\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"1551",leadTitle:null,fullTitle:"Mining Methods",title:"Mining Methods",subtitle:null,reviewType:"peer-reviewed",abstract:"An economic viability of a modern day mine is highly dependent upon careful planning and management. 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\r\n\tThere are many textbooks on international law, but these are generally written for students and legal academics and focus on the historical development of the various sub-fields of the discipline and on past judgments and decisions. This book adopts a different perspective: it is intended for practitioners, and these are numerous and varied. Apart from all those involved in diplomatic practice, they range from naval, coastguard, customs, and fisheries officers, to relief workers caring for refugees and following natural disasters, and many others. Everyone working on the ground needs practical advice, not history and caselaw. This book is therefore intended to be a practical handbook on a number of current and emerging themes in international law, focusing on the kinds of issues met in practice and describing what is legally and practically possible to address and resolve these issues. The individual authors are invited to use concrete examples or relevant scenarios to illustrate these problems and the processes required to achieve the desired practical and legal outcomes.
",isbn:"978-1-83768-054-2",printIsbn:"978-1-83768-053-5",pdfIsbn:"978-1-83768-055-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"c607e873911da868c0764770dc224313",bookSignature:"Dr. Michael Underdown",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11774.jpg",keywords:"Diplomatic Law, Consular Law, International Negotiations, Treaty Law, ICJ, International Arbitration, UNCLOS, Fisheries, ITLOS, Civil Aviation, Armed Warfare, Piracy, Smuggling, Human Rights",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 14th 2022",dateEndSecondStepPublish:"July 12th 2022",dateEndThirdStepPublish:"September 10th 2022",dateEndFourthStepPublish:"November 29th 2022",dateEndFifthStepPublish:"January 28th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A well-known maritime and port lawyer and Oriental historian, with extensive international experience as a scholar, diplomat, and lawyer. 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Professor Underdown studied Law and Oriental Studies in Australia, Belgium, Portugal and Germany and, in addition to academic appointments in Australia and New Zealand, has held research fellowships in the United Kingdom, Soviet Union, China and South Korea. He has ongoing research interests in law, history, philosophy, management and linguistics. He is admitted to the High Courts of Australia and New Zealand and has practised as both a solicitor and barrister, including as a Special Counsel at a “top tier” law firm. 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Physical frailty is a condition of marked vulnerability to negative events caused by the reduction of functional reserves of multiple systems of the organism because of the ageing process and chronic polypathology. It is a condition that represents a risk factor of disability, hospitalization, institutionalization, and death [1]. But what determines frailty - not necessarily physical, but also cognitive or interpersonal - in an elderly person?
Biomedical sciences, neuroscience and epigenetics have increasingly analyzed the mechanisms that regulate structural-functional changes in the body in relation to environmental influences. Each person has his/her own biography; each body and nervous system has its own development and use. Frailty and strength emerge in the course and within an individual story, according to a life-span perspective.
Frailty and strength constitute an oxymoron that often originates from the same semantic source. Paradoxically, it is the frailty condition that allows the discovery or rediscovery of resources and potentialities.
Frailty and strength are recognized, interwoven with affections, their formation and realization. It is the affective experiences that contribute in a decisive way to structuring an individual’s personality, the feeling of security or precariousness, or the prevalence of one over the other.
Quintus Horatius Flaccus (Odi: IV, 4, v.65) argued that «
Frailty and strength interact, alternate and are continually shaped throughout life. Affectivity often represents its seismograph, but vulnerability can at the same time constitute the metronome of one’s emotional instances, especially the deepest ones. The notions of “frailty” and “affectivity” recalls an ontological condition, as intrinsic to the human dimension, and offer original perspectives of investigation for multiple issues affecting the elderly. These perspectives are well highlighted by the analyses of numerous themes of both frailty-vulnerability and affectivity-emotivity in ageing developed by different disciplines (anthropology, sociology, philosophy, biology, psychology, neuroscience, medicine). It becomes relevant to understand how frailty and affectivity interact in the course of ageing, depending on what has been experienced and learned, and on what existence and life in society continue to offer.
The importance of a multidimensional assessment of the elderly to define their state of health and well-being has long been recognised. Indeed, cognitive, affective, behavioural and functional factors interact closely with somatic and socio-environmental ones.
A l bio-psycho-social model can help us to define the most appropriate interventions to promote health in terms of the best possible quality of life. This approach attributes health to the intricate and variable interaction of biological, psychological, and social factors [1, 2].
There is no single way of ageing, but there are as many different ageing processes as there are humans [2]. Indeed, ageing is a gradual and continuous process of natural mutation for which many bodily functions begin a gradual decline [2]. The life-span perspective recognizes changes in the functional state as characteristic of the human being ageing process [3] and are considered characteristic of the
Considering the continuum that goes from pure ageing to pathological ageing, one can define
Different types of ageing patterns (
This type of classification provides a molecular assessment of individual ageing, reflective of personal lifestyle and medical history; indeed, ageotypes highlight the potential health risk factors and may ultimately be useful in monitoring the ageing process [2, 5]. Multimorbidity and polypharmacotherapy weakens the body and can predispose to accelerated ageing, resulting in frailty.
Frailty is certainly the most problematic expression of the ageing population [1, 2]. It is an integrated [6] and multidimensional [7] condition in which biological, functional, psychological, and social variables interact with each other. It may be relevant in identifying older people at risk of deteriorating mental health [8] and cognitive decline [9].
In the face of such a complex picture, there is yet no unambiguous operational definition of frailty that would make it possible to define a gold standard of evaluation. Experts belonging to the European Innovation Partnership on Active and Healthy (EIP-AHA) have identified two main approaches: the first concerns physical determinants (biomedical approach), while the second considers biological, cognitive, psychological, and socio-economic factors (bio-psycho-social approach). Indeed, a reliable assessment cannot be separated from the analysis of the affective, cognitive, and relational components [1].
Vulnerability should be considered as a predisposition of an individual exposed to a critical situation to slip into a more severe critical situation. Vulnerability and criticality define respectively a property of a process and a state within that process [11]. In this sense the definition of frailty proposed by Rozzini and Zanetti is explanatory [12]: «frailty is a condition of risk and vulnerability in the face of noxae of various kinds, which challenge the homeostatic balance of an organism. Frailty is predisposition to breakage, to damage when subjected to pressure».
Considering the above:
The shift towards higher order critical issues is the recurring scenario in the problems of the elderly population [11]. Indeed, chronicity can be considered the final state of a path of depletion of plastic capacity (Figure 1). According to a
Logical concatenations between the concepts of criticality and vulnerability. Adapted by Micheli [
The understanding of the route linking ageing, frailty and 2nd order criticalities and the distinction between frailty and 2nd order criticalities have not only a pathophysiological significance. They open operational perspectives. It has been demonstrated that the route from pure ageing to 2nd order criticalities is not a one-way street, and that a regression from frailty to pre-frailty and from the latter to a “non-frailty condition” is possible [13]. Indeed, frailty might be reversible or attenuated by interventions put in place to avoid its evolution over time [14]. Many conditions of (pre)frailty can reverse their direction, so that they can move in the direction of successful ageing. This is most true when traditional therapeutic approaches are combined with the promotion of healthy lifestyles. In old age, the potential and limits of plasticity are often monitored in the neurocognitive and rehabilitative fields. The prestigious Nature has dedicated a special issue to these themes. In the cover article “Prevention: activity is the best medicine” [15] you can see two people dancing. The evidence in favor of the protective role of healthy lifestyles for the maintenance of cognitive functions is well established.
The task now is to move from lifestyle factors to interventions to find out how what kind and much exercise, what kind of intellectual activity, what kind of diet, what kind of social support and engagement (and at what stage each of them) could influence the directions of ageing.
The question of how to promote healthy lifestyles in the adult and elderly population as a prevention intervention no longer arises only at a scientific level but at a social and political level.
