General characteristics of the iodothyronine deiodinases.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"7251",leadTitle:null,fullTitle:"Organizational Culture",title:"Organizational Culture",subtitle:null,reviewType:"peer-reviewed",abstract:"It is stated that the concept of organizational culture reveals that the behavior of people in organizations is highly influenced by the established attitudes and values of their members, and objective characteristics of organizational culture are everything that exists regardless of its members' thoughts. A lot of researchers of organizational culture continue to look for answers about these relationships. Thus, organizational culture is a phenomenon that constantly receives both researchers' and practitioners' attention. This book supplies the reader with a comprehensive overview of the latest results of studies carried out by scientists from different countries. A lot of attention is given to role of national cultures, organizational culture as a determinant of competitiveness, organizational structures, model of culture for innovation, transformational leadership, leadership competencies, project activity etc.",isbn:"978-1-78984-451-1",printIsbn:"978-1-78984-450-4",pdfIsbn:"978-1-83881-790-9",doi:"10.5772/intechopen.74347",price:119,priceEur:129,priceUsd:155,slug:"organizational-culture",numberOfPages:176,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"b3327ed12ba56dbfd84812f7a34e8d38",bookSignature:"Jolita Vveinhardt",publishedDate:"November 28th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/7251.jpg",numberOfDownloads:15268,numberOfWosCitations:11,numberOfCrossrefCitations:12,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:18,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:41,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 31st 2018",dateEndSecondStepPublish:"February 21st 2018",dateEndThirdStepPublish:"April 22nd 2018",dateEndFourthStepPublish:"July 11th 2018",dateEndFifthStepPublish:"September 9th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"179629",title:"Prof.",name:"Jolita",middleName:null,surname:"Vveinhardt",slug:"jolita-vveinhardt",fullName:"Jolita Vveinhardt",profilePictureURL:"https://mts.intechopen.com/storage/users/179629/images/system/179629.jpg",biography:"Prof. dr. Jolita Vveinhardt – a chief researcher of the Vytautas Magnus University, a professor at the Management Department of the Faculty of Economics and Management at the Vytautas Magnus University (Lithuania). The scientist is heading three scientific groups: 'Neuro-Relationships” (Lithuanian Sports University (LSU)), 'Managerial Solutions to Violence in Sport” (LSU), 'The Group of Interdisciplinary Research on Working Environment” (Vytautas Magnus University (VMU)). Jolita Vveinhardt is the author and co-author of three monographs, four scientific studies, one textbook, and five educational books. The scientist is the editor of three books published by InTech publishing house 'Congruence of Personal and Organizational Values” 2017, 'Organizational Culture” 2018, 'Management Culture and Corporate Social Responsibility” 2018). For the past several years she explores the phenomena of mobbing and nepotism, climate of the organisation and other aspects related to human resource management. She has published more than 200 scientific articles, 90 of which were published in peer reviewed journals of Web of Science Core Collection (Clarivate Analytics) database and read more than 50 papers in national and international scientific conferences. She is a member of editorial boards of 14 scientific periodicals. Prof. Dr. Jolita Vveinhardt is a member of 15 associations and societies. She teaches the following subjects for Master’s degree programme students: Contemporary Organization Theories (VMU) and Novelties of Management Science (LSU). Her main research interests are destructive relationships among employees (mobbing, bullying, nepotism, favouritism, social loafing, social ostracism, organizational cynicism, cronyism, protectionism), business ethics, organizational culture, management culture, organizational climate, personal and organizational values, value congruence, corporate social responsibility, decision-making, neuromanagement, etc.",institutionString:"Vytautas Magnus University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"22",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Vytautas Magnus University",institutionURL:null,country:{name:"Lithuania"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"441",title:"Organizational Behavior Management",slug:"organizational-behavior-management"}],chapters:[{id:"63860",title:"Introductory Chapter: Organizational Culture - How Much Underused Potential Does Science Have?",doi:"10.5772/intechopen.81134",slug:"introductory-chapter-organizational-culture-how-much-underused-potential-does-science-have-",totalDownloads:1257,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Jolita Vveinhardt",downloadPdfUrl:"/chapter/pdf-download/63860",previewPdfUrl:"/chapter/pdf-preview/63860",authors:[{id:"179629",title:"Prof.",name:"Jolita",surname:"Vveinhardt",slug:"jolita-vveinhardt",fullName:"Jolita Vveinhardt"}],corrections:null},{id:"63886",title:"Model of Culture for Innovation",doi:"10.5772/intechopen.81002",slug:"model-of-culture-for-innovation",totalDownloads:2254,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"In the current economic panorama, innovation is considered to be an important source of sustainable competitive advantage. The literature indicates that organizational culture is one of the most important factors in innovation stimulation, given that influencing employee behavior promotes the acceptance of innovation as a fundamental organizational value and employee commitment to it. As such, organizations should concentrate on promoting an innovative culture that permits the institutionalization of innovation, which may occur by way of planned action or by means controlled by leaders or indirect mechanisms, such as structures, procedures, or institutional policy declarations. The importance of an innovative culture model which serves as a basis for cultural transformation emerges therefrom. Previous investigations have addressed innovative culture models focused on cultural traits and/or cultural determinants. The present study offers a holistic innovative culture model that in addition to addressing cultural traits and their determinants, as is done in other models, and takes into account management competencies and organizational capacities that are required to conform to cultural traits, to achieve innovative behavior on the part of the individuals of the organization.",signatures:"Julia C. Naranjo-Valencia and Gregorio Calderon-Hernández",downloadPdfUrl:"/chapter/pdf-download/63886",previewPdfUrl:"/chapter/pdf-preview/63886",authors:[{id:"247967",title:"Dr.",name:"Julia",surname:"Naranjo-Valencia",slug:"julia-naranjo-valencia",fullName:"Julia Naranjo-Valencia"},{id:"260915",title:"Dr.",name:"Gregorio",surname:"Calderon-Hernández",slug:"gregorio-calderon-hernandez",fullName:"Gregorio Calderon-Hernández"}],corrections:null},{id:"63695",title:"The Role of National Cultures in Shaping the Corporate Management Cultures: A Three-Country Theoretical Analysis",doi:"10.5772/intechopen.78051",slug:"the-role-of-national-cultures-in-shaping-the-corporate-management-cultures-a-three-country-theoretic",totalDownloads:5091,totalCrossrefCites:8,totalDimensionsCites:9,hasAltmetrics:1,abstract:"This chapter explores answers to the question that how national cultures influence the management cultures of organizations. In this case, therefore, differences and similarities among the national cultures of Pakistan, Mexico, and the USA are under investigation in order to analyze the impacts of such differences and similarities on the management cultures of organizations located in these countries. The outcomes of the analysis based on the existing literature suggest that differences in national cultures greatly influence the way organizations are managed in these countries. These findings present cross-cultural management challenges for organizations working in these countries, especially when they want to build trilateral or bilateral business partnerships. This is in addition to the fact that the USA and Mexico are geographically far from Pakistan.",signatures:"Mohammad Ayub Khan and Laurie Smith Law",downloadPdfUrl:"/chapter/pdf-download/63695",previewPdfUrl:"/chapter/pdf-preview/63695",authors:[{id:"247709",title:"Prof.",name:"Mohammad",surname:"Khan",slug:"mohammad-khan",fullName:"Mohammad Khan"},{id:"247712",title:"Prof.",name:"Laurie Smith",surname:"Law",slug:"laurie-smith-law",fullName:"Laurie Smith Law"}],corrections:null},{id:"62016",title:"Project Organizational Culture Framework in Construction Industry",doi:"10.5772/intechopen.78628",slug:"project-organizational-culture-framework-in-construction-industry",totalDownloads:1238,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Project organizational culture (POC) has been recognized as a significant influencing factor of the success or failure of a project. Although numerous studies on this topic have been conducted to develop organizational culture models, these have mainly been for generic business settings, and one has not yet been developed for construction organizations at the project level. The aim of this chapter was to perform this task in Vietnam. A case study shows that cultural artifacts were arranged into a five-factor project organizational culture framework: “Project goal setting,” “Contractor assurance,” “Cooperative emphasis,” “Empowerment assignment,” and “Workforce emphasis.” The chapter’s findings suggest that the construction contracting organizations are more focused on the culture of mission and adaptability, with a relatively higher emphasis on clear project goals and contractor assurance. They favored a culture of involvement less, with a relatively lower emphasis on empowerment and workforce.",signatures:"Luong Hai Nguyen and Tsunemi Watanabe",downloadPdfUrl:"/chapter/pdf-download/62016",previewPdfUrl:"/chapter/pdf-preview/62016",authors:[{id:"243375",title:"Ph.D.",name:"Luong Hai",surname:"Nguyen",slug:"luong-hai-nguyen",fullName:"Luong Hai Nguyen"},{id:"243408",title:"Prof.",name:"Tsunemi",surname:"Watanabe",slug:"tsunemi-watanabe",fullName:"Tsunemi Watanabe"}],corrections:null},{id:"61335",title:"Organizational Culture as a Determinant of Construction Companies’ Competitiveness: Case Study of Croatia",doi:"10.5772/intechopen.77165",slug:"organizational-culture-as-a-determinant-of-construction-companies-competitiveness-case-study-of-croa",totalDownloads:1317,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The aim of this chapter is to assess the organizational culture in construction industry in Croatia. The introductory part of the chapter highlights the purpose of the study presented in terms of learning the characteristics of the current and preferred organizational culture of the Croatian construction industry as well as understanding the relationship between the culture and competitiveness. Being a transitional country, Croatia is facing the need for behavior change of companies seeking competitive advantage, especially after becoming a part of the united European market. In a labor-intensive business like construction, adaptation of companies strongly depends on the underlying values and assumptions of their employees. Therefore, change management implies a need to learn about culture profiles. Results of the conducted research reveal culture profiles