Table of recurring translocation involved in T-ALL. The rearrangements are divided into those involving TCR and non-TCR loci.
\\n\\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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The authors from Norway, Estonia, Nigeria, Israel, USA, Slovakia, Turkey, Finland, Uruguay, and Italy bring ideas, studies, findings, and experiences to enhance our knowledge in the field of organizational conflict. The book is divided into two sections, and their respective chapters refer to two different perspectives of study. The first section covers Conceptual Frameworks on Organizational Conflict, considering management and conflict resolution, conflict in organizations as an indicator for organizational values, organizational trust as a conflict management tool, conflicts and social capital, and team conflict in complex adaptive systems. The second section deals with Empirical Studies on Organizational Conflict, emphasizing research on conflict resolution from the perspective of managers and project teams, resistance to change and conflict of interest, conflicts as a springboard for Metallica's success, drivers of innovation deployment affecting marketing relationships, and impacts of national culture on the use of bonuses for teamwork. Thus, we consider this book will be of interest to readers with a diverse group of interests in different specialties such as management, social psychology, education, law, and sociology.",isbn:"978-1-78923-505-0",printIsbn:"978-1-78923-504-3",pdfIsbn:"978-1-83881-389-5",doi:"10.5772/intechopen.69420",price:119,priceEur:129,priceUsd:155,slug:"organizational-conflict",numberOfPages:196,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"063f63db8b7aff55b3a6e5a5f01ca900",bookSignature:"Ana Alice Vilas Boas",publishedDate:"August 1st 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6305.jpg",numberOfDownloads:13793,numberOfWosCitations:7,numberOfCrossrefCitations:4,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:9,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:20,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 9th 2017",dateEndSecondStepPublish:"May 30th 2017",dateEndThirdStepPublish:"August 26th 2017",dateEndFourthStepPublish:"November 24th 2017",dateEndFifthStepPublish:"January 23rd 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"175373",title:"Dr.",name:"Ana Alice",middleName:null,surname:"Vilas Boas",slug:"ana-alice-vilas-boas",fullName:"Ana Alice Vilas Boas",profilePictureURL:"https://mts.intechopen.com/storage/users/175373/images/5450_n.jpg",biography:"Ana Alice Vilas Boas is a post-doctor by HEC-Montreal. She attended her PhD at the University of Reading – UK. She holds a Master in Management by the Federal University of Lavras. From 1993 up to 2008 she worked at the Federal University of Rio de Janeiro and then she moved back to Lavras – Minas Gerais – Brazil where she is Associated Professor in the Department of Management and Economics of the Federal University of Lavras - UFLA. She is an expert in Human Resources Management and related areas such as business strategy, entrepreneurship, quality of working life and distance learning. She supervised many Master dissertations and some PhD thesis. Author of papers, chapters and books published in Brazil and worldwide. Her main topics of interest nowadays are Quality of Working Life and Organizational Behavior.",institutionString:"Federal University of Lavras",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Federal University of Lavras",institutionURL:null,country:{name:"Brazil"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"440",title:"Organization Development",slug:"organization-development"}],chapters:[{id:"57835",title:"Management and Conflict Resolution: Conceptual Tools for Securing Cooperation and Organizational Performance",doi:"10.5772/intechopen.72132",slug:"management-and-conflict-resolution-conceptual-tools-for-securing-cooperation-and-organizational-perf",totalDownloads:1269,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In theories of conflict management, managers’ conflict resolution skills have often been understood as their relational attitudes and ability to communicate, but choices of conflict resolution strategies in organizational management should also depend on the types of conflicts managers face. Understanding how a complex conflict situation involves one or several conflict types is a matter of understanding the deep structure of the conflict. Knowledge of such deep structure is a key to realizing what the conflict is about and how it should be resolved. The chapter uses conflict theory to distinguish between six conflict types that are especially important from an organizational perspective: interpretation conflicts, argumentation conflicts, value conflicts, interest conflicts, role conflicts and personal conflicts. After having clarified their signifcance in an organizational context, the chapter elucidates how knowledge of the conflict types and how they are logically related to each other can be used in managers’ conflict resolution practices. The last part of the chapter uses the conflict types to develop a model for practical conflict resolution in management. The model can be used as a tool for analyzing conflict situations—to gain a deeper and more systematic understanding of how the situations should be resolved in accordance with the best interest of the organization.",signatures:"Halvor Nordby",downloadPdfUrl:"/chapter/pdf-download/57835",previewPdfUrl:"/chapter/pdf-preview/57835",authors:[{id:"212169",title:"Prof.",name:"Halvor",surname:"Nordby",slug:"halvor-nordby",fullName:"Halvor Nordby"}],corrections:null},{id:"60513",title:"Conflict in Organization: Indicator for Organizational Values",doi:"10.5772/intechopen.75496",slug:"conflict-in-organization-indicator-for-organizational-values",totalDownloads:1522,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Through the last decades, values have been one of the hot topics for researchers. Hundreds of researches and articles describe and analyze values of different level based on different theories. At the same time, construct of values has still remained a little bit mysterious, because we still do not fully understand and agree how the values shape and develop. Fortunately, most of the researchers agree on that organizational values and success (no matter how we define the success) are connected and dependent on each other. Often in organizations, the values are described and an effort made to propagate them to the employees and integrate into everyday actions. A more complex question remains how to evaluate if the desired values have imprinted themselves in the organization. The main aim of the chapter is to show how the conflicts in the organization might be used as the indicators of organizational real values. The chapter is based on the former researches of the authors and others. Results show that conflicts describe organizational real values and therefore organizational conflicts can be used as a tool to assess the implementation of organizational values.",signatures:"Eneken Titov, Anu Virovere and Karin Kuimet",downloadPdfUrl:"/chapter/pdf-download/60513",previewPdfUrl:"/chapter/pdf-preview/60513",authors:[{id:"198190",title:"Prof.",name:"Eneken",surname:"Titov",slug:"eneken-titov",fullName:"Eneken Titov"},{id:"212580",title:"Prof.",name:"Anu",surname:"Virovere",slug:"anu-virovere",fullName:"Anu Virovere"},{id:"212581",title:"MSc.",name:"Karin",surname:"Kuimet",slug:"karin-kuimet",fullName:"Karin Kuimet"}],corrections:null},{id:"58609",title:"Organizational Trust as a Conflict Management Tool in Contemporary Work Organizations",doi:"10.5772/intechopen.73092",slug:"organizational-trust-as-a-conflict-management-tool-in-contemporary-work-organizations",totalDownloads:1463,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Conflict between management and employees or among employees is an irresistible phenomenon in contemporary work organizations. Evidences gathered from past and present studies revealed that a lot of conflict situations have occurred in work organizations which have significantly impacted organizational performance and its survival in recent times. Consequently, several conventional strategies and techniques have been deployed to constructively manage conflict situation in work organization however, realities show that managing conflict in work organizations remain a challenge to managers in today’s world of work. This is partly due to the fact that conflict arises from different sources; hence it is inimical to subscribes to the idea of one-size-fit-all approach to management of conflict. Based on this momentum, this chapter examines organizational trust as a conflict management tool in contemporary work organizations using an explanatory design and a basic review of literature. The chapter therefore explains the concept of organizational conflict vis-a vis organizational trust within the context of work organization. It also discusses factors causing conflict situation. It examines the importance of trust and factors responsible for the development of trust in organizations. The chapter further examines some theories of trust and also develops a framework for dealing with conflict in work organization.",signatures:"Oludele Mayowa Solaja",downloadPdfUrl:"/chapter/pdf-download/58609",previewPdfUrl:"/chapter/pdf-preview/58609",authors:[{id:"211557",title:"Mr.",name:"Oludele",surname:"Solaja",slug:"oludele-solaja",fullName:"Oludele Solaja"}],corrections:null},{id:"58964",title:"Conflicts and Social Capital in Organizations",doi:"10.5772/intechopen.73387",slug:"conflicts-and-social-capital-in-organizations",totalDownloads:1072,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Social capital (SC) is a comprehensive concept, which refers to benefits derived from social interaction. In organizations, SC can be divided into 3 levels: personal SC, which refers to the benefits the individual receives from personal social connections, inside and outside the organization; intraorganizational SC, which refers to the benefits derived from good relationships within organizational units, and the organization as a whole; and external SC, which refers to the profits derived from interfaces of role holders, such as the CEO, with stakeholders. Organizational SC and conflicts in an organization are ostensibly very different in nature, whereas SC is an intangible that fits the positive psychology domain; conflicts are usually unwanted occurrences in organizations. Scholars noted that conflicts affect employee’s SC and usually reduce it, but the opposite was hardly investigated. This chapter examines how and why the conversion of social relationships into capital can result in conflicts at all organizational SC levels. To do this, the interface between the levels of SC in organizations and types of conflicts was examined. In conclusion, developing “C-type” conflicts, which are desirable conflicts, and avoiding “A-type” conflicts, which are destructive conflicts, depend on a good match between the different organizational SC levels.",signatures:"Batia Ben-Hador",downloadPdfUrl:"/chapter/pdf-download/58964",previewPdfUrl:"/chapter/pdf-preview/58964",authors:[{id:"211812",title:"Ph.D.",name:"Batia",surname:"Ben-Hador",slug:"batia-ben-hador",fullName:"Batia Ben-Hador"}],corrections:null},{id:"58821",title:"Complex Adaptive Systems: Adapting and Managing Teams and Team Conflict",doi:"10.5772/intechopen.72344",slug:"complex-adaptive-systems-adapting-and-managing-teams-and-team-conflict",totalDownloads:2612,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:1,abstract:"Complexity comes from dramatic structural changes to organizations and governments such as globalization, global competition, workforce diversity, and continual innovations. Complex adaptive systems (CAS) are organizations that are a composite of the interconnected whole. Teams must manage and operate in emerging ecosystems, understand factors that lead to team effectiveness when managing and facilitating teams and team conflict, and understand the development of conflict models. This chapter provides an overview of teams, CAS, conflict stages, and conflict models. This chapter presents adaptive leadership as one leadership style that offers organizations with the capabilities of reacting to changing environments quickly. Adaptive leadership offers a prescriptive approach for managers and leaders to follow when dealing with organizational conflict while operating in today’s complex and global environment.",signatures:"John R. Turner, Rose Baker and Mark Morris",downloadPdfUrl:"/chapter/pdf-download/58821",previewPdfUrl:"/chapter/pdf-preview/58821",authors:[{id:"211379",title:"Dr.",name:"John",surname:"Turner",slug:"john-turner",fullName:"John Turner"},{id:"211381",title:"Dr.",name:"Rose",surname:"Baker",slug:"rose-baker",fullName:"Rose Baker"},{id:"211383",title:"MSc.",name:"Mark",surname:"Morris",slug:"mark-morris",fullName:"Mark Morris"}],corrections:null},{id:"57429",title:"Conflict Resolution by Managers",doi:"10.5772/intechopen.71618",slug:"conflict-resolution-by-managers",totalDownloads:986,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Conflicts occur in a variety of areas, not excluding the work life. Conflict resolution methods are essential for further development of the conflict in terms of its escalation or de-escalation. The proposed chapter focuses on the issue of dispositional vs. situational approach to exploring the ways of conflict resolution. Results of the presented research projects are based mostly on the theories distinguishing between five conflict resolution styles: avoiding, competing, compromising, accommodating, and collaborating. The chapter also includes the results of the research, in which an original methodology for identification and specification of the differences in the conflict resolution methods within various situational contexts was used. Model conflict situations were placed into three different environments (work, home, and among friends) and associated with two different conflicts (backbiting and false accusations). The results also confirmed the differences in use of the conflict resolution methods by managers both in terms of the environment in which the conflict occurred and the content of the conflict. Within the framework of these studies, gender-based comparisons have also been carried out confirming several gender specificities in the selection of ways to resolve conflicts between men and women.",signatures:"Miroslav Frankovský, Zuzana Birknerová and Lucia Zbihlejová",downloadPdfUrl:"/chapter/pdf-download/57429",previewPdfUrl:"/chapter/pdf-preview/57429",authors:[{id:"210937",title:"Prof.",name:"Miroslav",surname:"Frankovský",slug:"miroslav-frankovsky",fullName:"Miroslav