Compartments of the hand.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6465",leadTitle:null,fullTitle:"Drones - Applications",title:"Drones",subtitle:"Applications",reviewType:"peer-reviewed",abstract:'Drone technologies have constantly been developing for over 100 years. The latest models exhibit a previously unseen set of specifications available to the end users. The collective effort of distinguished international researchers, within the field of drone technologies, has been incorporated into this textbook suitable to the broader audience. The book has been edited by Prof. George Dekoulis, Aerospace Engineering Institute (AEI), Cyprus, an expert on state-of-the-art implementations of reconfigurable space engineering systems. The book consists of four main sections, namely, "Introduction," "Drone History," "Drone Design," and "Drone Applications." We hope this book will be beneficial to professionals, researchers, and academicians and, moreover, to inspire the younger generations into pursuing relevant academic studies and professional careers within the drone industry.',isbn:"978-1-78923-285-1",printIsbn:"978-1-78923-284-4",pdfIsbn:"978-1-83881-478-6",doi:"10.5772/intechopen.70910",price:119,priceEur:129,priceUsd:155,slug:"drones-applications",numberOfPages:158,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"50a345acb86d524f7a505e09d1f2fc49",bookSignature:"George Dekoulis",publishedDate:"June 27th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6465.jpg",numberOfDownloads:11107,numberOfWosCitations:10,numberOfCrossrefCitations:21,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:25,numberOfDimensionsCitationsByBook:2,hasAltmetrics:0,numberOfTotalCitations:56,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 14th 2017",dateEndSecondStepPublish:"October 5th 2017",dateEndThirdStepPublish:"December 4th 2017",dateEndFourthStepPublish:"February 22nd 2018",dateEndFifthStepPublish:"April 23rd 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"9833",title:"Prof.",name:"George",middleName:null,surname:"Dekoulis",slug:"george-dekoulis",fullName:"George Dekoulis",profilePictureURL:"https://mts.intechopen.com/storage/users/9833/images/system/9833.jfif",biography:"Prof. George Dekoulis received his PhD in Space Engineering and Communications from Lancaster University, UK, in 2007. He was awarded a First Class BEng (Hons) degree in Communications Engineering from De Montfort University, UK, in 2001. He has received several awards from the Science and Technology Facilities Council (STFC), the Engineering and Physical Sciences Research Council (EPSRC), and the Hudswell International Research Scholarship (IET). He is currently the Dean of the Faculty of Sciences and Technology at the American University of Cyprus (AUCY), Cyprus. He was previously a professor at the Aerospace Engineering Institute (AEI), Cyprus. Founder of the IEEE Aerospace and Electronic Systems Society (AESS), Cyprus. General chair of IEEE Aerospace Engineering Innovations 2019 (IEEE AEI 2019), Limassol, Cyprus. He has worked as a professor in Space Computing & Engineering at various departments, such as Space & Planetary Physics, Aeronautical and Space Engineering, Professional Flight, Robotics/Mechatronics & Mechanical Engineering, Computer Science & Engineering, and Electrical and Electronics Engineering. His research focuses on the design of reconfigurable Space Computing and Engineering Systems.",institutionString:"Aerospace Engineering Institute",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"9",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1251",title:"Robotic Drones",slug:"robotic-drones"}],chapters:[{id:"61037",title:"Introductory Chapter: Drones",doi:"10.5772/intechopen.76943",slug:"introductory-chapter-drones",totalDownloads:1208,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:null,signatures:"George Dekoulis",downloadPdfUrl:"/chapter/pdf-download/61037",previewPdfUrl:"/chapter/pdf-preview/61037",authors:[{id:"9833",title:"Prof.",name:"George",surname:"Dekoulis",slug:"george-dekoulis",fullName:"George Dekoulis"}],corrections:null},{id:"60953",title:"Small to Medium UAVs for Civilian Applications in Indonesia",doi:"10.5772/intechopen.76426",slug:"small-to-medium-uavs-for-civilian-applications-in-indonesia",totalDownloads:1317,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Indonesian government needs a well-built, easy to operate unmanned aircraft systems (UAS) to perform various civilian missions as UAS are a well-known platform for dirty, dull, and dangerous missions. Hence, the Indonesian government has an organization that performs research and development of UAS, named as Aeronautic Technology Center. This organization is placed underneath Indonesian National Institute of Aeronautics and Space. The UAS developments in this institute are primarily driven by civilian uses; therefore, the UAS size, sensor types, and mission payload are optimized for civilian missions. In order to produce the decent to the best quality of the aerial image, which is the essential product for various civilian missions, the UAS regularly flies under the cloud. For this reason, the Aeronautic Technology Center is only developing the LASE (low altitude, short-endurance) and the LALE (low altitude, long endurance) UAS type as of now. The UAS development was begun with LSU-01, followed by LSU-02, LSU-03, and LSU-05. The LSU-01, LSU-02, and LSU-03 are in the operational phase, while the LSU-05 is in the experimental Phase. In this chapter, the specification of the platforms and the sensor capabilities that are relevant with the demands of users in the civilian sector are described.",signatures:"Fuad Surastyo Pranoto, Ari Sugeng Budiyanta and Gunawan Setyo\nPrabowo",downloadPdfUrl:"/chapter/pdf-download/60953",previewPdfUrl:"/chapter/pdf-preview/60953",authors:[{id:"223333",title:"M.Sc.",name:"Fuad",surname:"Pranoto",slug:"fuad-pranoto",fullName:"Fuad Pranoto"},{id:"223356",title:"MSc.",name:"Ari Sugeng",surname:"Budiyanta",slug:"ari-sugeng-budiyanta",fullName:"Ari Sugeng Budiyanta"},{id:"223357",title:"MSc.",name:"Gunawan Setyo",surname:"Prabowo",slug:"gunawan-setyo-prabowo",fullName:"Gunawan Setyo Prabowo"}],corrections:null},{id:"61524",title:"Smart Arduino Sensor Integrated Drone for Weather Indices: Prototype",doi:"10.5772/intechopen.76872",slug:"smart-arduino-sensor-integrated-drone-for-weather-indices-prototype",totalDownloads:1179,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Mostly, the conditions within an ecosystem as well as weather of a field affect crop productivity greatly. Different weather conditions produce different effects and different impact on the quality of the crop field or the ecosystem. Weather elements form a chain reaction, as the atmosphere is not the only one being affected. Atmospheric air temperature, vapor pressure and relative humidity or moisture content can act together and form diverse effects on crops. These diverse effects turn to reduce radiation which is necessary for plants, or increase rainfall patterns. Consistent high temperatures can increase the heat transfer to local bodies of water in addition to heating the air. Monitoring the climate and the weather conditions are important not only as an environmental baseline, but to maintain quality working conditions, marine studies and recreational safety. The parameters of climate are measurable, for example, atmospheric vapor pressure, temperature, precipitation and solar radiation, can be captured and recorded daily on the Smart Arduino Sensor Integrated Drone. Means and extreme datasets, maximum and minimum weather trends with deviations of lengthy time series would be calculated for each of these climate parameters which were considered in this study. These results are a simple form of climate indices, as they already describe changes in climate. All the readings and datasets are recorded on a cloud platform, as well as, in an installed microchip on the drone. Data synchronization is done with MAT-LAB and Arduino Programming Rule.",signatures:"Hanping Mao, Oppong K. Paul, Ning Yang and Lin Li",downloadPdfUrl:"/chapter/pdf-download/61524",previewPdfUrl:"/chapter/pdf-preview/61524",authors:[{id:"241627",title:"Dr.",name:"Paul",surname:"Oppong Kwabena Opk",slug:"paul-oppong-kwabena-opk",fullName:"Paul Oppong Kwabena Opk"},{id:"248142",title:"Prof.",name:"Han-Ping",surname:"Mao",slug:"han-ping-mao",fullName:"Han-Ping Mao"},{id:"248331",title:"Dr.",name:"Lin",surname:"Li",slug:"lin-li",fullName:"Lin Li"}],corrections:null},{id:"58576",title:"Generalized Control Allocation Scheme for Multirotor Type of UAVs",doi:"10.5772/intechopen.73006",slug:"generalized-control-allocation-scheme-for-multirotor-type-of-uavs",totalDownloads:1319,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Unmanned aerial vehicles (UAVs) are autonomous or remotely guided aircraft, which can potentially carry out a wide range of tasks. Multirotor type of UAV has unique ability to perform vertical take-off and landing (VTOL), a stationary and low-speed flight where certain configurations can achieve very complex and precise movements. Therefore, they are suitable for performing tasks such as delivery of first aid kit, firefighting, infrastructure inspection, aerial video, and many others. In this chapter, a generalized control allocation scheme for a multirotor UAV is presented, which describes the mapping of rotor angular velocities to the control vector of the aircraft. It enables control and design of multirotor configurations with diverse geometrical arrangement and characteristics of the propulsion subsystem depending on the task, which multirotor has to carry out. The inverted scheme, which is implemented as a motor mixer, maps the control inputs into a set of aircraft actuator outputs.",signatures:"Denis Kotarski and Josip Kasać",downloadPdfUrl:"/chapter/pdf-download/58576",previewPdfUrl:"/chapter/pdf-preview/58576",authors:[{id:"222226",title:"Ph.D.",name:"Denis",surname:"Kotarski",slug:"denis-kotarski",fullName:"Denis Kotarski"},{id:"237976",title:"Prof.",name:"Josip",surname:"Kasać",slug:"josip-kasac",fullName:"Josip Kasać"}],corrections:null},{id:"58158",title:"Uncertainty of Object-Based Image Analysis for Drone Survey Images",doi:"10.5772/intechopen.72332",slug:"uncertainty-of-object-based-image-analysis-for-drone-survey-images",totalDownloads:1073,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"With the recent developments in the acquisition of images using drone systems, object-based image analysis (OBIA) is widely applied to such high-resolution images. Therefore, it is expected that the application of drone survey images would benefit from studying the uncertainty of OBIA. The most important source of uncertainty is image segmentation, which could significantly affect the accuracy at each stage of OBIA. Therefore, the trans-scale sensitivity of several spatial autocorrelation measures optimizing the segmentation was investigated, including the intrasegment variance of the regions, Moran’s I autocorrelation index, and Geary’s C autocorrelation index. Subsequently, a top-down decomposition scheme was presented to optimize the segmented objects derived from multiresolution segmentation (MRS), and its potential was examined using a drone survey image. The experimental results demonstrate that the proposed strategy is able to effectively improve the segmentation of drone survey images of urban areas or highly consistent areas.",signatures:"Lei Ma, Gaofei Yin, Zhenjin Zhou, Heng Lu and Manchun Li",downloadPdfUrl:"/chapter/pdf-download/58158",previewPdfUrl:"/chapter/pdf-preview/58158",authors:[{id:"223550",title:"Dr.",name:"Lei",surname:"Ma",slug:"lei-ma",fullName:"Lei Ma"},{id:"223828",title:"Prof.",name:"Manchun",surname:"Li",slug:"manchun-li",fullName:"Manchun Li"},{id:"224985",title:"Dr.",name:"Heng",surname:"Lu",slug:"heng-lu",fullName:"Heng Lu"},{id:"232685",title:"Dr.",name:"Gaofei",surname:"Yin",slug:"gaofei-yin",fullName:"Gaofei Yin"},{id:"232686",title:"MSc.",name:"Zhenjing",surname:"Zhou",slug:"zhenjing-zhou",fullName:"Zhenjing Zhou"}],corrections:null},{id:"59130",title:"The Use of Unmanned Aerial Vehicles by Urban Search and Rescue Groups",doi:"10.5772/intechopen.73320",slug:"the-use-of-unmanned-aerial-vehicles-by-urban-search-and-rescue-groups",totalDownloads:1248,totalCrossrefCites:5,totalDimensionsCites:6,hasAltmetrics:0,abstract:"In the case of natural or man-made disaster, the top priority of urban search and rescue (USAR) groups is to localise the victim as quickly as possible. Even minutes might play a crucial role in the victim’s survival. A number of standard operating procedures may be applied to achieve best performance. Rescue dogs are trained