within construction industry in Croatia in respect of the size, core business, regional orientation and ownership of the analyzed companies. The preferences of existing engineers together with expectations of Generation Y have been also considered in order to anticipate the trends and necessary changes of organizational culture in construction industry in Croatia. Finally, findings of the cross-country analysis of culture’s implications on competitiveness will be presented, proving that culture’s role should be considered by decision makers trying to improve competitiveness.",signatures:"Ivana Šandrk Nukić",downloadPdfUrl:"/chapter/pdf-download/61335",previewPdfUrl:"/chapter/pdf-preview/61335",authors:[{id:"246557",title:"Ph.D.",name:"Ivana",surname:"Šandrk Nukić",slug:"ivana-sandrk-nukic",fullName:"Ivana Šandrk Nukić"}],corrections:null},{id:"62015",title:"Reflex-Adaptive Organizational Structure in the Implementation of Large-Scale Projects",doi:"10.5772/intechopen.78627",slug:"reflex-adaptive-organizational-structure-in-the-implementation-of-large-scale-projects",totalDownloads:1046,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"This work reflects the results of research on the study and creation of a new class of highly effective organizational structures of the reflex-adaptive type in the context of the implementation of a large-scale project. The research is based on the information paradigm of organizational structures’ formation. From this perspective, any manufacturing company is represented as a system that converts resources into a final product on the basis of an information imperative. The structure of the production management and executive subsystems is selected. The composition and functions of the subsystems and the formation of system elements’ feedbacks are described. Also, the development methodology of the management and executive subsystems is presented along with synthesis of these subsystems into the cybernetic type organizational structure. The chapter focuses on developing enterprise substructure of the executive subsystem, which is called the project matrix, which factually is its network model. Its properties, and transformation rules are described, and the algorithm of its formation is presented. The system properties of the organizational structure are examined in detail. The methodology for forming the reflex-adaptive organizational structure is presented. Particular attention is paid to the quantitative estimation of flexibility and stableness of organizational structures.",signatures:"Andrey Morozenko",downloadPdfUrl:"/chapter/pdf-download/62015",previewPdfUrl:"/chapter/pdf-preview/62015",authors:[{id:"246628",title:"Dr.",name:"Andrey",surname:"Morozenko",slug:"andrey-morozenko",fullName:"Andrey Morozenko"}],corrections:null},{id:"63974",title:"Leadership Competencies Affecting Projects in Organization",doi:"10.5772/intechopen.80781",slug:"leadership-competencies-affecting-projects-in-organization",totalDownloads:1670,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Leadership and organizational culture are linked to project performance. The culture of the organization exerts an influence on the leader and shapes the actions and competencies of the leader with the passage of time. For last few decades, project management has extensively been involved in management of projects but still projects are not guaranteed to be successful in various organizational environments. There are certain factors affecting management of projects in different situations where the competence of project leadership is one of the key factors. This chapter employed different keywords and methods for selection of articles synthesizing findings and research gaps of earlier studies. This chapter offers certain limitations and future directions for researchers. The outcomes of this chapter are expected to advance the body of knowledge and help the practitioners in the field of leadership and project management.",signatures:"Riaz Ahmed",downloadPdfUrl:"/chapter/pdf-download/63974",previewPdfUrl:"/chapter/pdf-preview/63974",authors:[{id:"195432",title:"Dr.",name:"Riaz",surname:"Ahmed",slug:"riaz-ahmed",fullName:"Riaz Ahmed"}],corrections:null},{id:"63543",title:"Transformational Leadership and Organizational Culture: Keys to Binding Employees to the Dutch Public Sector",doi:"10.5772/intechopen.81003",slug:"transformational-leadership-and-organizational-culture-keys-to-binding-employees-to-the-dutch-public",totalDownloads:1395,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In response to the growing ethnic and cultural diversity in Dutch society and its labor market, public organizations in the Netherlands are increasingly crafting diversity policies and conducting diversity interventions. Little is known, however, about the effectiveness of interventions that are used to improve employee engagement in the public sector. This chapter discusses the influence of diversity interventions related to the binding of employees with Dutch public organizations with an emphasis on the role of leadership and organizational culture. This chapter concludes that transformational leadership and organizational culture are the keys to the binding of employees to the public sector in today’s diverse Netherlands. An inclusive organizational culture in which there is a room for diversity is decisive for the success of interventions used in public organizations. It also appears that managers of these organizations play a critical role. The effect of diversity interventions on the binding of employees with their organizations appears to be less when the manager uses a transformational leadership style. This demonstrates the importance of an inclusive organizational culture and a people-oriented transformational leadership style in the Dutch public sector.",signatures:"Saniye Çelik",downloadPdfUrl:"/chapter/pdf-download/63543",previewPdfUrl:"/chapter/pdf-preview/63543",authors:[{id:"246109",title:"Dr.",name:"Saniye",surname:"Çelik",slug:"saniye-celik",fullName:"Saniye Çelik"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5858",title:"Congruence of Personal and Organizational Values",subtitle:null,isOpenForSubmission:!1,hash:"e59bb665f108a72351652ae2bb5a3bcd",slug:"congruence-of-personal-and-organizational-values",bookSignature:"Jolita Vveinhardt",coverURL:"https://cdn.intechopen.com/books/images_new/5858.jpg",editedByType:"Edited by",editors:[{id:"179629",title:"Prof.",name:"Jolita",surname:"Vveinhardt",slug:"jolita-vveinhardt",fullName:"Jolita Vveinhardt"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6673",title:"Dark Sides of Organizational Behavior and Leadership",subtitle:null,isOpenForSubmission:!1,hash:"27634eca6401e330ec9b04f3a1e7e770",slug:"dark-sides-of-organizational-behavior-and-leadership",bookSignature:"Maria Fors Brandebo and Aida Alvinius",coverURL:"https://cdn.intechopen.com/books/images_new/6673.jpg",editedByType:"Edited by",editors:[{id:"229002",title:"Dr.",name:"Maria",surname:"Fors Brandebo",slug:"maria-fors-brandebo",fullName:"Maria Fors Brandebo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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Science , IT and MCA level subjects such as C, C++, Java, OS, DBMS, MIS,OOAD,ERP, RTS,Web Technology, Computer Architecture, Computer Networks, Ubiquitous Computing, Mobile Computing, Software Engineering. She was the Organising Member in International Conferences - Springer ICACIE -2016, 2017, 2018 and IEEE ANTS-2017. 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On account of TH action can be controlled in individual cells through selective TH uptake and intracellular TH metabolism, the placenta is an important link in the maternal-fetal communication network for THs which are essential for the normal development and differentiation of the fetus [1-3]. Generally, intracellular activation or inactivation of L-thyroxine (T4) and 3,5,3\'-triiodothyronine (T3) in turn is determined by three types of iodothyronine deiodinases (Ds), namely DI, DII, and DIII [4-7]. The placenta transports and metabolizes maternal THs, and mainly expresses DIII, which inactivates T4 and other iodothyronines and thus limits the transfer of maternal active THs to the fetus in the late pregnancy [8]. DII is also active in the placenta and locally provides active T3 from the maternal prohormone T4 for placental metabolic functions [1,2]. The placental expression of DI, which also activates T4 to T3, is still controversial. Because of the lipophilic nature of THs, it was thought that they traversed the plasma membrane by simple diffusion [9,10]. The transport of T4 and T3 in and out of cells is controlled by several classes of transmembrane TH-transporters (THTs) [11], including members of the organic anion transporter family (OATP), L-type amino acid transporters (LATs), Na+/Taurocholate cotransporting polypeptide (NTCP), and monocarboxylate transporters (MCTs) [10,12]. Particularly, monocarboxylate transporter 8 (MCT8) has recently been identified as an active and specific TH transporter. Also, placental membranes are also involved in 4\'-OH-sulfation reactions of iodothyronines [8]. Sulfation (S) plays a role in TH metabolism by interacting between the deiodination and sulfation pathways of TH [13]. Interestingly, placental cells express high affinity, stereo-specific, energy-dependent uptake systems for T4 and T3. On the other hand, the cellular activity of THs is usually classified as genomic (nuclear) and non-genomic (initiated either at cytoplasm or at membrane TH receptors) [14-21]. Binding of T3 to its nuclear thyroid receptors (TRs) directly affects transcription of many genes that are important in development [22].
In general, pregnancy is accompanied by profound alterations in the thyroidal economy (hypo- or hyper-thyroidism), resulting from a complex combination of factors specific to the pregnant state, which together concur to stimulate the maternal thyroid machinery [1,23]. Also, clinical studies showed that maternal TH deficiency during the first trimester of pregnancy can affect the outcome of human neurodevelopment [24,25]. Experiments in rats showed that early maternal TH deficiency affects neuronal migration in the cortex [26], while maternal hyperthyroidism too can disturb fetal brain development [27]. Experimental data on the mechanisms regulating intracellular TH availability and action prior to the onset of fetal TH secretion, however, remain scarce. Thus, in this chapter will be aware about the significant roles of THs, their metabolism by Ds and sulfotransferases, their transport by THTs and their binding to TRs from the mother via the placenta to the fetal compartment especially during the gestation period in both human and animals.
The synthesis of THs is regulated through the hypothalamus–pituitary–thyroid (HPT) axis [28] and the follicular cells of the thyroid gland synthesize and secrete T4 and T3 [1,2,21]. This process is under the control of the circulating TH levels through negative feedback loops of this axis [28]. The availability of the active ligand T3 within tissues is locally determined by the action of the iodothyronine deiodinases (Ds) [29]. There are three selenocysteine monodeiodinase subtypes (DI, DII and DIII) [30]. Whilst T3 is generated by the activity of DI and DII, via 5\'- reductive or outer ring deiodination (ORD) of the T4 [31], DIII activity (and to a lesser extent that of DI) convert T4 to 3,3\',5\'-tri-iodothyronine (reverse T3; rT3) and T3 into 3,3\'-T2 via inner ring deiodination (IRD), in effect acting as a deactivating enzyme for THs [13,32].
