Heterogeneity of INK4A and p16 in melanoma specimens
\\n\\n
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:null},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:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"}]},book:{item:{type:"book",id:"2079",leadTitle:null,fullTitle:"Problems, Perspectives and Challenges of Agricultural Water Management",title:"Problems, Perspectives and Challenges of Agricultural Water Management",subtitle:null,reviewType:"peer-reviewed",abstract:"Food security emerged as an issue in the first decade of the 21st Century, questioning the sustainability of the human race, which is inevitably related directly to the agricultural water management that has multifaceted dimensions and requires interdisciplinary expertise in order to be dealt with. The purpose of this book is to bring together and integrate the subject matter that deals with the equity, profitability and irrigation water pricing; modelling, monitoring and assessment techniques; sustainable irrigation development and management, and strategies for irrigation water supply and conservation in a single text. The book is divided into four sections and is intended to be a comprehensive reference for students, professionals and researchers working on various aspects of agricultural water management. The book seeks its impact from the diverse nature of content revealing situations from different continents (Australia, USA, Asia, Europe and Africa). Various case studies have been discussed in the chapters to present a general scenario of the problem, perspective and challenges of irrigation water use.",isbn:null,printIsbn:"978-953-51-0117-8",pdfIsbn:"978-953-51-5233-0",doi:"10.5772/2488",price:139,priceEur:155,priceUsd:179,slug:"problems-perspectives-and-challenges-of-agricultural-water-management",numberOfPages:470,isOpenForSubmission:!1,isInWos:1,hash:"183bb777195754e887da67131255661f",bookSignature:"Manish Kumar",publishedDate:"March 9th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/2079.jpg",numberOfDownloads:67017,numberOfWosCitations:65,numberOfCrossrefCitations:28,numberOfDimensionsCitations:73,hasAltmetrics:0,numberOfTotalCitations:166,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 3rd 2011",dateEndSecondStepPublish:"March 31st 2011",dateEndThirdStepPublish:"August 5th 2011",dateEndFourthStepPublish:"September 4th 2011",dateEndFifthStepPublish:"January 2nd 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"102967",title:"Dr.",name:"Manish",middleName:null,surname:"Kumar",slug:"manish-kumar",fullName:"Manish Kumar",profilePictureURL:"https://mts.intechopen.com/storage/users/102967/images/system/102967.jpg",biography:"After completing Ph.D from the University of Tokyo",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Tezpur University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"311",title:"Plant Genetics",slug:"agronomy-plant-genetics"}],chapters:[{id:"31494",title:"Equity in Access to Irrigation Water: A Comparative Analysis of Tube-Well Irrigation System and Conjunctive Irrigation System",doi:"10.5772/31559",slug:"equity-in-access-to-irrigation-water-a-comparative-analysis-of-tube-well-irrigation-system-and-conju",totalDownloads:2313,totalCrossrefCites:2,totalDimensionsCites:4,signatures:"Anindita Sarkar",downloadPdfUrl:"/chapter/pdf-download/31494",previewPdfUrl:"/chapter/pdf-preview/31494",authors:[{id:"87717",title:"Dr.",name:"Anindita",surname:"Sarkar",slug:"anindita-sarkar",fullName:"Anindita Sarkar"}],corrections:null},{id:"31495",title:"Irrigation Water: Alternative Pricing Schemes Under Uncertain Climatic Conditions",doi:"10.5772/29715",slug:"irrigation-water-alternative-pricing-schemes-under-uncertain-climatic-conditions",totalDownloads:1554,totalCrossrefCites:2,totalDimensionsCites:3,signatures:"Gabriele Dono and Luca Giraldo",downloadPdfUrl:"/chapter/pdf-download/31495",previewPdfUrl:"/chapter/pdf-preview/31495",authors:[{id:"79067",title:"Dr.",name:"Luca",surname:"Giraldo",slug:"luca-giraldo",fullName:"Luca Giraldo"},{id:"79072",title:"Prof.",name:"Gabriele",surname:"Dono",slug:"gabriele-dono",fullName:"Gabriele Dono"}],corrections:null},{id:"31496",title:"Irrigation Development: A Food Security and Household Income Perspective",doi:"10.5772/30865",slug:"irrigation-development-food-security-and-household-income-perspective",totalDownloads:3701,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Kenneth Nhundu and Abbyssinia Mushunje",downloadPdfUrl:"/chapter/pdf-download/31496",previewPdfUrl:"/chapter/pdf-preview/31496",authors:[{id:"84562",title:"Dr.",name:"Abbyssinia",surname:"Mushunje",slug:"abbyssinia-mushunje",fullName:"Abbyssinia Mushunje"}],corrections:null},{id:"31497",title:"Water Rights Allocation, Management and Trading in an Irrigation District - A Case Study of Northwestern China",doi:"10.5772/31182",slug:"water-rights-allocation-management-and-trading-in-an-irrigation-district-a-case-study-of-northwester",totalDownloads:2225,totalCrossrefCites:1,totalDimensionsCites:2,signatures:"Hang Zheng, Zhongjing Wang, Roger Calow and Yongping Wei",downloadPdfUrl:"/chapter/pdf-download/31497",previewPdfUrl:"/chapter/pdf-preview/31497",authors:[{id:"85947",title:"Dr.",name:"Hang",surname:"Zheng",slug:"hang-zheng",fullName:"Hang Zheng"}],corrections:null},{id:"31498",title:"Effects of Irrigation-Water Pricing on the Profitability of Mediterranean Woody Crops",doi:"10.5772/31436",slug:"effects-of-irrigation-water-pricing-on-the-profitability-of-mediterranean-tree-and-woody-crops",totalDownloads:1383,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"M. A. Fernández-Zamudio, F. Alcon and M. D. De-Miguel",downloadPdfUrl:"/chapter/pdf-download/31498",previewPdfUrl:"/chapter/pdf-preview/31498",authors:[{id:"87106",title:"Dr.",name:"Maria-Angeles",surname:"Fernandez-Zamudio",slug:"maria-angeles-fernandez-zamudio",fullName:"Maria-Angeles Fernandez-Zamudio"},{id:"87108",title:"Dr.",name:"Francisco",surname:"Alcon",slug:"francisco-alcon",fullName:"Francisco Alcon"},{id:"87109",title:"Dr.",name:"Maria-Dolores",surname:"De-Miguel",slug:"maria-dolores-de-miguel",fullName:"Maria-Dolores De-Miguel"}],corrections:null},{id:"31499",title:"Irrigation Institutions of Bangladesh: Some Lessons",doi:"10.5772/28991",slug:"irrigation-institutions-of-bangladesh-some-lessons",totalDownloads:4483,totalCrossrefCites:1,totalDimensionsCites:2,signatures:"Nasima Tanveer Chowdhury",downloadPdfUrl:"/chapter/pdf-download/31499",previewPdfUrl:"/chapter/pdf-preview/31499",authors:[{id:"76122",title:"Ms.",name:"Nasima",surname:"Chowdhury",slug:"nasima-chowdhury",fullName:"Nasima Chowdhury"}],corrections:null},{id:"31500",title:"Modelling Current and Future Pan-European Irrigation Water Demands and Their Impact on Water Resources",doi:"10.5772/29106",slug:"modelling-future-pan-european-irrigation-water-demands-and-their-impact-on-water-availability",totalDownloads:1879,totalCrossrefCites:1,totalDimensionsCites:2,signatures:"Tim Aus der Beek, Ellen Kynast and Martina Flörke",downloadPdfUrl:"/chapter/pdf-download/31500",previewPdfUrl:"/chapter/pdf-preview/31500",authors:[{id:"76531",title:"Dr",name:"Tim",surname:"Aus Der Beek",slug:"tim-aus-der-beek",fullName:"Tim Aus Der Beek"}],corrections:null},{id:"31501",title:"Basics and Application of Ground-Penetrating Radar as a Tool for Monitoring Irrigation Process",doi:"10.5772/29324",slug:"basics-and-application-of-ground-penetrating-radar-as-a-tool-for-monitoring-irrigation-process",totalDownloads:10703,totalCrossrefCites:11,totalDimensionsCites:17,signatures:"Kazunori Takahashi, Jan Igel, Holger Preetz and Seiichiro Kuroda",downloadPdfUrl:"/chapter/pdf-download/31501",previewPdfUrl:"/chapter/pdf-preview/31501",authors:[{id:"77296",title:"Dr.",name:"Kazunori",surname:"Takahashi",slug:"kazunori-takahashi",fullName:"Kazunori Takahashi"},{id:"77738",title:"Dr.",name:"Seiichiro",surname:"Kuroda",slug:"seiichiro-kuroda",fullName:"Seiichiro Kuroda"},{id:"77739",title:"Dr.",name:"Jan",surname:"Igel",slug:"jan-igel",fullName:"Jan Igel"},{id:"77740",title:"Dr.",name:"Holger",surname:"Preetz",slug:"holger-preetz",fullName:"Holger Preetz"}],corrections:null},{id:"31502",title:"A Low Cost Remote Monitoring Method for Determining Farmer Irrigation Practices and Water Use",doi:"10.5772/29770",slug:"a-low-cost-remote-monitoring-method-for-determining-farmer-irrigation-practices",totalDownloads:1721,totalCrossrefCites:1,totalDimensionsCites:2,signatures:"Kristoph-Dietrich Kinzli",downloadPdfUrl:"/chapter/pdf-download/31502",previewPdfUrl:"/chapter/pdf-preview/31502",authors:[{id:"26575",title:"Dr.",name:"Kristoph-Dietrich",surname:"Kinzli",slug:"kristoph-dietrich-kinzli",fullName:"Kristoph-Dietrich Kinzli"}],corrections:null},{id:"31503",title:"Critical Evaluation of Different Techniques for Determining Soil Water Content",doi:"10.5772/30633",slug:"critical-evaluation-of-different-techniques-for-determining-soil-water-content",totalDownloads:3765,totalCrossrefCites:2,totalDimensionsCites:3,signatures:"Alejandro Zermeño-González, Juan Munguia-López, Martín Cadena-Zapata, Santos Gabriel Campos-Magaña, Luis Ibarra-Jiménez and Raúl Rodríguez-García",downloadPdfUrl:"/chapter/pdf-download/31503",previewPdfUrl:"/chapter/pdf-preview/31503",authors:[{id:"83447",title:"PhD.",name:"Alejandro",surname:"Zermeno-Gonzalez",slug:"alejandro-zermeno-gonzalez",fullName:"Alejandro Zermeno-Gonzalez"}],corrections:null},{id:"31504",title:"Precision Irrigation: Sensor Network Based Irrigation",doi:"10.5772/31909",slug:"precision-irrigation-sensor-network-based-irrigation-to-improve-water-use-efficiency-in-agriculture",totalDownloads:5568,totalCrossrefCites:0,totalDimensionsCites:4,signatures:"N. G. Shah ancd Ipsita Das",downloadPdfUrl:"/chapter/pdf-download/31504",previewPdfUrl:"/chapter/pdf-preview/31504",authors:[{id:"89255",title:"Dr",name:"Narendra G.",surname:"Shah",slug:"narendra-g.