to search for alive victims; special inspection cameras are used, before heavy equipment is being implemented. To improve the effectiveness of USAR group operations, innovative technologies might be implemented. The most recent solution is currently designed in MOBNET project, founded by EU under the Horizon 2020 programme. The scope of the project is to combine both cellular technology and early Galileo services to localise the smartphones of potential victims. Integration tests give some promising outcomes. The following chapter looks at typical applications, real needs of public services as well as the performance of the novel system.",signatures:"Marzena Półka, Szymon Ptak, Łukasz Kuziora and Aneta Kuczyńska",downloadPdfUrl:"/chapter/pdf-download/59130",previewPdfUrl:"/chapter/pdf-preview/59130",authors:[{id:"226977",title:"Dr.Ing.",name:"Szymon",surname:"Ptak",slug:"szymon-ptak",fullName:"Szymon Ptak"},{id:"240085",title:"Prof.",name:"Marzena",surname:"Półka",slug:"marzena-polka",fullName:"Marzena Półka"},{id:"240086",title:"MSc.",name:"Łukasz",surname:"Kuziora",slug:"lukasz-kuziora",fullName:"Łukasz Kuziora"},{id:"240087",title:"MSc.",name:"Aneta",surname:"Kuczyńska",slug:"aneta-kuczynska",fullName:"Aneta Kuczyńska"}],corrections:null},{id:"58901",title:"New Applications of 3D SLAM on Risk Management Using Unmanned Aerial Vehicles in the Construction Industry",doi:"10.5772/intechopen.73325",slug:"new-applications-of-3d-slam-on-risk-management-using-unmanned-aerial-vehicles-in-the-construction-in",totalDownloads:1134,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Risk Management is an integral part of the Corporate Governance of the Companies, whose objective is to estimate the risks related to each line of business and to make appropriate decisions regarding the adoption of preventive measures. The construction industry, due to its peculiar characteristics about occupational risks, is a sector that must pay particular attention to this issue. Unmanned aerial robots are part of a generation of new technologies, which are emerging in the attempt to develop robust and efficient algorithms capable of obtaining 3D models of structures under construction, to support the assessment of the situation in case of an eventuality, before the direct human intervention. This article proposes to develop a risk management strategy for the construction industry based on obtaining 3D models of work environments using drones, which will allow safe evaluation of risks present in construction zones.",signatures:"Alfredo Toriz Palacios, José Maria Enrique Bedolla Cordero,\nModesto Raygoza Bello, Edgar Toriz Palacios and Jessica L. Martínez\nGonzález",downloadPdfUrl:"/chapter/pdf-download/58901",previewPdfUrl:"/chapter/pdf-preview/58901",authors:[{id:"223703",title:"Ph.D.",name:"Alfredo",surname:"Toriz Palacios",slug:"alfredo-toriz-palacios",fullName:"Alfredo Toriz Palacios"},{id:"239438",title:"M.A.",name:"José María Enrique",surname:"Bedolla Cordero",slug:"jose-maria-enrique-bedolla-cordero",fullName:"José María Enrique Bedolla Cordero"},{id:"239439",title:"Dr.",name:"Modesto",surname:"Raygoza Bello",slug:"modesto-raygoza-bello",fullName:"Modesto Raygoza Bello"},{id:"239440",title:"MSc.",name:"Edgar",surname:"Toriz Palacios",slug:"edgar-toriz-palacios",fullName:"Edgar Toriz Palacios"},{id:"239441",title:"MSc.",name:"Jessica Lisbeth",surname:"Martínez González",slug:"jessica-lisbeth-martinez-gonzalez",fullName:"Jessica Lisbeth Martínez González"}],corrections:null},{id:"60327",title:"Land Use Information Quick Mapping Based on UAV Low- Altitude Remote Sensing Technology and Transfer Learning",doi:"10.5772/intechopen.74475",slug:"land-use-information-quick-mapping-based-on-uav-low-altitude-remote-sensing-technology-and-transfer-",totalDownloads:1219,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Obtaining surface spatio-temporal data rapidly, automatically and accurately is an important issue in agriculture informationization and intellectualization. Samples obtained by conventional manual visual interpretation are difficult to adapt the demands of land resources information extraction. Low altitude remote sensing technology as a kind of emerging technology for earth observation in recent years. Based on this, spatio-temporal data mining technology was introduced, and knowledge transfer learning mechanism was used, a novel landuse information classification method based on knowledge transfer learning (KTLC) was proposed. Firstly, new image was segmented by improved mean shift algorithm to obtain image objects. Secondly, the vector boundary of the objects and former historical landuse thematic map were matched and nested, invariant objects were obtained through overlay analysis, and purification of invariant object was finished by spectral and spatial information threshold filtering. The historical features category knowledge of thematic map was transferred to the new image objects. Finally, current images classification mapping was completed based on decision tree, and landuse classification mapping results were completed by the KTLC and eCognition for landuse information mapping classification (EC). The experimental results showed that KTLC could obtain accuracies equivalent to EC, and also outperforms EC in terms of efficiency.",signatures:"Lu Heng, Fu Xiao, Liu Chao, Li Longguo, Li Naiwen and Ma Lei",downloadPdfUrl:"/chapter/pdf-download/60327",previewPdfUrl:"/chapter/pdf-preview/60327",authors:[{id:"223550",title:"Dr.",name:"Lei",surname:"Ma",slug:"lei-ma",fullName:"Lei Ma"},{id:"224985",title:"Dr.",name:"Heng",surname:"Lu",slug:"heng-lu",fullName:"Heng Lu"},{id:"224196",title:"Dr.",name:"Naiwen",surname:"Li",slug:"naiwen-li",fullName:"Naiwen Li"},{id:"225003",title:"Dr.",name:"Xiao",surname:"Fu",slug:"xiao-fu",fullName:"Xiao Fu"},{id:"240274",title:"Dr.",name:"Chao",surname:"Liu",slug:"chao-liu",fullName:"Chao Liu"},{id:"240275",title:"Dr.",name:"Longguo",surname:"Li",slug:"longguo-li",fullName:"Longguo Li"}],corrections:null},{id:"58775",title:"Unmanned Aerial Systems for Magnetic Survey",doi:"10.5772/intechopen.73003",slug:"unmanned-aerial-systems-for-magnetic-survey",totalDownloads:1411,totalCrossrefCites:3,totalDimensionsCites:6,hasAltmetrics:0,abstract:"Placing a magnetometer on unmanned aerial vehicle (UAV) seems to be an easy task as the sensor is rather lightweight in comparison with other geophysical sensors. But, the realization of an unmanned aeromagnetic system (UAMS) faces multiple technical complications, and, as a result, very few of many attempts to build a UAMS have succeeded. Even less projects have produced results of real magnetic survey. Different platforms (helicopters, multirotor, and fixed wing UAVs) and different kinds of magnetometers for UAMS have different pros and cons for the purpose. For the quality of magnetic survey, the most important is the issue of a platform’s (UAV) magnetic noise and its influence on a magnetic sensor. Workbench experimental studies as well as results of magnetic surveys with multirotor UAMS in Leningrad region, Republic Sakha-Yakutia, and Kazakhstan demonstrate solutions facilitating state-of-the-art high-quality measurements of magnetic anomalies for geological, archeological, and other purposes.",signatures:"Sergey Cherkasov and Dmitry Kapshtan",downloadPdfUrl:"/chapter/pdf-download/58775",previewPdfUrl:"/chapter/pdf-preview/58775",authors:[{id:"224731",title:"Dr.",name:"Sergey",surname:"Cherkasov",slug:"sergey-cherkasov",fullName:"Sergey Cherkasov"},{id:"224762",title:"MSc.",name:"Dmitry",surname:"Kapshtan",slug:"dmitry-kapshtan",fullName:"Dmitry Kapshtan"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6003",title:"Robotics",subtitle:"Legal, Ethical and Socioeconomic 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Neimyer, Kailey Roberts,\nWendy Lichtenthal, Jun Hu and Matthias Rauterberg",dateSubmitted:"September 5th 2017",dateReviewed:null,datePrePublished:null,datePublished:"October 18th 2017",book:{id:"6456",title:"Proceedings of the Conference on Design and Semantics of Form and Movement",subtitle:"Sense and Sensitivity, DeSForM 2017",fullTitle:"Proceedings of the Conference on Design and Semantics of Form and Movement - Sense and Sensitivity, DeSForM 2017",slug:"proceedings-of-the-conference-on-design-and-semantics-of-form-and-movement-sense-and-sensitivity-desform-2017",publishedDate:"October 18th 2017",bookSignature:"Miguel Bruns Alonso and Elif Ozcan",coverURL:"https://cdn.intechopen.com/books/images_new/6456.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"156855",title:"Dr.",name:"Elif",middleName:null,surname:"Ozcan",slug:"elif-ozcan",fullName:"Elif Ozcan"}],productType:{id:"2",title:"Proceeding",chapterContentType:"conference paper",authoredCaption:"Edited by"}},authors:[{id:"221149",title:"Dr.",name:"Wan Jou",middleName:null,surname:"She",fullName:"Wan Jou She",slug:"wan-jou-she",email:"lave@lavendershe.com",position:null,institution:null}]}},chapter:{id:"57127",slug:"toward-the-development-of-a-monitoring-and-feedback-system-for-predicting-poor-adjustment-to-grief",signatures:"Wan Jou She, Laurie Burke, Robert A. Neimyer, Kailey Roberts,\nWendy Lichtenthal, Jun Hu and Matthias Rauterberg",dateSubmitted:"September 5th 2017",dateReviewed:null,datePrePublished:null,datePublished:"October 18th 2017",book:{id:"6456",title:"Proceedings of the Conference on Design and Semantics of Form and Movement",subtitle:"Sense and Sensitivity, DeSForM 2017",fullTitle:"Proceedings of the Conference on Design and Semantics of Form and Movement - Sense and Sensitivity, DeSForM 2017",slug:"proceedings-of-the-conference-on-design-and-semantics-of-form-and-movement-sense-and-sensitivity-desform-2017",publishedDate:"October 18th 2017",bookSignature:"Miguel Bruns Alonso and Elif Ozcan",coverURL:"https://cdn.intechopen.com/books/images_new/6456.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"156855",title:"Dr.",name:"Elif",middleName:null,surname:"Ozcan",slug:"elif-ozcan",fullName:"Elif Ozcan"}],productType:{id:"2",title:"Proceeding",chapterContentType:"conference paper",authoredCaption:"Edited by"}},authors:[{id:"221149",title:"Dr.",name:"Wan Jou",middleName:null,surname:"She",fullName:"Wan Jou She",slug:"wan-jou-she",email:"lave@lavendershe.com",position:null,institution:null}]},book:{id:"6456",title:"Proceedings of the Conference on Design and Semantics of Form and Movement",subtitle:"Sense and Sensitivity, DeSForM 2017",fullTitle:"Proceedings of the Conference on Design and Semantics of Form and Movement - Sense and Sensitivity, DeSForM 2017",slug:"proceedings-of-the-conference-on-design-and-semantics-of-form-and-movement-sense-and-sensitivity-desform-2017",publishedDate:"October 18th 2017",bookSignature:"Miguel Bruns Alonso and Elif Ozcan",coverURL:"https://cdn.intechopen.com/books/images_new/6456.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"156855",title:"Dr.",name:"Elif",middleName:null,surname:"Ozcan",slug:"elif-ozcan",fullName:"Elif Ozcan"}],productType:{id:"2",title:"Proceeding",chapterContentType:"conference paper",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11662",leadTitle:null,title:"Limnology - The Importance of Monitoring and Correlations of Lentic and Lotic Waters",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThe book aims to collect the state of the art of techniques and technologies for monitoring lentic and lotic environments so important for the ecological role they perform.
\r\n\r\n\tThe knowledge relating to the chemical, physical and biological characteristics of the still or slow-moving waters - the so-called "lentic environments": lakes, swamps, ponds - but also fresh and salty waters, are to be deepened. Contributions related to their interaction with lotic waters - streams, rivers - will also be well appreciated. All those elements useful to represent the quality of these environments will be considered and treated also in relation to the ecological role they play.
\r\n\r\n\tStudies based on observations made and aimed at forecasting transformations (understood as the evolution of environments over time) will be collected. We also want to collect contributions relating to the influence of the surrounding environment such as those due to human disturbance or even to causes of natural origin. In addition, also studies relating to the management of inland waters and related indicators to identify the more common problems of pollution. Finally, we also want to collect contributions relating to best practices (the most significant experiences, procedures, actions, or in any case those that have allowed the best results to be obtained in relation to the conservation of these environments) through intelligent, low-cost systems.