Frankovský"},{id:"212397",title:"Dr.",name:"Zuzana",surname:"Birknerová",slug:"zuzana-birknerova",fullName:"Zuzana Birknerová"},{id:"212398",title:"M.A.",name:"Lucia",surname:"Zbihlejová",slug:"lucia-zbihlejova",fullName:"Lucia Zbihlejová"}],corrections:null},{id:"57527",title:"Resistance to Change and Conflict of Interest: A Case Study",doi:"10.5772/intechopen.71578",slug:"resistance-to-change-and-conflict-of-interest-a-case-study",totalDownloads:1734,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Change for organizations is a necessity. Today’s businesses are aware of the need to keep up with the environmental changes and change demands. If the change process is not handled properly in the business, it will bring major problems with it. Every change will absolutely and definitely face resistance. Similarly, conflicts are considered to be inherent in organizations. The important thing is to prevent conflicts from taking over organizational interests. If conflicts arise in situations where personal interests constitute a source, it is an issue that needs to be discussed seriously. This study is intended to reveal elements that create a potentially resilient potential, in particular protecting personal interests. A case study method was utilized in the study. This method is preferred because it is appropriate to examine in detail the history, current situation and environmental functioning of a particular person or group and to obtain appropriate information in order to provide statistical methods. In particular, the case study, which reveals a reflection of the conflict of interest that is valued as a consequence of the functions of exchange resistance and as a consequence thereof, reflects the relationship between resistance and conflict of interest.",signatures:"Cem Karabal",downloadPdfUrl:"/chapter/pdf-download/57527",previewPdfUrl:"/chapter/pdf-preview/57527",authors:[{id:"217906",title:"Dr.",name:"Cem",surname:"Karabal",slug:"cem-karabal",fullName:"Cem Karabal"}],corrections:null},{id:"57716",title:"Conflicts as Springboard for Metallica’s Success",doi:"10.5772/intechopen.71579",slug:"conflicts-as-springboard-for-metallica-s-success",totalDownloads:1341,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The purpose of this chapter is to understand how Metallica has utilized conflicts in creating changes in the music industry and growing as the biggest heavy metal band of the world and sustained in this position for 25 years. The study was conducted as a qualitative and longitudinal case study. The study confirmed that conflicts have been a crucial factor in Metallica’s success. The interpersonal conflicts and the conflicts between the band founders have been pivotal. The duo has competed and collaborated against and with each other, and this way urging Metallica to better achievements. The same type of action has extended to collaboration with other inner circle members of Metallica. Different kinds of conflict stimulation techniques have been used to increase conflicts. Many dysfunctional outcomes have also arisen but Metallica as a band has nearly always been above them. The ways of handling conflicts have changed during the band’s lifecycle. In the introduction phase, competing was emphasized; in the growth phase, collaboration increased and in the current mature phase, compromising and accommodating have strengthened. Nowadays, Metallica is still a relevant band with huge number of fans, but the best creative power has run dry.",signatures:"Erno Salmela",downloadPdfUrl:"/chapter/pdf-download/57716",previewPdfUrl:"/chapter/pdf-preview/57716",authors:[{id:"101139",title:"Dr.",name:"Erno",surname:"Salmela",slug:"erno-salmela",fullName:"Erno Salmela"}],corrections:null},{id:"57743",title:"Drivers of Innovation Deployment Affecting the Marketing and Sales Relationship",doi:"10.5772/intechopen.71987",slug:"drivers-of-innovation-deployment-affecting-the-marketing-and-sales-relationship",totalDownloads:864,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This study investigates the antecedents of information management and its effect on formalization and joint planning as drivers of the marketing-sales functions perceived relationship effectiveness during the formalized process of new product deployment (NPD). We examine the effect of communication as perceived by the marketing and sales functions based on two components: communication amount/frequency (CA) and communication quality (CQ). Finally, we investigate how process formalization and joint planning affect the perceived relationship effectiveness of marketing and sales during the NPD process. The quantitative study uses 152 matched responses from top-level managers, responsible for the innovation deployment of six South American subsidiaries of a global consumer packaged goods company. The qualitative research, via in-depth interviews, confirms the importance of various behaviors of sales and marketing staff during the process of new product launches in the market. While numerous studies have researched the drivers of innovation process, this is the first chapter that studies the NPD implementation process based on the cross-functional relationship between marketing and sales. These drivers can help managers implement effective team processes to enhance innovation deployment results.",signatures:"Teresa Cometto and Gaston J. Labadie",downloadPdfUrl:"/chapter/pdf-download/57743",previewPdfUrl:"/chapter/pdf-preview/57743",authors:[{id:"211657",title:"Ph.D.",name:"Teresa",surname:"Cometto",slug:"teresa-cometto",fullName:"Teresa Cometto"},{id:"211658",title:"Dr.",name:"Gaston J.",surname:"Labadie",slug:"gaston-j.-labadie",fullName:"Gaston J. Labadie"}],corrections:null},{id:"60296",title:"Impact of National Culture on the Bonus’ Use for Teamwork",doi:"10.5772/intechopen.75909",slug:"impact-of-national-culture-on-the-bonus-use-for-teamwork",totalDownloads:941,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Today, organizations use teams as primary work units adopting team rewards and incentives in which group members’ pay is at least partly contingent on measurable group performance. It is the process of compensating a group of employees based on their combined contribution to a particular project or goal. They could be monetary (for example: team bonuses, team commission, shopping vouchers for each team member, etc.) and nonmonetary (team celebration—gateaway bonding activity, team dinner, tickets to a sports event etc., team trip/holiday—may include spouses, team merchandise—team jacket, pin, emblem to build team identity, recognition certificates, team recognition award—public mention and appreciation, team time off away from work). This chapter overviews the empirical research on team-based bonuses and aims to understand if cultural dimensions can interfere or facilitate the diffusion of bonus for teams and suggests directions for future research. The analysis demonstrates that culture may play a critical role in the success of team-based reward programs or in the employee resistance to teams.",signatures:"Ginevra Gravili",downloadPdfUrl:"/chapter/pdf-download/60296",previewPdfUrl:"/chapter/pdf-preview/60296",authors:[{id:"233756",title:"Prof.",name:"Ginevra",surname:"Gravili",slug:"ginevra-gravili",fullName:"Ginevra Gravili"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5761",title:"Quality of Life and Quality of Working Life",subtitle:null,isOpenForSubmission:!1,hash:"f6000bc0eeed7fcf0277a2f8d75907d9",slug:"quality-of-life-and-quality-of-working-life",bookSignature:"Ana Alice Vilas Boas",coverURL:"https://cdn.intechopen.com/books/images_new/5761.jpg",editedByType:"Edited by",editors:[{id:"175373",title:"Dr.",name:"Ana Alice",surname:"Vilas Boas",slug:"ana-alice-vilas-boas",fullName:"Ana Alice Vilas Boas"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5826",title:"Issues of Human Resource Management",subtitle:null,isOpenForSubmission:!1,hash:"82f12348a5b3544c8caae7b1d1731f9b",slug:"issues-of-human-resource-management",bookSignature:"Ladislav Mura",coverURL:"https://cdn.intechopen.com/books/images_new/5826.jpg",editedByType:"Edited by",editors:[{id:"85474",title:"Associate Prof.",name:"Ladislav",surname:"Mura",slug:"ladislav-mura",fullName:"Ladislav Mura"}],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:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],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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\r\n\tHomeostasis is the condition of optimal functioning of the organism and includes many variables, such as body temperature and fluid balance being kept within certain pre-set limits (homeostatic range). Other variables include the pH of extracellular fluid, the concentrations of sodium, potassium, and calcium ions, as well as that of the blood sugar level, and these need to be regulated despite changes in the environment, diet, or level of activity. Each of these variables is controlled by one or more regulators or homeostatic mechanisms, which together maintain life.
\r\n\tHomeostasis is brought about by a natural resistance to change when already in the optimal conditions, and equilibrium is maintained by many regulatory mechanisms. All homeostatic control mechanisms have at least three interdependent components for the variable to be regulated: a receptor, a control center, and an effector. The receptor is the sensing component that monitors and responds to changes in the environment, either external or internal. Receptors include thermoreceptors and mechanoreceptors. Control centers include the respiratory center and the renin-angiotensin system. An effector is a target acted on to bring about the change back to the normal state. At the cellular level, receptors include nuclear receptors that bring about changes in gene expression through up-regulation or down-regulation and act in negative feedback mechanisms. An example of this is in the control of bile acids in the liver.
\r\n\tSome centers, such as the renin-angiotensin system, control more than one variable. When the receptor senses a stimulus, it reacts by sending action potentials to a control center. The control center sets the maintenance range—the acceptable upper and lower limits—for the particular variable, such as temperature. The control center responds to the signal by determining an appropriate response and sending signals to an effector, which can be one or more muscles, an organ, or a gland. When the signal is received and acted on, negative feedback is provided to the receptor that stops the need for further signaling.
\r\n\tThe cannabinoid receptor type 1 (CB1), located at the presynaptic neuron, is a receptor that can stop stressful neurotransmitter release to the postsynaptic neuron; it is activated by endocannabinoids (ECs) such as anandamide (N-arachidonoylethanolamide; AEA) and 2-arachidonoylglycerol (2-AG) via a retrograde signaling process in which these compounds are synthesized by and released from postsynaptic neurons, and travel back to the presynaptic terminal to bind to the CB1 receptor for modulation of neurotransmitter release to obtain homeostasis.
\r\n\tThe polyunsaturated fatty acids (PUFAs) are lipid derivatives of omega-3 (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) or of omega-6 (arachidonic acid, ARA) and are synthesized from membrane phospholipids and used as a precursor for endocannabinoids (ECs) mediate significant effects in the fine-tuning adjustment of body homeostasis.
\r\n\t
\r\n\tThe aim of this book is to discuss further various aspects of homeostasis, information that we hope to be useful to scientists, clinicians, and the wider public alike.
Many molecular alterations are involved in the morphogenesis of T-cell acute leukemia (T-ALL), classified as lymphoblastic leukemia/lymphoma by the World Health Organization. T-ALL is a malignant disease of the thymocytes which accounts for approximately 15% of pediatric acute lymphoblastic leukemia (ALL) and 20-25% of adult ALL. Frequently, it presents with a high tumor load accompanied by rapid disease progression. About 30% of T-ALL cases relapse within the first two years following diagnosis with long term remission in 70-80% of children and 40% of adults [1]-[4]. This poor prognosis is a consequent of our insufficient knowledge of the molecular mechanisms underlying abnormal T-cell pathogenesis. Understanding the abnormal molecular changes associated with T-ALL biology will provide us with the tools for better diagnosis and treatment of lymphoblastic leukemia. Recent improvements in genome-wide profiling methods have identified several genetic aberrations which are associated with T-ALL pathogenesis. For simplification these molecular changes can be separated into 4 different groups: chromosome aberrations, gene mutations, gene expression profiles, and epigenetic alterations. This chapter will discuss these molecular changes in depth.
The progenitors for T lymphocytes arise in the bone marrow as long-term repopulating hematopoietic stem cells (LT-HSCs) (Figure 1). These cells then differentiate, generating short-term repopulating hematopoietic stem cells (ST-HSCs) and lymphoid-primed multipotent progenitor (LMPP)[5]-[7]. LMPPs, which migrate via the blood and a chemotaxis process to the thymus [8], phenotypically resemble early T-cell progenitors (ETP)[9],[10]. ETP cells, also called double negative 1 (DN1), are capable of differentiating into either T-cells or myeloid cells and phenotypically belong to a CD3-CD4-/lowCD8-CD25-CD44-KIT+ (Figures 1 and 2). If ETP cells commit to the T-cell lineage they progress to double negative 2 (DN2), followed by double negative 3 (DN3) and finally to double negative 4 (DN4) T-cell development stages. This process starts with the downregulation of c-KIT receptor resulting in the cell surface phenotype CD4-CD8-CD25+CD44- for DN2 cells, next CD44 is lost for a cell surface phenotype of CD4-CD8-CD25+CD44- for DN3 cells, and finally CD25 is lost for a cell surface phenotype of CD4-CD8-CD25-CD44- for DN4 cells (Figures 1 and 2) [9],[11]-[13]. This differentiation from ETP to DN4 cells occurs within the thymus in intimate contact with the epithelial stromal cells, which express Notch ligands, essential growth factors (interleukin-7), and morphogens (sonic hedgehog proteins) important for T-cell development. Before differentiation into double positive cells (DP) which have the cell surface phenotype CD4+CD8+, DN4 cells lose their dependence on Notch ligand, interleukin-7 and sonic hedgehog (Shh) [14],[15]. Once they are DP cells, they undergo positive and negative selection. Following selection, αβ T-cell receptor (TCR)+ T cells migrate from the thymus to secondary lymphoid organs to manifest their immune function. These mature cells are single positive (SP) with the cell surface phenotype of either CD4+ or CD8+ [9],[11].