-shah",fullName:"Narendra G. Shah"},{id:"109328",title:"Dr.",name:"Ipsita",surname:"Das",slug:"ipsita-das",fullName:"Ipsita Das"}],corrections:null},{id:"31505",title:"Using Wireless Sensor Networks for Precision Irrigation Scheduling",doi:"10.5772/31236",slug:"using-sensor-networks-for-precision-irrigation-control",totalDownloads:2425,totalCrossrefCites:1,totalDimensionsCites:15,signatures:"John D. Lea-Cox",downloadPdfUrl:"/chapter/pdf-download/31505",previewPdfUrl:"/chapter/pdf-preview/31505",authors:[{id:"86163",title:"Prof.",name:"John",surname:"Lea-Cox",slug:"john-lea-cox",fullName:"John Lea-Cox"}],corrections:null},{id:"31506",title:"Comparison of Different Irrigation Methods Based on the Parametric Evaluation Approach in West North Ahwaz Plain",doi:"10.5772/29190",slug:"comparison-of-different-irrigation-methods-based-on-the-parametric-evaluation-approach-in-west-north",totalDownloads:3667,totalCrossrefCites:0,totalDimensionsCites:2,signatures:"Mohammad Albaji, Saeed Boroomand Nasab and Jabbar Hemadi",downloadPdfUrl:"/chapter/pdf-download/31506",previewPdfUrl:"/chapter/pdf-preview/31506",authors:[{id:"76813",title:"Dr.",name:"Mohammad",surname:"Albaji",slug:"mohammad-albaji",fullName:"Mohammad Albaji"}],corrections:null},{id:"31507",title:"Guideline for Groundwater Resource Management Using the GIS Tools in Arid to Semi Arid Climate Regions",doi:"10.5772/30178",slug:"guideline-for-groundwater-resource-management-using-the-gis-tools-in-arid-to-semi-arid-climate-regio",totalDownloads:3115,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Salwa Saidi, Salem Bouri, Brice Anselme and Hamed Ben Dhia",downloadPdfUrl:"/chapter/pdf-download/31507",previewPdfUrl:"/chapter/pdf-preview/31507",authors:[{id:"81180",title:"Dr.",name:"Salwa",surname:"Saidi",slug:"salwa-saidi",fullName:"Salwa Saidi"},{id:"81294",title:"Prof.",name:"Salem",surname:"Bouri",slug:"salem-bouri",fullName:"Salem Bouri"},{id:"81295",title:"Prof.",name:"Hamed",surname:"Ben Dhia",slug:"hamed-ben-dhia",fullName:"Hamed Ben Dhia"},{id:"81296",title:"Prof.",name:"Brice",surname:"Anselme",slug:"brice-anselme",fullName:"Brice Anselme"}],corrections:null},{id:"31508",title:"Soil, Water and Crop Management for Agricultural Profitability and Natural Resources Protection in Salt-Threatened Irrigated Lands",doi:"10.5772/29720",slug:"soil-water-and-crop-management-for-agricultural-profitability-and-natural-resources-protection-in-sa",totalDownloads:1786,totalCrossrefCites:0,totalDimensionsCites:2,signatures:"Fernando Visconti and José Miguel de Paz",downloadPdfUrl:"/chapter/pdf-download/31508",previewPdfUrl:"/chapter/pdf-preview/31508",authors:[{id:"79081",title:"Dr.",name:"Fernando",surname:"Visconti",slug:"fernando-visconti",fullName:"Fernando Visconti"},{id:"87216",title:"Dr.",name:"José Miguel",surname:"De Paz",slug:"jose-miguel-de-paz",fullName:"José Miguel De Paz"}],corrections:null},{id:"31509",title:"Criteria for Evaluation of Agricultural Land Suitability for Irrigation in Osijek County Croatia",doi:"10.5772/29789",slug:"criteria-for-evaluation-of-agricultural-land-suitability-for-irrigation",totalDownloads:2898,totalCrossrefCites:4,totalDimensionsCites:4,signatures:"Lidija Tadić",downloadPdfUrl:"/chapter/pdf-download/31509",previewPdfUrl:"/chapter/pdf-preview/31509",authors:[{id:"79316",title:"Dr.",name:"Lidija",surname:"Tadić",slug:"lidija-tadic",fullName:"Lidija Tadić"}],corrections:null},{id:"31510",title:"Rationalisation of Established Irrigation Systems: Policy and Pitfalls",doi:"10.5772/29759",slug:"rationalization-of-established-irrigation-systems-policy-and-pitfalls",totalDownloads:1614,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Francine Rochford",downloadPdfUrl:"/chapter/pdf-download/31510",previewPdfUrl:"/chapter/pdf-preview/31510",authors:[{id:"79203",title:"Dr.",name:"Francine",surname:"Rochford",slug:"francine-rochford",fullName:"Francine Rochford"}],corrections:null},{id:"31511",title:"Optimal Design or Rehabilitation of an Irrigation Project's Pipe Network",doi:"10.5772/29109",slug:"optimal-design-or-rehabilitation-of-the-irrigation-project-s-pipe-network",totalDownloads:3045,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Milan Cisty",downloadPdfUrl:"/chapter/pdf-download/31511",previewPdfUrl:"/chapter/pdf-preview/31511",authors:[{id:"76540",title:"Dr.",name:"Milan",surname:"Cisty",slug:"milan-cisty",fullName:"Milan Cisty"}],corrections:null},{id:"31512",title:"An Algebraic Approach for Controlling Cascade of Reaches in Irrigation Canals",doi:"10.5772/30684",slug:"an-algebraic-approach-for-controlling-cascade-of-reaches-in-irrigation-canals",totalDownloads:1478,totalCrossrefCites:0,totalDimensionsCites:3,signatures:"Mouhamadou Samsidy Goudiaby, Abdou Sene and Gunilla Kreiss",downloadPdfUrl:"/chapter/pdf-download/31512",previewPdfUrl:"/chapter/pdf-preview/31512",authors:[{id:"83741",title:"Dr",name:"Abdou",surname:"Sene",slug:"abdou-sene",fullName:"Abdou Sene"},{id:"87652",title:"PhD.",name:"Mouhamadou Samsidy",surname:"Goudiaby",slug:"mouhamadou-samsidy-goudiaby",fullName:"Mouhamadou Samsidy Goudiaby"},{id:"123946",title:"Prof.",name:"Gunilla",surname:"Kreiss",slug:"gunilla-kreiss",fullName:"Gunilla Kreiss"}],corrections:null},{id:"31513",title:"Spatial Variability of Field Microtopography and Its Influence on Irrigation Performance",doi:"10.5772/29761",slug:"spatial-variability-of-field-microtopography-and-its-influence-on-irrigation-performance",totalDownloads:1384,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Meijian Bai, Di Xu, Yinong Li and Shaohui Zhang",downloadPdfUrl:"/chapter/pdf-download/31513",previewPdfUrl:"/chapter/pdf-preview/31513",authors:[{id:"79223",title:"Dr.",name:"Meijian",surname:"Bai",slug:"meijian-bai",fullName:"Meijian Bai"},{id:"84712",title:"Prof.",name:"Di",surname:"Xu",slug:"di-xu",fullName:"Di Xu"},{id:"84713",title:"Prof.",name:"Yinong",surname:"Li",slug:"yinong-li",fullName:"Yinong Li"},{id:"125083",title:"Dr.",name:"Shaohui",surname:"Zhang",slug:"shaohui-zhang",fullName:"Shaohui Zhang"}],corrections:null},{id:"31514",title:"Performance of Smallholder Irrigation Schemes in the Vhembe District of South Africa",doi:"10.5772/29182",slug:"performance-of-smallholder-irrigation-schemes-in-the-vhembe-district-of-south-africa",totalDownloads:4444,totalCrossrefCites:2,totalDimensionsCites:3,signatures:"Wim Van Averbeke",downloadPdfUrl:"/chapter/pdf-download/31514",previewPdfUrl:"/chapter/pdf-preview/31514",authors:[{id:"76788",title:"Prof.",name:"Wim",surname:"Van Averbeke",slug:"wim-van-averbeke",fullName:"Wim Van Averbeke"}],corrections:null},{id:"31515",title:"Decision Strategies for Soil Water Estimations in Soybean Crops Subjected to No-Tillage and Conventional Systems, in Brazil",doi:"10.5772/29711",slug:"decision-strategies-of-soil-water-substitutio-in-soybean-subjected-to-no-tilleage-and-conventional-s",totalDownloads:1878,totalCrossrefCites:0,totalDimensionsCites:3,signatures:"Lucieta G. Martorano, Homero Bergamaschi, Rogério T. de Faria and Genei A. Dalmago",downloadPdfUrl:"/chapter/pdf-download/31515",previewPdfUrl:"/chapter/pdf-preview/31515",authors:[{id:"79055",title:"Dr.",name:"Lucieta",surname:"Martorano",slug:"lucieta-martorano",fullName:"Lucieta Martorano"},{id:"87316",title:"Dr.",name:"Homero",surname:"Bergamaschi",slug:"homero-bergamaschi",fullName:"Homero Bergamaschi"},{id:"87318",title:"Dr.",name:"Rogério",surname:"Faria",slug:"rogerio-faria",fullName:"Rogério Faria"},{id:"87320",title:"Dr.",name:"Genei",surname:"Dalmago",slug:"genei-dalmago",fullName:"Genei Dalmago"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},relatedBooks:[{type:"book",id:"3060",title:"Plant Breeding from Laboratories to Fields",subtitle:null,isOpenForSubmission:!1,hash:"5b517f307caac739435f7fbaed5326ac",slug:"plant-breeding-from-laboratories-to-fields",bookSignature:"Sven Bode Andersen",coverURL:"https://cdn.intechopen.com/books/images_new/3060.jpg",editedByType:"Edited by",editors:[{id:"79388",title:"Prof.",name:"Sven Bode",surname:"Andersen",slug:"sven-bode-andersen",fullName:"Sven Bode Andersen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3554",title:"Rice",subtitle:"Germplasm, Genetics and Improvement",isOpenForSubmission:!1,hash:"4bd6a333920f0f208c44c2e9fbfdd215",slug:"rice-germplasm-genetics-and-improvement",bookSignature:"Wengui Yan and Jinsong Bao",coverURL:"https://cdn.intechopen.com/books/images_new/3554.jpg",editedByType:"Edited by",editors:[{id:"94348",title:"Dr.",name:"Wengui",surname:"Yan",slug:"wengui-yan",fullName:"Wengui Yan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1404",title:"Aflatoxins",subtitle:"Detection, Measurement and Control",isOpenForSubmission:!1,hash:"e3a2b9bd1c46dd47875d6a0f3d8b2a39",slug:"aflatoxins-detection-measurement-and-control",bookSignature:"Irineo Torres-Pacheco",coverURL:"https://cdn.intechopen.com/books/images_new/1404.jpg",editedByType:"Edited by",editors:[{id:"62984",title:"Dr.",name:"Irineo",surname:"Torres-Pacheco",slug:"irineo-torres-pacheco",fullName:"Irineo Torres-Pacheco"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1782",title:"Agricultural Science",subtitle:null,isOpenForSubmission:!1,hash:"5a4e92f7ffd1fabdcfe769a0ad54d48b",slug:"agricultural-science",bookSignature:"Godwin Aflakpui",coverURL:"https://cdn.intechopen.com/books/images_new/1782.jpg",editedByType:"Edited by",editors:[{id:"93100",title:"Dr.",name:"Godwin",surname:"Aflakpui",slug:"godwin-aflakpui",fullName:"Godwin Aflakpui"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"597",title:"Crop Production Technologies",subtitle:null,isOpenForSubmission:!1,hash:"7f87c31dfd7e38f3e10cf7ec02df2201",slug:"crop-production-technologies",bookSignature:"Peeyush Sharma and Vikas Abrol",coverURL:"https://cdn.intechopen.com/books/images_new/597.jpg",editedByType:"Edited by",editors:[{id:"73200",title:"Dr.",name:"Peeyush",surname:"Sharma",slug:"peeyush-sharma",fullName:"Peeyush Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3800",title:"World Cotton Germplasm Resources",subtitle:null,isOpenForSubmission:!1,hash:"c8454ec008f1d20ebe7387b1be02b2db",slug:"world-cotton-germplasm-resources",bookSignature:"Ibrokhim Y. Abdurakhmonov",coverURL:"https://cdn.intechopen.com/books/images_new/3800.jpg",editedByType:"Edited by",editors:[{id:"213344",title:"Dr.",name:"Ibrokhim Y.",surname:"Abdurakhmonov",slug:"ibrokhim-y.-abdurakhmonov",fullName:"Ibrokhim Y. Abdurakhmonov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1248",title:"Resource Management for Sustainable Agriculture",subtitle:null,isOpenForSubmission:!1,hash:"3445faea41382312cdb15ca628229a20",slug:"resource-management-for-sustainable-agriculture",bookSignature:"Vikas Abrol and Peeyush Sharma",coverURL:"https://cdn.intechopen.com/books/images_new/1248.jpg",editedByType:"Edited by",editors:[{id:"136230",title:"Dr.",name:"Vikas",surname:"Abrol",slug:"vikas-abrol",fullName:"Vikas Abrol"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3232",title:"Organic Farming and Food Production",subtitle:null,isOpenForSubmission:!1,hash:"3610c43696a531a171044145a3a528c6",slug:"organic-farming-and-food-production",bookSignature:"Petr Konvalina",coverURL:"https://cdn.intechopen.com/books/images_new/3232.jpg",editedByType:"Edited by",editors:[{id:"77330",title:"Dr.",name:"Petr",surname:"Konvalina",slug:"petr-konvalina",fullName:"Petr Konvalina"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2030",title:"Research in Organic Farming",subtitle:null,isOpenForSubmission:!1,hash:"11136b8e73780b3196ddb1ef0ce1571e",slug:"research-in-organic-farming",bookSignature:"Raumjit Nokkoul",coverURL:"https://cdn.intechopen.com/books/images_new/2030.jpg",editedByType:"Edited by",editors:[{id:"87654",title:"Dr.",name:"Raumjit",surname:"Nokkoul",slug:"raumjit-nokkoul",fullName:"Raumjit Nokkoul"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3357",title:"Crop Production",subtitle:null,isOpenForSubmission:!1,hash:"6ed9774e3d9e1d7664640db03e659146",slug:"crop-production",bookSignature:"Aakash Goyal and Muhammad Asif",coverURL:"https://cdn.intechopen.com/books/images_new/3357.jpg",editedByType:"Edited by",editors:[{id:"97604",title:"Dr.",name:"Aakash",surname:"Goyal",slug:"aakash-goyal",fullName:"Aakash Goyal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"69566",slug:"corrigendum-to-a-brief-overview-of-ophthalmic-ultrasound-imaging",title:"Corrigendum to: A Brief Overview of Ophthalmic Ultrasound Imaging",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/69566.pdf",downloadPdfUrl:"/chapter/pdf-download/69566",previewPdfUrl:"/chapter/pdf-preview/69566",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/69566",risUrl:"/chapter/ris/69566",chapter:{id:"65491",slug:"a-brief-overview-of-ophthalmic-ultrasound-imaging",signatures:"David B. Rosen, Mandi D. Conway, Charles P. Ingram, Robin D. Ross and Leonardo G. Montilla",dateSubmitted:"November 6th 2018",dateReviewed:"December 12th 2018",datePrePublished:"February 5th 2019",datePublished:"September 4th 2019",book:{id:"8633",title:"Novel Diagnostic Methods in Ophthalmology",subtitle:null,fullTitle:"Novel Diagnostic Methods in Ophthalmology",slug:"novel-diagnostic-methods-in-ophthalmology",publishedDate:"September 4th 2019",bookSignature:"Anna Nowinska",coverURL:"https://cdn.intechopen.com/books/images_new/8633.