",isbn:"978-1-80356-537-8",printIsbn:"978-1-80356-536-1",pdfIsbn:"978-1-80356-538-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"f1043cf6b1daae7a7b527e1d162ca4a8",bookSignature:"Dr. Carmine Massarelli and Dr. Claudia Campanale",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11662.jpg",keywords:"Sampling Techniques, Water, Soil, Sediments, Ecological Networks, Ecosystem Health, Remote Sensing, Remote Environments, Temporary Environments, Geodatabase, Sensors and Cameras, Open-Source",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 10th 2022",dateEndSecondStepPublish:"May 10th 2022",dateEndThirdStepPublish:"July 9th 2022",dateEndFourthStepPublish:"September 27th 2022",dateEndFifthStepPublish:"November 26th 2022",remainingDaysToSecondStep:"9 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"With a Ph.D. from the University of Foggia in Italy, Dr. Massarelli is an environmental technologist and expert in the development of Smart Technologies for water management, environmental monitoring, and integration of spatial data.",coeditorOneBiosketch:"A pioneering researcher in monitoring emerging pollutants in environmental matrices and extreme environments, Dr. Camapanale received her Ph.D. degree at the University of Bari, Italy. Her multidisciplinary approach is based on analytical evidence integrated by a biological and ecological vision.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"315689",title:"Dr.",name:"Carmine",middleName:null,surname:"Massarelli",slug:"carmine-massarelli",fullName:"Carmine Massarelli",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002qpfU1QAI/Profile_Picture_1640002411379",biography:"Dr. Carmine Massarelli (Environmental technologist at Italian National Council of Research, Water Research Institute)is an expert in the development of Smart Technologies for water management and environmental monitoring, characterization and monitoring of contaminated and degraded sites, integration of spatial data such as standard methodologies, interoperability and data infrastructures.\r\nHe is also an expert in Geographic Information Systems, database administration, programming and IT-related roles, maintenance and creation of geographic data (accuracy and quality), use of scripting, and building cartographic output applying the principles of cartography using open-source IT systems for the processing, analysis, and integration of remote sensing data with airborne and satellite sensors for thematic purposes.",institutionString:"National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:{id:"315745",title:"Dr.",name:"Claudia",middleName:null,surname:"Campanale",slug:"claudia-campanale",fullName:"Claudia Campanale",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002qpiKlQAI/Profile_Picture_1640002388093",biography:"Dr. Claudia Campanale is a pioneering researcher in monitoring emerging pollutants in environmental matrices and extreme environments through a multidisciplinary approach and based on analytical evidence integrated by a biological and ecological vision. \r\nShe uses Py-GC-MS and micro FTIR techniques for purification and characterization methods. Her microplastic research is focused on identifying and quantifying persistent organic pollutants sorbed on microplastics to investigate the role of these contaminants of emerging concern as carriers of hazardous chemicals to marine environments.\r\nShe is an expert in analytical chemistry techniques such as HPLC-MS, GC-MS, ICP-MS to characterize and quantify pollutants (inorganic and organic) in environmental matrices (water, soil, sediment).\r\nHard work, dedication, and passion are the basis of research.",institutionString:"National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"10",title:"Earth and Planetary Sciences",slug:"earth-and-planetary-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"278926",firstName:"Ivana",lastName:"Barac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/278926/images/8058_n.jpg",email:"ivana.b@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Acute compartment syndrome (ACS) of the hand is rare, as compared to other areas of the human body, but the consequences are detrimental if treated suboptimally. Severe functional disability of the hand, due to muscles’ contractures, is the inevitable result of a neglected compartment syndrome. Diagnosis of this urgent situation is challenging and it is based mainly on the clinical examination [1, 2, 3].
In case there is any doubt towards the diagnosis of ACS or for insensate patients, intracompartmental pressure measurement is used to aid the evaluation [4]. Good knowledge of the special anatomy of the hand is necessary, in order to manage compartment syndrome appropriately. Disproportionate pain, severe swelling and a relevant mechanism should raise a strong suspicion of a compartment syndrome [5]. Once the diagnosis of an ACS is made, treatment should be implemented promptly. Intervention varies from simple actions, such as splitting a tight cast, to a surgical decompression [2]. Correct timing of fasciotomies is of paramount importance, in order to achieve a good functional outcome [6].
This chapter aims to present the current concepts regarding hand compartment syndrome. Special features of the hand compartments’ anatomy are reported. Pathophysiology is described briefly, as it is analyzed in extension in other parts of this book. Etiology, diagnosis, treatment and complications are mentioned as well, emphasizing towards the proper technique of fasciotomies.
Hand contains basically ten myofascial compartments: the adductor pollicis compartment, four dorsal interossei and three palmar interossei compartments, the thenar and the hypothenar compartment. The thenar compartment includes the Abductor Pollicis Brevis (AbPB), the Flexor Pollicis Brevis (FPB) and the Opponens Pollicis (OP) muscles. They are innervated by the recurrent motor branch of the median nerve, apart from the deep head of the FPB, which is innervated by the deep branch of the ulnar nerve [2]. The hypothenar compartment includes the Opponens Digiti Minimi (ODM), the Abductor Digiti Minimi (AbDM) and Flexor Digiti Minimi (FDM) muscles. They are all innervated by branches of the ulnar nerve (Figure 1). Although located basically in the wrist, the carpal tunnel is frequently mentioned as a compartment of the hand. Cleland and Grayson ligaments also compartmentalize digital space. All compartments of the hand along with their muscles and nerves are presented on the Table 1 [2, 4, 7]. It is highlighted here that the compartments of the hand contain predominantly motor nerves. Intracompartmental sensory nerves of the hand are only the digital nerves and the median nerve inside the carpal tunnel. This characteristic anatomy is reflected to the clinical image of the compartment syndrome of the hand [4, 5, 8].
Hand compartments cross sectional anatomy. (from: Reichman EF. Compartment syndrome of the hand: A little thought about diagnosis. Case rep Emerg med. 2016;2016 [
Compartment | Muscles | Nerves | Incision |
---|---|---|---|
Adductor Pollicis | Adductor Pollicis | Sensory: None Motor: Branches of the ulnar nerve | Dorsal over the second metacarpal (radial aspect) |
Interossei compartments | 4 dorsal interossei, 3 palmar interossei | Sensory: None Motor: Branches of the ulnar nerve | Two Dorsal incsions over the second and fourth metacarpal |
Thenar | AbPB, OP, FPB | Sensory: None Motor: Recurrent motor branch of the median nerve, apart from the deep head of the FBP (ulnar nerve) | Radial aspect of the first metacarpal |
Hypothenar | AbDM, FDM, ODM | Sensory: None Motor: Ulnar nerve | Ulnar aspect of the fifth metacarpal |
Carpal tunnel | None (FPL, 4 FDS, 4 FDP tendons/not muscles) | Sensory: Median nerve Motor: Recurrent motor branch of the median nerve | Midpalmar incision |
Digital | None (digital tendons/not muscles) | Sensory: digital nerves Motor: None | Lateral midaxial incision |
Compartments of the hand.
AbPB: abductor pollicis brevis, OP: opponens pollicis, FPB: flexor pollicis brevis, AbDM: abductor digiti minimi, FDM: flexor digiti minimi, ODM: opponens digiti minimi, FPL: flexor pollicis longus, FDS: flexor digitorum superficialis, FDP: flexor digitorum profoundis.
Several variations of the hand compartments have been described. Difelice et al. [7] found that in 52% of the hands, the thenar space is separated in two discrete compartments. In 76% of the hands the hypothenar demonstrated at least two compartments. The second, third and fourth interossei group demonstrated different dorsal and volar compartment in the 48%, 67% and 38% of the hands respectively. The fasciotomies used for the treatment of hand ACS are designed based on this anatomic model. Whether further subcompartmentalization of the thenar and hypothenar area has any clinical significance is controversial. Gyuton et al. [9] found through a cadaveric study that fascia between dorsal and volar interrossei muscles subsides at pressures as low as 15 mmHg, putting its clinical relevance in question.
The pathophysiology of acute compartment syndrome is based on Matsen’s arteriovenous gradient theory. According to this model, interstitial edema increases the local venous pressure (Pv). Local blood flow (LBF) equals to arteriovenous pressure difference (Pa - Pv), divided by vascular resistance (R). Thus, the increase of the local venous pressure decreases local blood flow. Tissue ischemia increases small vessels permeability as well as extravascular osmolality, leading to a further fluid extravasation and subsequent more interstitial edema. Viscious cycle is continued through the former mechanism. Local and systemic inflammatory response is exacerbated by the release of cytokines, as a result of impaired tissue blood supply [4, 10].
Muscle damage due to compartment syndrome occurs prior to nerve impairment and it is reversible for the first 4 hours. The time frame after which muscle necrosis is occurred is still controversial, with a reported range among studies between 8 to 12 hours [2, 4, 11]. Experimental studies of canine model showed permanent tissue necrosis and nerve conduction arrest with interstitial pressures of more than 40 mmHg for at least 8 hours [12].
Intracompartmental pressure increases by either extrinsic or intrinsic causes or combination of both. Tight dressings or casts represent extrinsic factors, via external pressure application to the compartments of the hand [13].
Intrinsic causes of hand compartment syndrome are:
Trauma: fractures, soft tissue injury, crush syndrome (Figure 2),
Burns,
High pressure injection injuries (Figure 3),
Iatrogenic: arterial injury, reperfusion surgery, intravenous material extravasation (Figure 4),
Infection: abscess, septic tenosynovitis, necrotizing fasciitis,
Bites (snake, insect),
Anticoagulation medications,
Hand crush syndrome. Compartment syndrome due to extensive soft tissue injury and concomitant third and fourth metacarpal fractures, after prolonged compression of the hand by a heavy object.
Index finger compartment syndrome (delayed presentation), due to high pressure injection injury, complicated with septic tenosynovitis.
Hand compartment syndrome due to extravasation contrast material. Hand is sitting in intrinsic minus position. Excessive swelling and skin blisters are noticed (from: Stavrakakis IM et al. hand compartment syndrome as a result of intravenous contrast extravasation. Oxf med case rep. 2018;2018(12):omy098 [
Patient’s history, clinical image and physical examination are the keystones for the diagnosis of acute compartment syndrome [2]. Localized swelling and disproportionate pain, unresponsive to analgesics, along with a relative mechanism of injury should raise the suspicion of ACS [2, 4, 13]. As mentioned in the anatomy section, sensory nerves of the hand are located outside the compartments, with the exception of the median and digital nerves. Hence, tingling and paresthesia are not always present, unless the carpal tunnel or digits are involved [4, 5].
Serial clinical examination is of paramount importance, in order to detect ACS early. On inspection, severe swelling is noticed. Blisters might also be visible. The hand is sitting in intrinsic minus position, i.e. the metacarpophalangeal joints (MCPJs) are in extension and the interphalangeal joints (IPJs) are in slight flexion (Figure 4) [1, 4, 8]. Digital palpation reveals great tension of the hand. Pain on passive stretching of the intracompartmental muscles is an early sign of impaired blood perfusion. Specifically for the hand, each compartment should be stretched individually. The interossei compartments are stretched by passively abducting and adducting the digits and at the same time keeping the MCPJs in flexion and the IPJs in extension (bring the hand from the intrinsic minus position to the intrinsic plus position - “intrinsic stretch test”). The lumbricals are stretched by passively extending the MCPJ and flexing the proximal IPJ. The adductor pollicis is checked by passively abducting the thumb. Passive adduction of the thumb is used to test the thenar compartment and finally the hypothenar compartment is evaluated by passive adduction and extension of the small finger [2, 13]. In case the five P’s of tissue ischemia are already present (pain, pallor, pulselessness, paresthesia and paralysis), then the diagnosis is considered delayed and irreversible muscle damage is very likely. Clinical examination has high specificity as well as high negative predictive value, meaning that it can exclude ACS better than confirming it [15].
In case there is any doubt regarding the diagnosis of ACS after clinical examination, or for unconscious patients, more subjective tools for evaluation should be used. Intracompartmental pressure measurement (ICP) is considered to be the main adjunct to the diagnosis. It is generally accepted that a pressure difference (ΔP) between the diastolic blood pressure (Pd) and the compartmental pressure (Pc) less than 30 mmHg necessitates surgical decompression (ΔP = Pd – Pc < 30 mmHg). This difference is more reliable than an absolute intracompartmental pressure of more than 30 mmHg [15, 16]. Several modalities of measuring the pressure of the compartments have been described, such as the infusion Whiteside apparatus, the slit catheter technique and the handheld intracompartmental pressure monitoring [13]. Straight catheters have the least accuracy as compared to the slit catheter and side port needle. It is also reported that the Whiteside apparatus overestimates the intracompartmental pressure, which can potentially lead to an unnecessary fasciotomy [2, 15]. Current trend is towards a continuous pressure measurement, which is probably more reliable than a single one, as the latter approach is associated with a high false positive rate [17, 18]. As there are cases of silent compartment syndrome described in the literature, i.e. severe swelling with no excruciating pain, whenever there is a slight suspicion of ACS, ICP measurement should be performed [18].