Stages in T-cell development. The different regions of the adult thymic lobule are indicated to the rights. The progression of hematopoietic stem cells (HSC), multipotent progenitors (MPP), and the common lymphoid progenitors (CLPs) are shown to the left in the bone marrow. Lymphoid progenitors migrated through the blood to the thymus. The migration and differentiation from immigrant precursor to early T-cell precursors (ETP), to double negative (DN), to double positive (DP), and to single positive (SP) stages is illustrated within the distinct microenvironments of the thymus. Complete commitment to the T-cell lineage is indicated with a line between the DN2b and DN3a stages. β or γδ selection is indicated between the DN3a and DN3b stages. This figure is modified form Aifnatis 2008 and Rothenberg 2008 [
Regulatory factors in early T-cell development. The different stages of the cell differentiation are shown in the center starting with hematopoietic stem cells (HSC) and progressing to single positive cells. Above and below the line regulatory factors involved in the progression from one stage to another are indicated. Red lines indicated negatively active factors. The triangles at the top of the illustration indicate regulatory factors which are either upregulated or downregulated at indicated stages. For example, Tal1 expression decreases from the DN2 stage to the DN3a stage whereas Lef1 expression increased during that same transition. The solid blue line indicates the β-selection checkpoint with the long blue arrow indicating the TCRβ-dependent stages. At the bottom of the illustration the different cell surface phenotypes are shown below the corresponding stage in T-cell development. This figure is modified from Rothenberg 2008 [
Chromosomal translocations which alter gene function were among the first clues to the genes and molecular mechanisms involved in abnormal T-cell biology. In T-ALL, approximately 50% of cases have cytogenetically detectable chromosomal abnormalities. There are at least two distinct molecular mechanisms of chromosomal translocations that can lead to abnormal T-cell biology (Figure 3). In one mechanism a strong regulatory element such as a promoter or enhancer is rearranged next to a gene resulting in abnormal expression of this gene. The affected gene typically encodes a transcription factor or a protein involved in cell cycle regulation. In the second mechanism the translocation results in a fusion protein. Frequently this fusion creates a novel protein that affects normal cell cycle regulation [16]. One of the hallmark features of T-ALL is translocations involving T-cell receptor genes, which are observed in majority of T-ALL patients. The bulk of these recurring aberrations involve strong transcriptional regulator elements from the T-cell receptor (TCR) genes being juxtaposed with genes encoding transcription factors. These alterations are frequently caused by erroneous V(D)J recombination events during T-cell development. Overall these chromosomal abnormalities lead to aberrant gene expression and proteins that alter normal growth, differentiation, and survival of T-cells and their precursors.
Two mechanisms of aberrant activities caused by chromosomal translocations. A. A strong promoter or enhancer is rearranged next to a proto-oncogene resulting in abnormal expression of the proto-oncogene. The TCR loci elements and recurring gene targets involved in T-cell leukemogenesis are indicated to the left. B. Chromosomal rearrangement between two transcription factors result in a chimeric transcription factor with oncogenic activity. Recurring gene fusions in T-cell leukemogenesis are indicated in the center below the arrow.
Approximately 35% of the observed cytogenetic abnormalities in T-ALL involve translocations that include the TCR alpha/delta chain at 14q11.2, the TCR beta chain at 7q34, and the TCR gamma chain at 7p14 (Table1). Among this group, rearrangements with the HOX11, HOX11L2, TAL1, TAL2, LYL1, BHLHB1, LMO1, LMO2, LCK, NOTCH1, and cyclin D2 genes are most frequently observed in patients [11]. Overexpression of LMO1, LMO2, or TAL1 is caused by rearrangements to the TCR delta chain in 3-9% of patients. About 3% of pediatric T-ALL is caused by ectopic TAL1(1p32) expression due to the t(1;14)(p32;q11) rearrangement [17]-[21]. Overexpression of HOX11(TLX1) is observed in greater than 30% of adult T-ALL when rearranged to the promoters of the TCR delta or TCR beta chains[22]. About 3-5% of patients have HOXA-TCR beta rearrangements. For example, the inv(7)(p15q34) and t(7;7)(p15;q34) rearrangement which results in up-regulation of the HOXA9, HOXA10 and HOXA11 genes [23],[24]. Rare translocations involving juxtaposition of the TCR gamma or the TCR alpha/delta chains to the LYL1 (19p13), TAL2 (9p32), or BHLH1(21q22) resulting in overexpression of these genes are also observed [25]-[28].
Several chromosomal translocations do not involve the TCR locus (Table1). In 10-25% of TAL1 positive T-ALL patients, TAL1 is expressed as result of an intrachromosomal deletion between the upstream ubiquitously expressed SIL gene as a result and TAL1 (SIL-TAL1)[29]-[31]. 20% of pediatric and 4% of adult cases of T-ALL have HOX11L2 (TLX3)-BCL11B fusion. This fusion causes ectopic expression of the HOX11L2/TLX3 gene [32],[33]. 8% of patients have the (10;11(p13;q14)/PICALM-MLLT10 rearrangement. In this case leukemogenesis is mediated through HOX gene upregulation via mistargeting of hDOT1l and H3K79 methylation [34],[35]. ABL1, a cytoplasmic tyrosine kinase, fusion genes have been identified in approximately 8% of T-ALL case. The NUP214-ABL1 fusion, which results in a constitutively active tyrosine kinase with oncogenic potential, occurs in 6% of both adult and children patients and is the most frequent ABL1 fusion gene observed. EMl1-ABL1, BCR-ABL1, and ETV6-ABL1 gene fusions are rarely observed in T-ALL but are frequent in other hematologic malignancies [36],[37]. ETV6, which is an important hematopoietic regulatory factor, fusion genes have been observed in both B-ALL (9.6%) and T-ALL patients (5%)[38],[39]. A significant cytogenetically visible deletion on chromosome 9p involves CDKN2A and CDKN2B genes, incidence of which varies from being rare to 70% in T-ALL cases [40]-[42]. In 5-10% of T-ALL patients, gene rearrangements involving MLL gene are observed. The MLL gene can fuse to at least 36 different translocation partner genes [43],[44]. Although there are a wide variety of chromosomal aberrations, the number of genes affected is relatively small. All of these genes are important for normal T-cell development.
Several genes associated with T-ALL pathogenesis have mutations which are not cytogenetically visible. Some of the most frequently mutated genes are NOTCH1, FBXW7, PTEN, CDKN2A/B, CDKN1B, 6q15-16.1, PHF6, WT1, LEF1, JAK1, IL7R, FLT3, NRAS, BCL11B, and PTPN2 (Table2). Many of these genes were identified by gene expression profiling using microarrays or by whole genome sequencing analysis. Below some of these genes and their role in T-ALL is described briefly.
\n\t\t\t\t | \n\t\t|||||
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t||||
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
TAL1 | \n\t\t\tt(1;14)(p32;q11) t(1;7)(p32;q34) | \n\t\t\t~3 of T-ALL | \n\t\t\tTAL1 | \n\t\t\tSTIL-TAL1 (1p32 deletion) | \n\t\t\t12-25% T-ALL | \n\t\t
TAL2 | \n\t\t\tt(7;9)(q34;q32) | \n\t\t\trare | \n\t\t\tHOXA | \n\t\t\tPICALM-MLLT10 (t(10;11)(p13;q14)) MLL-MLLT1 (t(11;19)(q23;p13)) SET-NUP214 9q34 deletions | \n\t\t\t\n\t\t |
LMO1 | \n\t\t\tt(11;14)(p15;q11) t(7;11)(q34;p15) | \n\t\t\t6-8% of T-ALL | \n\t\t\tABL1 | \n\t\t\tEML1-ABL1 (t(9:14)(q34;q32)) BCR-ABL1 (t(9;22)(q34;q11)) ETV6-ABl1 (t(9;12)(q34;p13)) NUP214-ABL1 | \n\t\t\t8% T-ALL for ABL1 6% T-ALL for NUP214 | \n\t\t
LMO2 | \n\t\t\tt(11;14)(p13;q11) t(7;11)(q34;p13) 11p13 deletions | \n\t\t\t\n\t\t\t | ETV6 | \n\t\t\tETV6-JAK2 (t(9;12)(p24;p13) ETV6-ARNT (t(1;12)(q21;p13) | \n\t\t\tRare | \n\t\t
HOX11 | \n\t\t\tt(10;14)(q24;q11) t(7;10)(q34;q24) | \n\t\t\t30% of T-ALL | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
HOX11L2 | \n\t\t\tt(5;14)(q35;q32) | \n\t\t\t20% Childhood T-ALL 4% Adult T-ALL | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
HOXA | \n\t\t\tInv(7)(p15q34) t(7;7)(p15;q34) | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
LYL1 | \n\t\t\tt(7;19)(q34;p13) | \n\t\t\trare | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
Table of recurring translocation involved in T-ALL. The rearrangements are divided into those involving TCR and non-TCR loci.
\n\t\t\t\t | \n\t\t||
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Notch1 | \n\t\t\tSequence mutations | \n\t\t\t~50% of T-ALL | \n\t\t
FBW7 | \n\t\t\tSequence mutations | \n\t\t\t~20% of T-ALL | \n\t\t
PTEN | \n\t\t\tDeletions/Sequence mutations | \n\t\t\t6-8% of T-ALL | \n\t\t
CDKN2A/B | \n\t\t\tDeletions | \n\t\t\t30-70% of T-ALL | \n\t\t
CDKN1B | \n\t\t\tDeletions/Sequence mutations | \n\t\t\t12% of T-ALL | \n\t\t
6q15-16.1 | \n\t\t\tDeletions | \n\t\t\t12% of T-ALL | \n\t\t
PHF6 | \n\t\t\tDeletions/Sequence mutations | \n\t\t\t16% of childhood T-ALL 38% of adult T-ALL | \n\t\t
WT1 | \n\t\t\tFrameshift mutations | \n\t\t\t13% childhood T-ALL 12% of adult T-ALL | \n\t\t
LEF1 | \n\t\t\tFocal deletions/sequence mutations | \n\t\t\t15% of childhood T-ALL | \n\t\t
JAK1 | \n\t\t\tSequence mutations | \n\t\t\t18% of adult T-ALL | \n\t\t
IL7R | \n\t\t\tGain of function mutation | \n\t\t\t9% of T-ALL | \n\t\t
FLT3 | \n\t\t\tInternal tandem duplication | \n\t\t\t4% of adult T-ALL 3% of childhood T-ALL | \n\t\t
NRAS | \n\t\t\tSequence mutations | \n\t\t\t10% childhood T-ALL | \n\t\t
BCL11 | \n\t\t\tDeletions/Sequence mutations | \n\t\t\t9% of all T-ALL case 16% of T-ALL cases with HOX11 overexpression | \n\t\t
PTPN2 | \n\t\t\tDeletion | \n\t\t\t6% of T-ALL | \n\t\t
Table indicating recurring genetic alterations in T-ALL. The type of alteration and frequency of occurrence in T-ALL cases is indicated.
Activating or loss of function NOTCH1 mutations are observed in ~34-71% of T-ALL and is one of the most significant T-ALL oncogene [45]-[49]. NOTCH is involved in the regulation of several cellular processes including differentiation, proliferation, apoptosis, adhesion, and spatial development [50],[51]. The importance of NOTCH1 in leukemogenesis was first discovered in a rare translocation t(7;9) that fuses the intracellular form of NOTCH1 to the TCR beta promoter and enhancer sequences. This rare fusion leads to a truncated and constitutively activated form of NOTCH1 termed TAN1 [52]. Other Notch isoforms also show oncogenic activity. Notch2 sequences were able to induce leukemogenesis in cats and overexpression of Notch3 in mice resulted in multi-organ infiltration by T lymphoblasts [53],[54]. The majority of T-ALL cases with active Notch1 arise due to mutations in the Notch1\'s heterodimerization (HD) domain and/or the PEST domain (proline-, glutamic-acid-, serine-, and threonine-rich domain)[46]. Mutations in the HD domain appear to make the NOTCH1 receptor susceptible to ligand-independent proteolysis and activation (Figure 4b), whereas, mutations in the PEST domain interfere with recognition of the intracellular form of NOTCH1 by the FBW7 ubiquitin ligase (Figure 4c) [45],[46],[55]-[62]. Notch1 is a single-transmembrane receptor with an extracellular, transmembrane, and intracellular subunits. Initially the cell-membrane-bound Notch protein is a single protein. After maturation when the protein is cleaved into two subunits the extracellular and intracellular subunits are linked non-covalently via the HD domains. On the extracellular domain multiple epidermal growth factor (EGF)-like repeats bind ligands namely, Delta-like ligand (DLL1), DLL2, DLL4, Jagged1 and Jagged 2. Ligand binding initiates two cleavage events by the ADAM family of metalloproteinases and the γ-secretase complex to release the intracellular form of NOTCH from the membrane. Two nuclear localization domains in NOTCH lead to its translocation to the nucleus [62]. Once in the nucleus, NOTCH associates with CSL (CBF1/suppressor of hairless/Lag1). Transcriptional activation of NOTCH-target genes begins once the NOTCH/CSL complex recruits the co-activator proteins like mastermind-like 1 and the histone acetyl transferase p300 (Figure 4a) [63]. The C-terminal domain of NOTCH contains the PEST domain. This domain is targeted for ubiquitination by FBW7 and subsequent proteasome-mediated degradation. Mutations in the PEST domain can increase the half-life of NOTCH protein resulting in aberrant activation of NOTCH-target genes [58],[59],[61]. Together, aberrant stabilization or activation of the intracellular form of NOTCH1 directly links to T-cell leukemogenesis.