Recent studies have underlined the existence of a significant association between lifestyle and frailty [16, 17]. All older people are at risk of developing frailty, although risk levels are substantially higher among people with comorbidities, poor socio-economic status, poor nutrition and sedentary lifestyles [16]. However, inappropriate lifestyles and some clinical risk factors are potentially counteracted by specific interventions and preventive actions [16].
The EIP-AHA Action Group A3 has developed several multidimensional tools capable of predicting short-term negative outcomes [18]. Several factors have been highlighted as useful for proper health planning: malnutrition, polypharmacotherapy, impairment of physical function and social isolation have been identified as those on which to act to mitigate fragility and its consequences [18].
Data from a recently published study [19] also point in this direction. The Barcelona Brain Health Initiative is a longitudinal cohort study initiated in 2017 that aims to understand and characterize the determinants of brain health and intellectual efficiency in middle-aged adults. A cohort of 4686 individuals aged between 40 and 65 has been established, with no history of neurological and/or psychiatric illness. The researchers collected demographic, socio-economic, clinical and health data, associating them with assessments of perceived health status and lifestyles (general health, physical activity, cognitive activity, socialization, sleep, diet and so on). The results underline the importance of healthy lifestyles to support brain health and intellectual efficiency [19].
Consistently with the above, it is believed that the prevention and treatment of frailty can only be based on:
promotion of healthy lifestyles.
promotion of social inclusion and social engagement
promotion of emotional relationships.
timely identification of clinical-functional fluctuations and “sentinel events” (falls, urinary incontinence, sensory deficit, delirium, …), which must be considered potential 1st order criticalities
diagnosis and treatment of all pathologies that can be responsible for asthenia, weight loss, reduced tolerance to effort, reduced physical strength and physical activity
intensive and frequent clinical monitoring of the elderly at risk
adaptation of daily living environments
reduced exposure of the frail elderly to environmental stresses (including hospitalization and unnecessary medical procedures)
Active and healthy ageing is a multidimensional concept referring to a situation where the elderly persists to participate in the formal labour market, engage in voluntary activities, and live healthy, independent, and safe lives as they get older.
Active ageing policies therefore require addressing several factors: encourage healthy lifestyles, ensure social involvement, provide opportunities for independent living, and enable possibilities for longer working life. Monitoring such policy implementation requires a comprehensive tool that encompasses the multitude of aspects of active and healthy ageing. The European Commission has made the Active Aging Index (AAI) available precisely to meet this need.
The AAI captures various facets of active ageing by measuring 22 indicators grouped into 4 domains: employment, participation in society, independent health and secure living, and capacity and enabling environment for active ageing (Figure 2). The AAI also provides a breakdown of results by gender to highlight potential differences in ageing between men and women. The index values range from 0 to 100. Higher values indicate a greater capacity to realize the unexpressed potential in old age. AAI offers a flexible framework that can be applied to different countries and at national as well as regional/local levels. It depicts the current situation and highlights the areas where future gains can be made. If computed on a regular basis, AAI allows to measure progress over time and helps to identify effective policy actions. The 2018 Active Ageing Index Analytical report reveals that since 2008 most European countries have improved their overall AAI scores [20]. This progress is probably due to increased attention to the elderly by society and politics and to the spread of a multidimensional and bio-psycho-social approach to the fight against frailty.
The AAI has been developed within the framework of the 2012 European Year for Active Ageing and Solidarity between Generations (EY2012). The index is made up by four domains each of which reflects a different aspect of active ageing.
The implementation of a bio-psycho-social approach to frailty allows an active and proactive management of a condition strongly related to chronicity, disability, and mortality. Frailty early identification can prevent or slow down the evolution towards negative outcomes, with a significant positive impact on the quality of life of the ageing population and on the health system and society as a whole [1].
The question is what the best screening protocols are and what types of intervention to carry out given the uniqueness of everyone’s ageing and the type of ageotype associated with it. Indeed, the lack of effectiveness of a purely pharmacological management of frailty should be analyzed in the light of its pathophysiology.
A progressive alteration of several physiological systems induced by the interaction between the ageing process (pure ageing) with several morbid processes and multiple psycho-social and environmental conditions are involved [2, 6, 7]. After all, if the pathogenesis of frailty is multifactorial, intervention on a single physiological system will not in itself resolve frailty or even prevent it [21]. The probability of becoming frail older people increases non-linearly in relation to the number of abnormal physiological systems, and the number of abnormal systems would seem to be more predictive than the individual abnormal system involved [21]. Notably, the non-linear relationship of accelerating likelihood of frailty as the number of abnormal systems escalates suggests that there could be a threshold beyond which there is an adverse downward spiraling nature to frailty etiology and progression. Implications are that a threshold loss of complexity, as indicated by number of systems abnormal, may undermine homeostatic adaptive capacity, leading to the development of frailty and its associated risk for subsequent adverse outcomes [21]. It also indicates that the replacement of any defective system may not be sufficient to prevent or ameliorate the whole health condition [21].
What has been indicated refers to the importance of a multidimensional approach to the elderly - and especially to the frail elderly - both in the evaluation and in taking charge of the individuals. To date, the comprehensive geriatric evaluation (CGA) is the most fruitful process to assess elderly people to optimize their subsequent management. Indeed, CGA has consistently shown its significant benefits for over 30 years [22].
However, the high speed with which the world’s population ages and is affected by chronic diseases, polypathology and functional impairment is unfortunately not yet accompanied by a strong, competent, and aware geriatric culture. This unfulfilled need contributes to the further exponential increase in adverse outcomes (2° order criticalities) and to the loss of psychophysical well-being and health (which means complete happiness, as we have previously defined it) in older people.
It is increasingly evident that there is a dual need to put existing applied health research knowledge into practice (the “
Gladman et al. [23] discussed several barriers to the implementation of the GCA, including guiding factors, professional factors, patient factors, professional interactions, incentives, resources, capacity for organizational change, as well as social, political, and legal factors. There is little point in not actively working on
Everything discussed urges geriatrics - nowadays a true medicine of complexity - to refine its cultural and operational tools and to make them available to a health system grappling with the growing problems posed by a progressively aging population.
The medicine of complexity suggests a model in which psychophysical well-being and disease are the result of complex, dynamic and unique interactions in the individual under examination: i.e., interactions between different components of the entire system. The human body is made up of interconnected, inter-reacting physiological systems, while the individual maintains a behaviour determined by experience and on the ability to adapt and interact with the environment.
The individual is therefore a dynamic, interacting, adaptable system in which the disease - and even more the polypathology - triggers a cause-and-effect model that cannot be considered linear. To this follows a situation of complexity that requires a new type of taking charge of the elderly patient. This approach to the patient accepts unpredictability and proposes solutions based on elements that are sometimes imperceptible but emerging to the clinical sensitivity of the health professional. Considering the above, two elements become substantial for a successful CGA: to conceive the individual frail elderly person as unique and complex; to put the clinical methodology at the heart of the patient approach. These concepts are having profound consequences, introducing working methodologies based on multidisciplinary, integration, implementation, contextualized work.
To make this a concrete reality, it is essential that geriatrics share with other professionals involved in the field the cultural values that belong to them, promoting multidisciplinary confrontation and integration, so that it is possible to build a vision of intent common to all specialists and operators of the multidisciplinary team that acts around the frail elderly.
Ageing has always affected and often frightened humans, which since ancient times has been well aware that the biological changes connected with the passing of the years induce a progressive weakening of functional capacities, a decay of physical or mental conditions, an increasing difficulty in carrying out tasks that were once easy to perform.
Publio Terenzio Afro (160 B.C.) referred to the physical ailments and privations that usually accompany senescence with the well-known sentence «
Health should be considered as the ability to identify and realize one’s aspirations, to satisfy one’s needs and to positively modify the surrounding environment. The elderly is in good health if they maintain a condition of self-sufficiency as much as possible, psychophysical well-being, and positive thinking about the future.
Frailty in the elderly requires a customized multidimensional approach that cannot be segmented into isolated interventions for each pathology, taking into account individual differences - not only clinical but also socio-relational and environmental differences - according to the principle of “taking care of the patient and not only of the disease”.