Regardless of the apparatus used, it is crucial that a correct technique of pressure measurement is performed. General guidelines include perpendicular insertion of the needle on the skin [2], within 5 cm of the fracture site, but not in direct cοntact with the fracture [15, 16]. Particularly for the hand, each compartment’s pressure should be measured individually. The hand should rest at the level of the heart. For the thenar and hypothenar compartment the needle is inserted at the border of glabrous and nonglabrous skin. The adductor pollicis muscle is entered ulnarly to the first metacarpal. The interossei compartments are entered between the index-long, long-ring and ring-small finger metacarpal, 1 cm proximal to the metacarpal heads, superficial at first for the dorsal interrosei muscle and then 0,5 to 1 cm deeper for the volar interrosei. Needle insertion over the midpalmar lesion is also used for carpal tunnel pressure measurement (Figure 5) [2, 4].
Portals of intracompartmental pressure measurement of the hand.
Given the fact that clinical examination and intracompartmental pressure measurements have their own limitations, recent research is directed towards hemodynamic and metabolic parameters in an effort to achieve a more accurate diagnosis of ACS. These parameters include: a. Monitoring local oxygenation (via intramuscular partial oxygen pressure, oxygen saturation measurement or near infrared spectroscopy), b. monitoring local perfusion (via pulsed phased - locked loop ultrasound, photoplethysmography, laser Doppler flowmetry and scintigraphy), c. local metabolic analysis (intramuscular glucose monitoring, intramuscular pH monitoring) and d. serum biomarkers (white blood cell count, erythrocyte sedimentation rate, C - reative protein and creatinine kinase). However there is still no evidence of superiority over intracompartmental pressure measurement and there is still long way to go until they can be used safely in clinical practise [16].
Chronic exertional compartment syndrome is defined as a muscle dysfunction because of ICP rising due to excessive activity. Only few cases of chronic compartment syndrome located in the hand have been described in the literature and the most commonly affected compartments are the adductor pollicis, the first dorsal interosseous, the thenar and hypothenar compartments [19].
Muscles can tolerate a condition of reduced vascular supply for a time period of no more than 6 to 8 hours. Regarding the limbs there is evidence supporting that the time threshold after which necrosis occurs, is 8 hours [6]. There are though case series reporting a good outcome from fasciotomies which were performed within 12 hours [11]. Impeded compartment syndrome should be recognized early, in order to avoid loss of limb function. Once the diagnosis is made, every effort should be done to decrease the intracompartmental pressure. Conservative treatment includes simple releasing of dressings or splitting a tight cast. The hand should be elevated at the level of the heart, but not above it, in order to preserve the arteriovenous gradient. Oxygen supplementation, intravenous hydration and mannitol adminstration are additional adjuvants to operative treatment [10]. Surgical decompression through fasciotomies is the mainstay of treatment, if acute compartment syndrome is suspected [3, 13].
Faciotomies of the hand are performed through four skin incision. a. Two dorsal incisions over the second and the fourth metacarpal are recommended for decompression of the interossei’s and adductor pollicis’ compartments. Blunt dissection is carried out deeper through the fascia between the 1st dorsal interossei and the adductor pollicis and between the dorsal and palmar interossei muscles. b. One incision radial to the first metacarpal between the glabrous and nonglabrous skin for the thenar decompression. c. One incision ulnar to the fifth metacarpal for the hypothenar release. d. Carpal tunnel, although not a true compartment, it should be released through the traditional midpalmar longitudinal incision (Figure 6) [2, 3, 4]. e. If digits are involved, Cleland and Grayson ligaments are released through midaxial lateral incision, 4 cm long centered over the proximal interphallangeal joint (PIPJ), taking care of the neurovascular bundle. Dominant sensory nerves should be avoided, indicating a radial incision for the thumb and the small finger and ulnar incision for the index, middle and ring fingers [2, 13]. In delayed cases though, especially if they are complicated with infection, a volar Brunner incision is suggested (Figure 7). After the procedure, the wounds are generally left opened and the hand is splinted in a safe position of function. In case of severe skin damage (burns), which precludes the splint application, the metacarpophallangeal (MTPJ) joints are pinned in flexion and the PIPJs in extension (intrinsic plus position) [2, 4]. The wounds are inspected every 2 to 3 days and a second debridement is suggested, if signs of infection or necrosis are identified. As soon as edema subsides and circulation is restored, the wounds can either be closed primarily or they can receive a split thickness graft. Priority is given to the coverage of tendons and nerves. Physiotherapy is initiated as early as possible [2, 10]. Proposed treatment algorithm of acute hand compartment syndrome is presented on the Table 2.
Hand fasciotomies. Two dorsal incisions over the second and fourth metacarpal are used to decompress the adductor pollicis and interossei compartments. One incision radial and palmar to the first metacarpal for the thenar compartment. One incision ulnar to the fifth metacarpal for the hypothenar compartment. One midpalmar incision for carpal tunnel release. (from: Stavrakakis IM et al. hand compartment syndrome as a result of intravenous contrast extravasation. Oxf med case rep. 2018;2018(12):omy098 [
Surgical decompression of index finger’s compartment syndrome, due to high pressure injection injury, complicated with septic tenosynovitis of the patient of the
Algorithm of hand ACS management. ΔP: pressure difference, BPd: diastolic blood pressure, ICP: intracompartmental pressure.
A good functional outcome can be expected after ACS, if surgical release is performed early. In case of a neglected compartment syndrome, it is widely accepted that delayed fasciotomies (more than 24 hours since initial presentation), are no beneficial to the patient, and they actually carry a risk of serious complications, such as infection, septicemia and amputation. Fasciotomies are also associated with stiffness, pain, cosmetic problems, nerve injury and chronic venous insufficiency [15, 16]. If the hand compartment syndrome is not managed properly, permanent loss of function is inevitable. Muscle contractures are developed and the hand sits in intrinsic minus position, with the MCPJs in extension and the PIPJs in flexion. Intrinsic plus contraction though is possible, if lumbricals muscles are predominantly affected. The first web space is contracted as well [2, 20].
Hand ischaemic contractures includes three groups. Group 1: All interrosei and thenar muscles are involved (typical Volkmann contracture). Group 2: thenar or interossei muscles are involved. Deformity concerns the thumb or the fingers. Group 3: one or more fingers are affected. Established intrinsic muscles contractures are treated with appropriate operative releases. The first web space is released and the tendons of the interossei muscles are released at the level of the metacarpal necks. Fibrotic tissue is removed. Detailed description of these operations are beyond the scope of this chapter [20, 21].
Hand compartment syndrome is an urgent condition which demands early recognition and treatment, otherwise it results to a permanent loss of function. Several controversies regarding diagnosis and management still exist in the contemporary literature. Future research should target on how a more accurate and early diagnosis can be achieved and the time frame beyond which fasciotomy is not beneficial to the patient. Fasciotomies of the hand are the cornerstone of treatment, and if they are performed early, they guarantee a good functional outcome. The surgeon should demonstrate a low threshold towards surgical release if compartment syndrome is suspected. Knowledge of the special anatomical features of the hand is necessary, in order for the physician to offer to the patient a sufficient treatment.
The immune checkpoint cell surface proteins like programmed death-ligand 1 (PD-L1), programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CLTA-4) represent important pathways of cancer immune evasion. Immune checkpoint inhibitors (ICIs) are identified as potent key players in providing therapeutic benefit in a range of solid cancers as well as in a subgroup of hematological malignancies. However, the response rates to these immune-modulatory molecules are sub-optimal and predictive biomarkers allowing to select for responsive cancer patients are lacking. The study of the dynamics of the immune system and of the tumors under immune checkpoint blockade has greatly improved knowledge on the mechanisms of action of ICIs, allowing the identification of a number of novel candidate dynamic biomarkers predictive of ICI treatment response meriting further exploration in validation trials.
Tumor biopsy of tissue from primary or metastatic site is a major mainstay of treatment decisions as the molecular features and histology can reveal the complex cancer landscape. However, tissue biopsy has various limitations such as high heterogeneity, invasive nature of tissue sampling and skilled expertise/techniques required for analyzing and reporting making it a difficult specimen especially for treatment monitoring purpose [1]. Therefore, emphasis on utility of liquid biopsies as prognostic and predictive soluble biomarkers especially in cancer immunotherapy is gaining a lot of attention. The main advantages of blood-based specimens are that these are easy to extract and analyze with limited skilled expertise or techniques. Furthermore, biomarkers in the blood can represent dynamic alterations of the evolving cancer in response to treatment and can help in longitudinal monitoring. In addition to this, these can also be utilized for risk prediction of immune-related adverse events (irAE) which is an important and critical monitoring parameter [2].
In this chapter, we attempt to discuss in relevant details the purpose and role of immune modulatory molecules and of the different serum soluble biomarkers in various human and animal models with an aim to show insight on to their mechanisms of action and resistance, thus conveying information predictive of therapeutic response.
PD-1 is an important immune checkpoint expressed on activated T cells and known to regulate their functional activity. By binding to its ligands, PD-L1 or PD-L2, which are expressed on tumor cells and a variety of immune cells [3], PD-1 is able to inhibit downstream signaling of the T cells receptor (TCR) [4]. Hence, ICIs targeting the PD-1/PD-L1 axis are developed to modulate this negative feedback loop and restore T cells activity. Indeed, response to anti PD-1 drugs is characterized by the upregulation of genes associated with activation of effector T cells [5, 6, 7]. Moreover, the blocking of PD-1 has been linked to an expansion of CD8+ effector T cells within the tumor. Interestingly, this CD8+ T cells expansion was found to follow a specific gradient that decreases from the margins of the tumor into its center [5, 8, 9]. In addition, the noted expansion in CD8+ T cells was also found to coincide with an increase in CD8+ T cell clonality in the tumor microenvironment (TME) [8]. This is clearly indicative of the fact that CD8+ T cells expanded in the tumor upon blocking PD-1 are indeed tumor-reactive and stand as a consistent correlate of treatment benefit.
Another interesting aspect is the heterogeneity noted in the tumor infiltrating CD8+ T cells depending on their different phenotypes and functional states. One such subset is known to express high levels of PD-1 and co-express the following immune modulating proteins: the T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), the lymphocyte-activation gene-3 (LAG-3), the T cell immunoreceptor with Ig and ITIM domains (TIGIT) and CD39, which are all linked to T cells exhaustion [Tex] [10, 11]. Exhausted CD8+ T cells represent a dysfunctional cell state that develops due to chronic antigen exposition. However, exhausted CD8+ T cells in the TME have a higher potential for tumor antigens recognition and a higher clonal distribution than any other CD8+ T cells subset in the TME [12, 13]. Further, the Tex phenotype also defines an impaired capacity of producing effector cytokines such as IL-2, TNF-α and IFN-γ [12]. The inhibition of the PD-1/PD-L1 axis was initially suggested to reinvigorate the anti-tumoral immune response by reversing the state of these terminally exhausted tumor-reactive T cells. However, this function is challenged by the fact that this state of terminal exhaustion is characterized by a distinct epigenetic profile which limits its reversibility [14, 15, 16]. In support of this, recent evidence has shown that anti-PD-1 therapy can engage progenitor Tex subsets that co-express PD-1 and the lineage-determining transcription factor 1 (tcf-1), instead of terminally exhausted subsets [17, 18]. Similarly, certain studies on animal models also show that blocking PD-1 leads to the engaging of PD-1+/tcf-1+/CD8+ T cells inducing their self-regeneration or differentiation into effector tcf-1− cells that eventually develop functional states of exhaustion [19, 20]. Interestingly, it has been shown that Tex subsets might promote the recruitment of other immune cells into the TME and consequently support the anti-tumoral immune response [12]. In addition, anti-PD-1 treatment was shown to engage memory-precursor like CD8+ T cell subsets, leading to their accumulation in the TME [21] and to a subsequent enhanced cytotoxicity towards cancer cells [22]. The on-treatment increase in memory CD8+ T cells was suggested to correlate with response to anti-PD-1 therapy in both preclinical models and clinical studies [9, 23].
blocking of PD-1 is known to cause an increase in the proliferation of CD8+ T cells very early during the course of treatment [24, 25]. This proliferative response can be observed in the periphery, where it peaks as early as 7 days following the introduction of anti-PD-1 therapy [24, 26]. In one of our studies on a gastric cancer patient undergoing anti-PD-1 therapy, we observed that the frequency of peripheral cytotoxic T cells CD8+/CD107+ specific for the NY-ESO-1 cancer testis antigen closely correlated with the patient clinical outcome [27]. Another study has reported that the proliferative response of peripheral CD8+/PD-1+ T cells could be predictive of durable clinical benefit in patients with solid tumors receiving anti-PD-1 therapy [26]. Thus, these studies support the fact that the systemic CD8+ effector T cells response plays a key role in tumor management under anti-PD-1 treatment and suggest their importance as a predictive biomarker of response to PD-1 blockade. In Figure 1 we illustrate the dynamics of intra-tumoral effector T cells that are shown to correlate with anti-PD-1 treatment outcome.