Activities of all three iodothyronine deiodinase subtypes have been demonstrated in most rat placenta [33]. However, in contrast to man, rodent total serum T3 and T4 increase with gestation [34] and the predominant subtype expressed appears to be DIII [35], although DII is also present with significant activity [36]. Placental DIII activity is much greater (approx. 200 times) than DII activity; however, the activity and expression of both DII and DIII fall as gestation progresses [37-40]. Placental DII provides T3 for ‘housekeeping’ processes, and as indicated above, its activity is much less than that of D3 [40]. DII has been localized to the villous cytotrophoblasts in the first trimester and syncytiotrophoblasts in the third trimester, whereas DIII has been localized to the villous syncytiotrophoblasts in both the first and third trimesters of pregnancy [39]. Both DIII mRNA and activity are present at the implantation site in rodents, as early as gestational day 9 (GD 9), being expressed in mesometrial and antimesometrial decidual tissue [41]. Also, in rabbit [42] and pig [43], the placenta appears to express DIII activity predominantly. The positioning of the deiodinases, particularly DIII, suggests that they might regulate the amount of maternal TH reaching fetal circulation [40]. Interestingly, however, fetuses with total thyroid agenesis but with evidence of circulating maternal TH have normal placental DIII activity, suggesting that there might be other factors modulating T4 access to the deiodinases, such as intracellular protection of TH by TH-binding protein (THBP) [40,44]. Collectively, express placental Ds (II, III) may play a critical role in delivery of TH to the fetus as summarized in figure1 [2,45-47] and table 1 [1,2,31,48].
Summary about the interactions of maternal, placental and fetal thyroid metabolism. I, II and III denote deiodinases type 1 (DI), type two (DII) and type three (DIII). SO4 is a sulfation pathway and –SO4 is a desulfation pathway. CNS is central nervous system, TRH is thyroid releasing hormone, M-TRH is maternal thyroid releasing hormone, TSH is thyrotrophin, T2 is diiodothyronine, T3 is triiodothyronine, rT3 is reverse triiodothyronine, T4 is thyroxine, T2S is diiodothyronine sulfate, T3S is triiodothyronine sulfate, T4S is thyroxine sulfate, rT3S is reverse triiodothyronine sulfate, MCT8 is monocarboxylate transporter 8, OATP4A1 is organic anion transporter 4A1, TBG is thyroxin binding globulin, TTR is transthyretin, ACTH is adrenocorticotrophin and hCG is human chorionic gonadotrophin.
Characteristic | DI | DII | DIII | ||
Reaction kinetics | Ping-pong | Sequential | |||
Reaction catalyzed (Deiodination) | 5 or 5\' (ORD+IRD) | 5\' (ORD) | 5 (IRD) | ||
Main form | T4-T3, rT3- T2 | - T4- rT3, T3- T2 | - T4- rT3- T2 | ||
Substrate preference | 5: T4S"/>T3S"/>"/>T3, T4 5\': rT3, rT3S"/>T2S"/>"/>T4 | T4"/>rT3 | T3"/>T4 | ||
Sulfation of substrates | Stimulation | Inhibition | |||
Substrate limiting | 0.5 mM | 1–2 nM | 5–20 mM | ||
In vitro cofactor limiting | 1–10 Mm DTT | "/>10 mM DTT | =70 mM DTT | ||
Molecular mass (kDa) | 29 | 30 | 32 | ||
Selenocysteine | present | ||||
Homodimer | Yes | ||||
Location | - Liver, kidney, thyroid and pituitary. | - Pituitary, brain, BAT, thyroida, hearta and skeletal musclea. | - Brain, skin, uterus, placenta, fetus and in other sites of the maternal- fetal interface, such as the umbilical arteries and veins. | ||
Subcellular location | - Liver: endoplasmic reticulum. - kidney: basolateral plasma membrane | - Microsomal membranes | |||
Functions | - Production serum T3 and the clearance of serum rT3. | - Catalyzes the outer ring deiodination of T4 to T3 and is thus important for the local production of T3. | - Catalyzes the inner ring deiodination of T4 to rT3 and of T3 to 3,3\'-T2. | ||
Activity in hypothyroidism | - Decrease in liver and kidney. - increase in thyroid. | - Increase in all tissues. | - Decrease in brain. | ||
Activity in hyperthyroidism | - Unknown in liver and kidney. - Increase | - Decrease in most tissues. - Increase in thyroida. | - Increase in brain. | ||
Low-T3 syndrome | - Decrease | - No change | |||
Active site residues | - Selenocysteine histidine and phenylalanine. | - (Seleno-)cysteine? | - Selenocysteine | ||
Human gene structure and location | - 1p32-p33, 17.5 kb and 4 exons. | - 14q24.3, 2 exons, and 7.4-kb intron. | - 14q32 | ||
Promoter elements | - TRE, RXR, no CAAT or TATA box. | -- | |||
Propylthiouracil inhibitor | ++++ | + | +/- | ||
Aurothioglucose inhibitor | ++ | ||||
Iopanoic acid inhibitor | +++ | ++++ | +++ | ||
Thiouracils | ++++ | -/+ | - | ||
iodoacetate | + | ? | |||
flavonoids | + | +++ |
General characteristics of the iodothyronine deiodinases.
Membrane transporters mediate cellular uptake and efflux of TH [12,40,49]. The ability to transport TH has been described in members of different transporter groups including the monocarboxylate transporters (MCT), L-type amino acid transporters (LAT), Na+/Taurocholate cotransporting polypeptide (NTCP), and organic anion transporting polypeptides (OATP) [50]. With the exception of MCT8, these transporters do not exclusively transport TH and they all have slightly different affinities for specific forms of TH. To date six different THTs are known to be present in the placenta: MCT8, MCT10, LAT1, LAT2, OATP1A2 and OATP4A1 but their relative contributions to placental TH transport are unknown [50-55]. Also, their anatomical localization, ontogeny in the human placenta and relative affinity for the TH and thyronines are very complex. MCT8, MCT10, OATP1A2, OATP4A1 and LAT1 are expressed in villous syncytiotrophoblasts, and MCT8, MCT10 and OATP1A2 in cytotrophoblasts [50]. Although transporters in the apical syncytiotrophoblast membrane are well placed to maximize maternal cellular TH uptake early in gestation, the large numbers and variety of THTs are intriguing [51,53,55]. Moreover, the expression of MCT8 mRNA increased with advancing gestation [55] but there is limited information regarding the ontogeny of the other THTs. In addition, it is likely that the lower expression of MCT8, MCT10, OATP1A2 and LAT1 before 14 week compared to term, as well as the nadir in OATP4A1 expression in the late 1st and early 2nd trimester, may play a role in the necessary limitation of maternal-fetal TH transfer, particularly around the time of onset of endogenous fetal TH production in the early 2nd trimester [56]. Increased expression of THTs in late gestation is consistent with the proposal that there is continued/ increased maternal to fetal supply of TH in the 3rd trimester despite increasing fetal TH production [57]. It is also likely that increased expression of these transporters with gestation may also fulfil the increased need for other biological substances for fetal growth and development, such as amino acids. The most factors regulating the placental expression of these transporters are unknown until now. There are suggestions in rodents that the activity of system-L and the expression of MCT8 in non-placental tissues are influenced by thyroid status [58] suggesting that TH may be a regulator of its own transporters [50]. During the passage of THs from the maternal circulation to the fetal circulation, each THT is likely to have a specific role in each different plasma membrane layer, which might include cellular influx, efflux, or both [59]. To sum, THTs of the various placental cell types serve as channels that help to maintain the differences in the composition of THs and their metabolites between maternal and fetal circulations (figure1 [2,45-47] and tables 2 & 3 [51,52,55,59,60,61]). The relative contributions of these THTs to the transplacental transport of thyroid hormones are still a subject for research.
Transporter | Iodothyronine derivates | Specificity |
MCT8 | T3, T4, rT3, T2 | +++ |
MCT10 | T3, T4 | ++ |
OATP1A1 | T3, T4, rT3, T2, T4S, T3S, rT3S, T2S | + |
OATP1A2 | T4, T3, rT3 | |
OATP1A3 | T4, T3 | |
OATP1A4 | ||
OATP1A5 | ||
OATP1B1 | T4, T3, T3S, T4S, rT3S | |
OATP1B2 | T3, T4 | |
OATP1B3 | rT3, T4S, T3S, rT3S | |
OATP1C1 | T4, rT3, T3, T4S | ++ |
OATP2B1 | T4 | + |
OATP3A1 (V1/V2) | ++ | |
OATP4A1 | T3, T4, rT3 | + |
OATP4C1 | T3, T4 | |
OATP6B1 | ||
OATP6C1 | ||
LAT1 | T3, T4, rT3, T2 | |
LAT2 | ||
NTCP | T4, T3, T4S, T3S | ++ |
Types of thyroid hormone transporters and their iodothyronine derivates.