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"261466",title:"Dr.",name:"Anna",middleName:"Karolina",surname:"Nowinska",slug:"anna-nowinska",fullName:"Anna Nowinska"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null}},chapter:{id:"65491",slug:"a-brief-overview-of-ophthalmic-ultrasound-imaging",signatures:"David B. Rosen, Mandi D. Conway, Charles P. Ingram, Robin D. Ross and Leonardo G. Montilla",dateSubmitted:"November 6th 2018",dateReviewed:"December 12th 2018",datePrePublished:"February 5th 2019",datePublished:"September 4th 2019",book:{id:"8633",title:"Novel Diagnostic Methods in Ophthalmology",subtitle:null,fullTitle:"Novel Diagnostic Methods in Ophthalmology",slug:"novel-diagnostic-methods-in-ophthalmology",publishedDate:"September 4th 2019",bookSignature:"Anna Nowinska",coverURL:"https://cdn.intechopen.com/books/images_new/8633.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"261466",title:"Dr.",name:"Anna",middleName:"Karolina",surname:"Nowinska",slug:"anna-nowinska",fullName:"Anna Nowinska"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null},book:{id:"8633",title:"Novel Diagnostic Methods in Ophthalmology",subtitle:null,fullTitle:"Novel Diagnostic Methods in Ophthalmology",slug:"novel-diagnostic-methods-in-ophthalmology",publishedDate:"September 4th 2019",bookSignature:"Anna Nowinska",coverURL:"https://cdn.intechopen.com/books/images_new/8633.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"261466",title:"Dr.",name:"Anna",middleName:"Karolina",surname:"Nowinska",slug:"anna-nowinska",fullName:"Anna Nowinska"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"10367",leadTitle:null,title:"Chitin and Chitosan - Physicochemical Properties and Industrial Applications",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThe book, Chitin and Chitosan - Physicochemical Properties and Industrial Applications, provides an overview of the extraction, modification, characterization, and application of chitin and chitosan derivatives from crustacean by-products and their physicochemical properties. It presents and explains important studies and develops new and innovative methods of biological and physicochemical analysis in the fields of organic and mineral environmental pollution, corrosion inhibitors, drug delivery systems, superabsorbent materials, nanotechnology, textiles, biotechnology, and biomedical sciences.
\r\n\r\n\tOur book will distinguish itself from competing volumes by discussing the synthesis, purification, analysis, and properties of chitin-chitosan polymers as a renewable source of natural biodegradable polysaccharides and also by presenting various practical and potential new applications of these materials. It is highly recommended for industrial personnel involved in bioprocesses, biochemistry, microbiology, bioengineering, food engineering, medical and pharmaceutical industries as well as for readers interested in environmental protection and who wish to specialize in chitin and chitosan derivative technologies.
",isbn:"978-1-78984-425-2",printIsbn:"978-1-78984-424-5",pdfIsbn:"978-1-83968-695-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"7c3368aba02cb516b5ef5e0711ce4da2",bookSignature:"Prof. Mohammed Berrada",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10367.jpg",keywords:"Chemistry of Chitosan, Synthesis, Modification, Drug Delivery Systems, Wound dressings, Hydrogels, Corrosion Inhibitors, Polysaccharide-Based Superabsorbents Materials, Bioactivity of Chitin, Bioactivity of Chitosan, Adsorption of Industrial Waste. Elimination of Industrial Waste",numberOfDownloads:396,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 4th 2020",dateEndSecondStepPublish:"October 2nd 2020",dateEndThirdStepPublish:"December 1st 2020",dateEndFourthStepPublish:"February 19th 2021",dateEndFifthStepPublish:"April 20th 2021",remainingDaysToSecondStep:"5 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in polymer science, involved in numerous university-industry transfer technology projects. Appointed head of the Innovation and Technology Platform at Hassan II University. Member of the Quebec Order of Chemists and holder of more than ten registered patents.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"224783",title:"Prof.",name:"Mohammed",middleName:null,surname:"Berrada",slug:"mohammed-berrada",fullName:"Mohammed Berrada",profilePictureURL:"https://mts.intechopen.com/storage/users/224783/images/system/224783.jpg",biography:"Professor Berrada joined the Hassan II University of Casablanca in 1994 and assumed many responsibilities which led him to head the Casablanca Innovation and Technology Platform. He has set up in his Laboratory of Biomolecules and Organic Synthesis, a research program in the fields of thermostable and photosensitive materials, intelligent polymers, hydrogels, and nanoparticles for drug delivery systems, biodegradable superabsorbents, and corrosion inhibitors. Professor Berrada received a Ph.D. in Polymer Science from the Macromolecular Sciences Division of Pierre and Marie Curie University in 1992, and another Ph.D. in Organic Chemistry from Ben M\\'Sik Faculty of Sciences in 1998. He completed postdoctoral training at the Engineering Department of Tokyo University of Agriculture and Technology in Japan in 1994. From 2006 to 2009, Professor Berrada was Director of Research and Development Department at Intersand Inc., where he patented the innovative OdourLock litter technology which was a breakthrough and a huge success for the company. He joined Lysac Technologies in January 2003 and took on the task of creating and leading the Department of Polymer Chemistry. Prof. Berrada has also been involved in many University-Industry transfer technology projects. In 1998, he joined the Department of Radiation Oncology at McGill University. In 2000, he joined Biosyntech Inc. a Canadian pharmaceutical industry and was Director of the Therapeutic Delivery Department. Professor Berrada has published over 150 peer-reviewed scientific articles and conference proceedings and is the author of several published and industrially exploited patents.",institutionString:"Laboratory of Biomolecules and Organic Synthesis",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Hassan II Casablanca",institutionURL:null,country:{name:"Morocco"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:[{id:"75077",title:"The Application of Chitosan-Based Compounds against Metallic Corrosion",slug:"the-application-of-chitosan-based-compounds-against-metallic-corrosion",totalDownloads:41,totalCrossrefCites:0,authors:[null]},{id:"75105",title:"Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs by Co-Milling Technique",slug:"ternary-solid-dispersion-strategy-for-solubility-enhancement-of-poorly-soluble-drugs-by-co-milling-t",totalDownloads:33,totalCrossrefCites:0,authors:[null]},{id:"75157",title:"Innovative Separation Technology Utilizing Marine Bioresources: Multifaceted Development of a Chitosan-Based System Leading to Environmentally-Friendly Processes",slug:"innovative-separation-technology-utilizing-marine-bioresources-multifaceted-development-of-a-chitosa",totalDownloads:32,totalCrossrefCites:0,authors:[null]},{id:"74144",title:"A Novel Drug Delivery System Based on Nanoparticles of Magnetite Fe3O4 Embedded in an Auto Cross-Linked Chitosan",slug:"a-novel-drug-delivery-system-based-on-nanoparticles-of-magnetite-fe3o4-embedded-in-an-auto-cross-lin",totalDownloads:101,totalCrossrefCites:0,authors:[null]},{id:"74561",title:"Gastrointestinal Delivery of APIs from Chitosan Nanoparticles",slug:"gastrointestinal-delivery-of-apis-from-chitosan-nanoparticles",totalDownloads:113,totalCrossrefCites:0,authors:[null]},{id:"74941",title:"Modulating the Physicochemical Properties of Chitin and Chitosan as a Method of Obtaining New Biological Properties of Biodegradable Materials",slug:"modulating-the-physicochemical-properties-of-chitin-and-chitosan-as-a-method-of-obtaining-new-biolog",totalDownloads:34,totalCrossrefCites:0,authors:[null]},{id:"74877",title:"Characterization of Chitosan Membrane Modified with Silane-Coupled Nanosilica for Polymer Electrolyte",slug:"characterization-of-chitosan-membrane-modified-with-silane-coupled-nanosilica-for-polymer-electrolyt",totalDownloads:46,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.p@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. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6694",title:"New Trends in Ion Exchange Studies",subtitle:null,isOpenForSubmission:!1,hash:"3de8c8b090fd8faa7c11ec5b387c486a",slug:"new-trends-in-ion-exchange-studies",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6694.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"42240",title:"Overcoming Resistance to BRAF and MEK Inhibitors by Simultaneous Suppression of CDK4",doi:"10.5772/53620",slug:"overcoming-resistance-to-braf-and-mek-inhibitors-by-simultaneous-suppression-of-cdk4",body:'Melanoma is one of the most prevalent malignancies and has a very poor prognosis. Mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF) occur in approximately 50% of melanomas [4]. While the response to selective BRAF inhibitors (BRAFi) in BRAF-mutant melanoma is encouraging, virtually all patients rapidly develop secondary resistance [6, 7]. Based on the finding that the mitogen activated protein kinase/ERK kinase (MEK)-extracellular signal regulated kinase (ERK) pathway is frequently reactivated by various BRAFi resistance mechanisms, a combination trial of a selective mutant BRAF inhibitor (dabrafenib, GSK2118436) with a MEK inhibitor (trametinib, GSK1120212) is underway and has achieved clinical responses in 17% and disease control in 67% in patients who failed prior single-agent treatment with a BRAF inhibitor [9]. While these results are promising, there is a critical need to overcome resistance to BRAF and MEK inhibitors. The clinical efficacy of BRAFi and MEKi therapy is believed to rely on a functional retinoblastoma (RB) axis to inhibit cell proliferation. The inhibitor of cyclin-dependent kinase 4A (INK4A) gene encode the p16 protein, a critical cell cycle regulator that interacts with cyclin dependent kinase (CDK) 4, inhibiting its ability to phosphorylate and inactivate RB [12, 13]. Genetic disruption of INK4A occurs in approximately 50% of melanomas irrespective of BRAF mutation and has been detected in melanoma cells that developed resistance to BRAFi. Of note, cyclin D is still expressed even in the setting of maximum tolerance dosing of BRAF inhibitor [7]. We have reported that combination of BRAFi or MEKi with the expression of wild-type INK4A or a CDK4 inhibitor (CDK4i) significantly suppresses growth and enhances apoptosis in melanoma cells [1-3]. Currently, CDK4 inhibitors are in active clinical development (http://clinicaltrials.gov/). Based on our previous work and recent insights into molecular mechanisms of resistance to BRAF and MEK inhibitors, we hypothesize that simultaneous suppression of CDK4 is an effective strategy to overcome resistance to BRAF and MEK inhibitors. BRAF mutation assays have been used to guide treatment with BRAF and MEK inhibitors, development of sensitive and specific INK4A/p16 assays may serve as predictive biomarkers for treatment with CDK4 inhibitors.