There are many health problems in the elderly, and one wonders whether it is appropriate to take action not only as health professionals but also individually to counter them or to stem the consequences: if each of us adopted healthy habits and made ourselves the bearer of them we would have done something - perhaps modest on an individual level but important on a collective level to counter the “silver tsunami” which could jeopardize our old age and the stability of our society.
The fight against frailty takes place in a life-span perspective. A bio-psycho-social model can help us to define the most appropriate interventions to promote the best quality of life. This approach attributes health to the intricate and variable interaction of biological, psychological, and social factors.
Such a multidimensional approach is fundamental when it comes to the elderly and the promotion of healthy and active ageing.
No funding was available to the author.
The authors declare that the manuscript was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
There are many ways to age and grow old can be frightening: all sorts of losses to deal with, a body and mind less vigorous and brilliant than it once was, sometimes memory becomes clouded, self-awareness diminishes and loved ones disappear. However, there are older people who make you want to grow old. They have not been spared by life, but for them growing old is like continuing their adventure. They seem to keep in the form of inner riches those outer ones they have lost and discover new possibilities and freedom. I thank the senior students at the University of the Third Age of Turin for being a source of inspiration and teachers of life. To them, who taught me what it means to have a soul that is always young, every effort I make is dedicated.
Cancer or tumor cells express neoantigens that the immune system can identify from healthy neighboring cells due to genetic mutations. These changes typically result in a tumor-reactive T cell response, most notably CD8+ T cells. However, this mechanism is frequently ineffective at eradicating cancer cells [1]. One cause for this failure is the suppression of invading T cells by a wide range of immunosuppressive mechanisms found in the tumor microenvironment (TME), such as regulatory T cells (Tregs) or immunosuppressive cytokines [2, 3].
Furthermore, binding of the T cell receptor (TCR) to the antigenic peptide bound to the major histocompatibility complex (MHC) of the antigen-presenting cell (APC) is not adequate to yield an immune response, particularly to eradicate cancer cells. Thus, the additional stimulatory co-signal produced by co-receptors is required. These co-receptors play an essential role in modulating T cell responsiveness and balancing co-stimulatory and inhibitory (i.e., immune checkpoint) signals [4]. Extended TCR signals generated from T cells exposure to their cognate antigen result in enhanced and persistent expression of inhibitory co-receptors like cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death protein 1 (PD-1), or many other immune checkpoints. At this moment, T cells enter a state of dysfunction or exhaustion, allowing cancer cells to grow unchecked [5, 6]. Therefore, blockage to these immune checkpoints can reinvigorate the anti-tumor function of immune cells. This chapter aimed to elaborate on the involvement of immune checkpoints in cancer development. It includes the explanation of the normal trafficking and inhibitory signaling of each checkpoint, followed by discussions about how immune checkpoint contributes to cancer growth.
Immune checkpoints serve as the immune system’s gatekeepers and are required for sustaining self-tolerance, thus protecting the host from tissue damage. These immunological checkpoint molecules have modulated T cell responses to self-proteins, persistent infections, and tumor antigens. A few of them, including but are not limited to PD-1, CTLA-4, Lymphocyte activation gene 3 (LAG3; or known as cluster of differentiation 223 [CD223]), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoreceptor with immunoglobulin and ITIM—immunoreceptor tyrosine-based inhibitory motif—domain (TIGIT), and B and T lymphocyte attenuator (BTLA; or known as CD272), have been discovered and investigated as targets in cancer immunotherapy. In general, immune checkpoints are membrane proteins expressed in the endoplasmic reticulum (ER) and subsequently transported to the cell surface to perform their inhibitory roles, which requires the protein sorting system to transport them sequentially through the Golgi apparatus secretory vesicles. Glycosylation acts as quality control during surface delivery, ensuring that only mature and functional immunological checkpoints reach the cell surface. Immune checkpoints are internalized and recycled when they reach the cell surface, providing a quick regulatory pathway to control their surface levels. Immune checkpoints can be ubiquitinated and sorted to the proteasome or lysosome for destruction, another critical method for controlling protein levels. The surface level of immunological checkpoints is determined by several biological mechanisms, which affect cell signaling [7]. This section elaborates on the normal regulations and signaling of each immune checkpoints molecules before discussing its involvement in cancer development.
PD-1 trafficking in the membrane is regulated by the core fucosyltransferase 8 (fut8) in ER. Upon Tcell activation, PD-1 is internalized, then ubiquitinated by F-box protein 38 (FBXO38) for proteasome degradation or recycled back to the surface with the help of thymocyte selection-associated high mobility group box protein (Tox), thus prolonged PD-1 activity. Additionally, Tox expression induces Tcell depletion in hepatocellular cancer [7, 8]. Besides, another extension of PD-1 activity is caused by FBXO38’s low transcriptional level in the TME. Hence, the FBXO38-mediated PD-1 degradation pathway is defective. TCR signaling was the source of FBXO38 downregulation in the absence of concurrent CD28-CD80/86 signaling. CD28-CD80/86 binding provides critical signals for T cell activation in the presence of TCR stimulation. Persistent tumor antigen binding and low CD80/86 expression on cancerous cells might explain the lower FBXO38 expression in tumor-infiltrating lymphocytes (TILs) [7, 9].
Similar to PD-1, its first functionally identified ligand of PD-L1 (also known as B7 homolog 1 [B7-H1] or CD274) is constantly internalized, recycled, or degraded. Regulation of PD-L1 recycling is managed by CKLF-like MARVEL transmembrane domain containing 6 (CMTM6). Meanwhile, ubiquitination and degradation are regulated by multiple proteins such as cyclin D–CDK4 and the cullin 3–SPOP [10], β-TrCP [11], COP9 signalosome 5 (CSN5] [12], Huntingtin-interacting protein 1-related (HIP1R) [13], and others. Each protein is a drugable target to inhibit PD-L1 accumulation, thereby increasing T cell-mediated cytotoxicity.
Regarding the inhibitory signals following the binding of PD1 to PD-L1 or other ligands, it blocks kinases that play a role in activating T cells through the phosphatase SHP2. Besides, since PD1 inhibition blocks the TCR ‘stop signal’, this pathway can alter the length of T cell–APC or T cell–target cell interaction [14]. In detail, PD-1 is phosphorylated through immune receptor tyrosine-based switch motif (ITSM) and ITIM. Then, PD-1 binds the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2) or SHP1, which initiate its inhibitory effect by suppressing both TCR and CD28 co-stimulatory signaling [7, 15, 16, 17]. Moreover, PD-1 signaling also reduces cytokine production (interleukin [IL]-2, interferon [IFN]- α, tumor necrosis factor [TNF]-α), cell cycle progression, and pro-survival Bcl-xL gene expression by interfering with early TCR/CD28 signaling. PD-1/PD-L1 interaction is associated with IL-2-dependent positive feedback and transcription factors involved in effector functions such as GATA-3, T-bet, and Eomes. As signal transduction can only occur during TCR-dependent signaling, PD-1 activity is thus only relevant during simultaneous T cell activation. Mice without the receptor appear healthy at first. Still, they acquire autoimmune disorders such as lupus-like proliferative glomerulonephritis and arthritis, as well as enhanced inflammation after infections at a later age. In humans, genetic variations in the PD-1 region are more likely to suffer autoimmune disorders [18, 19].
Unlike PD-1/PD-L1, which is constitutively expressed on the membrane, CTLA-4 is primarily stored inside the cytoplasm of resting naïve T lymphocytes. The T cell receptor-interacting molecule (TRIM)/LAX/Rab8 complex and phospholipase D (PLD)/ADP ribosylation factor-1 (ARF1)-dependent exocytosis are required for CTLA-4 trafficking from trans Golgi network (TGN) to the cell surface [20]. Exocytosis of CTLA-4-containing vesicles causes upregulation of CTLA-4 on the cell surface due to stimulatory signals originating from TCR and CD28-B7 interaction. More robust TCR signaling causes more CTLA-4 to be translocated to the cell surface, and this process works in a graded feedback loop. CTLA-4 on the surface is rapidly internalized during normal physiologic conditions, resulting in relatively low expression. The clathrin-associated adaptor complex (AP-2) interaction to the unphosphorylated YVKM motif promotes rapid CTLA-4 internalization, which is then either destroyed in the lysosome or returned to the cell surface through LPS responsive beige-like anchor protein (LRBA). Besides, CTLA-4 in TGN may also be transported to the lysosome for destruction through AP-1 binding [7, 21, 22].
