration into a community after exiting the prison is the most important factor in preventing recidivism. Occupational therapy focuses on health and well-being by using meaningful and purposeful occupations. Occupation involves any activity that people perform or participate in, such as giving care to themselves or others, working, learning, playing games, and interacting with others. From this perspective, the role of occupational therapists in forensic settings is to determine the abilities of these individuals to congregate their deprived freedoms and use them to train them for an independent and autonomous life; to provide a professional orientation, career counseling, and self-esteem; to gain some habits for physical, spiritual and moral life and to reinforce.",book:{id:"6772",slug:"occupational-therapy-therapeutic-and-creative-use-of-activity",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Therapeutic and Creative Use of Activity"},signatures:"Esma Ozkan, Sümeyye Belhan, Mahmut Yaran and Meral Zarif",authors:null},{id:"70122",title:"Parkinson’s Disease Rehabilitation: Effectiveness Approaches and New Perspectives",slug:"parkinson-s-disease-rehabilitation-effectiveness-approaches-and-new-perspectives",totalDownloads:2029,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Parkinson’s disease has been considered one of the most important and common neurodegenerative diseases in the world. Its motor and nonmotor signs determine a huge functional loss, leading the individuals to lose their independence. Although the treatment requires a pharmacological approach, physical therapy has confirmed its importance in this process. Today, neurorehabilitation is indispensable to increase many of the cardinal signs of the disease. Using traditional or technological approaches, physical therapy has reached good results in improving motor and nonmotor functions, as well as the quality of life of Parkinsonians. However, it is important to develop and to fortify the physical therapy approach so that we can provide stronger evidence about our practice.",book:{id:"7543",slug:"physical-therapy-effectiveness",title:"Physical Therapy Effectiveness",fullTitle:"Physical Therapy Effectiveness"},signatures:"Luciana Auxiliadora de Paula Vasconcelos",authors:[{id:"98546",title:"Dr.",name:"Luciana Auxiliadora",middleName:null,surname:"De Paula Vasconcelos",slug:"luciana-auxiliadora-de-paula-vasconcelos",fullName:"Luciana Auxiliadora De Paula Vasconcelos"}]},{id:"62210",title:"Occupational Therapy’s Role in the Treatment of Children with Autism Spectrum Disorders",slug:"occupational-therapy-s-role-in-the-treatment-of-children-with-autism-spectrum-disorders",totalDownloads:2725,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Occupational therapists (OT) offer a wide range of therapies for individuals with ASD on the basis of specific deficits and difficulties. This chapter explores the role that OT plays, and the expertise, in relation to the interdisciplinary team. In addition, it discusses and presents empirical support for several therapeutic approaches commonly used by OTs working with individuals with ASD.",book:{id:"6772",slug:"occupational-therapy-therapeutic-and-creative-use-of-activity",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Therapeutic and Creative Use of Activity"},signatures:"Bryan M. Gee, Amy Nwora and Theodore W. Peterson",authors:null},{id:"55049",title:"Community Participation in People with Disabilities",slug:"community-participation-in-people-with-disabilities",totalDownloads:2405,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Despite the fact that participation is an important building and a valuable target, the conceptualization, identification and measurement methods vary widely. This chapter tried to gain an insider’s perspective from the obstacles that summarize what meaning participation means, how to characterize it, and what prevents and supports participation. Participation is seen as a right and a responsibility attributed to and attributed to both the person and the community. Participation does not take place in a vacuum; the environment dynamically influences participation. The effects of this conceptual framework are discussed for change at the level of evaluation, research and systems to support the participation of the people with disability.",book:{id:"5711",slug:"occupational-therapy-occupation-focused-holistic-practice-in-rehabilitation",title:"Occupational Therapy",fullTitle:"Occupational Therapy - Occupation Focused Holistic Practice in Rehabilitation"},signatures:"Gokcen Akyurek and Gonca Bumin",authors:[{id:"32431",title:"Prof.",name:"Gonca",middleName:null,surname:"Bumin",slug:"gonca-bumin",fullName:"Gonca Bumin"},{id:"197265",title:"Dr.",name:"Gokcen",middleName:null,surname:"Akyurek",slug:"gokcen-akyurek",fullName:"Gokcen Akyurek"}]}],onlineFirstChaptersFilter:{topicId:"198",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. 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He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). 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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. 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Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. He has served as guest editor for a number of special issues of peer-reviewed international journals.",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:19,paginationItems:[{id:"82196",title:"Multi-Features Assisted Age Invariant Face Recognition and Retrieval Using CNN with Scale Invariant Heat Kernel Signature",doi:"10.5772/intechopen.104944",signatures:"Kamarajugadda Kishore Kumar and Movva Pavani",slug:"multi-features-assisted-age-invariant-face-recognition-and-retrieval-using-cnn-with-scale-invariant-",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"82063",title:"Evaluating Similarities and Differences between Machine Learning and Traditional Statistical Modeling in Healthcare Analytics",doi:"10.5772/intechopen.105116",signatures:"Michele Bennett, Ewa J. 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(Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. 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He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. 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He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. 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Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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