Constitutive activation of RAS-RAF-MEK-ERK signaling pathway in melanomas.\n\t\t\t\tNRAS and BRAF mutations were found respectively in 10-20% and 60-80% melanomas [4]. NRAS and BRAF are components of the RAS-RAF-mitogen activated protein kinase/ERK kinase (MEK)-extracellular signal regulated kinase (ERK) signaling pathway (Fig. 1) [5]. This signaling pathway plays an essential role in cell proliferation, differentiation and survival [5, 14, 15]. Constitutive activation of the ERK pathway has been shown to mediate the transforming activity of mutant BRAF in melanoma cells [16-18]. Suppression of mutant BRAF expression has been shown to inhibit ERK pathway activation and subsequent suppression of melanoma cell proliferation and survival in vitro and in vivo [19-21]. Our previous data revealed that the inhibition of mutant BRAF decreased levels of phospho-ERK (p-ERK), a marker of ERK pathway activation in melanoma cells [5, 14, 15].
The high frequency of BRAF mutation in melanomas makes it an ideal target for therapy. Because normal cells require wild-type BRAF for survival [22], specifically inhibiting mutant, but not wild-type BRAF in tumor cells could avoid toxic side effects generated by targeting normal cells. The finding that mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF) occur in approximately 50% of melanomas led to extensive investigation of targeting BRAF for melanoma treatment, resulting in the first approved mutant specific BRAF inhibitor for treatment of advanced melanoma.
Combine BRAF and MEK inhibitors with chemotherapeutic agents. Intrinsic therapy resistance is a major limitation in the treatment of malignant melanomas. The mechanisms involved in the resistance of melanomas are largely unknown [23, 24]. It is believed that apoptosis and cytostasis (growth arrest/differentiation) are two of the main cellular responses to anticancer agents and loss of either process promotes treatment failure [25-27]. Activating BRAF mutations could drive cell proliferation and increase the cell death threshold through ERK pathway or alternative mechanisms [28-30], resulting in the blockage of both cytotoxic and cytostatic effects of therapeutic drugs [14, 31, 32]. It has been shown that inhibition of ERK pathway sensitizes melanoma cells to apoptosis induced by DNA damaging agents including cisplatin and ultra-violate (UV) irradiation [32, 33]. Rational combination of BRAF and MEK inhibitors with selective chemotherapeutic agents, for example, dacarbazine (DTIC), may generate additive/synergistic therapeutic effects.
ERK pathway activation and p16 in melanocytic lesions. Melanocytic lesions can be grouped into two main categories: nevi and melanomas. Nevi are divided into several different types based on histology. These include acquired melanocytic nevi, congenital melanocytic nevi, blue nevi, Spitz nevi, and dysplastic nevi. Melanoma can be further divided based on clinical and traditional histological methods as superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, and nodular melanoma. In early stages of melanomas, neoplastic cells are confined to the epidermis or with microinvasion into the dermis. In advanced melanomas, cancer cells expand in the dermis and generate tumor nodules and have a high potential for metastatic spread. In the metastatic phase, cancer cells disseminate to lymph nodes or distant organs [34, 35]. For the early diagnosed and localized melanomas, surgery is the choice of treatment. But there is currently no effective treatment for invasive and metastatic melanomas. Patients with late stage melanomas have a high mortality rate and life expectancy averages approximately 6-8 months after diagnosis.
p16-cyclin D/CDK4 modifies the outcome of RAS/RAF/MEK/ERK signaling activation. RAF relays RAS signals through MEK to ERK. The activation of this pathway has multiple effects on cell proliferation, differentiation, and survival depending on the cellular contexts [5]. Constitutive activation of growth factor signaling pathways or NRAS and BRAF activating mutations can trigger over-expression of p16 leading to proliferative senescence, which manifest as benign nevus [10, 11]. Loss of p16 by genetic and epigenetic changes allows activation of cyclin D/CDK4 and inactivation of RB, leading to E2F activation, cell cycle progression from G1 to S phase, cell proliferation and tumor formation [12, 13]. Further genetic changes cause tumor progression to malignant melanoma. Of the three RAS and three RAF genes, NRAS and BRAF are mutated in melanoma [4].
Of note, in addition to melanomas, BRAF mutations are found at high frequencies (70-80%) in benign melanocytic nevi [36, 37]. There are a large numbers of melanocytic nevi in the general population compared to the relatively low incidence of melanomas [34, 35]. Clinically, it is known that nevi often regress over time. This suggests that BRAF mutations alone are insufficient to induce malignant transformation in nevus cells. The growth arrest of nevi is believed to result from oncogene-induced senescence, which is known as a protective mechanism against unlimited proliferation that could result from BRAF mutations and activation of the ERK signaling pathway (nevus in Fig. 1) [10, 11]. Tumor suppressor genes have been found to be involved in senescence process. For example, p16 is one tumor suppressor found to be induced by ERK activation and telomere attrition involving cell senescence [8, 10, 11, 38]. The tumor suppressor p16 is encoded by INK4A (Fig. 2) and is often inactivated in a variety of human cancers, including 30-70% in melanomas [39, 40]. Most melanomas, but not nevi, have lost the expression of wild-type INK4A, either through DNA deletion/mutation or promoter hypermethylation [41-45]. It is possible that the loss-of-function of p16 in melanomas may make it possible to bypass the cellular senescence mechanism and function as an anti-tumor mechanism against ERK signal activation triggered by NRAS and BRAF oncogenic mutation (Fig. 1) [11, 46, 47].
Indirect evidence from cultured cells and animal models reveal that there may be a cooperative role between the constitutive activation of ERK pathway and the loss of p16 in tumor progression. Daniotti et al. [48] reported the co-existence of BRAF mutations and INK4A mutations/deletions/loss-of-expression in 26 of 41 (63%) short-term cell lines obtained from melanoma biopsies. Recent evidence suggests that growth arrest in benign nevi is due to cell senescence and that p16 at least partially contributes to the process of senescence in nevi [11, 46, 47].
INK4A and ARF share sequences in the CDKN2A locus. Exons are shown as rectangles. Alternative first exons (1α and 1β) are transcribed from different promoters (arrows). Exons 1α and 1β are spliced to the same splicing acceptor site in exon 2 but are translated in alternative reading frames. INK4A coding sequences in exons 1α, 2, and 3 and ARF coding sequences in exons 1β and 2 are indicated by different shading patterns. Adopted from Sherr [8]. INK4A lesions detected by FISH and Sanger sequencing may also affect ARF.
Resistance of melanoma to BRAF and MEK inhibitors. The finding that mutations in BRAF occur in melanomas led to extensive investigation of targeting BRAF for melanoma treatment. While the response to selective mutant BRAF inhibitors (BRAFi) in BRAF-mutant melanoma is encouraging, virtually all patients rapidly develop secondary resistance. Based on the finding that the mitogen activated protein kinase/ERK kinase (MEK)-extracellular signal regulated kinase (ERK) pathway is frequently reactivated by various BRAFi resistance mechanisms, the first combination trial of a selective BRAF inhibitor (dabrafenib, GSK2118436) with a MEK inhibitor (trametinib, GSK1120212) is underway and has achieved clinical responses in 17% and disease control in 67% in patients who failed prior single-agent treatment with a BRAF inhibitor [9]. While these results are promising, again, the treatment response is short-lived; there is a critical need for additional strategies to overcome this deadly disease [49, 50].
There is evidence that treatment response to BRAFi and MEKi relies on a functional p16-cyclin D-CDK4-retinoblastoma (RB) axis. INK4A mutations/deletions occur in most of the melanoma cells that demonstrated resistance to BRAFi (e.g.; 451Lu, Mel1617, WM983, WM902, A375, M238, SKMEL28, and A2058) [51-57]. Over-expression of cyclin D and deletion of RB confer treatment resistance to BRAFi [56, 58]. Unlike other components of the p16-cyclin D-CDK4-RB axis that harbor genetic changes at low frequency in melanomas (e.g., CDK4 and RB each approximately 3%) [59], and may not overlap with BRAF mutation (e.g., amplification of cyclin D1 gene CCND1 and CDK4) [60], INK4A lesions are frequently detected in melanomas (~50%) irrespective of BRAF mutation [59-61]; therefore, abnormal p16 is a major mechanism of RB-axis attenuation in BRAF-mutant melanoma cells. p16 binds to and inhibits the catalytic activity of CDK4, representing a crucial gatekeeper at the G1>S checkpoint [62, 63]. The relative abundance of CDK4-cyclin D and p16 can determine the activity of the CDK4 kinase, thus regulate RB and cell-cycle progression [62, 63]. BRAF-MEK-ERK signaling pathway upregulates/activates the cyclin D-CDK4 enzyme, which phosphorylates and inactivates RB leading to cell cycle progression in melanoma cells; such an effect can be blocked by tumor suppressor p16 [2, 3, 61]. Several pathways that confer BRAFi resistance, including COT, RAF splicing variants, RAF dimerization, NRAS, IGF-1R, and RTK can reactivate cyclin D-CDK4 through signaling pathways including MEK-ERK as well as PI3K-AKT [51-53, 55, 56, 64]. Although the addition of MEKi to BRAFi may suppress reactivation of MEK-ERK-cyclin D-CDK4, alternative resistance mechanisms, including growth factor receptors and PI3K-AKT pathway can activate cyclin D-CDK4 [52, 55, 64-66] in the absence of a functional p16, adding CDK4 inhibitor may help overcoming resistance to BRAFi and MEKi (Fig. 3). BRAF mutation assays have been used to direct BRAFi treatment. There is significant genotypic heterogeneity of INK4A including bi- and mono-allelic deletions, nonsense and missense mutations, and also different levels of epigenetic modification by promoter hyper-methylation. Characterization of whether these INK4A changes correlate with different treatment resistance to BRAFi/MEKi/CDK4i may lead to companion molecular tests to better manage melanoma patients under BRAFi, MEKi, and CDK4i therapy.
As shown in Fig. 4, in addition to BRAF and MEK inhibitors, several drugs designed to inhibit the activity of CDK4 are in active clinical trials for melanoma and other cancers including LEE011 (Novartis Pharmaceuticals ), LY2835219 (Eli Lilly and Company), PD-0332991 (Pfizer) (http://clinicaltrials.gov/).