Transporter family | Monocarboxylate transporters | System L amino acidtransporters | Organic anion transporting polypeptides | |||
MCT8 | MCT10 | LAT1 | LAT2 | OATP1A2 | OATP4A1 | |
Heterodimer | N/A | 4F2hc | N/A | |||
Additional molecules transported | N/A | Aromatic amino acids | Large neutral amino acids | Amphipathic organic compounds | ||
Localization in first and second trimestera | ST, CT, EVT | N/A | ||||
Localization in third trimesterb | ST | N/A | STap | N/A | STap | |
Km T4 (μM) | 4.7c | "/>Km T3d | 7.9 | 8.0 | "/>Km T3 | |
Km T3 (μM) | 4.0c | ≤4.0d | 0.8 | 6.5 | 0.9 | |
Km rT3 (μM) | 2.2c | N/A | 12.5 | N/A | ||
Km T2 (μM) | N/A | 7.9 | N/A |
Expression of the thyroid hormone transporters in human placenta.
Sulfation (S) appears to be an important pathway for the reversible inactivation of THs during fetal development [2,13,45-47]. Monique Kester and the group from Erasmus University have used a rat model to study the regulation of fetal TH status and have also extended their studies to human pregnancy [62]. The sulfotransferases catalyze the sulfation of the hydroxyl group of compounds, using 3\'-phosphoadenosine-5\'-phosphsulfate (PAPS) as the universal sulfate donor [63]. This co-factor PAPS is synthesized from two ATP molecules and inorganic sulfate. Neither the DII or DIII iodothyronines catalyze the deiodination of sulfated iodothyronines nor sulfation strongly facilitates the inner ring deiodination of T4 and T3 by DI, but blocks the outer ring deiodination of T4 (activation) [13,64]. The outer ring deiodination of rT3 by DI is not affected by sulfation [64]. Sulfation thus induces the irreversible degradation of TH. Thus, rapid inner ring deiodinations of T4S, T3S and out ring deiodination of rT3S lead to high concentrations of these sulfates in plasma of adult humans [13,65].
High concentrations of the different iodothyronine sulfates, T4S (thyroxine sulfate), T3S (triiodothyronine sulfate), rT3S (reverse triiodothyronine sulfate) and T2S (diiodothyronine sulfate), have been documented in human fetal and neonatal plasma as well as in amniotic fluid [65,66], and similar findings have been reported for sheep [67]. This has classically been explained by the low hepatic DI expression in the human fetus until the postnatal period [68] and lack of hepatic DI expression until birth in rats [69]. Also, in the rat placenta, where there are insignificant sulfotransferases activities but high DIII activity, irreversible inactivation of DIII appears to be the predominant pathway of iodothyronine metabolism [13]. In the rat fetal liver, sulfotransferase activity is present from the end of the third trimester (GD 17), a time when DI activity is relatively absent [69]. The TH-sulfates may accumulate under such circumstances to form a ‘reservoir’ of inactive TH from which active hormone may be liberated, in a tissue specific and gestational dependent manner by the action of arylsulfases [13]. To date, six members of this family (ARSAeARSF) have been identified in humans [13,70]. It is interesting that DIII is abundantly expressed in the human placenta [39] and deiodinates T4 and T3 to 3,3\'-T2 and rT3, respectively, thus providing substrates for these actions. In the human fetal circulation, T4S and in particular T3S, may represent a reservoir of inactive TH, from which active hormone may be liberated as required (vide supra) [13]. The iodothyronine sulfates in human fetal circulation and amniotic fluid may be derived, at least in part, from sulfation of THs by thermostabile phenol sulfotransferases in the uterus and placenta [13,45]. This may provide a route for the supply of maternal TH to the fetus in addition to placental transfer. Alternatively, iodothyronine sulfates may accumulate in the fetal circulation because of the absence of hepatic transporters which mediate their removal from plasma. It has been demonstrated recently that hepatic uptake of the different iodothyronine sulfates in rats is mediated at least in part through the NTCP and OATP families [71]. Thus, the TH-sulfation mechanism might be useful for non-invasive prenatal diagnostics of fetal thyroid function which is autonomously regulated. The overviews presented here are consistent with the evolving view that sulfation is a major chemical defense system in the maternal-fetal thyroid axis and will hopefully provide a basis for understanding more about these enzymes.
Although the thyroid gland predominantly secretes T4, T3 is the most active TH, since it has a higher affinity by the nuclear thyroid hormone receptors (TRs; α, β) (Figure 2A) [75], which mediate most actions of these hormones [72,73]. THs are released by the thyroid gland to the circulation where they are carried bound to proteins such as thyroxin binding globulin (TBG), transthyretin (TTR) or serum albumin (Table 4) [74]. The level of albumin, which has the lowest T4 affinity and enables a fast release of T4 [76], gradually decreases during pregnancy [77]. TBG is an active carrier and has a possibility to switch between the high-affinity and the low-affinity form [78]. TBG levels are the highest in the second and third trimester of pregnancy [79,80] and the same holds true for TH-binding ratio [81] and thyroid-binding capacity [82], which decreases as soon as 3-4 days after delivery.
A) Schematic representation of major thyroid hormone receptors (TRα, β) domains and functional sub-regions. (B) General model for genomic and non-genomic actions of TH in both adult and fetus; Schematic representation of thyroid hormones (THs; T4 and T3) genomic actions, initiated at the nuclear receptors (TRβ), and non-genomic actions, initiated at cytoplasmatic receptors (TRβ, TRα) and at the plasma membrane on the membrane receptors, particularly integrin αvβ3 receptor. T4 binding (but not T3) to cytoplasmic TRα may cause a change of state of actin. T3 binding (but not T4) to cytoplasmic TRβ activates the phosphatidylinositol 3-kinase (PI-3K) pathway leading to alteration in membrane ion pumps and to transcription of specific genes. TH binding to the integrin receptor results in activation of mitogen-activated protein kinase (MAPK/ERK1/2). Phosphorylated MAPK (pMAPK) translocates to the nucleus where it phosphorylates transcription factors including thyroid receptors (TRβ), estrogen receptor (ER) and signal transducer activators of transcription (STAT). Generally, activity is regulated by an exchange of corepressor (CoR) and coactivator (CoA) complexes.
TH-binding protein | Cellular location |
Transthyretin | Plasma |
T4-binding globulin | |
Serum albumin | |
Lipoproteins | |
Myosin light chain kinase | Cytoplasmic |
Pyruvate kinase, subtype M1 | |
Pyruvate kinase, subtype M2 | |
Prolyl 4-hydroxylase, b-subunit | |
Aldehyde dehydrogenase |
Types of thyroid hormone-binding proteins.
T4 and T3 enter the cell through transporter proteins such as MCT8 and 10 or OATPs. Inside the cells, deiodinases (DI, II) convert T4, the major form of thyroid hormone in the blood, to the more active form T3. DIII produces rT3 and T2 from T4 and T3, respectively [1,73,83]. T3 binds to nuclear TRs, TRα and TRβ, that activate transcription by binding, generally as heterodimers with the retinoid X receptor (RXR) (Table 5) [87], to thyroid hormone response elements (TREs) located in regulatory regions of target genes [84]. Activity is regulated by an exchange of corepressor (CoR) and coactivator (CoA) complexes. Negative TREs (nTRE) can mediate ligand-dependent transcriptional repression, although in this case the role of coactivators and corepressors is not well defined [73,85]. TRs can also regulate the activity of genes that do not contain a TRE through “cross-talk” with other transcription factors (TF) that stimulate target gene expression [28,86]. Both receptors and coregulators are targets for phosphorylation (P) by signal transduction pathways stimulated by hormones and growth factors [84,85]. Thus, the nuclear actions of T3 are sensitive to inhibitors of transcription and translation and have a latency of hours to days [9,73]. Thus, the genomic action will play a critical role in the cellular proliferations and differentiations.
Although T3 is known to exert many of its actions through the classical genomic regulation of gene transcription, a number of T3 effects occur rapidly and are unaffected by inhibitors of transcription and protein synthesis [88,89]. However, the levels of circulating THs are tightly regulated and stable and thus rapidly mediated responses must involve regulation of pre-receptor ligand metabolism, ligand membrane transport or receptor availability leading to local cell type specific variation in thyroid hormone signaling [87]. Non-genomic actions of THs have been described at the plasma membrane, in the cytoplasm and in cellular organelles [15,21,83,90,91]. They have included the modulation of Na+, K+, Ca2+ and glucose transport, activation of protein kinase C (PKC), protein kinase A (PKA) and mitogen-activated protein kinase (ERK/MAPK) and regulation of phospholipid metabolism by activation of phospholipase C (PLC) and D (PLD) [92-94]. Generally, binding of T3 to a subpopulation of receptors located outside the nuclei can also cause rapid “non-genomic” effects through interaction with adaptor proteins, leading to stimulation of signaling pathways. T4 can also bind to putative membrane receptors such as integrin receptor (αVβ3) inducing MAPK activity [18,73,95,96]. Thus, several observations suggest that the rapid nongenomic effects of TH are widespread and may be involved in multiple physiological processes in many different cell types [87]. However, no specific membrane associated TR isoform or thyroid hormone binding G protein-coupled receptors (GPCR) have been identified or cloned and thus the area remains controversial.
Compare face | Ligand | Receptor | Dimerization partners | Associated factors or signalling pathways | Actions |
Classical, genomic actions (hours to days) | |||||
Nuclear transcription | T3 | TRα and TRβ | RXR and TRs | - NCoR/SMRT Basal | - Transcriptional repression |
- SRC/p160/TRAPs | - Transcriptional activation and repression | ||||
Non-classical non-genomic actions (seconds to minutes) | |||||
Cell surface receptor | T4/T3 | Putative GPCR | Raf1/MEK/MAPK | TR phosphorylation and altered transcriptional activity p53 phosphorylation and general transcriptional activity | |
MEK/STATs | Increased STAT mediated transcription | ||||
Mitochondrial gene transcription | T3 | TRαp43 | mtRXR and mtPPAR | Co-factors? | Increased mitochondrial gene expression |
Mitochondrial oxidation | T3 | TRαp28 | ANT, UCPs | Increased thermogenesis | |
T2 | Cytochrome- | Increased oxidative phosphorylation |
General thyroid hormone actions.