The Notch1 signaling pathway and mutations involved in aberrant Notch1 activation. A. Depiction of normal Notch1 signaling. Binding of Notch ligand to the extracellular Notch1 triggers a conformation change in the heterodimerization domain (HD). This allows cleavage first by a metalloproteinase of the ADAM family and then by γ-secretase. These cleavages releases Notch1 from the membrane allowing it to translocate into the nuclease. Once in the nucleus, Notch1 associates with a transcriptional complex composed of CSL (CBF1/suppressor of hairless/lag1) and mastermind-like 1 (MAML1) to activate Notch1 target genes. Notch1 then becomes associated with FBW7 and is tagged for degradation following ubiquitination. B. Mutations in the HD domains (indicated by a red star) result in ligand independent cleavage allowing aberrant release of Notch1 from the membrane. C. Mutations in the PEST domain of Notch1 or mutations in FBW7 interfere with ubiquitination of Notch1. This allows accumulation of intracellular Notch1 by reducing its degradation. The figure is modified from Aifantis 2008 [
Because NOTCH1 plays a significant role in T-cell leukemogenesis, its regulation has been studied extensively. Nearly 40% of Notch-responsive genes are regulators of cell metabolism and protein biosynthesis [64]. c-MYC, a master regulator of multiple biosynthesis and metabolic pathways, is a direct transcriptional target of Notch1. Notch1 binding sites in the MYC promoter have been shown to be important for MYC expression in T-ALL [64]-[67]. Constitutively active Notch1 was shown to activate the NF-κB pathway [68], an important regulator of cell survival, cell cycle, cell adhesion and cell migration. This activation can occur by the direct transcriptional activation of Relb and Nfkb2 as well as via a Notch1 and IKK complex interaction. Another Notch1 target is PTEN (phosphatase and tension homologue). PTEN is negatively regulated by Notch1 through the activity of HES1 and MYC, resulting in the deregulation of the PI3K-AKT metabolic pathway [69]. Finally, Notch1 is also involved in the regulation of the NFAT signaling pathway, where it regulates the pathway by altering expression of calcineurin, a calcium-activated phosphatase [70]. Overall, these findings emphasize the role of Notch1 in inducing T-cell leukemogenesis through multiple cell signaling pathways capable of regulating cell survival, proliferation and metabolism.
As mentioned above, FBW7 (F-box and WD repeat domain containing 7), an E3 ubiquitin ligase located on chromosome 4q31.3, is observed to be mutated in T-ALL with a frequency ranging from 8.6% to 16% [59],[61],[71]. FBW7 is part of the SCF complex (SKP1-Cullin-1-F box protein complex), which can target MYC, JUN, cyclin E, and Notch1 for ubiquitination coupled proteosomal degradation [60]. The WD40 domain of FBW7 contains a degron-binding pocket domain. This domain recognizes phosphothreonine in the consensus sequence I/L/P-T-P-X-X-S/E of protein substrates. Roughly 20% of T-ALL patients have mutations in FBW7 that destroys the degron-binding pocket. Moreover, the degron sequence of Notch1 (LTPSPES) located in the distal portion of its PEST domain is found to be mutated in T-ALL, thus extending Notch1 half-life and altering downstream signaling cascades. Interestingly, T-ALL patients frequently have mutations in both the FBW7 degron binding pocket as well as in the Notch1 degron sequence (Figure 4c) [58],[59],[61]. These combined mutations elevate intracellular Notch1 activity and therefore, enhances leukemia manifestation. Current studies suggest FBW7 mutations induce T-cell leukemogenesis by disrupting Notch1 regulation.
PTEN (phosphatase and tensin homolog deleted on chromosome 10) is deleted or mutated in 6-8% of T-ALL cases. The major substrate of PTEN is PIP3 (phosphatidylinositol-3,4,5-triphosphate). PTEN activity prevents the accumulation of PIP3, thus limiting or terminating activation of a cascade of PI3K-dependent signaling molecules. The expression of PTEN has been shown to be negatively regulated by Notch1. PTEN appears to be required for optimal negative selection in the thymus. Loss of PTEN is characterized by overexpression of the c-myc oncogene and induction of lymphomagenesis within the thymus [69],[72]. Therefore PTEN appears to be an important tumor-suppressor involved in T-cell leukemogenesis.
Deletions in CDKN2A and CDKN2B are significant secondary abnormities in pediatric T-ALL. Loss of the tumor suppressor CDKN2A/B expression is observed in 30-70% of T-ALL cases and can occur due to chromosomal translocation, promoter hypermethylation, somatic mutation, or gene deletions [40],[42]. CDKN2A and CDKN2B are located adjacent on chromosome 9p21. CDKN2A encodes p16INK4a(cyclin-dependent kinase inhibitor)/p14ARFwhile CDKN2B encodes p15INKb. These genes block cell division during the G1/S phase of the cell cycle by inhibiting cyclin/CDK-4/6 complexes [73],[74]. The principle mode of CDKN2A inactivation occurs via genomic deletions which can usually be detected by FISH [41]. Loss of function of CDKN1B (cyclin-dependent kinase inhibitor 1B) gene, located on 12p13.2, have been observed in 12% of T-ALL cases [75]. Similar to CDKN2A and CDKN2B, CDKN1B acts as a tumor suppressor. Inactivation of CDKN1B leads to overexpression of D-cyclins, thereby inhibiting the cells ability to maintain quiescence in G0. Therefore, CDKN2/B and CDKN1B play an important role in abnormal T-cell biology by regulating cell cycle progression.
12% of pediatric T-ALL cases have deletion in 6q15-16.1 [75]. The single most down regulated gene in this region is caspase 8 associated protein 2 (CASP8AP2). Deletion of CASP8AP2 probably interferes with Fas-mediated apoptosis. In gene expression profiling study, loss of CASP8AP2 was not observed in any pre-B-ALL samples [75], indicating deletions to 6q15-16.1 maybe a hallmark of T-ALL.
The X-linked plant homeodomain (PHD) finger 6 (PHF6) gene has inactivating mutations in 16% of pediatric and 38% of adult primary T-ALL cases [76]. Mutations in PHF6 are limited to male T-ALL cases. Consequently, this gene may be responsible for the increased incidence of T-ALL cases in males. Loss of expression of the PHF6 gene was associated with leukemia driven by abnormal expression of the homeobox transcription factor oncogenes. PHF6 gene encodes a protein with two plant homeodomain-like zinc finger domains. A recent study demonstrated that PHF6 copurifies with the nucleosome remodeling and deacetylation (NuRD) complex, implicating its role in chromatin regulation [77].
The WT1 (Wilms tumor) tumor suppressor gene is mutated in 13.2% of pediatric and 11.7% of adult T-ALL cases [78],[79]. The WT1 is known to be a transcriptional activator of the erythropoietin gene. Loss of WT1 expression results in diminished erythropoietin receptor (EpoR) expression in hematopoietic progenitors, suggesting that activation of the EpoR gene by Wt1 is an important mechanism in normal hematopoiesis [80]. WT1 mutations are frequently prevalent in T-ALL cases harboring chromosomal rearrangements associated with abnormal expression of the homeobox transcription oncogenes, HOX11, HOX11L2, and HOXA9 [79]. This suggests that the recurrent genetic mutations in WT1 are associated with abnormal HOX gene expression in T-ALL period
Lymphoid enhance factor 1 (LEF1) gene is mutated in 15% of pediatric T-ALL cases [81]. Inactivation of LEF1 was associated with increased expression of MYC and MYC targets, a gene expression signature consistent with developmental arrest at a cortical stage of T-cell differentiation. Interestingly, T-ALL cases with LEF1 mutation lacked overexpression of TAL1, HOX11, HOX11L2 and HOXA genes suggesting that LEF1 acts via different molecular pathways in T-cell leukemogenesis. In fact, The LEF family of DNA-binding transcription factors interacts with nuclear β-catenin in the WNT signaling pathway. The loss of LEF1 may result in the relief of transcriptional repression of MYC in T-ALL cases. It was reported that LEF1 probably contributes to T-ALL pathogenesis by acting in concert with NOTCH1 to promote up-regulation of MYC expression. In this case LEF1 also relieves transcriptional repression of MYC to allow its maximum overexpression by Notch1 [81].
About 18% of adult and 2% of pediatric T-ALL cases have activating mutations in the Janus Kinase 1 (JAK1) [38]. The JAK family (JAK1, JAK2, JAK3, and TYK2) function as signal transducers to control cell proliferation, survival, and differentiation. They are nonreceptor tyrosine kinases that associate with cytokine receptors to phosphorylate tyrosine residues of the target proteins. This process regulates the recruitment and activation of STAT proteins. The JAK/STAT signaling cascade is an important regulator of normal T-cell development. Each JAK family member associates with a different subset of cytokine receptors. JAK1 regulates the class II cytokine receptors as well as receptors that use the gp130 or γc receptor subunit. These class of cytokine receptors are involved in controlling lymphoid development [82],[83]. The majority of the JAK1 kinase mutations observed in T-ALL cases result in unregulated tyrosine kinase activity. T-ALL cases with mutations in JAK1 appear to be associated with different T-ALL subgroups than patients harboring aberrant expressions of the homeobox transcription factors HOX11 and HOX11L2 [38]. JAK1 is involved in the regulation of both interleukin 7 receptor (IL7R) and protein tyrosine phosphatase non-receptor type 2 (PTPN2) [84],[85].
The interleukin 7 receptor (IL7R) has a gain-of-function mutation in exon 6 in 9% of T-ALL cases [85]. Several lines of evidence suggest IL7R plays an important role in T-cell leukemogenesis. IL-7 and IL7R signaling are essential for normal T-cell development. Deficiency of IL-7 and IL7R in mice caused reduction of non-functional T cells and showed an early block in thymocyte development [86]-[89]. Loss of IL7R function also results in severe combined immunodeficiency in humans [90]. Increased expression of IL7R was associated with spontaneous thymic lymphomas in mice. Furthermore, Notch1 has been shown to transcriptionally upregulate IL7R receptor gene [91]. Mutations in exon 6 of IL7R promotes de novo formation of intermolecular disulfide bonds between IL7R mutant subunits, which triggers constitutive activation of tyrosine kinase JAK1 regardless of regulation by IL-7, γc, or JAK3. Gene expression profiles for IL7R mutations are generally associated with the T-ALL subgroup harboring HOX11L2 rearrangements and HOXA deregulation [85].
Inactivation of protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene is observed in ~6% of T-ALL cases [84],[92]. PTPN2 encodes a tyrosine phosphatase, located on chromosome 18p11.3-11.2, that negatively regulates JAK/STAT pathway and NUP214-ABL1 kinase activity. Loss of PTPN2 results in activation of the JAK/STAT pathway and increased T-cell proliferation by cytokines. Unlike JAK1 mutations, deletions in PTPN2 gene appear to be restricted to T-ALL cases which specifically overexpress HOX11 [84]. Therefore mutations in PTPN2 probably play a role in T-cell leukemogenesis by deregulating tyrosine kinase signaling.
Activating mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are amongst the most common genetic aberrations in acute myeloid leukemia [93]-[95]. In T-ALL, FLT3 mutations are relatively rare with a frequency of approximately 4% in adult and 3% in pediatric cases. [96]-[98]. FLT3 encodes a class III membrane tyrosine kinase that is expressed in early hematopoietic stem cells. Normally FLT3 is activated when bound by the FLT3 ligand (FL). This interaction causes receptor dimerization and kinase activity resulting in activation of downstream signaling pathways such as Ras/MAP kinase, PIK3/AKT, and STAT5. The most frequent FLT3 mutation involves a duplication of the juxtamembrane (JM) domain. This mutation leads to dimerization of FLT3 in the absence of FLT3 ligand (FL), autophosphorylation of the receptor and constitutive activation of the tyrosine kinase domain, which triggers uncontrolled proliferation and resistance to apoptotic signaling though activation of the PIK3/AKT, Ras/MAPK and JAK2/STAT pathways [98]-[100].