The presence of functional p16 may offset resistance mechanisms that lead to activation of cyclin D-CDK4 in melanomas that progressed under BRAFi/MEKi treatment, whereas abnormal p16 may predict treatment failure in melanomas that develop resistance mechanisms un-opposed by BRAFi + MEKi treatment.
Combined inhibition of CDK4 potentiate the effect of MEKi. In order to design better strategies for the treatment of this devastating disease a better understanding of melanoma biology is necessary. Multiple genetic and environmental factors have been linked to the development and aggressive behavior of melanomas [49, 50]. BRAF mutations have been identified in approximately 60–80% of human melanomas, while NRAS mutations occur in about 10% of melanomas [4, 67]. Both NRAS and BRAF are components of the RAS-RAF-mitogen activated protein kinase/ERK kinase (MEK)-extracellular signal regulated kinase (ERK) signaling pathway. Apart from NRAS and BRAF mutation, other factors have been identified leading to constitutive activation of the ERK signaling, for example, amplification and somatic mutations of KIT and constitutive expression of hepatocyte growth factor (HGF) and fibroblast growth factor (FGF) [49, 50]. ERK signaling pathway controls cell proliferation, differentiation, and survival, and has been shown to be a targetable pathway in melanoma treatment [5, 14, 15, 68].
Deregulation of the p16-cyclin D:cyclin-dependent kinases (CDK) 4/6-retinoblastoma (RB) pathway is a common paradigm in malignancy including melanoma [12, 13, 39] and represents another attractive target in melanoma treatment. The great majority of melanoma cells have lost or reduced expression of wild-type INK4A caused by genetic and epigenetic changes including mutation, deletion, and promoter hypermethylation [69, 70]. Loss of p16 leaves cyclin D:CDK4 unoppressed to phosphorylate and inactivate RB and cell cycle progression [8, 13, 49, 50, 69, 70]. Amplification of cyclin D1 and CDK4 genes have also been identified, mostly in melanomas that harbor wild-type NRAS and BRAF [58]. A germ-line Arg24Cys (R24C) mutation in CDK4 was identified in familial melanoma patients [40, 58]. This mutation abolishes CDK4 inhibition by p16 and thus is believed to be a functional equivalent to p16 loss. Both ERK signaling and CDK4 kinase have been shown to regulate RB protein and cell cycle progression [58, 61]. Activation of BRAF-MEK-ERK signaling pathway can cause upregulation of cyclin D resulting in the activation of CDK4 [61]. Activated CDK4 phosphorylates and inactivated RB proteins result in the liberation of E2F transcription factors and cell cycle progression. It has been shown that in advanced melanoma cells, RB is highly phosphorylated and inactive, and E2F transcriptional activity is constitutively high ([5, 12].
Various resistance mechanisms have been identified that contribute to treatment failure of melanoma patients to BRAFi and MEKi therapy. Loss of p16 may represent a common gateway permitting the phenotypic expression of several resistance mechanisms to BRAFi and MEKi (Figs. 1 and 3), a hypothesis that has not been and is waiting to be tested in clinical trials. We reported that simultaneous expression of BRAF siRNA and INK4A cDNA in melanoma cells leads to dramatically increased apoptosis (17), suggesting that correcting the two most common genetic lesions could be effective in melanoma treatment. It is unclear whether the effect is specific to BRAF and INK4A or can be generalized to other components of the ERK and RB pathways. It has been shown that BRAF and INK4A may have activities independent of the corresponding canonical ERK and RB pathways, and the two pathways also mediate cellular signals independent of aberrant BRAF and INK4A. For example, RAF can act through apoptosis signal-regulating kinase-1 (ASK1)/c-Jun-NH2-kinase or mammalian sterile 20- like-kinase 2 (MST2) pathways ([71]; cyclin D:CDK4 can be activated by enhanced phosphatidylinositol 3-kinase (PI3K) and wingless (WNT) signaling pathways in melanomas [27, 72]. Therefore, we tested PD98059 and 219476, commercially available inhibitors of MEK and CDK4, respectively, in human melanoma cells.
BRAF, MEK and CDK4 inhibitors are in active clinical development and may be used in combination to increase treatment efficacy. Melanoma cells acquire resistance to BRAF and MEK inhibitors by mechanisms including activation of growth factor receptors and RAS signaling pathways. Activation of growth factor receptors and RAS pathways can cause overexpression of cyclin D and activation CDK4 kinase, leading to cell cycle proliferation, which is believed to play major roles in the emergence of treatment resistance. Adding CDK4 inhibitors may overcome resistance to treatment targeting BRAF and MEK. Apart from Vemurafenib (PLX4032, RO5185426) (Hoffmann-La Roche) that has been U.S. Food and Drug Administration (FDA) approved for treatment of melanoma, other mutant BRAF inhibitors including PLX3603 (RO5212054) (Hoffmann-La Roche) and GSK2118436 (dabrafenib) (GlaxoSmithKline) are in active clinical trials. There are clinical trials of MEK inhibitors PD-325901 (Pfizer), GSK1120212 (GlaxoSmithKline), MSC1936369B (EMD Serono), ARRY-438162 (MEK162) (Array BioPharma), AZD6244 (AstraZeneca), and BAY86-9766 (Bayer). Several drugs designed to inhibit the activity of CDK4 are also in active clinical trials for melanoma and other cancers including PD-0332991 (Pfizer), LY2835219 (Eli Lilly and Company), LEE011 (Novartis Pharmaceuticals) (http://clinicaltrials.gov/).
MEK inhibitor PD98059 (Calbiochem, San Diego, CA) was dissolved in dimethyl sulfoxide (DMSO) as a 50 mM stock solution, aliquoted and stored at -20C. CDK4 inhibitor 219476 (Cat. # 219476, Calbiochem, San Diego, CA) was dissolved in DMSO as a 2 mM stock solution and stored at 4C. Human melanoma cell lines 624Mel, A101D, and OM431 were kindly provided by Dr. Stuart Aaronson (Mount Sinai School of Medicine, New York, NY). Cells were maintained in Dulbecco\'s modified Eagle medium (DMEM) (Mediatech, Herndon, VA) supplemented with 10% fetal bovine serum (FBS; Sigma, St. Louis, MO) and 50 units/mL penicillin–streptomycin (Invitrogen, Carlsbad, CA) in a humidified incubator at 37C with 5% CO2. CellTiter 96® R AQueous One Solution Cell Proliferation Assay (MTS) kit (Promega Corporation, Madison, WI) was used to measure dehydrogenase enzyme activity found in metabolically active cells. Melanoma cells were seeded in a 96 well plate at a density of 2 ×104 cells/well in DMEM with 5% FBS. On the second day, the culture medium in each well was changed to 150 μL DMEM without phenol red and supplemented with 0.5% FBS. Cells were treated in triplicate for 24 and 48 hr with either vehicle solvent (control), 25 μM PD98059, 1 μM 219476, or their combination for 624Mel; control solvent, 50 μM PD98059, 1 μM 219476, or their combination for A101D; and control solvent, 50 μM PD98059, 2 μM 219476, or their combination for OM431 cells. CellTiter 96® AQueous One Solution Reagent (30 μL) was then added per well and cell cultures were returned to the incubator for another 4 hr. Subsequently, the absorbance of each well was measured at 450 nm with a Vmax Kinetic Microplate Reader (Molecular Devices, Sunnyvale, CA). The absorbance of the well with only medium and CellTiter 96® AQueous One Solution Regent was background and subtracted from each sample well. The average and standard deviation of three wells with the same treatment were calculated.
Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling of DNA fragments (TUNEL) method using in situ Cell Death Detection Kit, Fluorescein (Roche Applied Science, Indianapolis, IN). Melanoma cells were seeded in triplicate in a 6 well plate at a density of 2 × 105 cells/well in DMEM with 5% FBS and antibiotics. On the second day, cells were treated with PD98059 and 219476 under the same conditions as the MTS assay. After treatment with the respective chemicals for 48 hr, cells were harvested to detect apoptotic cells using the TUNEL assay according to the manufacturer’s instructions (Roche Applied Science, Indianapolis, IN). Using a cytospin, cells were placed onto Polysine glass slides (Fisher Scientific, Fair lawn, NJ), fixed in 4% paraformaldehyde (Fisher Scientific, Fair lawn, NJ) at room temperature for 1 hr, then permeabilized with a fresh prepared mixture of 0.1% Triton X-100 (MP Biomedicals, Inc. Solon, OH) and 0.1% sodium citrate (Fisher Scientific, Fair lawn, NJ) for 5 min at room temperature. Slides were rinsed with phosphate buffered saline (PBS), air dried, and incubated with 50 μL of TUNEL reaction mixture, containing terminal deoxynucleotidyl transferase (TdT)- and fluorescein isothiocyanate (FITC)-labeled dUTP, in a dark humidified atmosphere at 37C for 2 hr. For nuclei counterstaining, slides were cover-slipped with Vectashield mounting medium containing DAPI (Vector Laboratories, Burlingame, CA). Fluoresce positive cells were viewed with a Nikon Eclipse TE 2000-U inverted microscope (Nikon Corp., Tokyo, Japan) equipped with a FITC filter and a DAPI filter. The percentage of apoptotic cells was determined for each sample in a blind fashion by counting the number of green fluorescent nuclei (TUNEL positive) among a total of 300 or more 4\'-6-diamidino-2-phenylindole (DAPI)-stained blue nuclei in three random fields at magnification of 20/0.5 (objective) as described previously [1-3].
For Western blotting, 1 × 106 melanoma cells were seeded in a cell culture dish (10 cm) in DMEM containing 5% FBS and antibiotics. On the second day, cells were treated with PD98059 and 219476 at the same concentration as described in the MTS assay. For cell cycle regulators cyclin-dependent kinase inhibitor p27 kinase interacting protein 1 (KIP1) and RB, cells were treated with the chemicals in medium with 5% FBS for 24 hr and then harvested. For apoptosis-related protein B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (BCL2), BCL2-like 1 (BCL2L1 or bcl-xL), inhibitor of apoptosis family (IAP) protein baculoviral IAP repeat-containing 5 (BIRC5 or survivin), apoptosis facilitator BCL2 interacting mediator (BIM), cysteine-aspartic acid protease (caspase) 3, and poly (ADP-ribose) polymerase (PARP), cells were treated with the various chemicals in DMEM with 5% FBS for 48 hr and then harvested. For phospho- and total-ERK, cells were treated with the chemicals in medium with 0.5% FBS for 18 hr and then harvested. Western blots were performed as described [1-3]. Briefly, harvested cells were lysed in Lysis Solution (Cell Signaling, Danvers, MA) supplemented with Complete Mini Protease Inhibitor Cocktail Tablets (Roche Diagnostics Corporation, Indianapolis, IN). Protein concentration of lysates was determined using the Quick Start Bradford 1 × Dye Reagent (Bio-Rad, Hercules, CA). Lysates were separated in either 12 or 15% SDS-polyacrylamide gel, electrophoretically transferred to Immobilon-P membrane (Millipore Corp, Billerica, MA), and probed with primary antibodies followed by incubation with horseradish peroxidase-conjugated secondary antibodies. The following antibodies were used: BCL2 and tubulin, beta (Sigma-Aldrich, St. Louis, MO); BCL2L1 and BIRC5 (Santa Cruz Biotechnology, Santa Cruz, CA); phosphor-ERK, total ERK, Caspase 3, PARP, and PhosphoPlus(R) RB (Ser780, Ser795, Ser807/811) Antibody Kit (Cell Signaling, Boston, MA); p27KIP1 (BD Biosciences, San Jose, CA); and peroxidase-conjugated antimouse and antirabbit secondary antibodies (Calbiochem, San Diego, CA). Immunoreactive bands were visualized with SuperSignal chemiluminescence substrate (Pierce, Rockford, IL). The blots were exposed to blue sensitive blue X-ray film (Phenix Research, Candler, NC) [1-3].