There also are reports of nongenomic effects on cell structure proteins by THs. Actin depolymerization blocks DII inactivation by T4 in cAMP-stimulated glial cells, suggesting that an intact actin cytoskeleton is important for this downregulation of deiodinase activity [9,97]. Interestingly, T4, but not T3, can promote actin polymerization in astrocytes [98] and thus may influence the downregulation of DII activity by a secondary mechanism, perhaps by targeting to lysosomes [9,99]. Moreover, the regulation of actin polymerization and F-actin contents also could contribute to the effects of TH on arborization, axonal transport, and cell-cell contacts during brain development, where the regulation of these factors is fundamental for the organization of guidance molecules such as laminin on the astrocyte plasma membrane and modulates integrin–laminin interactions [3]. T4 was required for integrin clustering and attachment to laminin by integrin in astrocytes [100]. These data suggest that the non-genomic action may play an important role in promoting the normal development.
THs are essential for normal neonatal development in both humans and rodents [3,23,101-104] and the experimental work indicated that THs are transported from the mother to the fetus, albeit in limited amounts, and that the fetal brain is exposed to THs before initiation of fetal TH synthesis [1]. In addition, the maternal TH regulates early fetal brain development in human and animal models [2]. The TH of maternal origin can cross the placenta and reach the fetus [2,105,106] and that TRs are expressed in the fetal rat brain before the onset of fetal thyroid function [107]. Thus, the THs are essential for brain maturation from early embryonic stages onward [103,104,108]. However, TH-dependent stages of fetal brain development remain to be characterized. Notably, the maternal thyroid is the only source of T4 and T3 for the brain of the fetus because its thyroid gland does not start contributing to fetal requirements until midgestation in man, and days 17.5–18 in rats [109]. Therefore, the amount of maternal T4 that the fetus receives early in pregnancy will determine TH action in its brain because it depends on maternal T4 for its intracellular supply of the active form of the hormone, T3. However, fetal brain total T3 levels are low (ca. 100 pM) at this time [1], but receptor occupancy approximates 25% since free T3 concentrations are high in the nucleus relative to the cytosol [110]. In general, materno-fetal transfer of THs has been demonstrated in early fetal stages [111] and continues, at least in the case of fetal inability, to produce sufficient TH until term [44]. Actually, brain cells can protect themselves against higher fetal T4 and T3 values by decreasing DII and increasing DIII activity [2]. Taken together, thyroid activity undergoes many changes during normal pregnancy including [1,112-115]: (a) a significant increase in serum thyroxine-binding globulin, thyroglobulin, total T4, and total T3; (b) an increase in renal iodide clearance; and (c) stimulation of the thyroid by human chorionic gonadotropin (hCG). These changes can make diagnosis of thyroid dysfunction during pregnancy difficult.
THs are important for growth and differentiation of a variety of organs, including the brain. In developing brain, THs stimulate and coordinate processes such as neuronal proliferation, migration, growth of axons and dendrites, synapse formation and myelination [1,2]. Disturbance of these processes leads to abnormalities in the neuronal network and may result in mental retardation and other neurological defects, including impaired motor skills and visual processing [115]. If TH deficiency occurs at the perinatal stage, such as in congenital hypothyroidism, timely treatment may rescue most of the symptoms. A shortage of THs starting at the early stages of pregnancy, such as in cretinism, results in neurological deficits that cannot be rescued by exogenous TH addition at later stages [25].
The role of THs in brain development has been studied most extensively in the cerebellum [23,116]. The cellular proliferation and migration processes are disturbed by TH deficiency as investigated predominantly in rodents, where most of cerebellar maturation occurs in the early postnatal period [2]. In the hypothyroid cerebellum, the number and length of Purkinje cell dendrites is severely reduced [1]. At the same time the granule cell parallel fiber growth is reduced, leading to a reduction in axodendritic connections between the Purkinje cells and the granule neurons [117]. Additionally, other cell types such as astrocytes, Golgi epithelial cells, basket cells, and oligodendrocytes show abnormalities under hypothyroid conditions [116]. Several TH target genes have been identified over the years, including genes coding for myelin proteins, cytoskeletal proteins, neurotrophins and their receptors, transcription factors, and intracellular signaling proteins [118] and recent transcriptome analyses continue to increase their number [119-121]. Some of these genes only respond to thyroid status for a short and specific period during development, a feature that is typical for many TH target genes in brain [122]. Interestingly, a reduction or absence of TH during brain maturation yields molecular, morphological and functional alterations in the cerebral cortex, hippocampus and cerebellum [123-132].
Neonatal hyperthyroidism was described as a critical disease marked mainly by cardiac symptoms, poor weight gain and severe neurological manifestations [1,133-137]. Fetal thyrotoxicosis is the result of thyroid-stimulating antibody transfer to the fetus in the setting of maternal Grave’s disease [2,138]. It may present with a variety of clinical features, which include persistent sinus tachycardia, fetal hydrops, intrauterine growth restriction, goiter and fetal demise [1,139]. The vast majority of cases of excessive serum TH concentration seen in pregnancy are due to the overproduction of THs (Graves’ disease, toxic nodular goiter); in the postpartum period, thyrotoxicosis may be due to exacerbation of Graves’ hyperthyroidism or to the release of thyroid hormone due to an acute autoimmune injury to the thyroid tissue (postpartum thyroiditis-PPT) [2,140].
The management of hyperthyroidism in pregnancy, which most often is caused by Graves’ disease, has been reviewed recently [141,142]. Hyperthyroidism occurs in about 0.2–0.4% of all pregnancies. Hyperthyroidism should be distinguished from gestational transient thyrotoxicosis, which is due to the TSH-receptor stimulating effects of hCG [143,144]. This hCG-induced hyperthyroidism is mostly mild and need not be treated. Only rare cases with extremely high hCG (i.e. due to a hydatidiform mole) might induce severe thyrotoxicosis [145]. The signs and symptoms of hyperthyroidism due to Graves’ disease may aggravate in the first trimester and thereafter may become mild. Untreated hyperthyroidism is associated with severe effects on maternal and neonatal outcome. The risk for premature fetal loss, preeclampsia, preterm delivery, intrauterine growth retardation and low birth weight is significantly increased [144]. It has to be considered that the transfer of stimulating receptor antibodies (TSAbs) are transferred from the mother to the child, and therefore the fetus is at risk to develop Graves’ disease. Close monitoring of the fetus is, therefore, strictly recommended, even in mothers treated by thyroidectomy before pregnancy but have still elevated TSAbs [142].
Different cases of hyperthyroidism.
Taken together, there are two known causes of central hyperthyroidism [1,146]; (1) TSH-producing pituitary tumors (TSHomas) and (2) the syndrome of pituitary resistance to thyroid hormone (PRTH). In general, thyrotoxicosis is the syndrome resulting from an excess of circulating free T4 and/or free T3 [147,148]. Babies likely to become hyperthyroid have the highest TSH receptor antibody titer whereas if TSH receptor antibodies are not detectable, the baby is most unlikely to become hyperthyroid (Figure 3) [1,2,149]. In the latter case, it can be anticipated that the baby will be euthyroid, have transient hypothalamic-pituitary suppression or have a transiently elevated TSH, depending on the relative contribution of maternal hyperthyroidism versus the effects of maternal antithyroid medication, respectively [150].
about the developmental thyroid hormone mechanisms (deiodinases, transporters, sulfotransferases and receptors) in human [1,2,50,52,127,130,151-154], rat [1,2,41,60,135,154-156] and chicken [7,157-170]. Note that the chicken is born early compared to the rat and human, as well as the rat is born early compared to the human (Table 6).