The intrinsic signaling of CTLA-4 that dampens T cell immune response has been widely contested with no agreement [23]. However, both CTLA-4 and CD28 interact with the identical ligands, CD80 (B7–1) and CD86 (B7–2). Because CTLA-4 has a 20-fold higher binding affinity than CD28, the intrinsic inhibitory signal rises once CTLA-4 outcompetes CD28, even if CTLA-4 is activated later [24, 25]. In addition to T cell response intrinsic inhibition, CTLA-4 is hypothesized to decrease extrinsic T cell signaling. For example, CTLA-4 suppresses CD80/86 expression on APCs via trans-endocytosis or by increasing tumor growth factor β (TGFβ), which in turn suppresses CD80/86 expression [26]. CTLA-4 is phosphorylated when it binds to its ligands, activating phosphoinositide 3-kinase (PI3K) pathways leading to dephosphorylation of the CD3 chain, decreasing the TCR’s signaling potential. CTLA-4 also prevents T cells from proliferating by inhibiting IL-2 transcription. Additionally, CTLA-4 stimulates the production of indoleamine 2,3-dioxygenase (IDO) in dendritic cells via CD80/86 ligation, resulting in T cell suppression [27].
TIM-3 is expressed on both T cells and innate immune cells. Four ligands have been identified: carcinoembryonic antigen cell adhesion molecule 1 (Ceacam1), C-type lectin galectin9 (Galectin9), high-mobility group box 1 (HMGB1), and non-protein ligand phosphatidylserine (PtdSer). Ceacam1 is a transmembrane protein that interacts in
TIM-3 is more related to co-stimulatory proteins induced in activated T cells than to a dominant inhibitory protein like PD-1; thus, TIM-3 signaling remains a matter of debate. As checkpoint proteins, TIM-3 is a repressor of IFN-γ-secreting CD4+ Th1 and CD8+ T cells. These findings confirmed that inhibiting TIM-3 might correct the defective phenotype of T cells in vivo. In contrast, TIM-3 lacks a conventional ITIM or ITSM in its intracellular domain and lacks structural features that facilitate the recruitment of inhibitory phosphatases. Rather than that, both murine and human TIM-3 cytoplasmic tails include five conserved tyrosine residues, two of which, Y256 and Y263 in mice (Y265, Y272 in humans), have been demonstrated to be crucial for coupling to downstream signaling pathways. Y256 and Y263 in TIM-3’s C-terminal tail interact with Bat3 in the absence of ligand-mediated TIM-3 signaling. Bat3 binds the catalytically active form of Lck in this state, resulting in the formation of an intracellular molecular complex with TIM-3 that retains and maybe enhances T cell signaling while repressing TIM-3-mediated cell death and exhaustion [31, 32]. TIM-3 activation on exhausted effector T cells is closely attributed to PD-1 expression, confirming the functional relationship between TIM-3 and PD-1 throughout the development of T cell exhaustion [33]. Concomitant therapy of anti-TIM-3 and anti-PD-1 is significantly more successful in these models, resulting in more significant tumor regression than either TIM-3 or PD-1 inhibition alone. TIM-3 inhibition in the setting of adaptive resistance to PD-1 treatment may be a useful way to treat individuals who develop resistance to anti-PD-1 therapy. This therapy regimen may be particularly beneficial for malignancies with resistance and immune escape from PD-1 inhibition [34, 35].
Like CTLA-4 and CD28, TIGIT and CD226 can interact with identical ligands, CD112 and CD155. TIGIT is a co-inhibitory receptor, while CD226 is a co-stimulatory receptor. Nevertheless, TIGIT possesses a higher affinity to its ligands than CD226; thus, TIGIT can inhibit co-stimulation signals by outcompeting CD226 ligands binding. TIGIT can bind directly to CD226 in
TIGIT’s signaling is mostly studied in natural killer (NK) cells and activated CD4 and CD8 T cells. The cytoplasmic region of TIGIT comprises an ITIM motif and an immunoglobulin tail tyrosine (ITT)-like motif. Several studies demonstrate that tyrosine (Tyr225) phosphorylation in either the ITIM or ITT-like motif is required for TIGIT’s inhibitory action in human NK cells. According to Liu et al. (2013), the ITT-like motif recruits Src homology domain-containing inositol phosphatases (SHIP1) via cytosolic adaptor proteins Grb2. Recruited SHIP1 then suppresses phosphatidyl-inositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signal to abolish NK cell function. Furthermore, TIGIT signaling can modulate the IFN-γ production of NK cells via the NF-κB pathway. In this context, β-arrestin 2, another TIGIT adaptor, is involved in phosphorylating TIGIT and then inhibits TNF receptor-associated factor 6 (TRAF6) autoubiquitination, hence inhibiting NF-κB activation and suppressing IFN-γ production [38, 39, 40].
LAG3 inhibits CD4-dependent T cell activity by binding to MHC-II due to being structurally homologous with four extracellular immunoglobulin superfamily-like domains. Other investigations demonstrated that LAG3’s inhibitory activity is not dependent on CD4 competition, but rather LAG-3 inhibited T cells responding to stable peptide-MHC-II by transducing inhibitory signals via its intracellular domain. Thus, LAG-3 may act more selectively, allowing tolerance to dominant autoantigens to persist [41, 42]. Alternatively, LAG3 can interact with another ligand like Galectin3 in TME and mediate the suppression of CD8 T cells [43]. Besides, liver sinusoidal endothelial cell lectin (LSECtin) can bind to LAG3 in human melanoma, causing tumor growth by abolishing IFN-γ production and proliferation of tumor-specific T cells [44]. Lastly, fibrinogen-like protein 1 (FGL1) was recently discovered as a novel LAG3 ligand. FGL1 is typically produced in trace amounts into the bloodstream by the liver. However, overexpression of FGL1 has been observed in some human malignancies. Inhibiting the interaction between FGL1 and LAG3 by monoclonal antibodies improves T cells’ anticancer activity [45].
The signal transduction mechanism of LAG3 is regulated by two transmembranes, a disintegrin and metalloproteinase domain-containing protein 10 and 17 (ADAM10 and ADAM17)-mediated cleavage. TCR signaling enhances ADAM10 and ADAM17 cleavage activity, releasing sLAG3. The function of sLAG3 remains controversial as some studies consider this does not have a biological process, while the others state that sLAG3 allows effective T cell proliferation and function [46]. Besides, sLAG3 affects monocyte differentiation into macrophages and DCs, which have decreased immunostimulatory capacity [47].
BTLA and CD160 inhibit T cell activity via the same ligand, herpesvirus entry mediator (HVEM). BTLA-HVEM is an example of crosstalk between two superfamilies in which the ligand is a member of the TNF/TNFR superfamily. However, HVEM interaction with members of the TNF superfamily LIGHT (Lymphotoxins, Inducible, competes with herpes simplex virus (HSV) Glycoprotein D for HVEM, expressed by T cells) produces a co-stimulatory signal on B and T cells. Hence, HVEM may be considered as a molecular switch that enables co-signaling between stimulatory and inhibitory T cells. Additionally, signaling between HVEM and its ligands appears to interact bidirectionally. The cis interaction between BTLA and HVEM inhibits the trans-ligation of HVEM by LIGHT and thus inhibits HVEM stimulatory signaling triggered by LIGHT binding [7, 48, 49].