Regulation of ERK phosphorylation, RB phosphorylation, and p27KIP1 expression by PD98059 and 219476, alone and in combination. Human melanoma cell lines 624Mel, A101D, and OM431 were treated with either vehicle solvent (Con), PD98059 (PD), 219476 (CD), or PD98059 plus 219476 (PC) as described in Materials and methods. Western blot was performed using 20 μg total cell lysates, tubulin was used as loading control, as described previously [1-3].
Cytotoxicity by PD98059, 219476, and combinatorial treatment. MTS cytotoxicity assay was performed in 624Mel, A101D, and OM431 cells after (A) 24-hr and (B) 48-hr treatment in medium supplemented with 0.5% FBS. The results are given as means ± SD from three independent tests, as described previously [1-3].
We have shown previously that human melanoma cell lines 624Mel, A101D, and OM431 cell lines harbor heterozygous BRAF T1799A mutation and loss of wild-type INK4A [1, 61]. Cells were treated, alone or in combination, with MEK inhibitor PD98059 (22) and CDK4 inhibitor 219476 (23). As anticipated, ERK phosphorylation was reduced in cells treated with PD98059, and PD98059 plus 219476 (Fig. 4A). Phosphorylation of S780, S795, and S807/811 of RB, known cyclin D:CDK4 and cyclin E:cyclin dependent kinase 2 (CDK2) targets (7),was decreased in cells treated with either PD98059 or 219476 (except S780 and S807/811 in OM431 cells), and further reduced in cells with combinatorial treatment (Fig. 4B). Of note, total RB was decreased under combinatorial treatment with PD98059 and 219476 in all three melanoma cells (Fig. 4B). Levels of p27KIP1, a negative regulator of cyclin E:CDK2, were increased in cells treated with either PD98059 or 219476, and further increased in cells with combinatorial treatment (Fig. 4C).
PD98059 and 219476 inhibit tumor cell growth in a dose dependent manner [1, 2]. In order to make it possible to monitor the additional therapeutic effects of the combinatorial treatment, both chemicals were used at dosages lower than that which would lead to maximal effect by either agent. The cytotoxicity of PD98059 and 219476 was examined 24 and 48 hr after treatment using the MTS assay that measures the dehydrogenase enzyme activity found in metabolically active cells. After 24-hr treatment, there was no significant difference in cell viability between control, single, and combined treatment groups of 624Mel cells (p = .05, R-square 0.57320, ANOVA). Small but significant differences were observed in A101D and OM431 cells (p = .05, R-square 0.7136 and 0.8091 in A101D and OM431 cells, respectively, ANOVA); the differences were between the combined treatment vs. control and PD98059 in A101D cells, and between the combined treatment vs. control and single treatment of either PD98059 or 219476 in OM431 cells (Figure 2(a), HSD Test at 0.05 significance level). After 48-hr treatment, a significant difference in MTS counts existed for the control, PD98059, 219476, and PD98059 plus 219476 groups in all the three cell lines (p <.0001, R-square 0.981444, 0.956956, and 0.991102 in 624Mel, A101D, and OM431, respectively, ANOVA). Further analysis showed that simultaneous treatment with PD98059 and 219476 after 48-hr treatment resulted in significantly reduced numbers of cell survival than control-treatment or monotreatment as measured by MTS in all the three cell lines (Fig. 6B, HSD Test at 0.05 significance level).
Next, we performed the TUNEL DNA fragmentation assay to identify loss of viability due to programmed cell death after 48-hr treatment. As shown in Figure 3, at the drug concentrations used, significantly different levels of apoptosis exist among control for PD98059, 219476, and combinatorial treatment groups (p < .0001, R-square 0.973862, 0.990697, and 0.987900 in 624Mel, A101D, and OM431, respectively, ANOVA). Treatment with PD98059 alone resulted in no difference in apoptosis over controls in all three cell lines; 219476 enhanced apoptosis in OM431 but not in the other two cell lines; However, combined treatment dramatically increased apoptosis over that seen for the control-treatment and monotreatment (Fig. 7. HSD Test at 0.05 significance level).
As apoptosis was the major effect observed when melanoma cells were exposed simultaneously to MEK and CDK4 inhibitors, we examined the expression of several pro-apoptotic and anti-apoptotic proteins. Mono-treatment with PD98059 or 219476 caused a decreased or no change in the expression of anti-apoptotic proteins BCL2, BCL2L1, and BIRC5. While there were variations in the patterns of expression of BCL2, BCL2L1, and BIRC5 among the different cell lines (Fig. 8), combinatorial treatment caused a comprehensive down-regulation of the proteins in all three cell lines (Fig. 8). In addition, apoptosis facilitator BIM-EL was increased following treatment with PD98059 and PD98059 plus 219476 in all three cell lines. It was also increased in OM431 cells following treatment with 219476. Consistent with increased apoptosis, caspase 3 was activated by simultaneous treatment with PD98059 plus 219476 in all three cell lines, as shown by decreased procaspase 3, increased levels of the active form of caspase 3 (cleaved caspase 3), and degradation of PARP, a direct substrate of active caspase 3 (Fig. 8).
MEK and CDK4 inhibitors induce apoptosis of melanoma cells. TUNEL Assay was performed in 624Mel, A101D and OM431 cells after 48h treatment with vehicle solvent, PD98059, 219476, or PD98059 plus 219476 in medium with 0.5% FBS. The results were given as means ± SD from three independent assays, as described previously [1, 2].
Changes in the expression of pro-survival and pro-apoptotic proteins. Cells were treated with solvent vehicle control (1), PD98059 (2), 219476 (3), and PD98059 plus 219476 (4) for 48 h in medium containing 5% FBS. Western blotting of 20 μg total cell extracts from 624Mel, A101D and OM431 cells using BCL2, BCL2L1, BIRC5, BIM, caspase-3, and PARP antibodies; tubulin was used as loading control, as described previously [1, 2].
In this study, we simultaneously inhibited MEK and CDK4 kinases using pharmacological inhibitors PD98059 and 219476 and observed significantly increased apoptosis compared to control and single agent treatment. This is consistent with our previous report that simultaneous knockdown of BRAF using small interfering RNA (siRNA) and expression of INK4A cDNA in melanoma cells leads to a significant increase in apoptosis [1, 3]. These results demonstrate that an increase in apoptosis can be achieved through combinatorial targeting of ERK and RB pathways. It has been well established that constitutive activation of the ERK signaling induces the expression of cyclin D [1, 2, 61], which binds to and activates CDK4 leading to the phosphorylation of RB protein facilitating cell cycle entry [1, 2, 61]. Consistent with an epistatic regulation between ERK pathway and cyclin D:CDK4, amplification of cyclin D1, and CDK4 genes have been identified mainly in melanomas that harbor wild-type NRAS and BRAF [58, 60]. Additionally, cyclin D:CDK4 mediates resistance to inhibitors of the ERK signaling pathway [58]. Therefore, the enhanced apoptosis and decreased proliferation by simultaneously inhibiting ERK and RB pathways could result from the double hitting of ERK-cyclin D:CDK4-RB that regulate cell cycle progression and cell survival. Alternatively, in support of our previous results that BRAF and INK4A have a nonlinear functional interaction [1, 61], additional cellular processes could be affected when cells are exposed to both PD98059 and 219476. ERK pathway has pleiopotent activities that regulate cell proliferation, survival, and differentiation through both cyclin D:CDK4 dependent and independent routes [5, 61]. Likewise, cyclin D:CDK4 can be regulated and converges multiple cellular signals. For example, while PI3K signaling can activate CDK4 through downregulation of INK4A and upregulation of cyclin D [73], WNT signaling can turn on CDK4 through suppression of INK4A transcription [72], It is conceivable that inhibition of MEK and CDK4 not only affects ERK and RB pathways, but also PI3K, WNT, and other ERK signaling activities not mediated through the RB pathway. Therefore, simultaneous targeting of both ERK and RB pathways can generate enhanced effects by targeting both linear and nonoverlapping activities.
Apoptosis resistance is a critical factor for therapy failure in melanoma patients. Encouragingly, combined treatment with PD98059 and 219476 leads to significant apoptosis in all the three melanoma cell lines studied (Fig. 7). The apoptotic rate caused by the combined treatment is higher than the combined apoptosis by monotreatment, suggesting that MEK and CDK4 kinases mediate each other’s pro-survival effect. The apoptotic effect is associated with changes of apoptosis-related proteins (Fig. 8). PD98059 and 219476 combined treatment leads to significant down-regulation of the pro-survival proteins BCL2, BCL2L1, and BIRC5, and up-regulation of the pro-apoptotic protein BIM. We showed previously that BCL2 and BIM were regulated by BRAF and INK4A [1, 61]. BCL2L1 and BIRC5 are highly expressed in melanoma cells, and increased expression correlates with tumor progression [74, 75]. A straightforward explanation for the observed apoptosis is that the changes in the pro-apoptotic and anti-apoptotic factors offset the balance and lead to apoptosis [1]. Sequencing analysis of TP53 cDNA [1, 3] showed that 624Mel and OM431cells respectively harbor a T1076G (Cys275Trp) and a G1048A (Gly266Glu) mutations in the DNA binding domain that is likely to compromise the transcription and apoptosis function of p53 [76]. No TP53 mutation has been detected in A101D cells. Although apoptosis is enhanced in all the three cell lines, it is more pronounced in A101D than 624Mel and OM431 cells (Fig. 7), suggesting that TP53 status may influence the magnitude of apoptosis. Combinatorial-treated cells have further inhibited phosphorylation of ERK and RB, reduced total RB, and increased expression of p27KIP1 (Fig. 5). We observed similar effects on ERK and p27KIP1 in a previous report of simultaneous expression of BRAF siRNA, and INK4A cDNA in melanoma cells [1, 3]. Yu et al. demonstrated that loss of Rb causes apoptosis without effect on cell proliferation [77], and Wang et al. found that overexpression of p27KIP1 leads to apoptosis in melanoma cells [78]. The mechanisms of these changes in relationship to each other and to the observed cooperative effects need to be further investigated. To our knowledge, this study is the first to demonstrate that combined inhibition of MEK and CDK4 using pharmacological inhibitors can cooperate to trigger significant apoptosis in melanoma cells. Deregulation of the RAS-RAF-MEK-ERK and p16-cycylin D:CDK4-RB pathways are common in human malignancies and appears to be important for melanoma development. There has been significant effort to target components of these pathways in cancer treatment. Pharmacologic agents targeting components of the ERK and RB pathways have been developed. However, clinical studies as monotherapy showed that the clinical responses have failed expectations and maximum tolerated doses are often reached before reaching clinical efficacy. Our current study further reinforces the notion that combination targeting of ERK and RB pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations.
Development of biomarkers to predict treatment response to BRAF, MEK, and CDK4 inhibitors. Apart from BRAF mutation, there is no other validated molecular assay to direct BRAFi and MEKi treatment. Comprehensive and standardized INK4A molecular assays have not been established in the context of BRAFi and MEKi treatment. Technical and clinical validation of INK4A molecular assays may lead to the clinical use of new molecular companion biomarkers to accurately predict clinical response to BRAF and MEK inhibitors, and may also direct future combination treatment that includes CDK4 inhibitors for metastatic melanoma. Because CDK4 is important in both normal and cancerous cells, CDK4 inhibitors are expected to decrease the ability of the bone marrow to make white blood cells, platelets, and red blood cells. Although these effects are expected to be reversible, they can increase the risk of infection, bleeding and fatigue. Like BRAF inhibitors, these drugs are also expected to be expensive. Therefore, development of predictive molecular markers, as in the case of BRAF mutation assay for BRAFi, should help selecting patients that are likely to response to the treatment, therefore to maximize efficacy and avoid unnecessary side-effect and treatment cost [79, 80].