Human | Rodent (rat) | Chicken | |||
Week post conception | Day post conception | Incubation day | |||
1 W | - DIII is detected | 1 GD | DII and DIII are observed in uterine wall. | 5 h (blastula stage) | - TRα mRNA is noticed and the levels markedly increased during neurulation. |
3 W | - Thyroid gland begins. | 7 -8.5 GD | - Time of implantation process. - Very high DIII activity is detected in decidual tissue. | 24 h | - mRNA levels of DI, DII and DIII are detected in whole embryos. |
4-6 W | - TBG is observed in thyroid follicle cells at GD 29. - TRH is detected in fetal whole-brain at 4.5 weeks of gestation. - T4 is transferred | 9 GD | - Thyroid gland is first visible as an endodermal thickening in the primitive buccal cavity. - TH is detected in rat embryotrophoblasts | 48 h | - OATP1c1 expression appears. |
5-11 W | - Maternal-embryo transfer of THs has been detected in embryonic coelomic fluid and amniotic fluid. - All the mRNAs encoding THTs are expressed in placenta from 6 W and throughout pregnancy. | ||||
8 W | - T4, T3 and rT3 are detected in coelomic/amniotic fluids. - TRs, DII and DIII are noticed in fetal brain. | 10 GD | - T4, T3 and TRβ are detected in embryo/trophoblast unit. | E2-E4 | - T3, THTs, Ds and TRs are expressed in whole embryos. |
10 W | - TSH is first detected in the fetal pituitary. | E4 | - OATP1c1 expression is more than 10-fold higher in the telencephalon and diencephalon compared to the mesencephalon and rhombencephalon. - DII mRNA levels are highest in the diencephalon. | ||
8-10 W | - The fetus is able to produce THs during this period, but prior to that time, is totally dependent on maternal THs. | E5 | - TRα mRNA is widely distributed in fore-, mid- and hind-brain. | ||
11 W | - TBG levels are detected in fetal serum and increased through gestation. | E6 | - T4 and T3 are detected in embryonic brain. | ||
8-11 W | - TRH is detected in fetal hypothalamus. | E7 | - DII activity is observed in the brain before the onset of thyroid function and increases significantly. | ||
12 W | - T4 and T3 are observed in serum and brain. - Total serum T4 and T3 are low, free T4 is relatively high. - rT3 is noticed in serum relatively high. - TH synthesis begins in fetal thyroid. - Decreased mRNA expression of OATP1A2 but no change for OATP4A1 at 9–12 W compared to term. | 13 GD | - Placental circulation established. - TRs and TH are observed in fetal brain. - DIII and DII are detected in uterus and placenta. | E8 | - DII mRNA is noticed in cell clusters throughout the brain, particularly in rhombencephalon. - OATP1c1 levels are declined substantially in all brain regions. |
14 W | - Expressions of mRNAs encoding MCT8, MCT10, OATP1A2 and LAT1 are significantly lower prior to 14 W compared to term | 14 GD | - TRH mRNA is detected in neurons of the fetal hypothalamus. | E4-E8 | - DIII mRNA levels are markedly different in the telencephalon and diencephalon but remain stable, while the levels in mesencephalon and rhombencephalon show a sharp decrease and increase, respectively, during these days. |
15 GD | - Pituitary TSH mRNA expression begins. - TRH mRNA is detected in the developing paraventricular nuclei of the hypothalamus. | E9-10 | - Several elements of the TH action cascade are present in the brain of embryos long before their own thyroid gland starts hormone secretion. | ||
16 W | - DIII is observed in placenta and fetal epithelial cells. - DIII and TRs are detected in fetal liver. - DI is noticed in heart and lung. - Significant fetal TH secretion begins. | 16-19.5 GD | - TRs are observed in liver, heart and lung. - DI and DII are noticed in fetal tissues. - TRH is produced in low levels in hypothalamus and increases approximately threefold by GDI9.5. | E10 | - The thyroid gland is fully functional. |
16-20 W | - Duplication of TBG concentrations. | 17 GD | - TH synthesis begins in fetal thyroid - TSH protein and Sulfotransferase are observed. | E13 | - Brain DII is elevated at the peak of neuroblast proliferation. |
18 -22 GD | - The total T4 and T3 concentrations in fetuses are increased drama-tically because of maturation of hormone synthesis of the fetal thyroid gland. - The coordination between THTs and Ds is regulated both transplacental TH passage from mother to fetus and the development of the placenta itself through the progress of gestation. | E14 | - The strong increase in intracellular T3 has been observed. | ||
20 W | - A steady increase in serum TH levels begins and continues to term. | 19 GD | - Significant fetal TH secretion begins. - Marked rise in serum TH but levels at birth still below those in adult. | E15 | - Plasma T4 levels start rising markedly around this day. |
22-32 W | - Serum total and free T4 and T3 near and below adult levels, respectively. - The HPT axis begins to mature during the second half of gestation. - LAT1 and OATP4A1 have been localized only during the third trimester. | 22 GD | - Birth state. - Thyroid system is less developed. - As much as 17.5% of THs found in the newborn are of maternal origin. | E16 | - The decrease in DI activity in gonads is combined with the relatively high DIII activity. - A significant increase in T3 production and in DII-activity and -mRNA expression are combined with a decreased in DIII activity. |
40 W | - Birth state. - Complete maturation of thyroid system. - MCT8 has been localized in the placenta in all three trimesters of pregnancy. - High concentrations of the different iodothyronine sulfates, T4S, T3S, rT3S and T2S, have been documented in human fetal and neonatal plasma as well as in amniotic fluid during the pregnancy. | 10 PND | - Brain development equivalent to human birth. | E13/14–E17 (synaptogenesis) | - Brain DII activity is moderately elevated, whereas DIII activity and mRNA expression are highest between these days, followed by a dramatic decrease thereafter. |
10-20 PND | - Serum TH levels continue to rise and are higher than adult levels between these days. | E18 | - DI and DIII are expressed in the granule cells, whereas DII is found mostly in the molecular layer and the Purkinje cells at that time. | ||
14-50 PND | - The levels of pituitary and serum TSH slowly decrease from PND 14–16 until reaching adult levels at PND 40. - TRH levels increase to adult levels by PNDI7–29, then decrease transiently between PND 31–41; adult levels are once again reached at PND 50. - Adult TRH mRNA expression patterns are present at PND 22. | E19 | - The increase in brain T3 production correlates with the appearance of TRβ expression in the cerebellum, telencephalon and optic lobes. | ||
E20 (at the moment of pipping) | - The brain is quite well developed at the time of hatching. - The gradual increases in plasma T4 and hepatic DI are detected. - DIII levels are decreased in spleen and increased in skin and the lungs towards hatching. - T3 production seems to be elevated markedly in liver. - The rise of T4 is much more pronounced than in plasma. - Diminished T4 sulfation is detected. | ||||
30 PND | Complete maturation of thyroid gland. | E14-E19/20 | - The T3 breakdown capacity by DIII is high in liver but low in kidney. | ||
E15/16-E20 | - T4 levels in plasma increase gradually during these days. - In contrast to TRα expression which increases gradually towards hatching, expression of TRβ shows an abrupt elevation in late development, especially in the cerebellum. - The majority of tissues express DIII together with either DI or DII. | ||||
E17-E20 | - The levels of DIII activity present in liver are rapidly drop by more than 90%. - DI levels in testis and ovary strongly decrease around hatching. | ||||
E18–E20 | - Brain DII activity is moderately decreased, whereas DIII activity is low. | ||||
E19-E20 | - The low T3/T4 ratio is associated with high T3 breakdown in liver and with high T4 inactivation or T3 secretion in kidney. | ||||
E20-C0 | - DI activity gradually increases, reaching a maximum around these period, and decreases slowly to posthatch levels thereafter. | ||||
C1 (first day post-hatch) | - The expression of DI is limited to the mature granule cells and that of DIII to the Purkinje cells exclusively, whereas DII remains clearly present in the molecular layer. | ||||
C2 | - Highest DI-activities and -mRNA expressions are detected in the liver, kidney, and intestine. | ||||
C1-C7 | - The circulating T3/T4 ratio started to increase gradually during the first week after hatching. |
Summary about the developmental thyroid hormone mechanisms (deiodinases, transporters, sulfotransferases and receptors) in human, rat and chicken.
The actions of THs are highly pleiotropic, affecting many tissues at different developmental stages. As a consequence, their effects on proliferation and differentiation are highly heterogeneous depending on the cell type, the cellular context, and the developmental or transformation status.
Maternal THs are important in promoting normal fetal development especially the placental and CNS development. Clinical epidemiological and basic findings clearly show that maintaining normal TH regulation from the beginning of pregnancy is important to reduce the risk of obstetric complications and to ensure optimal neurodevelopment of the offspring.
In normal pregnancy, transplacental TH passage is modulated by plasma membrane THTs, Ds, sulfotransferases, TRs and several different proteins within placental cells.
In pathological/abnormal pregnancies with either maternal or fetal THs disturbances (hypo- or hyper-thyroidism), the placenta lacks the full compensatory mechanisms necessary to optimize the maternal–fetal transfer of THs to achieve the normality of TH levels in the fetus.
Further studies are still needed to improve our understanding of the mechanisms mediating the transplacental transport of THs in both human and animals, particularly the role of the different THTs, and the mechanisms that ensure that sufficient amounts of THs are protected from D3 inactivation during their transit across the placenta. Such knowledge would facilitate the development of interventions to increase TH passage in pathological situations, in order to ensure normal fetal development. A better understanding of these mechanisms would also permit us to refine the timing and dosage of the increase in levothyroxine therapy in hypothyroid pregnant women and to establish whether thyroxine on its own is indeed the best form of TH replacement in pregnancy.
Elucidation of tissue-, cell-, and sex-specific expression of individual Ds and THTs during the development of both human and animals, in the adult, during aging and when sick.
I hope that new insights into the complex actions by which the THs and their receptors control cell proliferation and differentiation will be provided in the near future.
Chronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Source | Type of trial | Interferon | Diagnosis | No. | Prior treatment status | Response rate |
---|---|---|---|---|---|---|
Yacoubet al. [15] | Phase II, multicenter | Pegylated IFN alfa-2a | PV | 50 | Resistance to HU or HU intolerance | CR:22% PR:38% |
ET | 65 | CR:43% PR:26% | ||||
Masarova et al. [16] | Phase II, single-center | Pegylated IFN alfa-2a | PV | 43 | Untreated or previously treated with cytoreductive therapy | CR:77% PR:7% |
ET | 40 | CR:73% PR:3% | ||||
Samuelsson et al. [18] | Phase II | Pegylated IFN alfa-2b | PV | 21 | Untreated or previously treated with cytoreductive therapy | CR: 69% for the entire group |
ET | 21 | |||||
Huang BT et al. [19] | Open label, multicenter | IFN alfa-2b | PV | 136 | Untreated or previously treated with cytoreductive therapy | OHR:70% Molecular response:54.7% |
ET | 123 | OHR (JAK2+ patients):83% CHR:23 cases OHR (JAK2-patients): 61.4% CHR:12 cases | ||||
Gisslinger et al. [23] | phase III, multicenter | Ropeginterferon | PV | 257 | Previously treated | OHR:53% |
Quintás-Cardama et al. [26] | phase II | Pegylated IFN alfa-2a | PV | 40 | Untreated or previously treated with cytoreductive therapy | OHR:80% CR:70% Molecular remission:54% |
ET | 39 | OHR:81% CR:76% Molecular remission:38% | ||||
Sørensen et al. [36] | Phase III, multicenter, COMBI | Pegylated IFN alfa-2a with ruxolitinib or Pegylated IFN alfa-2b with ruxolitinib | PV | 32 | Untreated or previously treated with cytoreductive therapy | OHR:44% CR:28% |
MF | 18 | OHR:31% CR:9% | ||||
Casassus et al. [40] | Open label, multicenter | IFN alpha-2b | Mastocytosis | 20 | Untreated and previously treated | PR:35% Minor remission: 30% |
Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; HU: hydroxycarbamide/hydroxyurea; CR: complete remission; PR: partial remission; and OHR: overall hematological response.