Effect of immune checkpoint inhibition on effector T cells.
When T cells are engaged in an active immune response, the expression of the surface protein CTLA-4, a homolog of CD28 with high affinity to B7–1 and 2 ligands, will be upregulated. CTLA-4: B7–1/2 binding acts as a co-inhibitor of the TCR signal [28]. Thus, the primary role of the CTLA-4 checkpoint is to negatively regulate T cell activation especially during the priming phase upon binding to the B7 ligands expressed by antigen presenting cells (APC). In accordance with this, a major aspect of anti-CTLA-4 therapy is its ability to reinvigorate T cell proliferation and activation. Indeed, the effects of anti-CTLA-4 therapy are evident in several studies on mouse models. For example, CTLA-4 deficient mice were found to display rapidly lethal lymphoproliferation [29]. On the other hand, anti-CTLA-4 therapy led to the expansion of both CD4+ and CD8+ effector T cells in the tumor [30]. Although both T cells subsets are necessary in mediating tumor immune control [31], the increase in CD4+ T cells appeared to be of a greater importance than that of CD8+ T cells [30].
In few studies, CD8+ T cells expansion has been shown to translate into an effective response to immune checkpoint blockade therapy [7, 32]. However, a study on advanced melanoma patients undergoing treatment with the anti-CTLA-4 antibody tremelimumab, reports no association between the expansion of CD8+ effector T cells and successful anti-tumor response [33] despite similar CD8+ T cells activation profiles observed in lesions that responded to anti-CTLA-4 therapy and those that did not respond to this therapy [33]. These findings, possibly explained by the action of immunosuppressive elements in the TME, highlight that adequate CD8+ effector T cells function is necessary but not sufficient for complete suppression of tumor growth under immunotherapy [34]. Another interesting effect noted upon CTLA-4 blockade is the enhanced expansion of memory CD8+ T cell [35] which will help to promote long-term tumor control post-therapy. Moreover, this expansion of memory CD8+ T cells is considered as an indicator of treatment benefit in a few clinical studies [36, 37].
CD4+ T cells expanding in the tumors of mouse models under anti-CTLA-4 treatment are found to exhibit a Th1-like effector phenotype with a noticeable expression of ICOS, a known marker of follicular T helper cells [30]. Interestingly, this phenotype of CD4+ T cell was observed in mice after genetic knock-down of negative co-inhibitory molecules such as CTLA-4 [38]. Moreover, ICOS-deficient mice showed an impaired anti-tumor T cell response to anti-CTLA-4 therapy [39]. In addition, a tumor microenvironment that is rich in CD4+ Th1 effector T cells infiltration was shown to be critical to develop response to anti-CTLA-4 therapy in castration resistant prostate cancer [40]. Furthermore, a higher expression of Th1 associated genes was observed in melanoma tumors of patients responding to ipilimumab compared to non-responders, supporting the functional relevance of a Th1- response in CTLA-4 inhibitor treatment benefit [41]. Interestingly, while the presence of CD4+ Th1 cells is predictive of response to anti-CTLA-4, a peripheral blood profile rich in Th17 cells was reported to be rather predictive of autoimmune toxicity under anti-CTLA-4 therapy [42]. Moreover, several clinical studies have reported an increase of ICOS+/CD4+ T cells in the tumor and peripheral blood of patients treated with anti-CTLA-4 [43, 44, 45, 46, 47, 48, 49]. Additionally, an increased proliferation of both peripheral CD4+ and CD8+ T cells is observed as early as 3 weeks after the first dose of anti-CTLA-4 treatment [50, 51, 52]. Such a response may partly be due to the bulk expansion in the periphery of specific T cells against known tumor antigens in anti-CTLA-4 treated patients [53, 54, 55]. Of note, an increase in absolute lymphocyte count (ALC) was shown to correlate with enhanced overall survival and response to ipilimumab in several studies [56, 57, 58, 59].
The distribution of the TCR repertoire may be described by different metrics. For example, TCR richness invoke the number of unique T cell clones while its evenness refers to the frequency of their distribution. Some studies reported an increase in the richness of the TCR repertoire under anti-CTLA-4 therapy [60, 61]. On the contrary, the evenness of the TCR repertoire under anti-CTLA-4 therapy is comparatively less impacted [60, 62, 63]. This increase in richness of the TCR repertoire under the effect of anti-CTLA-4 therapy is indicative of unleashed T-cell priming possibly allowing for enhanced tumor immune control through the promotion of new anti-tumor T cells responses [64]. However, in a study on metastatic melanoma and prostate cancer, it has been shown that enhanced clinical outcomes under CTLA-4 blockade are associated with less clonotype loss and on-treatment stability of existing high-frequency TCR clonotypes [61]. These findings suggest that response to anti-CTLA-4 treatment occurs despite the remodeling of the peripheral TCR repertoire rather than as a result of it. In Figure 1 we illustrate the dynamics of intra-tumoral effector T cells that are shown to correlate with anti-CTLA-4 treatment outcome.
Regulatory T cells (Tregs), an immunosuppressive subset of T cells, are known to be closely involved in the regulation of the immune responses to cancer [65, 66, 67]. The tumor-infiltrating subsets of Tregs are characterized by their high surface expression of PD-1 [68, 69, 70] and the PD-1/PD-L1 axis is known to modulate Tregs function via cell-intrinsic pathways. For example, the blocking of PD-1 in animal models reduced the immunosuppressive function of Tregs and declined their expression in the TME [71, 72]. Moreover, studies on murine models have shown that PD-1/PD-L1 pathway mediates the conversion of CD4+ Th1 effector T cells into induced Foxp3+ Tregs (iTregs) [73, 74]. Conversely, certain preclinical studies show that anti-PD-1 therapy is associated with an increase rather than a decrease in Tregs infiltration in the TME [24, 75]. The proliferation of Tregs under anti-PD-1 therapy could be explained by a treatment-induced reversal of the exhausted state of PD-1Hi in the TME [76, 77]. The expansion of Tregs upon blockade of PD-1/PD-L1 axis has been observed at the tumor level as well as in the peripheral blood. One particular study showed that patients with gastric adenocarcinoma responding to anti-PD-1 displayed an on-treatment decrease in intra-tumoral Tregs, whereas non-responders had post-treatment tumor biopsies exhibiting an infiltration of highly proliferative effector Tregs (Foxp-3hi/CD45− CD4+) [78]. This suggests that on-treatment changes in intra-tumoral T reg infiltration could be a relevant dynamic parameter to account for in predicting anti-PD-1/PD-L1 treatment response. The predictive insight provided by the on-treatment dynamics of circulating Tregs under PD-1/PD-L1 blockade has also been investigated. In a study conducted on melanoma patients exposed to nivolumab, an expansion of circulating Tregs under therapy was shown to positively correlate with treatment benefit [79]. These observations suggest that Tregs dynamics under anti-Pd-1 therapy may contribute predictive insight into treatment benefit when monitored both in the TME and in the periphery.
Interestingly, another immunosuppressive CD4+ T cell subset found to be regulated by anti-PD-1 therapy has been recently identified. These cells known as 4PD-1Hi express high levels of PD-1 while lacking Foxp-3 expression [80]. Also, these 4PD-1Hi cells were shown to accumulate in the tumor and to inhibit T cells effector function. Therefore, 4PD1Hi cells are considered as a marker of tumor progression. Anti-PD-1 treatment was shown to reduce the proliferation of 4PD-1Hi cells, whereas anti-CTLA-4 treatment showed an exactly opposite effect on these cells. In line with this interesting observation, the downregulation of 4PD-1Hi cells under anti-PD-1 treatment was further documented as a biomarker of treatment response under anti-PD-1 pembrolizumab antibody in a melanoma patient cohort. In addition, some preclinical studies support the fact that anti-PD-1 therapy can induce the expansion of specific CD8+ T cells immunosuppressive subsets [30]. Indeed, a recent study showed that PD-1 blockade in sub-optimally primed T cell conditions supported the proliferation of dysfunctional immunosuppressive CD8+ T cells expressing PD-1 and high levels of CD38 and this effect was associated with treatment failure and tumor resistance in cancer patients [81]. The dynamics of these T cell subsets under treatment may therefore provide valuable predictive information, pending the validation of these candidate biomarkers in larger scale studies. The proposed mechanisms of anti-PD-1 action on Tregs subsets are summarized in Figure 2.
Effect of immune checkpoint inhibition on immune suppressive T cells.
Several observations suggest the action of anti-CTLA-4 on Tregs to be key in mediating treatment effects on the tumor. Indeed, some studies involving murine tumor models reported anti-CTLA-4 treatment to simultaneously induce an increased expansion of peripheral Tregs and a decreased expansion of intra-tumoral Tregs [82, 83, 84]. This dual action of anti-CTLA-4 on Tregs proliferation could be due to the higher expression of CTLA-4 on exhausted tumor-infiltrating Tregs, where their decline under treatment is suggested to be mediated by a distinct Fc-gamma receptor dependent mechanism of anti-body-mediated cell-mediated cytotoxicity (ADCC) [85]. This feature was suggested to play a key role in tumor control under CTLA-4 blockade since it has been demonstrated that an on-treatment increase in intra-tumoral Teffs: Tregs ratio stands as the correlate of an optimal treatment response [82, 83, 86, 87]. Moreover, in another study in different murine models, the therapeutic activity of ipilimumab was found to essentially rely on this Fc-dependent Tregs depletion and not on the checkpoint inhibitor action of the drug [88]. However, there is noticeable inconsistencies in observed Tregs dynamics under CTLA-4 blockade in humans. Indeed, certain studies document a remarkable expansion of Tregs in the peripheral blood of patients treated with anti-CTLA-4 [51, 89, 90, 91], while other studies report a declined or unchanging frequency of peripheral Tregs during this therapy [37, 49, 92]. In addition, the ability of the peripheral Tregs dynamics to predict a treatment response to anti-CTLA-4 treatment is also quite unclear. For example, their change in frequency is found to correlate both negatively [93] and positively [90] with anti-CTLA-4 treatment benefit. Yet some other studies show no correlation at all between the change in Tregs frequency and a treatment response to anti-CTLA-4 therapy [56, 94, 95]. Observations of the intra-tumoral Tregs dynamics under anti-CTLA-4 is also inconclusive. A contradictory effect is put forth by a cohort on regionally advanced melanoma patients treated with 2 neoadjuvant doses of ipilimumab. This study reported a reversed association between the change in intra-tumoral Tregs frequency and treatment benefit [90]. Similarly, another study reported a marked decline in intra-tumoral Tregs levels in melanoma patients responding to ipilimumab compared to non-responding ones [96]. On the contrary, two other studies report increasing frequencies of Tregs in biopsies of patients undergoing anti-CTLA-4 therapy [13, 32]. It is interesting to note that the accumulation of Tregs within the tumors upon CTLA-4 blockade may be induced by a feedback loop triggered by a successful cytotoxic T cell response [97]. This may account for the positive correlation between the intra-tumoral levels of Tregs and patient long-term survival as reported by some studies involving solid tumors [98, 99]. These observations nonetheless suggest that Tregs dynamics under CTLA-4 treatment, in the TME and possibly in the periphery, should be accounted for when monitoring for treatment effects. The depletion of intra-tumoral Tregs under CTLA-4 blockade is illustrated in Figure 2.