Regarding the inhibitory signaling of BTLA, it follows the mechanism of PD-1/PD-L1 involving ITIM and ITSM to recruit SHP1/SHP2 [50]. In B-chronic lymphocytic leukemia (B-CLL), both HVEM and BTLA are overexpressed. This co-expression of HVEM and BTLA in CLL cells implies that an unsuccessful autocrine inhibitory loop is triggered. In addition, BTLA is typically downregulated during the development of human CD8+ T cells to effector cells. However, BTLA expression was more significant in melanoma-specific CD8+ T lymphocytes specialized for tumor antigens (TA). Despite effector differentiation, BTLA expression remained persistent, confounding T cell proliferation and IFN-y production. Thus, BTLA may function similarly to PD1 as a T-cell inhibitory receptor in TME [51].
Recent studies have established that immune checkpoint molecules drive cancer growth via various anticancer strategies. The first one is the overexpression of immune checkpoints in cancer cells, immune cells, or the surrounding environment leading to incapabilities of the tumor-specific immune response. Subsequently, immune checkpoints can interfere with metabolic pathways and deplete nutrients needed by immune cells. Lastly, immune checkpoints cripple cancer-specific immune responses by collaborating with regulatory T cells. This section deliberates each strategy thoroughly to get insight into how to combat those actions.
Accumulating evidence showed that several immune checkpoint molecules are overexpressed not only on the surface of cancer cells but also in T cells, Tregs, or even in TME. Here, we thoroughly describe how the immune checkpoint is upregulated and then inhibits antitumor activity. PD-1/PD-L1 are overexpressed on the surface of many cancer cells. Several proinflammatory mediators, which are secreted by activated T cells (types I and II IFN-γ, TNF-α, IL-10, and IL-4) or produced in TME (GM-CSF and VEGF), upregulate PD-L1 expression in the cancer cells resulting in suppression of PD1+ T cells activity. Moreover, cancer cells commonly carry altered PTEN (phosphatase and tension homolog deleted on chromosome ten)—PD-L1 suppressor gene—which may activate the S6K1 gene, resulting in a significant increase in PD-L1 mRNA to polysomes, which promotes PD-L1 mRNA translation and plasma membrane expression [6]. In pancreatic cancer cells, PTEN gene deletion influences PD-L1 expression at the translational level by activating the PI3K/AKT downstream mTOR-S6K1 signaling pathway, thereby increasing PD-L1 production and T lymphocyte apoptosis [52, 53].
Furthermore, amplification and translocation of CD274 on chromosome 9p24.1 have been associated with elevated expression of PD-L1 in Hodgkin’s lymphoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lymphoma, Epstein-Barr virus (EBV)-positive gastric cancer, and oral squamous cell carcinoma (OSCC). In SCLC, chromosomal rearrangements produce CD274 amplification without changing the open reading frame. It is found in various organs, but it is most commonly found in activated T and B lymphocyte cells, dendritic cells, monocytes, and other types of TCs. The CD274/PD-L1 gene is highly conserved, with homologs discovered across the vertebrate lineage (from
PD-L1 induction has also been associated with inflammatory stimuli such as IL-1b, IL-4, IL-6, IL-10, IL-12, IL-17, IL-27, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β). Among the several soluble inflammatory agents, IFN-ϒ is the most important in promoting PD-L1 expression. IFN-ϒ is a proinflammatory cytokine primarily generated by T and NK cells. IFN-ϒ attaches to its receptor, the interferon-gamma receptor (IFNGR), activating the JAK-STAT signaling pathway via STAT1. As a result, it increases the expression of transcription factors, particularly interferon-responsive factors (IRFs). IRF1 is a critical downstream signaling molecule of STAT1 that causes IFN-induced PD-L1. Other proinflammatory agents, IL-4 and TNF-α, have a synergistic impact on the activation of PD-L1 in renal cell carcinoma (RCC) via activating signaling molecules such as NF-κB, IκB, and STAT6. In dendritic cells and monocytes, blocking PD-L1 was associated with decreased IL-10 levels. Furthermore, IL-10 levels on Tyro3, Axl, and Mer (TAM) were closely connected to PD-L1 expression. In monocyte-derived macrophages, IL-12 upregulates PD-L1 expression, but in THP-1-derived macrophages, it downregulates PD-L1 expression. In monocytes, IL-17 is involved in the induction of PD-L1. IL-17 and TNF-α activate NF-κB signaling in prostate cancer and NF-κB and ERK1/2 in colon cancer, respectively, and upregulate PD-L1 expression. PD-L1 expression in dendritic cells is upregulated by IL-1b and IL-27. Furthermore, IL-27 activates phospho-STAT1 and phospho-STAT3 to enhance PD-L1 expression [54, 56].
Meanwhile, CTLA-4 is often constitutively overexpressed on Tregs and has been demonstrated to alter Tregs-mediated immune control. In multiple myeloma patients, FOXP3 and CTLA-4 genes from bone marrow samples were considerably overexpressed [57]. Another sample from peripheral blood mononuclear cells (PBMC) of breast cancer patients showed significantly higher mRNA expression of FOXP3 and CTLA-4 than healthy individuals [58]. Taken together, these results indicated the pivotal role of CTLA-4 in the accumulation of immunosuppressive Tregs in TME, leading to repression of anti-tumor immunity.
Regarding TIM-3 overexpression, it is induced by cytokine stimulation, especially in NK cells. TIM-3 is also extensively expressed on tumor-infiltrating lymphocytes. Similar to its expression pattern during persistent viral infection, TIM-3 is generally co-expressed with PD-1 and represents the most dysfunctional T cell subgroup. TIM-3 overexpression in human malignancies, particularly on immune cells, might be a predictive biomarker for a range of cancers. TIM-3 expression on CD4+ and CD8+ T lymphocytes was enhanced in individuals with hepatitis B virus-related hepatocellular carcinoma (HCC). TIM-3+T cells were replicative senescent and exhibited senescence-related surface and genomic markers. Furthermore, the quantity of tumor-infiltrating cells in TIM-3+ was inversely linked with HCC patient survival [59].
Furthermore, LAG3 is mainly expressed in activated T and natural killer (NK) cells, and it has been identified as a marker for CD4+ and CD8+ T cell activation. Increased LAG3 expression on T cells was observed in combination with other inhibitory receptors such as PD-1, TIGIT, TIM-3, CD160, and 2B4 under pathological conditions such as chronic inflammation or in TME, resulting in T cell exhaustion and reduced cytokine release. In melanoma and colon cancer, LAG3 expression was identified in tissue-infiltrating lymphocytes and peripheral Tregs, tumor-involved lymph nodes, and inside the tumor tissue itself. LAG3 was found on tumor-infiltrating Tregs in patients with head and neck squamous cell carcinoma and non-small cell lung cancer [60].
Similar to other checkpoint molecules, TIGIT is also significantly expressed on Tregs taken from PBMC of cancer patients, and it is further elevated in the TME. Increased TIGIT expression in Tregs is coupled with hypomethylation and FOXP3 binding at the TIGIT gene, distinguishing Tregs from activated effector CD4+ T cells. Furthermore, the Fap2 protein from
Due to cancer cells’ resource intake and vascularization defects, TME is typically deficient in nutrients and oxygen. Cancer cells’ increased need for glucose promotes competition in the TME, which has a detrimental effect on surrounding cells, such as immune cells. Immune checkpoint proteins have been shown to modulate the metabolic energetics of tumor cells, TME, and the tumor-specific immune response, resulting in metabolic reprogramming of both cancerous and immune cells. For instance, CD80 (B7–1) activated the mTOR kinase in naïve CD8+ T cells via the PI3K and STAT4 pathways in solid tumors. mTOR signaling is required to promote glycolysis via hypoxia-inducible factor-1α (HIF-1α) and protein synthesis for supporting cancer cell growth. This activation shifts nutrition balance, and cancerous cells outcompete the immune cells, then evading immune surveillance [62, 63].