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
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Respiratory monitoring is vital including detection of sleep apnea and measurement of respiratory rate. The automatic detection of breathing patterns is equally important in other respiratory rehabilitation therapies, for example, magnetic resonance exams for respiratory triggered imaging, and synchronized functional electrical stimulation. In this context, the goal of many research groups is to create wearable devices able to monitor breathing activity continuously, under natural physiological conditions in different environments. Therefore, wearable sensors that have been used recently as well as the main signal processing methods for breathing analysis are discussed. The following sensor technologies are presented: acoustic, resistive, inductive, humidity, acceleration, pressure, electromyography, impedance, and infrared. New technologies open the door to future methods of noninvasive breathing analysis using wearable sensors associated with machine learning techniques for pattern detection.",book:{id:"7654",slug:"wearable-devices-the-big-wave-of-innovation",title:"Wearable Devices",fullTitle:"Wearable Devices - the Big Wave of Innovation"},signatures:"Taisa Daiana da Costa, Maria de Fatima Fernandes Vara, Camila Santos Cristino, Tyene Zoraski Zanella, Guilherme Nunes Nogueira Neto and Percy Nohama",authors:[{id:"192464",title:"Ph.D.",name:"Percy",middleName:null,surname:"Nohama",slug:"percy-nohama",fullName:"Percy Nohama"},{id:"285706",title:"MSc.",name:"Taísa Daiana",middleName:null,surname:"Da Costa",slug:"taisa-daiana-da-costa",fullName:"Taísa Daiana Da Costa"},{id:"285707",title:"MSc.",name:"Maria de Fatima Fernandes",middleName:null,surname:"Vara",slug:"maria-de-fatima-fernandes-vara",fullName:"Maria de Fatima Fernandes Vara"},{id:"285708",title:"BSc.",name:"Camila Santos",middleName:null,surname:"Cristino",slug:"camila-santos-cristino",fullName:"Camila Santos Cristino"},{id:"285709",title:"Prof.",name:"Guilherme Nunes",middleName:null,surname:"Nogueira Neto",slug:"guilherme-nunes-nogueira-neto",fullName:"Guilherme Nunes Nogueira Neto"},{id:"293109",title:"BSc.",name:"Tyene",middleName:null,surname:"Zoraski Zanella",slug:"tyene-zoraski-zanella",fullName:"Tyene Zoraski Zanella"}]},{id:"41411",title:"Textile Dyes: Dyeing Process and Environmental Impact",slug:"textile-dyes-dyeing-process-and-environmental-impact",totalDownloads:20676,totalCrossrefCites:101,totalDimensionsCites:320,abstract:null,book:{id:"3137",slug:"eco-friendly-textile-dyeing-and-finishing",title:"Eco-Friendly Textile Dyeing and Finishing",fullTitle:"Eco-Friendly Textile Dyeing and Finishing"},signatures:"Farah Maria Drumond Chequer, Gisele Augusto Rodrigues de Oliveira, Elisa Raquel Anastácio Ferraz, Juliano Carvalho Cardoso, Maria Valnice Boldrin Zanoni and Danielle Palma de Oliveira",authors:[{id:"49040",title:"Prof.",name:"Danielle",middleName:null,surname:"Palma De Oliveira",slug:"danielle-palma-de-oliveira",fullName:"Danielle Palma De Oliveira"},{id:"149074",title:"Prof.",name:"Maria Valnice",middleName:null,surname:"Zanoni",slug:"maria-valnice-zanoni",fullName:"Maria Valnice Zanoni"},{id:"153502",title:"Ph.D.",name:"Farah",middleName:null,surname:"Chequer",slug:"farah-chequer",fullName:"Farah Chequer"},{id:"153504",title:"MSc.",name:"Gisele",middleName:null,surname:"Oliveira",slug:"gisele-oliveira",fullName:"Gisele Oliveira"},{id:"163377",title:"Dr.",name:"Juliano",middleName:null,surname:"Cardoso",slug:"juliano-cardoso",fullName:"Juliano Cardoso"},{id:"163393",title:"Dr.",name:"Elisa",middleName:null,surname:"Ferraz",slug:"elisa-ferraz",fullName:"Elisa Ferraz"}]},{id:"70242",title:"Advancements in the Fenton Process for Wastewater Treatment",slug:"advancements-in-the-fenton-process-for-wastewater-treatment",totalDownloads:1985,totalCrossrefCites:13,totalDimensionsCites:26,abstract:"Fenton is considered to be one of the most effective advanced treatment processes in the removal of many hazardous organic pollutants from refractory/toxic wastewater. It has many advantages, but drawbacks are significant such as a strong acid environment, the cost of reagents consumption, and the large production of ferric sludge, which limits Fenton’s further application. The development of Fenton applications is mainly achieved by improving oxidation efficiency and reducing sludge production. This chapter presents a review on fundamentals and applications of conventional Fenton, leading advanced technologies in the Fenton process, and reuse methods of iron containing sludge to synthetic and real wastewaters are discussed. Finally, future trends and some guidelines for Fenton processes are given.",book:{id:"9415",slug:"advanced-oxidation-processes-applications-trends-and-prospects",title:"Advanced Oxidation Processes",fullTitle:"Advanced Oxidation Processes - Applications, Trends, and Prospects"},signatures:"Min Xu, Changyong Wu and Yuexi Zhou",authors:[{id:"307479",title:"Dr.",name:"Changyong",middleName:null,surname:"Wu",slug:"changyong-wu",fullName:"Changyong Wu"},{id:"307546",title:"Prof.",name:"Yuexi",middleName:null,surname:"Zhou",slug:"yuexi-zhou",fullName:"Yuexi Zhou"},{id:"311139",title:"Dr.",name:"Min",middleName:null,surname:"Xu",slug:"min-xu",fullName:"Min Xu"}]}],onlineFirstChaptersFilter:{topicId:"24",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82676",title:"Electrospinning of Fiber Matrices from Polyhydroxybutyrate for the Controlled Release Drug Delivery Systems",slug:"electrospinning-of-fiber-matrices-from-polyhydroxybutyrate-for-the-controlled-release-drug-delivery-",totalDownloads:13,totalDimensionsCites:0,doi:"10.5772/intechopen.105786",abstract:"The submission provides an overview of current state of the problem and authors’ experimental data on manufacturing nonwoven fibrous matrices for the controlled release drug delivery systems (CRDDS). The choice of ultrathin fibers as effective carriers is determined by their characteristics and functional behavior, for example, such as a high specific surface area, anisotropy of some physicochemical characteristics, spatial limitations of segmental mobility that are inherent in nanosized objects, controlled biodegradation, and controlled diffusion transport. The structural-dynamic approach to the study of the morphology and diffusion properties of biopolymer fibers based on polyhydroxybutyrate (PHB) is considered from several angles. In the submission, the electrospinning (ES) application to reach specific characteristics of materials for controlled release drug delivery is discussed.",book:{id:"11127",title:"Electrospinning - Material Technology of the Future",coverURL:"https://cdn.intechopen.com/books/images_new/11127.jpg"},signatures:"Anatoly A. Olkhov, Svetlana G. Karpova, Anna V. Bychkova, Alexandre A. Vetcher and Alexey L. Iordanskii"},{id:"82600",title:"Impact of the Spreading of Sludge from Wastewater Treatment Plants on the Transfer and Bio-Availability of Trace Metal Elements in the Soil-Plant System",slug:"impact-of-the-spreading-of-sludge-from-wastewater-treatment-plants-on-the-transfer-and-bio-availabil",totalDownloads:12,totalDimensionsCites:0,doi:"10.5772/intechopen.103745",abstract:"The spreading of sludge from sewage treatment plants increased the production of durum wheat and rapeseed. Their richness in nitrogen, phosphorus, and potassium gives them a beneficial effect on crops. However, the application of the sludge can induce increases in the concentration of metals in plant tissues. This increase can generate disturbances at the level of the cell and organelles, such as mitochondria and chloroplasts, which can be altered. Repeated applications of the sludge on the same site tend to increase the accumulation of heavy metals in the soil, so that an cause toxicities for soil microorganisms, animals, and humans, via the food chain. However, it is important to specify that these nuisances mainly concerned industrial sludge, but the use of this sludge is strictly prohibited. In addition, the high doses used in our field experiments are significantly higher than those authorized in agricultural practice. Finally, the risk assessment by calculating both the level of consumer exposure and the number of years for soil saturation shows that the use of urban sludge is safe, especially in the short and medium-term. Nevertheless, the quality of the sludge to be spread must be constantly monitored.",book:{id:"11173",title:"Wastewater Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/11173.jpg"},signatures:"Najla Lassoued and Bilal Essaid"},{id:"81249",title:"Electrospun Polymeric Substrates for Tissue Engineering: Viewpoints on Fabrication, Application, and Challenges",slug:"electrospun-polymeric-substrates-for-tissue-engineering-viewpoints-on-fabrication-application-and-ch",totalDownloads:8,totalDimensionsCites:0,doi:"10.5772/intechopen.102596",abstract:"Electrospinning is the technique for producing nonwoven fibrous structures, to mimic the fabrication and function of the native extracellular matrix (ECM) in tissue. Prepared fibrous with this method can act as potential polymeric substrates for proliferation and differentiation of stem cells (with the cellular growth pattern similar to damaged tissue cells) and facilitation of artificial tissue remodeling. Moreover, such substrates can improve biological functions, and lead to a decrease in organ transplantation. In this chapter, we focus on the fundamental parameters and principles of the electrospinning technique to generate natural ECM-like substrates, in terms of structural and functional complexity. In the following, the application of these substrates in regenerating various tissues and the role of polymers (synthetic/natural) in the formation of such substrates is evaluated. Finally, challenges of this technique (such as cellular infiltration and inadequate mechanical strength) and solutions to overcome these limitations are studied.",book:{id:"11127",title:"Electrospinning - Material Technology of the Future",coverURL:"https://cdn.intechopen.com/books/images_new/11127.jpg"},signatures:"Azadeh Izadyari Aghmiuni, Arezoo Ghadi, Elmira Azmoun, Niloufar Kalantari, Iman Mohammadi and Hossein Hemati Kordmahaleh"},{id:"82145",title:"Slope Casting Process: A