Genetic and epigenetic changes of INK4A have been identified in 30-70% of melanomas irrespective of BRAF mutation [59, 70, 81]. Bi-allelic deletion of INK4A (p16 null) occurs in 10-27% of melanomas [60, 82]. Other changes include mono-allelic deletion, point mutation, or promoter hypermethylation, resulting in various levels of p16 expression/activity (Table 1) [57, 60, 81-83]. It is believed that the acquisition of p16 lesions allows melanoma cells to bypass senescence/growth arrest during melanoma development [84]. Although preliminary results with combination therapy of BRAFi and MEKi are encouraging with better clinical response over single agent BRAFi treatment [9], levels of treatment responses vary under the combination treatment [9]. We hypothesize that clinical response to combination therapy of BRAFi and MEKi correlates with status of INK4A/p16 (Table 2). The development of clinically useful INK4A assays requires an understanding of the underlying biology and access to technology that allows high quality assay performance. Recent advances in molecular technology enable accurate, rapid, and cost-effective INK4A molecular testing that can be performed routinely on tumor specimens. However, validation of the technical performance characteristics of INK4A assays and understanding of assay limitations are necessary for the accurate interpretation of test results.
\n\t\t\t\t\n\t\t\t\t\tINK4A status\n\t\t\t\t\n\t\t\t | \n\t\t\t\n\t\t\t\tp16 protein sequence and expression\n\t\t\t | \n\t\t
Wild-type | \n\t\t\tNormal sequence | \n\t\t
Various mutations | \n\t\t\tHeterogeneous sequence changes | \n\t\t
Bi-allelic deletion | \n\t\t\tProtein null | \n\t\t
Promoter hypermethylation | \n\t\t\tLower levels of p16 | \n\t\t
Heterogeneity of INK4A and p16 in melanoma specimens
As examples, Table 2 is a list of molecular assays to comprehensively examine INK4A/p16 lesions in melanoma specimens. Technical and clinical validation studies are necessary before the routine use of these assays in the clinic.
Test | \n\t\t\tMethod | \n\t\t\tReference | \n\t\t
\n\t\t\t\tINK4A deletion | \n\t\t\tfluorescent in situ hybridization (FISH) (p16 SpectrumOrange/ chromosome 9 centromeric probe (CEP9) SpectrumGreen Probe, Abbott Molecular, Des Plaines, IL) | \n\t\t\t[85, 86] | \n\t\t
\n\t\t\t\tINK4A mutation | \n\t\t\tSanger sequencing | \n\t\t\t[86, 87] | \n\t\t
\n\t\t\t\tINK4A promoter methylation | \n\t\t\tPyrosequencing (PyroMark Q24 CpG p16 Kit, Qiagen, Valencia, CA) | \n\t\t\t[82, 88, 89] | \n\t\t
p16 expression | \n\t\t\tImmunohistochemical staining (IHC) | \n\t\t\t[90, 91] | \n\t\t
Summary of molecular assays
These assays need to be validated both technically and clinically with defined cut-off values. There should be correlation of results among assay methods; for example, cells with bi-allelic INK4A deletion show negative p16 IHC staining and cells with mono-allelic INK4A deletion show mutations with loss of heterozygosity (LOH), and p16 expression inversely correlates with levels of INK4A promoter methylation. The major obstacles in testing tumor specimens are the presence of non-tumor cells in the samples, the cellular heterogeneity within tumor specimens, and degradation/damage of nucleic acid and protein during sample processing. To ensure accurate testing results, SOPs need to be established with clearly defined instructions on the selection and handling of tumor specimens. For example, FISH assay requires fixation time between 6-48 hrs [92]. Alterations in INK4A may also affect the overlapping ARF gene (Fig. 2). Although the proposed study focuses on INK4A, changes in INK4A may also affect ARF, which may also be analyzed. Assay clinical sensitivity, clinical specificity, positive predictive value, and negative predictive value of INK4A biomarkers for a given treatment response can be calculated as described in Table 4.
\n\t\t\t\t\n\t\t\t\t\tINK4A result\n\t\t\t\t\n\t\t\t | \n\t\t\t\n\t\t\t\tTreatment resistant case\n\t\t\t | \n\t\t\t\n\t\t\t\tTreatment sensitive case\n\t\t\t | \n\t\t\t\n\t\t |
Lesion +ve | \n\t\t\tA | \n\t\t\tB | \n\t\t\tPositive predictive value = A / (A + B) | \n\t\t
Lesion -ve | \n\t\t\tC | \n\t\t\tD | \n\t\t\tNegative predictive value = D / (C + D) | \n\t\t
\n\t\t\t | Sensitivity = A / (A + C) | \n\t\t\tSpecificity = D / (B + D) | \n\t\t\t\n\t\t |
Calculation of clinical sensitivity, clinical specificity and predictive values
Patients with metastatic melanoma have a median survival of 6-8 months [93]. Recently, ipilimumab (Yervoy, Bristol-Myers Squibb), an inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and vemurafenib (PLX4032, Zelboraf, Plexxikon/Roche), an inhibitor of mutant BRAF, gained FDA approval to treat patients with metastatic melanoma. Although both drugs offer new approaches to the treatment of advanced melanoma, their therapeutic efficacy is limited. Both drugs typically lengthen life by only several months in patients that initially responded to the treatment [94, 95]. There is mounting evidence that acquired resistance to BRAFi frequently correlates with reactivation of the RAS-RAF-MEK-ERK signaling pathway [52, 53, 64]. This finding led to clinical trials combining BRAFi and MEKi in patients with BRAF-mutant metastatic melanoma who progressed on a prior BRAFi treatment regimen [94]. Dabrafenib (GSK2118436, GlaxoSmithKline) is a potent and selective inhibitor of mutant BRAF and is comparable in safety and efficacy to vemurafenib. In phase I testing, it achieved a 67% response rate in metastatic melanoma patients with BRAF V600 mutations [96]. Trametinib (GSK1120212, GlaxoSmithKline) is a potent and selective inhibitor of MEK1/2, achieved a clinical response of 40% in patients with an activating BRAF mutation in phase I study [97]. A multicenter phase I/II trial of combined treatment with dabrafenib and trametinib demonstrated a disease control rate of 67% (12/18) in patients who failed prior single-agent treatment with a BRAFi [9]. We hypothesize that although reactivation of MEK-ERK-cyclin D-CDK4 in tumors previously treatment with BRAFi may be suppressed by the combination of dabrafenib and trametinib, cyclin D-CDK4 can also be reactivated by alternative resistance mechanisms that cannot be suppressed by the addition of MEKi (e.g.; activation of growth factor receptor and PI3K-AKT pathway) [51-53, 55, 56, 65, 66], if unopposed by p16, can lead to resistance to the BRAFi and MEKi combination therapy (Fig. 1). It has been shown that melanoma cells that harbor abnormal INK4A are more sensitive than INK4A wild-type cells to the growth inhibitory effect of a p16-mimicking peptide [98] or of flavopiridol, a pan-CDK inhibitor [99], and combination of BRAFi or MEKi with the expression of wild-type INK4A or a CDK4 inhibitor significantly suppresses growth and enhances apoptosis in melanoma cells [2, 3]. Therefore, melanoma combination treatments that include CDK4 inhibitors may overcome treatment resistance and enhance efficacy. There is a critical need to identify predictive markers for therapies not only to improve treatment outcomes, but to help avoid ineffective toxic therapies, also because of the likely high cost of combination regimens. Like BRAF mutation assay, testing of INK4A-p16 may predict which patients will response to BRAF, MEK, and CDK4 inhibitors. Therefore, INK4A biomarkers may also have great potential to guide future melanoma combination treatments that include CDK4 inhibitors.
ASK1: apoptosis signal-regulating kinase-1
ARF: alternative open reading frame
BCL2: B-cell chronic lymphocytic leukemia/lymphoma 2
BCL2L1: BCL2-like 1
BIM: BCL2 interacting mediator
BIRC5: baculoviral IAP repeat-containing 5, also known as survivin
BRAF: v-raf murine sarcoma viral oncogene homolog B1
BRAFi: BRAF inhibitor
Caspase: cysteine-aspartic acid protease
CDK2: cyclin-dependent kinase 2
CDK4: cyclin-dependent kinase 4
CDK4i: CDK4 inhibitor
CEP9: chromosome 9 centromeric probe
CLL: chronic lymphocytic leukemia
DAPI: 4\'-6-diamidino-2-phenylindole
DMEM: Dulbecco\'s modified Eagle medium
DMSO: dimethyl sulfoxide
DTIC: dacarbazine
ERK: extracellular-signal-regulated kinase
FBS: fetal bovine serum
FDA: Food and Drug Administration
FGF: fibroblast growth factor
FISH: fluorescent in situ hybridization
FITC: fluorescein isothiocyanate
HGF: hepatocyte growth factor
IAP: inhibitor of apoptosis family
IHC: immunohistochemical staining
INK4A: inhibitor of cyclin-dependent kinase 4A; part of cyclin-dependent kinase inhibitor 2A gene (CDKN2A), also known as multiple tumor suppressor 1 (MTS1)
KIP1: kinase interacting protein 1
LOH: loss of heterozygosity
MEK: mitogen-activated protein kinase/ERK kinase
MEKi: MEK inhibitor
MST2: sterile 20- like-kinase 2
PAGE: polyacrylamide gel electrophoresis
PARP: poly (ADP-ribose) polymerase
PBS: phosphate buffered saline
PI3K: phosphatidylinositol 3-kinase
p-ERK: phopho-ERK
RAF: v-raf murine sarcoma viral oncogene homolog. Human has three RAF: CRAF, BRAF, and ARAF
RAS: rat sarcoma viral oncogene homolog. Human has three RAS: HRAS, NRAS, and KRAS (KRAS4A and KRAS4B proteins arise from alternative splicing)
RB: retinoblastoma proteins including pRB, p107, and p103
SDS: sodium dodecyl sulfate
siRNA: small interfering RNA
TdT: terminal deoxynucleotidyl transferase
TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling
UV: ultra violate
WNT: wingless
We thank Dr. Stuart Aaronson for human melanoma cell lines. This work was supported by Bill Walter III Melanoma Research Fund, Harry J. Lloyd Charitable Trust, and Cancer and Leukemia Group B Foundation (to J.D.).
This chapter provides a technical overview of HPGe detectors and their applications, both in science and day-to-day life. This overview covers the applications of HPGe as a material for γ-ray detection and its other more recent use in particle physics. It represents an introduction rather than a complete and exhaustive description of possible detector applications of HPGe.
\nSince the 1970s, photon detectors (γ and X) have been developed from high purity germanium [1]. The reason why HPGe has remained in use for such a long time as high-resolution γ- and X-ray detector material is mainly because it contains a very low concentration of electrically active defects [2, 3] which may be lower than 109 cm−3. Such value is difficult to reach in compound semiconductors. Even for detector-grade silicon, the doping level is slightly higher. High electron density (Z = 32), together with low average energy, is needed for e-h pair generation. Above 1 keV of initial particle energy, germanium is a good choice for the detection of photon or ionizing particles. See \nTable 1\n and Refs. [4, 5, 6, 7, 8, 9, 10] for studies, both theoretical and experimental, on ionization in semiconductors. In the early days of germanium γ-ray detection, less purified material was used. The compensation method for net doping density reduction was based on the lithium drifting technique [11]. With an applied voltage bias, the drift of the interstitial Li+ ions through the detector is made possible leading to the neutralization of acceptors by the creation of Li+ acceptor pairs. However, progress in Ge purification led to the obsolescence of compensation techniques. Lithium is still used as a doping ion for the creation of n+ contacts, even though ion-implantation is now a mainstream technique for this purpose. Room-temperature γ-ray detection is still a challenge as the best candidate material exhibits higher defect concentrations and/or is difficult to grow into large crystals. Cadmium telluride is a material of choice for photo-detection, and gallium arsenide is another option. However, considerable progress would be necessary to match the easiness of use of HPGe in its present-day applications, despite the need for cryogenic apparatus.