Monocytes, macrophages and dendritic cells are involved in antigen presentation and T cells priming and thereby serve as a bridge between the innate and adaptive immune response. However, chronic inflammation arising due to cancer disturbs the myeloid cell line maturation process, leading to the generation of myeloid derived suppressor cells [MDSCs] and tumor-associated macrophages [TAMs], that are both suppressors of the anti-tumor immune response [100]. These tumor associated monocytes and macrophages are known to display a wide variety of phenotypes with both pro-inflammatory [M1] and immunosuppressive [M2] functions [101]. Likewise, several studies on animal models have found that treatment with ICIs has the ability of bringing about a spectacular transformation of the intra-tumoral myeloid cell compartment from an immunosuppressive configuration to a more pro-inflammatory one [102, 103]. It has been suggested that the increased INF-γ secretion by renewed T cells would possibly indirectly mediate this myeloid cell reprogramming in the TME under immune checkpoint therapy [102]. Also, it was observed that dual PD-1 and CTLA-4 blockade induces an increase in intra-tumoral pro-inflammatory macrophages, as shown in animal models [104]. In addition, potential direct mechanisms of regulation of MDSCs by anti-PD-1 or anti-CTLA-4 treatment were also identified. As an example, an induced expression of CTLA-4 on monocyte-derived dendritic cells [mDCs] acts as a negative regulator of mDCs-associated cytokine secretion and antigen-specific CD4+ T cell proliferation [105]. Moreover, subsets of intra-tumoral MDSCs that express PD-1 and CTLA-4 are found to display decreased arginase 1 expression and activity upon anti-CTLA-4 or anti-PD-1 treatment in mice [106]. In murine models, it has been shown that arginase 1 impairs T cells functions and contributes to immune evasion [107]. Furthermore, it has been recently reported that anti-PD-1 therapy was able to prevent the block in myeloid cell lineage maturation, thereby allowing the myeloid precursors to maturate into effector macrophages and dendritic cells contributing favorably to the anti-tumoral immune response [108].
A decline in circulating MDSCs under anti-CTLA-4 is found to correlate with patient outcome in several studies [37, 90, 109, 110], although this association is not universally reported [111]. Moreover, these studies showed discordant observations regarding the dynamics and predictive value of the major MDSCs subsets (monocytic MDSCs (mo-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) subsets) [112]. In addition, several studies showed that anti-PD-1 treatment had no effect on the level of circulating mo-MDSC and PMN-MDSC subsets [9, 113, 114]. Yet a particular study revealed a prominent restructuration of the myeloid compartment after initiation of anti-PD-1 therapy in metastatic melanoma patients when studied under the lens of high dimensional single cell analysis platforms [113]. Therefore, the ability to monitor the evolution of myeloid cells under immune checkpoint blockade appears to be of great predictive value, considering the important role that this cell compartment possibly plays in the modulation of the anti-tumoral immune response by either promoting or preventing the effector T cells response observed upon these therapies. One example of the described mechanisms of anti-PD-1 and anti-CTLA-4 effect on myeloid cells compartment is illustrated in Figure 3.
Effect of PD-1 and CTLA-4 blockade on myeloid cells.
In the subsections below, we will focus on blood-based candidate biomarkers that can be utilized as predictive or prognostic markers in cancer immunotherapy.
Changes in the blood cell counts and their ratios including neutrophils, lymphocytes, neutrophil to lymphocyte ratio as well as C-Reactive Protein (CRP) and Lactate Dehydrogenase (LDH) have been reported as prognostic/predictive outcome markers for immunotherapy [2]. Several studies have shown that low neutrophils and high lymphocytes are associated with overall survival (OS) in cancer patients [58, 115, 116]. For example, melanoma patients on nivolumab treatment having absolute lymphocyte counts of >1000/μL and absolute neutrophil count of <4000/μL were observed to have better overall survival [115]. On the other hand, pre-treatment neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR) can also serve as an index of the systemic inflammatory response and therefore considered as useful indicators of response in immunotherapy. Pre-treatment NLR/dNLR levels and survival association studies in advanced cancers including melanoma, non-small-cell lung cancer (NSCLC) and genitourinary have reported that high pre-treatment NLR and dNLR levels are associated with poor progression free survival (PFS)/OS with increased risks of death in immunotherapy treated patients indicating their usefulness as predictive and prognostic biomarkers [117, 118, 119, 120].
CRP is an inflammatory marker that induces the expression of acute-phase proteins such as neutrophils and has been correlated with poor prognosis in several cancers [121, 122]. With regards to immunotherapy, post treatment increased CRP levels have been associated with inflammation, disease progression and in some cases immune-related adverse events. On the other hand, low CRP levels post immunotherapies have been associated with better antitumor response/survival [93, 123].
LDH is a final enzyme in the glycolysis pathway that catalyzes the interconversion of pyruvate and lactate. In cancers, high levels of LDH leads to increased utilization of glycolysis as their energy requirement in the microenvironment [124]. Studies have confirmed that LDH is a significant negative prognostic factor for immunotherapy treated stage 4 melanoma patients [125]. Elevated baseline LDH in melanoma and lung cancer patients treated with pembrolizumab/nivolumab is associated with poor OS and higher risk of death [126, 127, 128]. Similar results have been reported for advanced esophageal squamous cell carcinoma patients treated with the anti-PD-1 immune checkpoint inhibitor camrelizumab where elevated LDH levels were found to correlate with poor OS [129].
The fact that blood cell counts/ratios, CRP and LDH tests are performed as part of a routine diagnosis and also are highly assessable/measurable at various treatment timelines in patients making them attractive dynamic biomarkers.
Soluble forms of immune checkpoints (sICs) are shed in the plasma/serum and have been associated with modulation of the immune system by affecting the binding capacity of immunotherapeutic drugs and thus influencing the efficiency of immune system. Studies have demonstrated that sICs can serve as markers for prognosis, response to treatment and overall response rate (ORR) in immunotherapy treated patients [130]. In addition to this, these markers can also be important for prediction of immune related adverse events which is an area poorly explored with respect to these biomarkers. Here, in this sub-section, we will discuss sICs evidenced in literature as prognostic and predictive markers in ICIs treatment.
sPD-1 has been documented to inhibit all three PD-L1/PD-1 interactions: PD-L1/CD80, PD-L1/PD-1, and PDL2/PD-1 [131]. Researchers have demonstrated that expressed sPD-1 blocks PD-L1/PD-1 interactions that can lead to inhibition of tumor growth via various mechanisms including blockade of PD-L1 on tumor cells, upregulation of CD8+ T cells, reduction in the expression of IL-10, increased production of inducible nitric oxide synthase, TNF-α and IFN-γ and enhancement of the immune response through interaction with immune cells [132, 133, 134]. sPD-1 has been reported as a modulator of immune response during ICIs treatment in serum of cancer patients. A study on 22 NSCLC patients observed that sPD-1 decreased significantly in clinically responding patients during Nivolumab treatment. In addition to this, patients with performance status of 0 had a decreased sPD-1 during treatment and these patients were found to have better immune fitness with low levels of immunosuppression [135]. Similarly, a study on 177 unresectable metastatic melanoma patients treated with anti-PD-1 showed interesting results. High pre-treatment serum concentrations of PD-1 and PD-L1 were correlated with poor prognosis and survival. The authors postulated that circulating serum PD-1 molecules might be directly targeted by therapeutic anti-PD-1 antibodies and this interaction might impair the effectiveness of anti-PD-1 therapy via neutralization. It is possible that this is a tumor escape mechanism that facilitates poor outcome. Thus, quantification of circulating PD-1 and PD-L1 molecules can translate into prognostic and predictive factors in immunotherapy treated patients [136].
sPD-L1 is produced by tumor cells/activated mature DCs and is known to have structural similarities to mPD-L1 [137]. It has been postulated that sPD-L1 has the capability to exert a competing effect against anti-PD-L1 drugs. A study by
sPD-L2 is a splice variant protein product that lacks transmembrane domain and is secreted into the blood. Distinct expression pattern of PD-L2 variants in leukocytes of distinct cellular status have been observed suggesting that modulation of sPD-L2 expression may have an influence on the outcome of the immune response [142]. However, limited data on sPD-L2 as an immune related biomarker is available. A study by
The major source of sCTLA-4 is Tregs, monocytes and immature DCs [144]. sCTLA-4 has been reported in several studies as a plausible marker for response in ICIs treatment. For example, in melanoma patients treated with ipilimumab, high pre-treatment expression of sCTLA-4 was associated with response to treatment and longer OS [145]. Another study on metastatic melanoma patients treated with ipilimumab showed similar results with high levels of sCTLA-4 at baseline associated with disease responsiveness and survival. Interestingly, the study observed that in responding patients, sCTLA-4 concentration increased with subsequent treatment cycles while in progressing patients, sCTLA-4 decreased subsequently indicating that sCTLA-4 can serve as a valuable dynamic marker for treatment monitoring. In addition to this, it was also observed that patients with high pre-treatment sCTLA-4 were at a higher risk of developing immune related adverse events providing further insight into its utility as a biomarker of response/adverse event monitoring [146]. However, in different cancers, its utility may be distinct based on its interaction with other molecules and subsequent immune modulation. For example, a recent study on NSCLC patients treated with nivolumab showed that lower concentration of sCTLA-4 at 3 months of clinical evaluation was associated with response. In addition to this, patients with performance status of 0 consistently maintained a lower expression of sCTLA-4 from the time of treatment initiation until 3 months of clinical evaluation indicating that sCTLA-4 can be an indicator of immune fitness in ICIs treated patients [135]. It is postulated that during ICIs treatment, sCTLA-4 might be involved in enhancing the ability of host cytotoxic T cells to attack tumor cells and thereby enhancing the antitumor effect of immunotherapy.
sTIM-3 secreted in blood lacks mucin and transmembrane domains. It is postulated that sTIM-3 is shed from the cell surface due to metalloproteinase-dependent cleavage and may serve as a decoy receptor for TIM-3 ligands thereby interfering with the inhibitory function of TIM-3 [147]. However, the exact function of sTIM-3 is still unknown. A study on plasma levels of sTIM-3 in ICIs treated patients observed that NSCLC patients treated with nivolumab had a lower level of sTIM-3 at three months of clinical evaluation and this correlated with the response and longer survival of the patient [135]. Though, the study does give an indication of sTIM-3 as biomarker of response, further studies are needed to understand its dynamic nature in ICIs treatment.
sLAG-3 plays a role in immune pathways and has been associated as a Th1 activity marker in serum. sLAG-3 has been reported to bind to MHC class II and induce maturation of dendritic cells thereby facilitating attack on tumor cells [148, 149]. This makes sLAG-3 an attractive biomarker in ICIs treatment. Though several studies on LAG-3 and cellular response has been documented, there is paucity of data on the utility of sLAG-3 in serum of ICIs treated patients. A study on nivolumab treated NSCLC patients reported that sLAG-3 was significantly increased during treatment and this increase was retained in non-responding patients. In addition to sLAG-3, other soluble mediators including sPD-1 and sPDL-2 were also increased in these patients indicating the dynamic interactive nature of LAG-3 and its role as predictive marker [135].
Indoleamine 2,3-dioxygenase (IDO) is an enzyme that acts as an immune checkpoint and inhibits T-cell proliferation by starving the cells from tryptophan (trp) in order to sensitize them to apoptosis [150]. IDO facilitates tumor immune escape and several preclinical studies have associated IDO activity with immunotherapeutic resistance [151]. A study on nivolumab treated NSCLC patients found that lower baseline level of IDO activity in serum was significantly associated with better PFS/OS while higher levels were associated with early progression indicating that high serum levels can serve as early marker of response/indicator of resistance to anti-PD-1 treatment [152]. On the other hand, a larger study on 27 NSCLC patients treated with nivolumab indicated the dynamic nature of sIDO at baseline, 2 months and at disease progression. The study aimed to evaluate the dynamic nature of IDO as a predictor of response. Interestingly, the authors observed that at baseline, IDO activity was higher in responding patients than non-responding patients. However, in patients who did not benefit from immunotherapy, a statistically significant increase was observed between baseline sample and sample taken at the time to disease progression indicating the potential utility of IDO as therapeutic resistance marker to anti-PD-1 treatment [153].