The B-cell chronic lymphocytic leukemia (CLL)/lymphoma 11B (BCL11B) gene has mutations in 16% of T-ALL patients with HOX11 overexpression. However, in unselected patients, deletions or missense mutations for BCL11B were observed in only 9% of cases. This suggests that BCL11 mutations probably occur across all subtypes of T-ALL [101]. BCL11B is located on human chromosome 14q32.2 and encodes a kruppel-like C2H2 zinc finger protein which acts as a transcriptional repressor. Loss of function mutations in BCL11B gene in mice leads to developmental arrest of T-cell in DN2-DN3 stage, acquisition of NK-like features, and aberrant self-renewal activity. Transcriptional activation of IL-2 expression in activated T-cell is mediated by BCL11B via its interaction with p300 co-activator at the IL-2 promoter [102]-[106]. Because of BCL11B’s role in normal T-cell development, it plays an important role in T-cell leukemogenesis.
Approximately 10% of childhood T-ALL cases have mutations in NRAS oncogene located on chromosome 1p13.2, which is involved in the malignant transformation of many cells [107]. The recurrence of NRAS mutations in T-ALL cases suggests that NRAS is involved in abnormal T-cell biology.
Whole genome sequencing and gene expression profiles provide a more comprehensive view of the genetic alterations involved in T-cell leukemia. A recent microarray-based gene expression study classified T-ALL cases into major subgroups corresponding to leukemic arrest at different stages of thymocyte differentiation. Currently there are 3 subtypes of T-ALL cases which include the HOXA/MEISI, TLX1/3 and TAL1-overexpressing subtype [108], the LEF1-inactivated subtype [81], and the early T-cell precursor phenotype [109] (Figure 5). Leukemic arrest at early pro-T thymocytes (DN2 cells) were characterized by high levels of expression of the LYL1 gene. Arrest in early cortical thymocytes (DN3 cells) were characterized by changes in HOX11/TLX1 expression. Arrest in late cortial thymocytes (DP cells) were characterized by changes in the TAL1/LMO1 expression. Aberrant HOX11L2/TLX3 activation was also identified as being involved in T cell leukemogenesis (Figure 4) [108]. TAL1 and LYL1 are members of the basic helix-loop-helix (bHLH) family of transcription factors, LMO1 is member of the LIM-only domain genes (LMO), and HOX11 and HOX11L2 belongs to the homeobox gene family.
Gene subtypes resulting in differentiation arrest at specific stages of T-cell development. The illustration shows the progression of T-cell development from the double negative stages to the mature single positive stage. The colored rectangles indicates stages of leukemic arrest. Overexpression of LYL, HOX11, TAL1, and HOXA lead to differentation arrest at the double negative stage, early cortical stage, late cortical stage, and positive selections stage, respectively. Loss of Lef1 expression results in early cortical leukemic arrest. The table below indicates the molecular subtypes leading to differentiation arrest at specific stages of T-cell development and the molecular subtypes occurring across all the stages of T-cell development.
Recently whole genome sequencing of early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) identified several genes involved in abnormal T-cell biology [10]. 15% of T-ALL cases are ETP-ALL. Phenotypically ETP-ALL is negative for the cell surface markers CD1a and CD8, has little to no expression of CD5, and has aberrant expression of myeloid and hematopoietic stem cell markers. This study performed whole genome sequencing on 12 children with ETP-ALL. The frequency of the mutations identified from these 12 cases was then accessed in 94 cases of T-ALL. Of these 94 cases 52 cases had ETP and 42 had a non-ETP pediatric T-ALL. Even though an average of 1140 sequence mutations and 12 structural variations in the genome were identified per ETP case, they were able to narrow down the number of affected genes to 3 group and 3 novel genes (DNM2, ECT2L, and RELN). 67% of the cases were characterized by activating mutations in genes involved in the regulation of cytokine receptor and RAS signaling. These genes included NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF. 58% of the cases were characterized by inactivating lesions that disrupted hematopoietic development. These genes included GATA3, ETV6, RUNX1, IKZF1, and EP300. 48% of the cases were characterized by changes in histone modifying genes (EZH2, EED, SUZ12, SETD2, and EP300) [10]. From gene expression profiling and whole genome sequencing we are beginning to obtain a more complete picture of the genes involved in abnormal T-cell biology.
MicroRNA expression profiling found 10 detectable miRNAs in human T-ALL cells, five of these miRNAs (miR-19b, miR-20a, miR-26a, miR-92, and miR223) were predicted to target tumor suppressors genes implicated in T-ALL [110]. These five miRNA\'s were able to accelerate leukemia development in a mouse model. Furthermore, it was shown that these five miRNAs produced overlapping and cooperative effects of the tumor suppressor genes IKAROS, PTEN, BIM, PHF6, NF1 and FBXW7 in T-ALL pathogenesis. miR223 appears to be the most overexpressed miRNA in leukemia. These results indicate the important role that miRNA\'s play in abnormal T-cell biology.
As mentioned early, some of the most common recurrent chromosomal aberrations in abnormal T-cell biology involved chromosomal translocations of the TCR gene to the basic helix-loop-helix (bHLH) genes (MYC, TAL1, TAL2, LYL1, bHLHB1), the cysteine-rich (LIM-domain) genes (LMO1, LMO2), or the homeodomain genes (HOX11/TLX1), HOX11L2/TLX3, members of the HOXA cluster) (Table1). The most common bHLH gene with aberrant expression observed in T-ALL cases is the transcriptional regulator TAL1 (T-cell acute lymphocytic leukemia 1; also known as SCL). It was first identified in T-ALL patients with the t(1;14)(p32;q11) translocation [17],[18],[20],[21]. This chromosomal rearrangement, which is observed in 3% of cases, causes ectopic TAL1 expression by placing TAL1 under control of the TCRδ oncogene [19]-[21],[111]. 12%-25% of T-ALL cases have a submicroscopic 90-kb deletion that fuses the TAL1 coding sequence to the first exon of the SIL gene (SCL interrupting locus). This rearrangement leads to dysregulation of TAL1 expression [17],[29]-[31]. The majority of T-ALL cases, up to 60%, show ectopic TAL1 expression with no detectable TAL1 gene rearrangements [112]. Gene expression profiling has shown that ectopic expression of TAL1 results in leukemic arrest in late cortical thymocytes (Figure 5) [108]. These results show that activation of TAL1 gene is required for the leukemic phenotype of T-cells.
The TAL1 gene, located on chromosome 1p32, encodes a class II basic helix-loop-helix factor [113]. The protein binds DNA as a heterodimer with the ubiquitously expressed class I bHLH genes known as E-proteins such as E2A or HEB. These heterodimers recognize an E box sequence (CANNTG)[114]. TAL1 positively and negatively modulates transcription of targets gene as a large complex consisting of an E-protein, the LIM-only proteins LMO1/2, GATA1/2, Ldb1, and other associated coregulators. This complex usually binds a composite DNA elements containing an E box and a GATA-binding site separated by 9 or 10 bp (Figure 6) [115]-[117]. It was shown recently that in T-ALL cells TAL1, GATA-3, LMO1, and RUNX1 together form a core transcription regulatory circuit to reinforce and stabilize the TAL1-directed leukemogenic program [118].
Model of TAL1 complexs and target sites. A. TAL1 complex binding to an E-box and GATA box. B. TAL1 complex binding to a double E-box. C. TAL1 complex binding to a single E-box. D. TAL1 complex binding to a single GATA site showing activation of either the RALDH-2 or NKX3.1 genes. E. TAL1 complex binding to a GC-box with activation of c-kit. The table to the lower right shows the different TAL1 regulator partners. The partners are divided into three categories transcription factors, co-activators, or co-repressors.
TAL1 expression is essential for hematopoiesis. It is required for specification of hematopoietic stem cells during embryonic development and it is necessary for erythroid maturation. Normal expression of TAL1 is restricted to the DN1-DN2 subset of immature CD4-/CD8- thymocytes with ectopic expression resulting in leukemic arrest in late cortical thymocytes [108].
Two models have been proposed for TAL1-induced leukemogenesis. In the prevailing model TAL1 acts as a transcriptional repressor by blocking the transcriptional activities of E2A, HEB, and/or E2-2 through its heterodimerization with these E-proteins. TAL1 may mediate its inhibitory effect by interfering with E2A-mediated recruitment of chromatin-remodeling complex which activate transcription [114],[119]-[121]. It also been shown to associate with several corepressors including HDAC1, HDAC2, mSin3A, Brg1, LSD1, ETO-2, Mtgr1, and Gfi1-b (Figure 6) [122]. In human T-ALL TAL1 transcriptional repression may be mediated by TAL1-E2A DNA binding and recruitment of the corepressors LSD1 and/or HP1-α [123]. In the other model TAL1 induces leukemogenesis through inappropriate gene activation [124]. At least two genes RALDH2 and NKX3.1 are transcriptionally activated by TAL1 and GATA-3 dependent recruitment of the TAL1-LMO-Ldb1 complex [125],[126]. As a transcriptional activator TAL1 has been shown to associate with the coactivators p300 and P/CAF (Figure 6) [127],[128]. Both of these complexes contain HAT activities. The prevalence of histone-modifying enzymes in TAL1 complexes suggests that one function of TAL1 is to regulate chromatin states of its target genes.
TAL1 and the lymphoblastic leukemia-derived sequence 1 (LYL1) share 90% sequence identity in their bHLH motif [26]. Like TAL1, LYL1 role in leukemogenesis was discovered by studying chromosomal rearrangements. It is expressed by adult hematopoietic cells and is overexpressed in T-ALL. Gene expression profiling showed that overexpression of LYL1 resulted in leukemic arrest at pro T-cell (Double negative) stage of T-cell differentiation (Figure 5) [108]. In mouse embryos LYL1 and TAL1 expression overlaps in hematopoietic development, developing vasculature and endocardium. At the molecular level LYL1 controls expression of several genes involved in the maturation and stabilization of the newly formed blood vessels [129]. Therefore, bHLH proteins play an important role in abnormal T-cell biology.
Aberrant expression of the LMO1 and LMO2 proteins is observed in 45% of T-ALL cases. The discovery of the LMO1 and LMO2 genes adjacent to the chromosomal translocations t(11;14)(p15q11) and t(11;14)(p13;q11) was the first indication that these proteins were involved in T-cell leukemogenesis [130]-[132]. The LMO family (LMO1, LMO2, LMO3, and LMO4) encodes genes that have two cysteine-rich zinc coordinating LIM domains. The LIM domain is found in a variety of proteins including the homeodomain-containing transcription factors, kinases, and adaptors. Despite the presence of 2 zinc finger motifs, LMO1 and LMO2 genes do not appear to bind DNA. Instead the LMO proteins probably act as scaffolding protein to form multiprotein complex through their interaction with the LIM domain binding protein 1 (LDB1) (Figure 6) [116].
Leukemogenesis by aberrant expression of LMO1 or LMO2 is thought to occur via two mechanisms. In the first mechanism aberrant expression or abnormal LMO proteins forms a dysfunctional multiprotein complexes that alters the expression of the target genes by directly binding to their promoters [133]-[136]. In the second mechanism abnormal LMO1 or LMO2 complexes displace the LMO4 complex. This results in arrest of T-cell development at the DP stage [137].
LMO2 function is necessary for normal T-cell development. In fact, LMO2 has been shown to interact with several factors involved in aberrant T-cell biology. As mentioned above TAL1 may regulate its target genes through the TAL1-LMO-Ldb1 complex (Figure 6). Ectopic expression of LMO1 and LMO2 leads to accumulation of immature DN T cells in mice with subsequent leukemia manifestation with a long latency, suggesting the role of LMO is important for the development of tumors but is not self-sufficient [26],[138],[139]. Ectopic expression of both TAL1 and LMO1 in mice accelerated the progression to leukemogenesis (Figure 7). In this case thymic expression of the TAL1 and LMO1 oncogenes induced expansion of the ETP/DN1 to DN4 population and lead to T-ALL in ~120 days. The acquisition of a Notch1 gain-of-function mutation was proposed to be the rationale behind this increase in leukemia penetrance. In fact, thymic expression of all three oncogenes Notch1, TAL1 and LMO1 induced T-ALL with high penetrance in 31 days, the time necessary for clonal expansion (Figure 7) [140]. These studies suggest that aberrant LMO proteins are key players in abnormal T-cell biology.