Because amino acids are the building blocks of proteins, their availability is critical for tumor development. At the same time, immune cells need amino acids to differentiate and perform their effector activities, hence regulating tumor formation. Given this, a greater knowledge of how each cell species use amino acids in the TME looks critical for successfully stimulating anti-tumor immunity. Tryptophan deficiency impairs CD8+ T cell functions and enhances CD4+ Tregs cell functions, resulting in immunosuppression mediated by the CTLA-4 and PD-1/PD-L1 pathways. The effects are achieved mechanistically by activating the stress response kinase GCN2, which inhibits mTORC2 and its downstream target AKT [64, 65]. The other amino acids, such as glutamine and arginine, are also extensively consumed by the tumors and directly impoverish T cells, leading to the development of immunosuppressive TME [66]. Additionally, tumors may produce and accumulate toxic compounds like aerobic glycolysis byproduct (lactate) in TME, leading to local acidification. Lactate acidosis and hypoxia can activate HIF-1α and then upregulate PD-L1, further inhibiting T-cell responses specific to tumors. Besides, an acidic condition in the surrounding tumors environment suppresses cytokine production (IFN-γ) and limits the activity of T cell cytotoxic, NK cells, and dendritic cells [66, 67].
In contrast to the effector T cells, glucose deprivation may exert a negligible effect on intratumoral Tregs and lactic acid found in the TME may offer nourishment, thus supporting the immunosuppressive function of Tregs [68]. In addition, Tregs differentiation and recruitment is also supported by kynurenine, a metabolite produced from tryptophan through indoleamine 2,3 dioxygenase (IDO)-catabolization in TME [69]. Furthermore, hypoxia and fatty acids production may facilitate Tregs accumulation, thereby favoring its suppressive function [70].
Another immune checkpoint favoring cancer growth strategy is its interaction with Tregs cells either by the expression on Tregs surface or inducing Tregs population and function. Treg cells function in the immune system to regulate and suppress other effector T cells. These cells are responsible for the homeostatic process of the immune system to maintain its unresponsiveness to self-antigens and protect the body from autoimmune reactions or excessive inflammation [71]. However, in this context, the interaction of two immunosuppressive mechanistics is critical in cancer survival from immunosurveillance and progression.
Almost all of the immune checkpoint molecules discussed in this chapter, except BTLA, are expressed in Tregs [72]. CTLA-4 is expressed constitutively on Tregs and induced on effector T cells when activated. CTLA-4 deficiency in Tregs was shown to affect their suppressive effects in animal models. Upon TCR stimulation, CTLA-4 is constitutively recruited on the Tregs cell surface, allowing continuous transendocytosis signaling. Hence, Tregs (CD4+ Foxp3+) can outperformed activated conventional T cells (CD4+ Foxp3−) [73]. Subsequently, downregulation of B7 ligands on APCs leading to diminished CD28 co-stimulation is another way by which Tregs are hypothesized to govern effector T cells [74, 75].
In tumor tissue of non-small cell lung cancer (NSCLC) patients, the PD-L1 expressing CD25+ CD4+ (PD-L1hiTregs) population is higher than in blood or normal tissue. Interestingly, PD-L1hiTregs also correlated with PD-1+ CD8 [76]. In another cancer, highly expressed PD-L1 glioblastoma cells can induce Tregs expansion and maintain its immunosuppressives through PD-1/PD-L1 stimulation. Disrupting the PD-L1/PD-1 axis could target two immunosuppressive mechanisms: inhibition of signaling due to PD-1/PD-L1 ligation and stimulatory proliferation of Tregs cells, which indirectly promotes immunoresistance of high PD-L1 cancers. Thus, Tregs abundance may be a predictive biomarker for patients likely to react to anti-PD-1/anti-PD-L1 therapy or monitor treatment response [77].
Multiple immune checkpoints protein can coexpress and accumulate on the T cell surface, thus increasing dysfunctionality. On CD8+ TILs, it is found that TIGIT is coexpressed with TIM-3, PD-1, and LAG-3 [78]. Although, further investigation is needed to show whether these pathways synergize and whether coblockade is becoming a more efficient immunotherapeutic approach.
Immunological tolerance is normally maintained so that the immune system can recognize and distinguish between self and non-self antigens or neoantigens. Although the immune system is expected to protect the host from exposure to non-self antigens, its robust effector mechanism allows to reverse the attack and disrupt the homeostasis of the immune system. Immune checkpoints, which have gained notoriety as possible cancer therapy targets, are essential immunoregulatory processes found throughout the body. Dysregulation of immune checkpoints promotes tumor cell evasion and plays a significant role in cancer pathogenesis. Therefore, several monoclonal antibodies have been made to block the interaction between ligand and receptor of immune checkpoints, enhancing host immunologic competence against tumors. The list of immune checkpoints inhibitors (ICI), which gained Food and Drug Administration (FDA) approval or are in ongoing clinical trials, is comprehensively summarized in [79]. However, only a tiny proportion of patients respond meaningfully to these therapies due to the signaling complexity and overlapped pathways as mentioned above. Thus, new routes and compounds are being investigated to enhance therapeutic responsiveness and applicability. In clinical practice, the difficulties in treating cancer patients revolve on eliminating the tumor and alleviating symptoms such as pain, fatigue, nausea/vomiting, cough, and diarrhea. Then, concomitant use of medications is negligible and generates new threats for drug interaction such as analgesics [80], steroids [81], antibiotics [82], or many others. Moreover, the use of ICI is often associated with immune-related adverse effects (irAEs). A retrospective study reported that among 1091 patients receiving ICI therapy, 487 (44.63%) patients experienced adverse effects. The most common is fatigue (13.9%), then dermatologic irAEs (12%), endocrine-related irAEs (9.89%), gastrointestinal toxicities (8.4%) and hepatotoxicities (4.94%) [83].
The authors thank our institutions Akademi Farmasi Surabaya and the University of Surabaya, for the support.
The authors declare no conflict of interest.
IntechOpen - where academia and industry create content with global impact
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\\n\\nSara Uhac, COO
\\n\\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
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\\n\\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\\n\\nDr Alex Lazinica
\\n\\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
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\n\nCo-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
\n\nBut, one thing we have in common is -- we are all scientists at heart!