CD163 is the hemoglobin/haptoglobin complex scavenger receptor expressed exclusively on circulating monocytes/tissue macrophages. It is involved in anti-inflammatory functions associated with macrophages and therefore plays an important role in suppressing anti-tumor immune responses [154]. sCD163 is secreted in plasma via proteolytic shedding and is considered a specific marker for TAM. To demonstrate the utility of sCD163 as a marker of response in immunotherapy,
NKG2D is an activating immunoreceptor of cytotoxic lymphocytes and is expressed on T, NK, and NKT cells. NKG2D has eight ligands including MIC (MICA and MICB) or ULBP (ULBP1, ULBP2, ULBP3, ULBP4, RAET1G, and RAET1L) family. These NKG2D ligands are absent on normal cells but are usually overexpressed on tumor cells. Soluble NKG2D ligands (sNKG2DLs) are generated by proteolytic shedding of tumor cells which boosts tumor immune escape by binding and subsequent endocytosis/degradation of NKG2D receptor on NK/T cells thus suppressing antitumor immune responses [156, 157]. Various sNKG2DLs have been studied as predictive biomarkers of response in immunotherapy. A study in melanoma patients by
CD27 is expressed in lymphocytes and is activated by its ligand, CD70, which is a member of the tumor necrosis factor receptor superfamily. Upon binding of CD70 to CD27, soluble CD27 (sCD27) is cleaved off by metalloproteinases and is secreted in serum, plasma, and urine samples. Studies have suggested that changes in sCD27 levels reflect the activity of systemic immunity [159]. In various hematological malignancies increased levels of sCD27 have been reported to correlate with poor prognosis [160]. A study on 16 advanced lung cancer patients on anti-PD-1 treatment were tested for their pretreatment sCD27 levels and correlated with their response patterns. It was observed that a sCD27 level was higher in patients with longer survival and in such patients the duration of treatment was shorter. The authors suggested that sCD27 levels can serve as prognostic marker for predicting effectiveness of ICIs in advanced lung cancer [161].
CD28 is a second messenger of T cell activation and is a critical immune checkpoint for recognition of dendritic cells by T cells. Previous studies have suggested that PD-1 antibodies rely on the activation of the CD28/B7 pathway to rescue the depletion CD8+ T cells and then achieve anti-tumor effects [162]. Soluble sCD28 has been reported as a modulator of T cells for proliferation and is therefore considered an attractive biomarker of response to ICIs treatment [163]. Recently, a study on 44 patients with various cancers (lung, tongue, esophageal and nasopharyngeal, colorectal, cholangiocarcinoma, gastric, duodenal adenocarcinoma, renal cell carcinoma, hepatocellular carcinoma, and malignant melanoma) on anti-PD-1 treatment were tested for serum CD28 along with other soluble markers. It was observed that patients with higher baseline sCD28 expression had a longer PFS and responded better to treatment than non-responsive patients [164]. This dynamic change in sCD28 during treatment gives a credible index in terms of its predictive efficiency as a promising response marker. However, larger studies on this aspect are needed to understand the role of this marker.
Using ICIs have shown promising effect in treating cancers. However, only small group of patients are responsive to this treatment strategy. Tumor resistance to the immune response can be mediated by the involvement of several immunological pathways. In this chapter, we reviewed the different immunological pathways that can be modulated by immune checkpoint blockade and more specifically PD-1 and CTLA-4 inhibitors. We have summarized all the findings obtained in pre-clinical and clinical trials reporting an impact of anti-PD-1 and anti-CTLA-4 on intra-tumoral and peripheral immune response. Interestingly, the study of the dynamics of the immune system under CTLA-4 and PD-1 inhibitors shows a noticeable distinction in their regulatory mode of action on the anti-tumoral and peripheral immune response. Moreover, the findings discussed in this chapter show that CTLA-4 and PD-1 inhibitors do not only restore intra-tumoral effector T cells activity upon exhaustion but are also able to induce a consequential remodeling of the tumor microenvironment as well as the systemic immune response. Indeed, the field of immunological liquid biomarkers is fast evolving with many novel predictive and prognostics markers gaining attention. Though, liquid biopsies have many advantages including minimal invasiveness, longitudinal monitoring and simultaneous parallel testing with highly sensitive/specific high throughput applications. Although several studies state the utility of soluble ICIs markers, it is observed that the characteristic feature of these markers is to modulate the immune response in synergy with each other. This makes them attractive candidates as up and down regulation of a combination of markers can allow better understanding of the immune modulatory and dynamic nature of soluble immune molecules involved in ICIs treatment. However, there are several limitations that need to be addressed for these markers. Mainly, standardization of sampling/measurement techniques as well as larger validation studies are required to verify the utility of these markers as promising tools to guide and monitor treatment decisions in ICIs treated patients. Finally, identification of dynamic biomarkers for prediction of ICIs tumor control and for monitoring of patient response under treatment is gaining considerable knowledge through recent technologies including proteomics and transcriptomics. Progress along this approach is critical to build reasoning for novel therapeutic combinations and to set forth a more personalized cancer immunotherapeutic strategy.
immune checkpoint inhibitors programmed death-ligand 1 programmed death- 1 cytotoxic T-lymphocyte-associated protein 4 T cell receptor tumor microenvironment T-cell immunoglobulin and mucin-domain containing-3 lymphocyte-activation gene-3 T cell immunoreceptor with Ig and ITIM domains exhausted T cells effector T cells absolute lymphocyte count myeloid derived suppressor cells tumor-associated macrophages immune-related adverse events C-reactive protein lactate dehydrogenase overall survival neutrophil-to-lymphocyte ratio derived Neutrophil-to-lymphocyte ratio non-small-cell lung cancer progression free survival soluble forms of immune checkpoints immune checkpoint inhibitors overall response rate soluble programmed cell death protein 1 soluble programmed death-ligand 1 soluble programmed cell death 1 ligand 2 soluble cytotoxic T-lymphocyte-associated protein 4 soluble T-cell immunoglobulin and mucin domain-3 soluble lymphocyte-activation gene 3 soluble indoleamine 2,3-dioxygenase soluble cluster of differentiation 163 natural killer group 2D soluble natural killer group 2D ligands major histocompatibility complex class I-related chain A major histocompatibility complex class I-related chain B natural killer natural killer T cells UL-16-binding proteins 1,2,3,4 retinoic acid early transcript 1G retinoic acid early transcript 1 L soluble cluster of differentiation 27 soluble cluster of differentiation 28
IntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
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\\n\\n3.1. ERRATUM
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\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
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\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
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\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
\n\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
\n\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\n\nPolicy last updated: 2017-09-11
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Its main modulation concept lies in single photon generation on sidebands of optical carrier and determination of photons ground state through its registration and the amplitude value of its carrier frequency as reference channel. So, it is necessary to solve problems of signal-to-carrier ratio of single photon detector (SPD) and aspects of photon number splitting (PNS) attack, nonlinear phase modulation (NPM) between carrier and sidebands in fiber, and finally, spectral selection of carrier in receiver. The technologies, based on the modulation conversion of an optical carrier, are widely used in microwave photonics. Due to the natural symmetry of modulated signals and the highest achievable ratio of the modulation conversions, amplitude-phase modulation with complete or partial suppression of the optical carrier has found a particularly wide application in MPS. The characteristics of advanced MPS for QKD with frequency coding and carrier suppression based on tandem amplitude modulation and phase commutation are presented. New systems can have classical symmetric or non-classical asymmetric structure for QKD based only on spectral selection of carrier and subcarriers without re-modulation.",book:{id:"5779",slug:"advanced-technologies-of-quantum-key-distribution",title:"Advanced Technologies of Quantum Key Distribution",fullTitle:"Advanced Technologies of Quantum Key Distribution"},signatures:"Oleg G. Morozov, Airat J. Sakhabutdinov, Gennady A. Morozov and\nIl’daris M. Gabdulkhakov",authors:[{id:"69648",title:"Prof.",name:"Oleg",middleName:null,surname:"Morozov",slug:"oleg-morozov",fullName:"Oleg Morozov"},{id:"171722",title:"Prof.",name:"Gennady",middleName:null,surname:"Morozov",slug:"gennady-morozov",fullName:"Gennady Morozov"},{id:"196444",title:"Dr.",name:"Airat",middleName:null,surname:"Sakhabutdinov",slug:"airat-sakhabutdinov",fullName:"Airat Sakhabutdinov"},{id:"196445",title:"BSc.",name:"Il'Daris",middleName:null,surname:"Gabdulkhakov",slug:"il'daris-gabdulkhakov",fullName:"Il'Daris Gabdulkhakov"}]},{id:"63116",doi:"10.5772/intechopen.80450",title:"Quantum Key Distribution (QKD) over Software-Defined Optical Networks",slug:"quantum-key-distribution-qkd-over-software-defined-optical-networks",totalDownloads:1315,totalCrossrefCites:5,totalDimensionsCites:5,abstract:"Optical network security is attracting increasing research interest. Currently, software-defined optical network (SDON) has been proposed to increase network intelligence (e.g., flexibility and programmability) which is gradually moving toward industrialization. However, a variety of new threats are emerging in SDONs. Data encryption is an effective way to secure communications in SDONs. However, classical key distribution methods based on the mathematical complexity will suffer from increasing computational power and attack algorithms in the near future. Noticeably, quantum key distribution (QKD) is now being considered as a secure mechanism to provision information-theoretically secure secret keys for data encryption, which is a potential technique to protect communications from security attacks in SDONs. This chapter introduces the basic principles and enabling technologies of QKD. Based on the QKD enabling technologies, an architecture of QKD over SDONs is presented. Resource allocation problem is elaborated in detail and is classified into wavelength allocation, time-slot allocation, and secret key allocation problems in QKD over SDONs. Some open issues and challenges such as survivability, cost optimization, and key on demand (KoD) for QKD over SDONs are discussed.",book:{id:"7376",slug:"quantum-cryptography-in-advanced-networks",title:"Quantum Cryptography in Advanced Networks",fullTitle:"Quantum Cryptography in Advanced Networks"},signatures:"Yongli Zhao, Yuan Cao, Xiaosong Yu and Jie Zhang",authors:[{id:"199527",title:"Associate Prof.",name:"Yongli",middleName:null,surname:"Zhao",slug:"yongli-zhao",fullName:"Yongli Zhao"}]},{id:"62481",doi:"10.5772/intechopen.79456",title:"Blockchain and Digital Currency in the World of Finance",slug:"blockchain-and-digital-currency-in-the-world-of-finance",totalDownloads:1967,totalCrossrefCites:4,totalDimensionsCites:5,abstract:"High-tech enables payment evolution and global competition. The ambiguities surrounding of the digital currency still leave enough space for the analysis of its unreserved acceptance, trust and anticipation, which are the main driver for the spread of the network. Banks should carefully consider the technology underlying these cryptocurrencies as a potential generic new way of transferring ownership of the value over the long term. The chapter provides an analysis of the use of cryptocurrencies in general, especially Bitcoin as the technology adoption in the presence of network externalities. The objective attitude is the future of the digital currency in the moment is still unsolved issue due to the existence of “critical mass”. Further, the chapter explores financial privacy which is very sensitive issue in using digital currency (or cryptocurrency) and discuss about private choices versus political rules. The research has shown that the future of cryptocurrencies can be bright if some institutional-formal conditions are met due to the fact that success evolution of e-money requires building safety payments through three criteria–standardization, compatibility and innovation.