Model of progression to leukemia via TAL1, LMO1 and Notch1. The dashed line indicates the time of weaning. The number of days to differentiation arrest and finally T-ALL are shown above the cell stages. A. Shows the numbers of days to full T-ALL in mice with TAL1 and LMO1 oncogenes. Note the 70 day delay for a Notch1 gain of function mutation. B. Shows the number of days to full T-ALL in mice with TAL1, LMO1, and Notch1 oncogenes. Note the delay is ~30 days the time necessary for clonal expansion. This figure is modified from Tremblay et al 2010 [
Dysregulated expression of HOX-type transcription factors occurs in 30-40% of T-ALL cases [23],[24],[32]. The HOX genes play an important role in hematopoiesis [141]. The majority of the HOXA, HOXB and HOXC genes clusters are expressed in hematopoietic stem cells and immature progenitor compartments. Furthermore, these genes are down regulated during differentiation and maturation of hematopoiesis [142],[143]. In T-ALL dysregulation of the HOXA gene cluster is a frequent recurring aberration. Upregulation of HOXA9, HOXA10, and HOXA11 occurs in T-ALL cases when the TCR beta regulatory elements are juxtaposed with these genes [16].
Two orphan HOX proteins (HOX11 and HOX11L2) have been implicated in T-cell leukemogenesis [144]. Overexpression of HOX11 is observed in 30% of T-ALL cases because of two recurring translocation events. This gene is also frequently overexpressed in T-ALL cases in the absence of genetic rearrangements. Mice deficient in HOX11 fail to develop a spleen, implicating its role in spleen organogenesis [145]. Normally HOX11 is not expressed in thymocytes. Ectopic expression of HOX11 in T-cells caused a block at the DP stage of T-cell differentiation (Figure 5). This is consistent with genetic profiling studies which showed that overexpression of HOX11 results in leukemic arrest at early cortical thymocytes stage (Figure 5) [108]. Overexpression of HOX11 in hematopoietic stems cells of mice developed T-cell leukemia. However, the long latency of tumorigenesis suggests other genetic abnormalities are required [146]-[148]. It should be noted that nearly all HOX11 T-ALL cases have activating NOTCH1 mutation. It has been proposed that HOX11 binding to the Groucho-related TLE corepressor was necessary for maximal transcriptional regulation of Notch1-responsive genes. This suggests that HOX11 and Notch1 may synergistically regulate transcription in T-ALL [149].
Aberrant changes in DNA methylation and histone modifications occur frequently in all cancers. Estimates vary but studies suggest that there are approximately 100 epigenetic changes for every DNA based genetic mutation. Consequently epigenetic modifications will almost certainly play an important role in T-cell leukemogenesis.
Comparative genomic hybridization data of T-ALL primary samples has shown recurrent deletions in 25% of T-ALL cases in EZH2 and SUZ12 genes. These genes are members of the polycomb repressor complex 2 (PRC2) and involved in establishing the repressive H3K27me3 mark. Activation of Notch1 was shown to cause the loss of the H3K27me3 mark by antagonizing the activity of PRC2. This data implicates histone modifications and PRC2 as important regulatory factors in T-cell leukemogenesis [150].
The CpG island methylator phenotype (CIMP) has been used to characterize T-ALL patients. The CIMP+ phenotype has a large number of hypermethylated genes with the CIMP- having a low number of hypermethylated genes. Analysis of the methylation status of 20 genes, the majority of which are implicated in abnormal T-cell biology, in 61 pediatric T-ALL patients and 11 healthy children showed a difference in the CIMP pattern. On average patients had 2.4 hypermethylated loci where none of the normal individual\'s loci where hypermethylated [151]. Therefore changes in the patterns of CpG island methylation at critical genes can be associated with specific tumorigenesis and consequently may be playing an important role in T-cell leukemogenesis.
Although there are a large number of genes involved in the molecular morphogenesis of T-cell leukemogenesis, many of the genes act through related pathways. This has helped us clarify the different genetic subtypes of T-ALL improving our risk stratification of T-ALL. Furthermore understanding the different genetic subtypes is allowing for personalized chemotherapy. Powerful new tools such as next-generation sequencing aid in identifying more relevant recurring lesions in leukemogenesis. This is resulting in the development of better therapeutic agents and methods. Because of improved supportive care, better risk stratification and personalized chemotherapy the 5-year survival of pediatric acute lymphoblastic leukemia has increase to 85% [152]. Even though we have made significant progress in the understanding of the molecular morphogenesis of T-ALL there are still significant gaps in our knowledge of the genes involved in leukemogenesis.
The concepts of corporate social responsibility (CSR) and business ethics have been used interchangeably in the existing literature [1]. While ethics is the set of principles and values that guides business behaviour, CSR is the set of socially and environmentally responsible practices of the company [2]. In recent decades, CSR has become an element to be integrated into the core of a business to allow the creation of value beyond the economic and ensure company longer term economic social viability of the company [3, 4].
Recent literature states that CSR could be oriented towards the search for value creation in terms of innovation [5, 6]. Numerous papers have suggested that CSR and innovation are related [7, 8, 9, 10], but this relationship is not solidly proven and more research on the issue is necessary [9]. Some of this research states that their relationship increases operational efficiency by using cleaner technologies [11]. Another part of the research points out that CSR (if it were properly embedded across an organization) could improve performance through the development of innovative practices, processes, and products that enhance a company’s competitive advantage through differentiation and cost saving strategies [12, 13]. Finally, other research, unrelated to competitive and operational aspects, shows that CSR linked to stakeholder management drives innovation in response to stakeholder demands, by improving companies’ social performance [14, 15, 16]. Our research is included in this last group of studies and aims to analyse whether innovation is the consequence of CSR combined with the demands of company stakeholders.
One of the difficulties presented by the analysis of the relationship between CSR and innovation is the framework in which to place this object of study. The intuitive idea is clear: innovation and the concern for sustainability must be related and promote value in companies. However, possibly the biggest problem so far has been the lack of a business model that covers both concepts. The development of integrated reporting could provide a framework for studying these elements. The proposal of this type of report would be considered essential, as it would link the different responsibilities that companies assume. But the relationship between the different resources should first be demonstrated to justify the necessity of an integrated report [17]. Europe and the International Accounting Standards Board (IASB) are studying the suitability of making this type of report mandatory.
Integrated reporting provides an appropriate framework for CSR because in value creation, companies employ different types of capital, including natural capital, human capital, and social and relational capital [18] that, in the literature, have been grouped under the term CSR, which includes the responsibility assumed by the company in relation to these resources. CSR is a part of sustainability [19]. According to the Brundtland Report (1987), sustainable development is development that meets the needs of the present without compromising the needs of future generations [20]. Sustainability rests on three pillars: economic growth, environmental balance, and social responsibility. CSR can be defined as a company’s responsibility for its impact on society [21], which leads to the integration into its corporate strategy of social, environmental, ethical, and human rights, and consumer concerns and commitments [21]. Integrated reporting is based on an accounting model that considers the responsible use of different resources to ensure sustainability or long-term value creation. The report must take into account the effort and investments made in CSR. In an integrated report, the elements that compose intellectual capital are knowledge-based intangibles. Among them are intellectual property (patents, licences, rights of exploitation and use of symbols, etc.) and organisational capital (tacit knowledge, systems, procedure and protocols). The element that may be most closely related to CSR is industrial property, and so this will be the focus of this research. Industrial property is the result of a process of innovation. Innovation can be considered as a process of discovery and development that gives rise to new products and production processes [22, 23]. Innovation is the application of knowledge to gain new knowledge that may be disruptive or incremental [24]. Companies are currently making great efforts in the field of innovation; in fact, it can be considered an inevitable step for any company that wants to grow, maintain, or create competitive advantages and/or access to new markets [5, 6]. Its importance for the survival and success of companies is widely accepted in the literature.
The first objective of this work is to deepen the theoretical framework around the relationship and interaction between CSR and innovation, setting stakeholder orientation (as opposed to the usual orientation to the market) as the study’s approach to sustainability [14, 25]. This will serve to justify the interest of considering all these elements in a single document: an integrated report that is currently being considered for promotion by international organisations.
The second objective is to study the relationship between CSR and intellectual capital, specifically intellectual property. The results will allow us to verify contrast the integration of CSR and stakeholder orientation into the core business as a means of fostering innovation in companies. This justifies the importance that the holistic approach of integrated reporting will have in the study of value creation. The aim is to find that a company’s social and relational capital creates intellectual value. The previous research into integrated reporting has mainly focused on the analysis of its adoption and its extension, but qualitative research on the possibilities of this type of reporting is scarce [26]. This highlights the relevance of our research, as the findings on the relationship between non-financial elements will be highly relevant in deciding whether to make integrated reporting that offers a global view of companies a mandatory requirement.
To achieve these objectives, the study is focused on Europe, because of the interest and effort of the European Commission to promote the development and disclosure of financial and non-financial information as well as the fact that CSR programs have different content according to the geographical environment in which they are implemented [27, 28]. The study is carried out on a wide sample; a CSR measure that considers all dimensions is taken and uses panel data that allows for control of unobserved heterogeneity, giving robustness to the model.
The work is structured as follows: after reviewing the relevant literature, we present the theoretical framework and propose the hypotheses to be compared. Following this, we describe the methodology used and present and discuss the results and findings. Finally, conclusions are drawn.
In recent years, we have seen a growing trend in companies to consider multidimensional reporting that reflects the different elements involved in the development of business activity [29]. These reports integrate social, environmental, financial, and corporate governance information into a single document, the most widespread of which is the so-called integrated report, which aims to provide a synthesised and holistic view of organisations and their actions [17, 30].
In 2010, the International Integrated Reporting Council (IIRC) was formed with the participation of the main professional bodies and global accounting regulators - International Accounting Standards Board (IASB), Financial Accounting Standards Board (FASB), International Federation of Accountants (IFAC), and International Organization of Securities Commissions (IOSCO)- and other public bodies, the “Big Four” audit companies (Deloitte, EY, KPMG and PwC), leading multinationals, and representatives of institutions promoting social and environmental accounting [31]. The IIRC published the conceptual framework for integrated reporting, identifying a set of fundamental concepts and basic principles and contents for integrating sustainability into corporate objectives and reports [18, 32, 33].
Integrated reporting is based on two basic ideas. First, that a company’s results involve the participation of resources of a varied nature, some of which are internal, and so controlled or owned by the company, and others that are external to the company, such as natural resources (water, air, land, flora) or those generated by society (social cohesion, effective governments, infrastructures, educational systems). Both types of resource are present in value creation [17, 31, 34]. These elements have to be considered in an integrated report to the extent that the company is accountable for the management of the resources used.
The second idea refers to sustainability. Value creation is not only to be understood in a financial sense; it also implies that there is a balance between the variations experienced by the various capitals, both internal and external, in the development of the business activity. The decreases in some of the capitals, mainly the external ones, and should be properly justified. This leads to the need for a reporting model that goes beyond the financial model and comprehensively considers the resources that allow the creation of value. Such a report can be also used as a management tool.
The analysis of sustainability requires combined consideration of the ecological, economic, and social effects that occur in the development of business activity and that can affect the availability of resources in the future. It refers to the responsibility of organisations to integrate economic, environmental, and social aspects into operations and business strategy [21] to assure the viability of the enterprise in the medium and long term [26, 35, 36]. It is assumed that there are relationships between all these elements that companies use and that it is necessary to ensure that they are real. Therefore, these dimensions should not be considered in isolation but should take into account their synergies and interrelations [19], which lead to medium and long term value creation [18, 32]. The underlying idea is that the combined effect of the different capitals is greater than the individual contribution of each of them. This leads to the idea that there must be a relationship between these capitals, which can and should be analysed prior to the study of their contribution to value creation.
In relation to CSR disclosure, several theoretical frameworks have been used [37, 38]. The most widely used of these are: institutional theory, which is appropriate when it is necessary to analyse the incidence of normative, institutional, and cultural contexts, etc. [39, 40]; the legitimacy theory, which is based on the existence of a social contract or licence to operate between companies and society [38, 41]; and stakeholder theory, which states that the responsibilities of companies towards society have significantly expanded [42]. Stakeholder theory is the most used, useful, and dominant theory to explain sustainability practices and is applicable in the context of this research [43]. The non-financial aspect included in integrated reporting involves consideration of the participation of different resources and stakeholders in value creation and sustainability [30]. Integrated reporting requires CSR to be part of the corporate and core business strategy. According to stakeholder theory, suppliers of factors understood in a broad sense, i.e. the five types of capital indicated above, are involved and associated with the organisation and cooperate to ensure the survival and continuity of the firm [31]. An integrated report should respond to the needs and interests of key stakeholders (investors, consumers, employees, suppliers and community) [18].
The role of companies and their commitments to society, employees, other stakeholders, and the environment is changing [44, 45]. Stakeholder theory requires linking the behaviour of a company with the effects on its stakeholders. In this context, the company must take into account the stakeholders’ interests in products, behaviours, and programs developed by the entity. Stakeholders are an essential element in the success or failure of an entity [46]. An integrated report should respond to the interests of the groups involved and to some extent implies the application of accountability for the use of financial and non-financial resources, such as intellectual, social or relational capitals.