\n\nSara Uhac, COO
\n\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\n\nAdrian Assad De Marco
\n\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\n\nDr Alex Lazinica
\n\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
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Attama, Mumuni A. Momoh and Philip F. Builders",authors:[{id:"142947",title:"Prof.",name:"Anthony",middleName:null,surname:"Attama",slug:"anthony-attama",fullName:"Anthony Attama"}]},{id:"67939",doi:"10.5772/intechopen.85991",title:"Molecular Docking in Modern Drug Discovery: Principles and Recent Applications",slug:"molecular-docking-in-modern-drug-discovery-principles-and-recent-applications",totalDownloads:3898,totalCrossrefCites:27,totalDimensionsCites:60,abstract:"The process of hunt of a lead molecule is a long and a tedious process and one is often demoralized by the endless possibilities one has to search through. Fortunately, computational tools have come to the rescue and have undoubtedly played a pivotal role in rationalizing the path to drug discovery. Of all techniques, molecular docking has played a crucial role in computer aided drug design and has swiftly gained ranks to secure a valuable position in the modern scenario of structure-based drug design. In this chapter, the principle, sampling algorithms, scoring functions and diverse available software’s for molecular docking have been summarized. We demonstrate the interplay of docking, classical techniques of structure-based design and X-ray crystallography in the process of drug discovery. In addition, we dwell upon some of the limitations faced in docking studies. Finally, several success stories of molecular docking approaches in drug discovery have been highlighted, concluding with remarks on molecular docking for the future.",book:{id:"7867",slug:"drug-discovery-and-development-new-advances",title:"Drug Discovery and Development",fullTitle:"Drug Discovery and Development - New Advances"},signatures:"Aaftaab Sethi, Khusbhoo Joshi, K. 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It describe the bioactive compounds derived from natural resources, its phytochemical analysis, characterization and pharmacological investigation. It focuses on the success of these resources in the process of finding and discovering new and effective drug compounds that can be useful for human resources. From many years, natural products have been acting as a source of therapeutic agents and have shown beneficial uses. Only natural product drug discovery plays an important role to develop the scientific evidence of these natural resources. Research in drug discovery needs to develop robust and viable lead molecules, which step forward from a screening hit to a drug candidate through structural elucidation and structure identification through GC–MS, NMR, IR, HPLC, and HPTLC. The development of new technologies has revolutionized the screening of natural products in discovering new drugs. Utilizing these technologies gives us an opportunity to perform research in screening new molecules using a software and database to establish natural products as a major source for drug discovery. It finally leads to lead structure discovery. Powerful new technologies are revolutionizing natural herbal drug discovery.",book:{id:"8290",slug:"pharmacognosy-medicinal-plants",title:"Pharmacognosy",fullTitle:"Pharmacognosy - Medicinal Plants"},signatures:"Akshada Amit Koparde, Rajendra Chandrashekar Doijad and Chandrakant Shripal Magdum",authors:[{id:"268668",title:"Dr.",name:"Akshada",middleName:"Amit",surname:"Koparde",slug:"akshada-koparde",fullName:"Akshada Koparde"}]}],mostDownloadedChaptersLast30Days:[{id:"49459",title:"Pharmacokinetics of Drugs Following IV Bolus, IV Infusion, and Oral Administration",slug:"pharmacokinetics-of-drugs-following-iv-bolus-iv-infusion-and-oral-administration",totalDownloads:15480,totalCrossrefCites:16,totalDimensionsCites:24,abstract:null,book:{id:"4491",slug:"basic-pharmacokinetic-concepts-and-some-clinical-applications",title:"Basic Pharmacokinetic Concepts and Some Clinical Applications",fullTitle:"Basic Pharmacokinetic Concepts and Some Clinical Applications"},signatures:"Tarek A. 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It describe the bioactive compounds derived from natural resources, its phytochemical analysis, characterization and pharmacological investigation. It focuses on the success of these resources in the process of finding and discovering new and effective drug compounds that can be useful for human resources. From many years, natural products have been acting as a source of therapeutic agents and have shown beneficial uses. Only natural product drug discovery plays an important role to develop the scientific evidence of these natural resources. Research in drug discovery needs to develop robust and viable lead molecules, which step forward from a screening hit to a drug candidate through structural elucidation and structure identification through GC–MS, NMR, IR, HPLC, and HPTLC. The development of new technologies has revolutionized the screening of natural products in discovering new drugs. Utilizing these technologies gives us an opportunity to perform research in screening new molecules using a software and database to establish natural products as a major source for drug discovery. It finally leads to lead structure discovery. Powerful new technologies are revolutionizing natural herbal drug discovery.",book:{id:"8290",slug:"pharmacognosy-medicinal-plants",title:"Pharmacognosy",fullTitle:"Pharmacognosy - Medicinal Plants"},signatures:"Akshada Amit Koparde, Rajendra Chandrashekar Doijad and Chandrakant Shripal Magdum",authors:[{id:"268668",title:"Dr.",name:"Akshada",middleName:"Amit",surname:"Koparde",slug:"akshada-koparde",fullName:"Akshada Koparde"}]},{id:"48805",title:"Biopharmaceutics and Pharmacokinetics",slug:"biopharmaceutics-and-pharmacokinetics",totalDownloads:26159,totalCrossrefCites:2,totalDimensionsCites:7,abstract:null,book:{id:"4491",slug:"basic-pharmacokinetic-concepts-and-some-clinical-applications",title:"Basic Pharmacokinetic Concepts and Some Clinical Applications",fullTitle:"Basic Pharmacokinetic Concepts and Some Clinical Applications"},signatures:"S. Lakshmana Prabu, T.N.K. Suriyaprakash, K. Ruckmani and R.\nThirumurugan",authors:[{id:"91590",title:"Dr.",name:"Sakthivel",middleName:null,surname:"Lakshmana Prabu",slug:"sakthivel-lakshmana-prabu",fullName:"Sakthivel Lakshmana Prabu"},{id:"128690",title:"Dr.",name:"Suriyaprakash",middleName:null,surname:"Tnk",slug:"suriyaprakash-tnk",fullName:"Suriyaprakash Tnk"}]}],onlineFirstChaptersFilter:{topicId:"219",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81857",title:"Use of Oral Ketamine in Palliative Care",slug:"use-of-oral-ketamine-in-palliative-care",totalDownloads:39,totalDimensionsCites:0,doi:"10.5772/intechopen.104875",abstract:"Ketamine, an N-methyl-D-Aspartate receptor antagonist, has been used for more than 50 years. From its initial potential as an anesthetic drug, its use has increased in the fields of pain medicine, psychiatry, and palliative care. It is available in different formulations, of which oral use is promising due to its active metabolite, norketamine which reaches 2–3 times higher levels when administered orally in comparison with parenteral use. Oral use is also more feasible and easier to use in settings, where medical staff is not that present, such as home care or hospices. Oral solution of ketamine has not yet been officially licensed for use although there have been several reports which recommend its use in neuropathic pain, severe depression, airway obstruction, and anxiety. Palliative care is defined as total care for patients whose diseases do not respond to curative treatment. It encompasses good control of physical symptoms, and psychological, social and spiritual problems. Patients often experience pain, despite high doses of opioids, depression and anxiety, and dyspnea. Oral ketamine does not have the side effects of opioids therefore it represents a good alternative. It may also reduce the need for high opioid doses and be more suitable for patients who wish to avoid the necessary sedation.",book:{id:"11036",title:"Ketamine Revisited - New Insights into NMDA Inhibitors",coverURL:"https://cdn.intechopen.com/books/images_new/11036.jpg"},signatures:"Mateja Lopuh"},{id:"81722",title:"Ketamine for Chronic Pain",slug:"ketamine-for-chronic-pain",totalDownloads:21,totalDimensionsCites:0,doi:"10.5772/intechopen.104874",abstract:"The treatment of chronic pain is a chronic problem for many specialities. It is generally based on an approach with antidepressants, anti-epileptics and opioids as drugs of first choice. It has been worked by many different protocols. Ketamine, which is known as a good anaesthetic, has been used for chronic pain. When the pain has a neuropathic component, ketamine is a promising treatment for pain management. Ketamine: by inhibiting the N-methyl-D-aspartate receptor and having some other effects like enhancement of descending inhibition and anti-inflammatory effects at central sites, takes part in chronic pain management. Besides having analgesic effects, there are some concerns about the side effects of ketamine. Some psychedelic symptoms as hallucinations, memory defects, panic attacks, nausea and vomiting, somnolence, cardiovascular stimulation and sometimes hepatoxicity may be seen in patients. Ketamine is generally well-tolerated in clinical settings. Close monitoring of patients receiving ketamine should be mandatory in order to be aware of central nervous system, haemodynamic, renal and hepatic symptoms as well as abuse.",book:{id:"11036",title:"Ketamine Revisited - New Insights into NMDA Inhibitors",coverURL:"https://cdn.intechopen.com/books/images_new/11036.jpg"},signatures:"Cigdem Yildirim Guclu"},{id:"81646",title:"Cortical Plasticity under Ketamine: From Synapse to Map",slug:"cortical-plasticity-under-ketamine-from-synapse-to-map",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.104787",abstract:"Sensory systems need to process signals in a highly dynamic way to efficiently respond to variations in the animal’s environment. For instance, several studies showed that the visual system is subject to neuroplasticity since the neurons’ firing changes according to stimulus properties. This dynamic information processing might be supported by a network reorganization. Since antidepressants influence neurotransmission, they can be used to explore synaptic plasticity sustaining cortical map reorganization. To this goal, we investigated in the primary visual cortex (V1 of mouse and cat), the impact of ketamine on neuroplasticity through changes in neuronal orientation selectivity and the functional connectivity between V1 cells, using cross correlation analyses. We found that ketamine affects cortical orientation selectivity and alters the functional connectivity within an assembly. These data clearly highlight the role of the antidepressant drugs in inducing or modeling short-term plasticity in V1 which suggests that cortical processing is optimized and adapted to the properties of the stimulus.",book:{id:"11036",title:"Ketamine Revisited - New Insights into NMDA Inhibitors",coverURL:"https://cdn.intechopen.com/books/images_new/11036.jpg"},signatures:"Ouelhazi Afef, Rudy Lussiez and Molotchnikoff Stephane"},{id:"81561",title:"Ketamine and Low-Resource Countries",slug:"ketamine-and-low-resource-countries",totalDownloads:51,totalDimensionsCites:0,doi:"10.5772/intechopen.104651",abstract:"Safe anaesthesia and surgery are piloted to reduce the morbidity and mortality associated with anaesthesia and surgery, and improve surgical outcomes. This goal is far-fetched in developing countries as a result of limited manpower, poor operation theatre infrastructure, unavailability of equipment, life-saving drugs, and anaesthetic agents. Postoperative pain is also widely undertreated in this environment, mostly due to financial constraints patients and their relatives face and the unavailability of analgesics. Sometimes the physicians face problems associated with their resource-limited working environment, such as unreliable electricity, unavailability of compressed oxygen and other gases, sophisticated machines, and modern drugs. Thus, easy adaptability and proper utilisation of available resources have been described as a resounding quality required of anaesthetists working in developing countries, to thrive and provide anaesthetic services. Ketamine is readily available in resource-limited environments, and adaptability to the use of this drug has made it possible for the anaesthetist to provide anaesthesia, pain care services, sedation, and save lives.",book:{id:"11036",title:"Ketamine Revisited - New Insights into NMDA Inhibitors",coverURL:"https://cdn.intechopen.com/books/images_new/11036.jpg"},signatures:"Chimaobi Tim Nnaji"},{id:"81236",title:"The Role of Ketamine in Trauma",slug:"the-role-of-ketamine-in-trauma",totalDownloads:53,totalDimensionsCites:0,doi:"10.5772/intechopen.103655",abstract:"Early and effective pain control in trauma patients improves outcomes and limits disability, but analgesia is often missed in the unstable patient, or hemodynamically depressing medications are avoided for fear of losing stability. This chapter outlines the role of ketamine in managing traumatic emergencies in both out-of-hospital and hospital environment, and beyond. Low-dose ketamine also called a sub-dissociative dose is safe, efficient and effective analgesic that can be considered for trauma patients, pediatric or adults, as an alternative to opioids or in combination with opioids for on additive or synergistic effect, with minimal impact on hemodynamic stability. Ketamine at higher doses is also an excellent drug for induction of anesthesia in rapid sequence induction (RSI), post-intubation sedation maintenance or procedural sedation in the trauma patient. Also, can be used for acute agitation and excited delirium. In this chapter, we are describing this drug focusing on a deeper understanding of the safety and efficacy of this agent and, if supported, to encourage physicians to consider ketamine for pain control in trauma and beyond. Also, we are presenting the current literature surrounding ketamine’s evidences in the trauma condition to establish its utility and profile of safety for these patients.",book:{id:"11036",title:"Ketamine Revisited - New Insights into NMDA Inhibitors",coverURL:"https://cdn.intechopen.com/books/images_new/11036.jpg"},signatures:"Mihai Octavian Botea and Erika Bimbo-Szuhai"},{id:"81029",title:"Uses of Ketamine in the Paediatric Population",slug:"uses-of-ketamine-in-the-paediatric-population",totalDownloads:43,totalDimensionsCites:0,doi:"10.5772/intechopen.103658",abstract:"General anesthesia in pediatric patients can vary from light sedation to complete anesthesia with unconsciousness, amnesia and muscle relaxation. A wide variety of procedures are done under general anesthesia in children ranging from surgeries done for correction of congenital defects, cardiac surgeries, scoliosis surgery, hernia surgery etc. to procedures done outside the operating room (OR) for diagnostic and therapeutic purposes. Non-Operating room Anesthesia (NORA) may include painless procedures like CT scan, MRI, radiotherapy for cancer treatment etc. or painful procedures like biopsy, lumbar puncture, securing IV access, insertion of central line etc. done in ICU which requires a cooperative child. Ketamine has an important role in the pediatric population, both as an induction agent and as a sedative-analgesic drug especially in countries where newer drugs are not readily available. Ketamine helps to alleviate separation anxiety. Even procedures done under regional techniques in some older children require use of sedation. Ketamine can be administered through various routes-IV, IM, intranasal etc. It can be used along with other groups of drugs like Benzodiazepines, Barbiturates, Alpha 2 agonists, Propofol etc. Thus Ketamine is a versatile drug with various indications for use in the pediatric population which will be discussed in the current chapter.",book:{id:"11036",title:"Ketamine Revisited - New Insights into NMDA Inhibitors",coverURL:"https://cdn.intechopen.com/books/images_new/11036.jpg"},signatures:"Bhagyalakshmi Ramesh"}],onlineFirstChaptersTotal:17},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:333,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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He was elected a Yangtze River Scholars Distinguished Professor in 2013, a member of the International Statistical Institute (ISI) in 2016, a member of the board of the International Chinese Statistical Association (ICSA) in 2018, and a fellow of the Institute of Mathematical Statistics (IMS) in 2021. He received the ICSA Outstanding Service Award in 2018 and the National Science Foundation for Distinguished Young Scholars of China in 2012. He serves as a member of the editorial board of Statistics and Its Interface and Journal of Systems Science and Complexity. He is also a field editor for Communications in Mathematics and Statistics. His research interests include biostatistics, empirical likelihood, missing data analysis, variable selection, high-dimensional data analysis, Bayesian statistics, and data science. He has published more than 190 research papers and authored five books.",institutionString:"Yunnan University",institution:{name:"Yunnan University",country:{name:"China"}}},{id:"1177",title:"Prof.",name:"António",middleName:"J. R.",surname:"José Ribeiro Neves",slug:"antonio-jose-ribeiro-neves",fullName:"António José Ribeiro Neves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1177/images/system/1177.jpg",biography:"Prof. António J. R. Neves received a Ph.D. in Electrical Engineering from the University of Aveiro, Portugal, in 2007. Since 2002, he has been a researcher at the Institute of Electronics and Informatics Engineering of Aveiro. Since 2007, he has been an assistant professor in the Department of Electronics, Telecommunications, and Informatics, University of Aveiro. He is the director of the undergraduate course on Electrical and Computers Engineering and the vice-director of the master’s degree in Electronics and Telecommunications Engineering. He is an IEEE Senior Member and a member of several other research organizations worldwide. His main research interests are computer vision, intelligent systems, robotics, and image and video processing. He has participated in or coordinated several research projects and received more than thirty-five awards. He has 161 publications to his credit, including books, book chapters, journal articles, and conference papers. He has vast experience as a reviewer of several journals and conferences. As a professor, Dr. Neves has supervised several Ph.D. and master’s students and was involved in more than twenty-five different courses.",institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"11317",title:"Dr.",name:"Francisco",middleName:null,surname:"Javier Gallegos-Funes",slug:"francisco-javier-gallegos-funes",fullName:"Francisco Javier Gallegos-Funes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/11317/images/system/11317.png",biography:"Francisco J. Gallegos-Funes received his Ph.D. in Communications and Electronics from the Instituto Politécnico Nacional de México (National Polytechnic Institute of Mexico) in 2003. He is currently an associate professor in the Escuela Superior de Ingeniería Mecánica y Eléctrica (Mechanical and Electrical Engineering Higher School) at the same institute. His areas of scientific interest are signal and image processing, filtering, steganography, segmentation, pattern recognition, biomedical signal processing, sensors, and real-time applications.",institutionString:"Instituto Politécnico Nacional",institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"428449",title:"Dr.",name:"Ronaldo",middleName:null,surname:"Ferreira",slug:"ronaldo-ferreira",fullName:"Ronaldo Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428449/images/21449_n.png",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/165328/images/system/165328.jpg",biography:"Vahid Asadpour, MS, Ph.D., is currently with the Department of Research and Evaluation, Kaiser Permanente Southern California. He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). 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Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. 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