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Tatjana Boshkov",authors:[{id:"246137",title:"Ph.D.",name:"Tatjana",middleName:null,surname:"Boshkov",slug:"tatjana-boshkov",fullName:"Tatjana Boshkov"}]},{id:"59491",doi:"10.5772/intechopen.74234",title:"Security of Quantum Key Distribution Protocols",slug:"security-of-quantum-key-distribution-protocols",totalDownloads:1136,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Quantum key distribution (QKD), another name for quantum cryptography, is the most advanced subfield of quantum information and communication technology (QICT). The first QKD protocol was proposed in 1984, and since then, more protocols have been proposed. It uses quantum mechanics to enable secure exchange of cryptographic keys. In order to have high confidence in the security of the QKD protocols, such protocols must be proven to be secure against any arbitrary attacks. In this chapter, we discuss and demonstrate security proofs for QKD protocols. Security analysis of QKD protocols can be categorised into two techniques, namely infinite-key and finite-key analyses. Finite-key analysis offers more realistic results than the infinite-key one, while infinite-key analysis provides more simplicity. We briefly provide the background of QKD and also define the basic notion of security in QKD protocols. The cryptographic key is shared between Alice and Bob. Since the key is random and unknown to an eavesdropper, Eve, she is unable to learn anything about the message simply by intercepting the ciphertext. This phenomenon is beyond the ability of classical information processing. We then study some tools that are used in the derivation of security proofs for the infinite- and finite-length key limits.",book:{id:"5779",slug:"advanced-technologies-of-quantum-key-distribution",title:"Advanced Technologies of Quantum Key Distribution",fullTitle:"Advanced Technologies of Quantum Key Distribution"},signatures:"Mhlambululi Mafu and Makhamisa Senekane",authors:[{id:"196378",title:"Dr.",name:"Mhlambululi",middleName:null,surname:"Mafu",slug:"mhlambululi-mafu",fullName:"Mhlambululi Mafu"},{id:"210180",title:"Dr.",name:"Makhamisa",middleName:null,surname:"Senekane",slug:"makhamisa-senekane",fullName:"Makhamisa Senekane"}]},{id:"62627",doi:"10.5772/intechopen.79386",title:"Modeling Bitcoin Price and Bubbles",slug:"modeling-bitcoin-price-and-bubbles",totalDownloads:1660,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"The goal of this chapter is to present recent developments about Bitcoin1 price modeling and related applications. Precisely, we consider a bivariate model in continuous time to describe the behavior of Bitcoin price and of the investors’ attention on the overall network. The attention index affects Bitcoin price through a suitable dependence on the drift and diffusion coefficients and a possible correlation between the sources of randomness represented by the driving Brownian motions. The model is fitted on historical data of Bitcoin prices, by considering the total trading volume and the Google Search Volume Index as proxies for the attention measure. Moreover, a closed formula is computed for European-style derivatives on Bitcoin. Finally, we discuss two possible extensions of the model. Precisely, we investigate the relation between the correlation parameter and possible bubble effects in the asset price; further, we consider a multivariate framework to represent the special feature of Bitcoin being traded on several exchanges and we discuss conditions to rule out arbitrage opportunities in this setting.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Alessandra Cretarola and Gianna Figà-Talamanca",authors:[{id:"246178",title:"Prof.",name:"Alessandra",middleName:null,surname:"Cretarola",slug:"alessandra-cretarola",fullName:"Alessandra Cretarola"},{id:"246179",title:"Prof.",name:"Gianna",middleName:null,surname:"Figà-Talamanca",slug:"gianna-figa-talamanca",fullName:"Gianna Figà-Talamanca"}]}],mostDownloadedChaptersLast30Days:[{id:"62481",title:"Blockchain and Digital Currency in the World of Finance",slug:"blockchain-and-digital-currency-in-the-world-of-finance",totalDownloads:1967,totalCrossrefCites:4,totalDimensionsCites:5,abstract:"High-tech enables payment evolution and global competition. The ambiguities surrounding of the digital currency still leave enough space for the analysis of its unreserved acceptance, trust and anticipation, which are the main driver for the spread of the network. Banks should carefully consider the technology underlying these cryptocurrencies as a potential generic new way of transferring ownership of the value over the long term. The chapter provides an analysis of the use of cryptocurrencies in general, especially Bitcoin as the technology adoption in the presence of network externalities. The objective attitude is the future of the digital currency in the moment is still unsolved issue due to the existence of “critical mass”. Further, the chapter explores financial privacy which is very sensitive issue in using digital currency (or cryptocurrency) and discuss about private choices versus political rules. The research has shown that the future of cryptocurrencies can be bright if some institutional-formal conditions are met due to the fact that success evolution of e-money requires building safety payments through three criteria–standardization, compatibility and innovation.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Tatjana Boshkov",authors:[{id:"246137",title:"Ph.D.",name:"Tatjana",middleName:null,surname:"Boshkov",slug:"tatjana-boshkov",fullName:"Tatjana Boshkov"}]},{id:"63090",title:"Cryptocurrency Returns",slug:"cryptocurrency-returns",totalDownloads:1426,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"One of the most significant innovations in the world of finance has been the creation and evolvement of cryptocurrencies. These digital means of exchange have been the focus of extensive news coverage, especially the Bitcoin, with a primary focus on the tremendous potential return and the high level of accompanying risk. In this chapter, we examine the risk-return pattern for an array of cryptocurrencies, contrasting the pattern with those of conventional currency and equity investments. We find the measures of cryptocurrency returns and risk to be a very high multiple of those of conventional investments, and the pattern is determined to be robust relative to the time frame. Consequently, cryptocurrencies are determined to provide an alternative to investors that involves tremendously high risk and return.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Mike Cudd, Kristen Ritterbush, Marcelo Eduardo and Chris Smith",authors:[{id:"254939",title:"Dr.",name:"Mike",middleName:null,surname:"Cudd",slug:"mike-cudd",fullName:"Mike Cudd"}]},{id:"62430",title:"On the Origin of the Value of Cryptocurrencies",slug:"on-the-origin-of-the-value-of-cryptocurrencies",totalDownloads:1248,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Bitcoin and other cryptocurrencies received a lot of criticism during the last 9 years. It is not surprising that this criticism came from organizations that are threatened by the crypto revolution (banks, government, central banks, finance companies, etc.). Nevertheless, it is very surprising to hear criticism from economics schools, which oppose central banking and advocate free choice in currencies (such as the Austrian school of economics). Unlike the ordinary criticism (that Bitcoin is a scam, a bubble, etc.), which can easily be refuted, the criticism of part of the Austrian school economists is based on interesting arguments, which requires a different level of explanation. For example, it was claimed that Bitcoin should be worthless; otherwise, it contradicts Mises’ regression theorem. The object of the chapter is twofold: first to explain why the criticism is unfounded and second to analyze the origin of the value of Bitcoin and other cryptocoins from the perspective of the Austrian school of economics. In particular, it is explained that Bitcoin does not contradict the regression theorem for two reasons. First, the initial value estimation can be a random event, and second, the Bitcoin network (even now) has a nonmonetary value.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Er'el Granot",authors:[{id:"181601",title:"Prof.",name:"Er'El",middleName:null,surname:"Granot",slug:"er'el-granot",fullName:"Er'El Granot"}]},{id:"62627",title:"Modeling Bitcoin Price and Bubbles",slug:"modeling-bitcoin-price-and-bubbles",totalDownloads:1660,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"The goal of this chapter is to present recent developments about Bitcoin1 price modeling and related applications. Precisely, we consider a bivariate model in continuous time to describe the behavior of Bitcoin price and of the investors’ attention on the overall network. The attention index affects Bitcoin price through a suitable dependence on the drift and diffusion coefficients and a possible correlation between the sources of randomness represented by the driving Brownian motions. The model is fitted on historical data of Bitcoin prices, by considering the total trading volume and the Google Search Volume Index as proxies for the attention measure. Moreover, a closed formula is computed for European-style derivatives on Bitcoin. Finally, we discuss two possible extensions of the model. Precisely, we investigate the relation between the correlation parameter and possible bubble effects in the asset price; further, we consider a multivariate framework to represent the special feature of Bitcoin being traded on several exchanges and we discuss conditions to rule out arbitrage opportunities in this setting.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Alessandra Cretarola and Gianna Figà-Talamanca",authors:[{id:"246178",title:"Prof.",name:"Alessandra",middleName:null,surname:"Cretarola",slug:"alessandra-cretarola",fullName:"Alessandra Cretarola"},{id:"246179",title:"Prof.",name:"Gianna",middleName:null,surname:"Figà-Talamanca",slug:"gianna-figa-talamanca",fullName:"Gianna Figà-Talamanca"}]},{id:"62478",title:"The Condition of the Cryptocurrency Market and Exchanges in Poland",slug:"the-condition-of-the-cryptocurrency-market-and-exchanges-in-poland",totalDownloads:1008,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The development of the cryptocurrency market and the implications for the whole economy and finance for all traders cause a keen interest in this subject. The chapter discusses the functioning of a financial system based on cryptocurrencies and its significance for economies. In this chapter, the development of the global cryptocurrency market was presented and the history of the most popular cryptocurrency, bitcoin, was analyzed. The analysis and the assessment of the state and structure of the Polish cryptocurrencies market were presented on the background of the global cryptocurrency market. Also, we presented the possible development paths for the cryptocurrencies market in Poland and in the world.",book:{id:"7228",slug:"blockchain-and-cryptocurrencies",title:"Blockchain and Cryptocurrencies",fullTitle:"Blockchain and Cryptocurrencies"},signatures:"Ireneusz Miciuła",authors:[{id:"243649",title:"Dr.",name:"Ireneusz",middleName:null,surname:"Miciuła",slug:"ireneusz-miciula",fullName:"Ireneusz Miciuła"}]}],onlineFirstChaptersFilter:{topicId:"531",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,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:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:27,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:49,paginationItems:[{id:"80495",title:"Iron in Cell Metabolism and Disease",doi:"10.5772/intechopen.101908",signatures:"Eeka Prabhakar",slug:"iron-in-cell-metabolism-and-disease",totalDownloads:1,totalCrossrefCites:0,totalDimensionsCites:null,authors:null,book:{title:"Iron Metabolism - Iron a Double‐Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81799",title:"Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases",doi:"10.5772/intechopen.104978",signatures:"Richa Rai",slug:"cross-talk-of-purinergic-and-immune-signaling-implication-in-inflammatory-and-pathogenic-diseases",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81764",title:"Involvement of the Purinergic System in Cell Death in Models of Retinopathies",doi:"10.5772/intechopen.103935",signatures:"Douglas Penaforte Cruz, Marinna Garcia Repossi and Lucianne Fragel Madeira",slug:"involvement-of-the-purinergic-system-in-cell-death-in-models-of-retinopathies",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81756",title:"Alteration of Cytokines Level and Oxidative Stress Parameters in COVID-19",doi:"10.5772/intechopen.104950",signatures:"Marija Petrusevska, Emilija Atanasovska, Dragica Zendelovska, Aleksandar Eftimov and Katerina Spasovska",slug:"alteration-of-cytokines-level-and-oxidative-stress-parameters-in-covid-19",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}}]},overviewPagePublishedBooks:{paginationCount:27,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science and Technology from the Department of Chemistry, National University of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013. She relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the National Institute of Fundamental Studies from April 2013 to October 2016. She was a senior lecturer on a temporary basis at the Department of Food Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is currently Deputy Principal of the Australian College of Business and Technology – Kandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI) Ambassador to Sri Lanka.",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. Her research interests include microalgal biotechnology with an emphasis on microalgae-based products.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",institutionURL:null,country:{name:"Brazil"}}}]},{type:"book",id:"7953",title:"Bioluminescence",subtitle:"Analytical Applications and Basic Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7953.jpg",slug:"bioluminescence-analytical-applications-and-basic-biology",publishedDate:"September 25th 2019",editedByType:"Edited by",bookSignature:"Hirobumi Suzuki",hash:"3a8efa00b71abea11bf01973dc589979",volumeInSeries:4,fullTitle:"Bioluminescence - Analytical Applications and Basic Biology",editors:[{id:"185746",title:"Dr.",name:"Hirobumi",middleName:null,surname:"Suzuki",slug:"hirobumi-suzuki",fullName:"Hirobumi Suzuki",profilePictureURL:"https://mts.intechopen.com/storage/users/185746/images/system/185746.png",biography:"Dr. Hirobumi Suzuki received his Ph.D. in 1997 from Tokyo Metropolitan University, Japan, where he studied firefly phylogeny and the evolution of mating systems. He is especially interested in the genetic differentiation pattern and speciation process that correlate to the flashing pattern and mating behavior of some fireflies in Japan. He then worked for Olympus Corporation, a Japanese manufacturer of optics and imaging products, where he was involved in the development of luminescence technology and produced a bioluminescence microscope that is currently being used for gene expression analysis in chronobiology, neurobiology, and developmental biology. Dr. Suzuki currently serves as a visiting researcher at Kogakuin University, Japan, and also a vice president of the Japan Firefly Society.",institutionString:"Kogakuin University",institution:null}]}]},openForSubmissionBooks:{},onlineFirstChapters:{},subseriesFiltersForOFChapters:[],publishedBooks:{},subseriesFiltersForPublishedBooks:[],publicationYearFilters:[],authors:{}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular economy, Contingency planning and response to disasters, Ecosystem services, Integrated urban water management, Nature-based solutions, Sustainable urban development, Urban green spaces",scope:"