Review",slug:"slope-casting-process-a-review",totalDownloads:9,totalDimensionsCites:0,doi:"10.5772/intechopen.102742",abstract:"Semi solid processing is a near net shape casting process and one of the promising techniques to obtain dendritic free structure of metals. Semi solid casting gives numerous advantages than solid processing and liquid processing. Semi solid casting process gives, Laminar flow filling of die without turbulence, Lower metal temperature, Less shrinkage, Less porosity, Higher mechanical properties. Semi solid casting process is industrially successful, producing a variety of products with good quality. Slope Casting process is a simple technique to produce semi solid feed-stoke with globular microstructure and dendrite free structure castings. Slope casting process depends on different process parameters like slope length, slope angle, pouring temperature etc. The present study mainly focuses on review of various explorations made by researchers with different process parameters of the Slope casting process and explain the mechanisms that lead to microstructural changes which leads to good mechanical properties.",book:{id:"11119",title:"Casting Processes",coverURL:"https://cdn.intechopen.com/books/images_new/11119.jpg"},signatures:"Mukkollu Sambasiva Rao and Amitesh Kumar"},{id:"81861",title:"Emerging Human Coronaviruses (SARS-CoV-2) in the Environment Associated with Outbreaks Viral Pandemics",slug:"emerging-human-coronaviruses-sars-cov-2-in-the-environment-associated-with-outbreaks-viral-pandemics",totalDownloads:21,totalDimensionsCites:0,doi:"10.5772/intechopen.103886",abstract:"In December 2019, there was a cluster of pneumonia cases in Wuhan, a city of about 11 million people in Hubei Province. The World Health Organization (WHO), qualified CoVid-19 as an emerging infectious disease on March 11, 2020, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which spreads around the world. Coronaviruses are also included in the list of viruses likely to be found in raw sewage, as are other viruses belonging to the Picornaviridae family. SRAS-CoV-2 has been detected in wastewater worldwide such as the USA, France, Netherlands, Australia, and Italy according to the National Research Institute for Public Health and the Environment. In addition, the SARS-CoV-2 could infect many animals since it has been noticed in pigs, domestic and wild birds, bats, rodents, dogs, cats, tigers, cattle. Therefore, the SARS-CoV-2 molecular characterization in the environment, particularly in wastewater and animals, appeared to be a novel approach to monitor the outbreaks of viral pandemics. This review will be focused on the description of some virological characteristics of these emerging viruses, the different human and zoonotic coronaviruses, the sources of contamination of wastewater by coronaviruses and their potential procedures of disinfection from wastewater.",book:{id:"11173",title:"Wastewater Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/11173.jpg"},signatures:"Chourouk Ibrahim, Salah Hammami, Eya Ghanmi and Abdennaceur Hassen"},{id:"81797",title:"Study of Change Surface Aerator to Submerged Nonporous Aerator in Biological Pond in an Industrial Wastewater Treatment in Daura Refinery",slug:"study-of-change-surface-aerator-to-submerged-nonporous-aerator-in-biological-pond-in-an-industrial-w",totalDownloads:11,totalDimensionsCites:0,doi:"10.5772/intechopen.104860",abstract:"Daura refinery, with a capacity of 140,000 barrel per stream day as a refining capacity, wastewater discharged from refining and treatment processing units, polluted water as foul water, drainages, oil spills, blowdown of boilers and cooling towers, and many other polluted water sources, aims to remove pollutants and reject clean water to the river; wastewater treatment system takes place in this treatment process. Wastewater treatment system suffers from many problems and specifically biological stage; at this stage, activated sludge with bacteria, should be supplied with oxygen, aeration system done by surface aerators with four surface fans; these fans suffer from high vibration, loss support, and in consequence, lack in oxygen supply to aerobic bacteria less than 4 ppm. The nonporous aerator is suggested as an oxygen source for the biological pool. The pilot plant builds the aim to study the ability to apply the new aeration system at the biological pool, pilot plant build with 1 cubic meter capacity tank and continuous overflow of wastewater of 10 liters.min−1, air injected with the pressure of (0.5–0.75) bar(g), and airflow of (7.6–9.7) liter.min−1 respectively. Oxygen concentration was recorded as (3.4–6.0) ppm; in terms of consumption power, changing the aeration system reduces it to less than 20%.",book:{id:"11173",title:"Wastewater Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/11173.jpg"},signatures:"Omar M. Waheeb, Mohanad Mahmood Salman and Rand Qusay Kadhim"}],onlineFirstChaptersTotal:27},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:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,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:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{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"}}}}]},series:{item:{id:"23",title:"Education and Human Development",doi:"10.5772/intechopen.100360",issn:null,scope:"
\r\n\tEducation and Human Development is an interdisciplinary research area that aims to shed light on topics related to both learning and development. This Series is intended for researchers, practitioners, and students who are interested in understanding more about these fields and their applications.
",coverUrl:"https://cdn.intechopen.com/series/covers/23.jpg",latestPublicationDate:"August 12th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"280770",title:"Dr.",name:"Katherine K.M.",middleName:null,surname:"Stavropoulos",slug:"katherine-k.m.-stavropoulos",fullName:"Katherine K.M. Stavropoulos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRdFuQAK/Profile_Picture_2022-05-24T09:03:48.jpg",biography:"Katherine Stavropoulos received her BA in Psychology from Trinity College, in Connecticut, USA and her Ph.D. in Experimental Psychology from the University of California, San Diego. She completed her postdoctoral work at the Yale Child Study Center with Dr. James McPartland. Dr. Stavropoulos’ doctoral dissertation explored neural correlates of reward anticipation to social versus nonsocial stimuli in children with and without autism spectrum disorders (ASD). She has been a faculty member at the University of California, Riverside in the School of Education since 2016. Her research focuses on translational studies to explore the reward system in ASD, as well as how anxiety contributes to social challenges in ASD. She also investigates how behavioral interventions affect neural activity, behavior, and school performance in children with ASD. She is also involved in the diagnosis of children with ASD and is a licensed clinical psychologist in California. She is the Assistant Director of the SEARCH Center at UCR and is a faculty member in the Graduate Program in Neuroscience.",institutionString:null,institution:{name:"University of California, Riverside",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:2,paginationItems:[{id:"89",title:"Education",coverUrl:"https://cdn.intechopen.com/series_topics/covers/89.jpg",isOpenForSubmission:!1,editor:{id:"260066",title:"Associate Prof.",name:"Michail",middleName:null,surname:"Kalogiannakis",slug:"michail-kalogiannakis",fullName:"Michail Kalogiannakis",profilePictureURL:"https://mts.intechopen.com/storage/users/260066/images/system/260066.jpg",biography:"Michail Kalogiannakis is an Associate Professor of the Department of Preschool Education, University of Crete, and an Associate Tutor at School of Humanities at the Hellenic Open University. He graduated from the Physics Department of the University of Crete and continued his post-graduate studies at the University Paris 7-Denis Diderot (D.E.A. in Didactic of Physics), University Paris 5-René Descartes-Sorbonne (D.E.A. in Science Education) and received his Ph.D. degree at the University Paris 5-René Descartes-Sorbonne (PhD in Science Education). His research interests include science education in early childhood, science teaching and learning, e-learning, the use of ICT in science education, games simulations, and mobile learning. He has published over 120 articles in international conferences and journals and has served on the program committees of numerous international conferences.",institutionString:"University of Crete",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},editorTwo:{id:"422488",title:"Dr.",name:"Maria",middleName:null,surname:"Ampartzaki",slug:"maria-ampartzaki",fullName:"Maria Ampartzaki",profilePictureURL:"https://mts.intechopen.com/storage/users/422488/images/system/422488.jpg",biography:"Dr Maria Ampartzaki is an Assistant Professor in Early Childhood Education in the Department of Preschool Education at the University of Crete. Her research interests include ICT in education, science education in the early years, inquiry-based and art-based learning, teachers’ professional development, action research, and the Pedagogy of Multiliteracies, among others. 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He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"10",type:"subseries",title:"Animal Physiology",keywords:"Physiology, Comparative, Evolution, Biomolecules, Organ, Homeostasis, Anatomy, Pathology, Medical, Cell Division, Cell Signaling, Cell Growth, Cell Metabolism, Endocrine, Neuroscience, Cardiovascular, Development, Aging, Development",scope:"Physiology, the scientific study of functions and mechanisms of living systems, is an essential area of research in its own right, but also in relation to medicine and health sciences. The scope of this topic will range from molecular, biochemical, cellular, and physiological processes in all animal species. Work pertaining to the whole organism, organ systems, individual organs and tissues, cells, and biomolecules will be included. Medical, animal, cell, and comparative physiology and allied fields such as anatomy, histology, and pathology with physiology links will be covered in this topic. 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