Stakeholder theory requires that companies balance the legitimate but sometimes conflicting interests of stakeholders [46, 47]. This requires considering their management and providing them with information [46]. A company’s future success is linked to its consideration of and response to stakeholder expectations [48, 49].
Companies have to manage the stakeholders that directly or indirectly collaborate with the entity to achieve its objectives [45, 50]. This aspect of stakeholder theory fits into the framework of integrated reporting. Stakeholder theory has been widely considered in the literature as a solid justification for both social and environmental disclosure practices and for corporate governance mechanisms. In this sense, it is also applicable in the combined consideration of all these elements in a single report [26].
Although stakeholder theory is widely accepted in relation to CSR and innovation, most research focuses on competitiveness, obtaining competitive advantages, [5] and analysing the effects of programs on performance indicators [51, 52]. Emphasis has been placed on the effect of these practices on the market or investors. However, in the last few years, we have seen the model evolve towards a broader vision, where CSR and innovative practices could generate value beyond economic and commercial benefits [5].
Recent literature states that CSR could be oriented towards the search for value creation in terms of innovation for the company and society [5, 6]. Some of this research shows that CSR drives innovation in response to stakeholder demands [14, 15]. These works have focused on a more ethical vision of the relationship between CSR and innovation. Innovation in itself can generate social benefits, such as the generation of more economic products, the creation of new jobs [53], and the development of more sustainable business models [11, 54]. In this sense, entities could establish innovative practices that respond to the demands and expectations of stakeholders to ensure the creation of value.
Stakeholders often have unused or untapped knowledge that complements a company’s internal knowledge and is valuable in achieving the goal of sustainable value creation [12]. The importance given to stakeholders in the elaboration of CSR programs is evidenced by entities’ establishment of relational networks and new channels of communication to obtain information about stakeholder demands, expectations, and perceptions. Attention to suggestions made by environmental agencies, research institutes, community, consumers, employees, and investors and, where appropriate, integration into CSR programs can help strengthen stakeholder relations. Engaging with stakeholders allows companies to identify innovation opportunities [55]. The active participation of stakeholders helps in the detection stage and favours efficiency in the development of new proposals avoiding the development of ideas that are not in demand in the market. Subsequently, the consideration of different interests in management makes it possible to create situations of mutual benefit for companies and society [3, 56]. The interests of the different stakeholders can be aligned with the concept of shared value, the company survives in the market through innovation and the companies meet different needs of its stakeholders. The concept of shared value underlies the integrated report.
According to the above, there is a positive relationship between orientation to stakeholders and the development of innovative practices. As a result of companies’ focus on stakeholders in CSR programs, CSR is expected to have a greater impact on innovation. The following hypotheses are proposed:
Hypothesis 1. A company’s orientation towards stakeholders encourages innovation.
Hypothesis 2. A company’s stakeholder orientation positively moderates the effect of CSR on innovation.
CSR can be defined in many ways and measured using many different approaches. In the present study, we focus on a sample of European firms that form part of the Dow Jones Sustainability Index (DJSI). The firms in this index are leaders in the field of CSR. To qualify for incorporation into the index, they must conform to very demanding CSR guidelines (based on economic, social, and environmental indicators that will be included in the integrated report) and are rated according to these guidelines by the Sustainability Index of the Sustainable Asset Management (SAM) Group [57]. This score was utilised in the present study. The indexed companies develop practices that go beyond legal requirements and respond to ethical values and commitments demanded by society.
The period 2011–2015 is examined, obtaining an initial sample of 176 European firms that formed part of the DJSI. From the total number of European companies included in this index, we removed 41 that were dedicated to financial and insurance activities and a further 17 that have not been in the index throughout the entire period analysed. Accordingly, the final sample consisted of 118 firms.
The sample is distributed by country and sector as shown in Tables 1 and 2.
Country | Frequency (number of companies) | Percent |
---|---|---|
Belgium | 1 | .8 |
Denmark | 4 | 3.4 |
Finland | 3 | 2.5 |
France | 15 | 12.7 |
Germany | 14 | 11.9 |
Hungary | 1 | .8 |
Ireland | 1 | .8 |
Italy | 5 | .8 |
Netherlands | 8 | 4.2 |
Norway | 4 | 6.8 |
Portugal | 1 | 3.4 |
Spain | 9 | 7.6 |
Sweden | 9 | 7.6 |
Switzerland | 12 | 10.2 |
United Kingdom | 31 | 26.3 |
Total | 118 | 100 |
Countries in the sample.
Country | SIC CODE | Frequency (number of companies) | Percent |
---|---|---|---|
Mining, construction | 100–1979 | 15 | 12.7 |
Manufacturing | 2000–3999 | 56 | 47.5 |
Transportations, Communications, Electric, Gas and Sanitary service | 4000–4999 | 23 | 19.5 |
Wholesale Trade | 5000–5199 | 12 | 10.2 |
Retail | 5200–5999 | 12 | 10.2 |
Total | 118 | 100 |
Industries in the sample.
Innovation is the dependent variable. Innovation can be measured through output indicators (product and process innovations, patents) [58] or input indicators (R&D expenditure). Integrated reporting chooses to measure innovation through industrial property, i.e. innovation is measured by the number of patents registered (PAT) [59]. Patents have the advantage of being an objective element and a measure of the results obtained from R&D activities [60, 61]. Moreover, it provides a measure of a firm’s current technological capacities, efficiency, and potential future profits from R&D [62]. In addition, it constitutes a mechanism that favours the appropriation of the benefits obtained from innovation [63] and the capacity to create added value [64].
In Europe, the adoption of patent protection tends to increase as firms grow [65]. Patents have been considered the most believable proxy of innovation [65]. The patents corresponding to each of the firms in our study were compiled from information disclosed by the Spanish Patent and Trademark Office (OEPM) for each of the years considered in this study.
Stakeholder orientation and CSR were taken as the independent variables.
On the one hand, stakeholder orientation (STAKE) is measured through the existence of mechanisms and channels of communication that aid the active participation and collaboration of stakeholders and provide possibilities for interaction [66]. Specifically, the characteristics of interactivity, the existence of forums/chats, and the existence of web 2.0 technologies (websites and social networking sites that allow users to share information and interact with each other), online surveys, and information sheets are analysed [67, 68, 69]. To this end, the websites of the companies selected each year from those making up the sample are reviewed.
On the other hand, CSR is a multidimensional construct that takes into account various dimensions and aspects- social, environmental and economics- [25, 70, 71] in accordance with the aims of this study. Many researchers use a single CSR measure, such as environmental performance, philanthropic contributions, corporate policies, revealed misdeeds, transparency, or investment in health and safety [72]; but this only considers one aspect of CSR. Among the multidimensional measures most commonly used are Kinder Lydenberg Domini’s
We also included a moderating variable“STAKE*CSR”, to reflect the joint effect of the two variables. This will allow us to observe whether a company’s stakeholder orientation positively moderates the effect of corporate social responsibility on innovation.
Finally, control variables were included referring to the firm’s size, risk, and the industry sector in which it was active [9]. Size was measured using the logarithm of total asset (ASSETS) [71, 74]; the industrial sector (IND) was measured in accordance with the standard industrial classification code, thus creating a 5-block group [60, 75, 76]; and risk (RISK) was measured by the firm’s debt/asset ratio [75].
Panel data econometric analysis was used to test the hypotheses proposed in this paper. Specifically, a random effect model (GLS regression) was utilised after applying the Breusch-Pagan and Hausman tests. Panel data provide consistent data from samples for which repeated observations of cross-section data are available; in the present case, this refers to firms over a period of various consecutive years. Thus, no information is lost. In addition, the use of panel data makes it possible to control unobserved heterogeneity, which would otherwise bias the results [77, 78]. Therefore we eliminate the possibility of aggregation bias that can arise when using mean data for the variables, in time series models. The use of random effects has advantages over fixed effects, such as the problem of incidental parameters, being appropriate for random samples of large populations or allowing the treatment of omitted factors [79].
Panel data allow for the introduction of dynamic elements into the model. All this is why this analysis has been used in the recent literature on CSR and innovation [79, 80]. To test the hypotheses, the following model was considered:
Tables 3 and 4 show the descriptive statistics and correlations, and Table 5 shows the results obtained after applying the linear model to the panel data.
M | Std.Dev. | Min | Max | |
---|---|---|---|---|
Patents (PAT) | 19.92 | 28.36 | 0 | 233 |
Stakeholders Orientation (STAKE) | 2.04 | 0.41 | 1.83 | 4.16 |
CSR | 66.40 | 14.05 | 33 | 91 |
Assets | 7.36 | 7.63 | 3.39 | 8.41 |
Risk | 0.61 | 0.19 | 0.03 | 1.56 |
Industry (IND) | 3.55 | 1.41 | 1 | 5 |
Descriptive statistics of the variables used (N = 118).
1 | 2 | 3 | 4 | 5 | |
---|---|---|---|---|---|
PAT | 1.00 | ||||
STAKE | 0.19** | 1.00 | |||
CSR | 0.21** | 0.38** | 1.00 | ||
ASSETS | −0.02 | 0.01 | 0.02 | 1.00 | |
RISK | −0.22** | 0.02 | −0.11* | −0.00 | 1.00 |
INDUSTRY | 0.12* | 0.02 | 0.04 | 0.14* | 0.21** |
Correlations between dependent, independent and control variables.
*p < .05; **p < .01.
Pearson’s correlation coefficient.
Dependent variable | PAT | ||
---|---|---|---|
Model 1 (n = 118) | Model 2 (n = 118) | Model 3 (n = 118) | |
Constant | 5.09*** (5.51) | 15.32*** (3.50) | 1.30*** (5.97) |
CSR | 0.16*** (0.06) | 0.22*** (0.07) | |
Stake | 0.06** (0.02) | 0.33** (0.17) | |
Stake*CSR | 0.01† (0.00) | ||
Risk | −7.07 (4.45) | −9.52** (4.32) | −8.36** (4.38) |
Ind | −0.19 (0.74) | 0.05 (0.70) | −0.04** (0.72) |
Assets | 0.00 (0.00) | 0.00 (0.00) | 0.00 (0.00) |
Adjusted R Square | 0.281 | 0.286 | 0.299 |
Wald | 10.91 (4) | 9.57 (4) | 16.94 (6) |
Probability | 0.027 | 0.048 | 0.009 |
Rho | 0.172 | 0.133 | 0.141 |
Regression analysis.
†p < .10; **p < .05; ***p < 0.01.
Standard errors appear in parenthesis.
With respect to the indices of correlation (Table 4), there is evidently a positive, significant association between stakeholder orientation and innovation. The existence of communication channels to obtain information on stakeholder demands is a source of ideas that could allow the company to develop its capacity for innovation [55]. On the other hand, innovation in itself can generate social benefits, which justifies stakeholders’ demand for it [11, 53, 54]. In this respect, stakeholders could be promoting innovation practices in the company. This highlights the idea of shared value that underlies integrated reporting. The management of different capitals generates mutual benefits [3, 56]. In this case, the management of social and relational resources would develop entrepreneurial innovativeness.
The analysis of correlations shows a relationship between CSR and patents [68, 73, 75]. Greater effort in the field of CSR is reflected as a higher level of innovation (measured by the number of patents). The results of innovation are associated with CSR [9, 75]. In selecting differentiation strategies, some companies decide on CSR, and this strategy requires innovation activities [53, 81]. CSR constitutes an organisational resource that incorporates various policies, among which is that of innovation. CSR provides a framework for developing innovation [82, 83]. When planning innovation, companies must take into account the priorities determined by CSR. Thus, the latter may be utilised as a means of directing innovation [84]. They may also respond to the fact that the adoption of a CSR strategy requires changes be made to production processes or new products be introduced, ones that are more environment-friendly – and these considerations are relevant in the innovation process [85].
The positive correlation between CSR and stakeholder orientation shows that socially responsible companies address the demands and interests of their stakeholders and integrate them into their CSR practices [79]. In this sense, socially responsible companies could integrate stakeholders’ social and environmental demands into their innovation and development strategies. On the other hand, the correlation suggests that there is a stakeholder demand for corporate social responsibility practices [50, 86].
CSR practices are negatively and significantly associated with levels of debt, which could mean that companies with a lower level of financial risk are more likely to adopt CSR practices. The financial structure of the company determines its capacity for innovation. The greater capacity to access sources of financing allows a greater inflow of financial resources that can be applied to various strategies, including innovation [79]. Finally, the results show a significant correlation between the industry sector and innovation, which indicates that the sector in question is a significant factor with respect to the introduction of technological change [23]. Due to the need for mechanisation of their processes, certain industries have seen their capacity for innovation fostered.
Model 1 of Table 5 shows that CSR has a positive and significant effect on innovation. The companies analysed are leaders in sustainable and socially responsible practices, so it seems logical to think that they use CSR to generate intangible assets, such as industrial and intellectual property [82, 87]. From a management standpoint, the adoption of sustainability practices has a positive impact on value creation [13].
Model 2 describes the relationship between stakeholder orientation and innovation, and shows that the examined companies’ innovation efforts are positively associated with stakeholder orientation. These companies are implementing innovation as a means to respond to the interests of stakeholders. In this sense, we accept Hypothesis 1. In recent decades there has been an increasing demand for more environmentally friendly processes, practices, products, and services. This social demand has triggered a wave of innovation in companies that are more oriented towards stakeholders and society in general [79]. Thus, the results show that more stakeholder-oriented companies generate more patents. Relationships, networks, and collaborative mechanisms between the company and the groups of interest are effective mechanisms for capturing new social and environmental needs and developing innovation capabilities to address them [45, 50]. Table 6 shows the description of the variable stakeholder orientation.
Stakeholder orientation | ||
---|---|---|
1. Characteristics of interactivity |
| 0/0.33 on the basis of the absence-presence of each item |
2. Forums/chat |
| 0.5 if the online forum/chat used allows for discussion of general issues 1 if there is a specific forum/chat used for the discussion of CSR issues |
3. Web2.0 technology |
| 0/0.33 on the basis of the absence-presence of each item |
4. Online surveys |
| 0.5 if the online forum/chat used allows the discussion of general topics and 1 if there is a specific forum/chat used for the discussion of CSR topics. |
5. Newsletter |
| 0.5 if the online forum/chat used allows the discussion of general topics and 1 if there is a specific forum/chat used for the discussion of CSR topics. |
Model 3 shows the possible moderating effect of stakeholder orientation on the relationship between CSR and innovation. The variables in this model are of greater statistical significance, and thus we conclude that the impact of CSR is enhanced by stakeholder orientation. Stakeholder demands encourage the effect of CSR on innovation. Stakeholder orientation should be included in the business strategy to boost research and development in the company [55, 79]. In accordance with the above results, Hypothesis 2 is accepted. Thus, empirical research shows that in order to enhance the effect of corporate social responsibility on innovation, it is necessary for the company to know the demands and interests of its stakeholders, and communication channels are a good means of achieving that objective. In this sense, the results suggest that CSR generates intellectual capital when it generates social value by fostering relationships with stakeholders [14, 15]. The different business capitals are related as the integrated report points out.
The determinant relationships between innovation, CSR (social and environmental practices), and stakeholder orientation show that there is a real link among them, and as a result, it would be necessary for the company to adopt a holistic vision that takes into account different capitals (natural, human, social, and relational) to ensure the creation of value and the generation of assets [18]. In this sense, our study shows that CSR and stakeholder orientation promote intellectual capital, industrial property, in leading European companies in sustainability, and an integrated report that includes all the resources will allow for better management of them.
CSR constitutes a framework incorporating various policies, one of which is innovation. Some of the policies on innovation are related to those concerning CSR, which indicates that companies may seek to differentiate themselves from their competition by means of their CSR strategy. Innovation is a difficult factor to control but, as shown in the results, its links to CSR provide a suitable context for appropriate implementation. A finding of the research is that innovation policies are aimed at goals that are in accordance with CSR practices [87].
Moreover, taking CSR as a variable mediated by stakeholder orientation, we conclude that there is a joint effect on innovation. The integration of these two strategies generates a greater number of patents. The research shows that stakeholder orientation may require changes to production processes or products, and hence a re-orientation of innovation policy may be required [55]. An additional finding is that the resulting attention to the social and environmental demands of stakeholders could encourage more sustainable practices and processes, which could generate shared value [3, 48].
It would be interesting in subsequent research, to examine the extent to which CSR practices require innovations involving radical change or inventions, or whether the innovations made are mere developments of existing technology. In addition, it could be interesting to analyse concepts such as eco-innovation. Furthermore, as risk constitutes a significant factor, a further study should be made of the effect of a firm’s ownership structure on the CSR strategies adopted and on its innovation policy. Future research could study the impact of different stakeholders on innovation policies (such as employees and consumers) and analyse the possible impact of corporate governance, which could improve the analysis.
The authors declare that there is no conflict of interest.
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G.",authors:null}],mostDownloadedChaptersLast30Days:[{id:"65993",title:"Automatic Speech Emotion Recognition Using Machine Learning",slug:"automatic-speech-emotion-recognition-using-machine-learning",totalDownloads:4564,totalCrossrefCites:21,totalDimensionsCites:42,abstract:"This chapter presents a comparative study of speech emotion recognition (SER) systems. Theoretical definition, categorization of affective state and the modalities of emotion expression are presented. To achieve this study, an SER system, based on different classifiers and different methods for features extraction, is developed. Mel-frequency cepstrum coefficients (MFCC) and modulation spectral (MS) features are extracted from the speech signals and used to train different classifiers. Feature selection (FS) was applied in order to seek for the most relevant feature subset. Several machine learning paradigms were used for the emotion classification task. A recurrent neural network (RNN) classifier is used first to classify seven emotions. Their performances are compared later to multivariate linear regression (MLR) and support vector machines (SVM) techniques, which are widely used in the field of emotion recognition for spoken audio signals. Berlin and Spanish databases are used as the experimental data set. This study shows that for Berlin database all classifiers achieve an accuracy of 83% when a speaker normalization (SN) and a feature selection are applied to the features. 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This allows you to define a minimum surface limited by the contour of a two-dimensional image, which must or should not contain a minimum amount of optical flow vector associated with the movement of an object. The random tree will have the purpose of verifying the existence of superfluous vectors of optical flow by discarding them, defining a minimum number of vectors that characterizes the movement of the object. The results obtained were compared with those of the Lucas-Kanade algorithms with and without Gaussian filter, Horn and Schunk and Farneback. The items evaluated were precision and processing time, which made it possible to validate the results, despite the distinct nature between the algorithms. They were like those obtained in Lucas and Kanade with or without Gaussian filter, the Horn and Schunk, and better in relation to Farneback. This work allows analyzing the optical flow over small regions in an optimal way in relation to precision (and computational cost), enabling its application to area, such as cardiology, in the prediction of infarction.",book:{id:"10652",title:"Information Extraction and Object Tracking in Digital Video",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg"},signatures:"Ronaldo Ferreira, Joaquim José de Castro Ferreira and António José Ribeiro Neves"},{id:"81558",title:"Thresholding Image Techniques for Plant Segmentation",slug:"thresholding-image-techniques-for-plant-segmentation",totalDownloads:15,totalDimensionsCites:0,doi:"10.5772/intechopen.104587",abstract:"There are challenges in the image-based research to obtain information from the objects in the scene. Moreover, an image is a set of data points that can be processed as an object in similarity way. In addition, the research fields can be merged to generate a method for information extraction and pixel classification. A complete method is proposed to extract information from the data and generate a classification model capable to isolate those pixels that are plant from others are not. Some quantitative and qualitative results are shown to compare methods to extract information and create the best model. Classical and threshold-based state-of-art methods are grouped in the present work for reference and application in image segmentation, obtaining acceptable results in the plant isolation.",book:{id:"10652",title:"Information Extraction and Object Tracking in Digital Video",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg"},signatures:"Miguel Ángel Castillo-Martínez, Francisco Javier Gallegos-Funes, Blanca E. Carvajal-Gámez, Guillermo Urriolagoitia-Sosa and Alberto J. 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This combination is enriched with the discriminative learning power of deep neural networks and the fast detection capability of hand-crafted features SIFT. Thus, our method online adapts the variations occurring in real-time hand movement and exhibits high efficiency in cognitive recognition of hand trajectory. The empirical results shown in the chapter demonstrate that the approach can withstand the intrinsic as well as extrinsic challenges associated with visual tracking of hand gestures in RGB videos.",book:{id:"10652",title:"Information Extraction and Object Tracking in Digital Video",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg"},signatures:"Richa Golash and Yogendra Kumar Jain"},{id:"80064",title:"Robust Template Update Strategy for Efficient Visual Object Tracking",slug:"robust-template-update-strategy-for-efficient-visual-object-tracking",totalDownloads:62,totalDimensionsCites:0,doi:"10.5772/intechopen.101800",abstract:"Real-time visual object tracking is an open problem in computer vision, with multiple applications in the industry, such as autonomous vehicles, human-machine interaction, intelligent cinematography, automated surveillance, and autonomous social navigation. The challenge of tracking a target of interest is critical to all of these applications. Recently, tracking algorithms that use siamese neural networks trained offline on large-scale datasets of image pairs have achieved the best performance exceeding real-time speed on multiple benchmarks. Results show that siamese approaches can be applied to enhance the tracking capabilities by learning deeper features of the object’s appearance. SiamMask utilized the power of siamese networks and supervised learning approaches to solve the problem of arbitrary object tracking in real-time speed. However, its practical applications are limited due to failures encountered during testing. In order to improve the robustness of the tracker and make it applicable for the intended real-world application, two improvements have been incorporated, each addressing a different aspect of the tracking task. The first one is a data augmentation strategy to consider both motion-blur and low-resolution during training. It aims to increase the robustness of the tracker against a motion-blurred and low-resolution frames during inference. The second improvement is a target template update strategy that utilizes both the initial ground truth template and a supplementary updatable template, which considers the score of the predicted target for an efficient template update strategy by avoiding template updates during severe occlusion. All of the improvements were extensively evaluated and have achieved state-of-the-art performance in the VOT2018 and VOT2019 benchmarks. Our method (VPU-SiamM) has been submitted to the VOT-ST 2020 challenge, and it is ranked 16th out of 38 submitted tracking methods according to the Expected average overlap (EAO) metrics. VPU_SiamM Implementation can be found from the VOT2020 Trackers repository1.",book:{id:"10652",title:"Information Extraction and Object Tracking in Digital Video",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg"},signatures:"Awet Haileslassie Gebrehiwot, Jesus Bescos and Alvaro Garcia-Martin"},{id:"80109",title:"Siamese-Based Attention Learning Networks for Robust Visual Object Tracking",slug:"siamese-based-attention-learning-networks-for-robust-visual-object-tracking",totalDownloads:90,totalDimensionsCites:0,doi:"10.5772/intechopen.101698",abstract:"Tracking with the siamese network has recently gained enormous popularity in visual object tracking by using the template-matching mechanism. However, using only the template-matching process is susceptible to robust target tracking because of its inability to learn better discrimination between target and background. Several attention-learning are introduced to the underlying siamese network to enhance the target feature representation, which helps to improve the discrimination ability of the tracking framework. The attention mechanism is beneficial for focusing on the particular target feature by utilizing relevant weight gain. This chapter presents an in-depth overview and analysis of attention learning-based siamese trackers. We also perform extensive experiments to compare state-of-the-art methods. Furthermore, we also summarize our study by highlighting the key findings to provide insights into future visual object tracking developments.",book:{id:"10652",title:"Information Extraction and Object Tracking in Digital Video",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg"},signatures:"Md. Maklachur Rahman and Soon Ki Jung"},{id:"79005",title:"Smart-Road: Road Damage Estimation Using a Mobile Device",slug:"smart-road-road-damage-estimation-using-a-mobile-device",totalDownloads:112,totalDimensionsCites:0,doi:"10.5772/intechopen.100289",abstract:"Mexico is located on five tectonic plates, which when moving, generate telluric movements. These movements, depending on their intensity, affect the telecommunications infrastructure. Earthquakes tend to cause landslides, subsidence, damage to structures in houses, buildings, and roads. In the case of road damage, it is reflected in cracks in the pavement, which are classified according to their size, shape, and depth. The methods that are currently implemented to inspect roads mainly use human perception and are limited to a superficial inspection of the terrain, causing this process ineffective for the timely detection of damage. This work presents a method of road analysis using a drone to acquire images. For the processing and recognition of damages, a mobile device is used, allowing to determine the damage type on the road. Artificial intelligence techniques are implemented to classify them into linear cracks or zig-zag cracks.",book:{id:"10652",title:"Information Extraction and Object Tracking in Digital Video",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg"},signatures:"Izyalith E. Álvarez-Cisneros, Blanca E. Carvajal-Gámez, David Araujo-Díaz, Miguel A. Castillo-Martínez and L. 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For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"91",title:"Sustainable Economy and Fair Society",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",isOpenForSubmission:!0,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. 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He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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