\nSemiconductors that may be used for the direct detection of γ rays and their average energy for electron hole creation Ehn and other quantities, the linear energy transfer is indicated for high-energy charged-particle detection (at Minimum Ionization).
The main contributions to the development of high-purity germanium have been made already in the 1970s by the LBNL [1] and other US laboratories as well as industrial companies. There are presently a few corporations in Europe which supply such materials, without mentioning those from Eastern Europe. High-purity single crystals are usually grown in hydrogen atmosphere in a silica crucible [9, 12]. This prevents the introduction of oxygen and other electrically active impurities. However, this process introduces substitutional silicon, which is electrically inactive, similar to carbon. These crystals exhibit high levels of interstitial hydrogen, which may form complexes with some metallic impurities such as copper [13]. Good quality crystals (despite being small) may be fabricated in University labs [11, 14] which show that nowadays the availability of such crystals is better than ever. Gamma-ray detector manufacturers usually use commercially available crystals, which are subsequently processed, or in some cases fabricate the material itself. It should be noted that except for isotopically enriched crystals (for physics experiments), most crystals are made of natural germanium with a proportion of isotopes indicated in \nTable 2\n.
\nStable isotopes found in natural germanium with the nuclear moments and abundance.
In this chapter, we introduce the principle of γ-ray detection and spectroscopy. Most high-energy photons (100 keV–10 MeV) interact with the electrons in the HPGe material [15]. As the density of electrons is proportional to Z, Ge is a material close to the optimum among well-characterized semiconductors, together with CdTe and GaAs. As the absorption coefficient increases along with Z, this results in a good detection efficiency for a given detector volume compared for instance with silicon. Here are the three main processes by which gamma rays lose energy in the detecting media: the photoelectric effect, Compton scattering, and e+e− pair creation. The photoelectric process [16] is dominant at low energies (<100 keV approximately) and is related to emission of electrons from the atomic shells. This process depends on the energy of the photons and the atomic number of the detecting media. The energy of a photon is absorbed by an inner-shell electron and leads to its emission from the atom. Subsequently, the photoelectrons lose their kinetic energy in the semiconductor by electron-hole pair generation. This first term is the photoelectron energy (Ephotoelectron), and the second is the difference between the gamma energy (Eγ) and the electron binding energy (Ebindingenergy).
\nThe electron binding energy for K-shell valence electrons is of the order of 11 keV in Ge, compared to around 1.8 keV in silicon. Other, shallower shells may also be excited, contributing to the signal, which means that as the photon energy increases, inner shells can be excited gradually and the absorption will exhibit abrupt increase. This does not have a direct influence on the average number of electron-hole pairs generated per unit of energy deposited; we will discuss this in the following paragraph [8]. The absorption coefficient is proportional to:
\nThis means that the contribution of the photoelectric effect vanishes at high energies (E), when the other two processes of interaction of gamma rays with matter become dominant. In the intermediate energy range, Compton effect dominates, hence the absorption of the photon becomes a multistep process with Compton electrons (<1 MeV) being absorbed after traveling a short distance, while Compton photons are created and absorbed in subsequent steps. One should note that some photons can escape the detecting medium and consequently do not contribute to a full-energy peak. These induce a signal background (Compton background) that is particularly large in low volume detectors. Techniques exist to mitigate this drawback using a secondary detector surrounding the primary one. This secondary detector is referred to as a Compton shield [17]. This anticoincidence scheme with these two detectors eliminates the un-absorbed photon events. This shows that for high detection efficiency, a relatively large volume of the detector is necessary for γ-ray spectroscopy. This is much different for γ-ray tracking is, when detector granularity is required. Time coincidence between events in neighboring detectors is the way to proceed to identify the particles. The probability of interaction with the electrons of the solid through Compton effect increases when the density of electrons n increases, being roughly proportional to it. If ρ is the mass density of the solid and A the mass number, the average electron density is proportional to ρ/A, which is the atomic density, multiplied by Z, the number of electrons per atom [16].
\nThis shows that as the Z/A ratio is constant, it is reasonable to use very dense media. Hence, it proves that germanium is a better choice than silicon for this purpose, as would be CdTe or GaAs, if the defect concentration could be reduced to an acceptable level. We will discuss the problem of defects in the following paragraph. Present-day experiments benefit from simulation codes such as GEANT4 or others [18] for their design. HPGe γ-ray detectors are no exception. The other process that becomes important at higher photon energy is the electron-positron pair creation, which may appear at energies above 1022 keV. This kind of interaction is related to γ-nuclear coupling, where the γ-photon interacts with the nucleus resulting in a creation of a e−/e+ pair with a total kinetic energy equal to Ek = Eγ − 1.022 MeV (Ek is the kinetic energy of the e = e− pair, and Eγ is the energy of the incident gamma photon). Subsequently, the positron may annihilate with an electron in the material, which leads to the production of two γ-rays of 511 keV that may (but not have to) be absorbed in the detecting material through Compton or photoelectric effect processes. As one or both 511-keV photons may escape from the detector with no energy deposition, satellite peaks appear in the measured energy spectrum, called escape peaks and separated from the total absorption peak by a 511 keV energy difference (or 1022 keV for double escape). Again, some discrimination is possible to avoid this effect, although one should be interested in visualizing the different peaks to investigate how the incident particle has interacted with the detector medium. The e + e- pair creation is most important at energies above 10 MeV [16], which shows that HPGe is not a good choice for very energetic photons such as cosmic radiation or those generated by high-energy accelerators (~1 GeV) since huge monocrystals would be required to provide a significant detection efficiency. This is hardly possible, with the largest commercially available HPGe crystals weighing 1–2 kg (larger crystals have been grown for specific applications) and having a diameter of a few centimeters. If we consider photofission [19], it has been reported that it occurs in natural lead for 10 MeV range photons. However, as the dependence on the fissility parameter is sublinear in logarithmic scale, it should be considered as being very weak for a germanium nucleus. Let us compare with lead, the fissility parameters read:
\nHence, according to these figures, photofission should be much lower for natural Ge than for natural Pb. We therefore can consider this contribution as negligible in the energy range a few tens of MeV for the photons that are usually analyzed using HPGe spectrometers. This is the case in nuclear sciences for radioisotope identification and monitoring. Hence, for nuclear physics, HPGe is an adequate choice and widely used for detection of low energy and medium energy photons. In high-energy physics experiments, electromagnetic calorimeters are mostly based on dense liquids or solids and exhibit some granularity [20], while the energy resolution at high energy is not as good as for HPGe at low energies. Up to now, no high energy physics experiment has ever introduced HPGe as a semiconductor detector in calorimeters. Instead, silicon cells with absorbers are used in calorimeters and are proposed for several future detectors with the advantage of operation at room temperature, which is possible with semiconductors exhibiting a larger band gap, such as silicon.
\nFocusing on photon energy resolution criterion, HPGe still provides one of the best results. With a good quality material, the energy resolution is very close to the Fano limit [21, 22]. To obtain this, the readout electronics must be low noise. Historically, the front-end transistor was a JFET cooled to the temperature of the detector (77 K, liquid nitrogen temperature) [9, 23]. This reduced the energy resolution to less than 1 keV for 1 MeV photons. It would now be possible to use very low-noise room temperature CMOS μ electronic circuits [24] to match the low-noise specifications required for γ-ray spectrometry. The front-end readout electronics for these detectors is usually a charge-sensitive device, which is necessary for spectrometric measurements for which the generated charge is proportional to the energy deposited in the detectors. These CSA (charge-sensitive amplifiers) have an integrating pole followed by filtering stage (usually based on derivation-integration schemes for optimal filtering). This is done by a so-called shaper in order to optimize the signal/noise ratio and to reduce event pile up through fast operation. This channel is however slow (a few μs), so it may be supplemented by a fast current-sensitive channel, for coincidence, veto (anticoincidence) or timing purposes.
\nBecause a typical size of a HPGe detector is not optimum for timing measurements, the resolution obtained with a CFD (Constant Fraction Discriminator) is close to 400 ps [25], which is a high value compared with other fast detectors (PM or APD). In fact, this value was measured for a planar germanium detector of a volume of a few cubic centimeters, and it would be even higher for standard coaxial HPGe detectors.
\nIn order to reach optimum resolution of semiconductor detectors, the crystal defect density should be decreased, in particular for those that are electrically active. This has become possible when defect and impurity control in the process of crystal growth has reached a sufficient level of reliability. In addition to point defects and impurities, dislocations play a major role as they behave like a sink for impurities [1, 9, 12]. They can currently be revealed by chemical crystal etching. The pits observed using optical microscopes are related to dislocations, which allows determining the etch-pit density. These dislocations induce a broad DLTS signal in n-type high purity material [3]. These are moderately deep donor states with carrier capture cross section of the order of 10−13 cm−2 or more. The peak is at 50–60 K for a large emission rate window (56 s−1) [3]. This means that at 77 K, the emission rate is large enough to have no marked effect on carrier trapping as the electrons are released with a time constant that is low compared with the drift time. With σn higher than 10−13 cm−2, which is the case with a filling pulse shorter than 1 ms in duration (with a 1010 cm−3 carrier concentration, and 106 cm s−1 of thermal velocity at 50 K, in our DLTS measurements), the emission rate at 77 K exceeds the capture rate for an activation energy of 100 meV. The other fact is that the DLTS signal fades away above 65 K, so the contribution of the dislocation band should be low as long as the concentration remains at a reasonable level. This gives a rule of thumb [2] for the dislocation density that should not exceed 104 cm−2 and should be above 102 cm−2 for detector-grade material, at least for the material used in the 1980s–1990s. If the dislocation density is too low, the deep impurities such as those related with copper (substitutional or bound with hydrogen) will be higher, as they cannot precipitate onto the dislocation lines and have a higher density than isolated impurities. They give rise to deep hole traps that affect greatly the hole transport even at 77 K. These traps have an activation energy higher than 0.160 eV and capture cross sections above 10−13 cm−2, (similar to coulombic/attractive centers) with concentrations reaching 109 cm−3.
\nThe structures that have been used from the early days of Ge detectors are p+n−n+ and p+p−n+, usually with a Li-diffused n+ contact and a boron-implanted p+ contact, and a thin metallization of sputtered aluminum or electrolytically plated gold in old detectors. Following an appropriate surface treatment (etching with CP4 mixture after cleaning with solvents such as acetone) and rinsing with a slightly oxidizing mixture, the detectors are placed in secondary vacuum, and after surface desorbing, the leakage current can be stabilized at low values. The leakage dark current at 77 K with a reverse bias of 1 kV or more for large coaxial detectors can be reduced to the order of a few pA or less. Usually a thermal treatment above room temperature will allow surface desorbing, and consequently impurities on the surface will be eliminated. The question of passivation is still open, as germanium does not have the self-passivation properties of silicon, for which oxygen creates a stable oxide layer of a few nm at room temperature. Germanium oxides are not stable [26, 27, 28, 29] and react with water. More recent passivation methods are based on amorphous layer deposition such as a-Ge-H (amorphous hydrogenated germanium). These constitute a coating, rather than standard passivating layers. In spite of this, their effect is to stabilize leakage currents at 77 K at reasonable values. However, these values are higher than those for bare Ge material in vacuum.
\nAs the presence of defects mainly alters the transport of holes, efforts were made to reduce the mean-drift length of holes by an adequate electrode configuration [30]. For coaxial detectors, the hole-collecting electrode can be placed at the outer surface of the detectors. This is usually a p+ outside implant, which is shallower than the n+ electrode, which is placed on the axis of the detector. Holes have a shorter drift distance than the electrons, the p+ electrode being negatively biased. This configuration is less sensitive to cumulative nonionizing radiation effects. N-type material is used contrary to p-type material with opposite electrode configuration in the conventional detectors. The same is true for planar detectors, for which the collecting length is reduced to values well below 1 cm. The cumulative radiation effects are mainly deep defects introduced by irradiation by nonionizing particles, such as hadrons (particularly neutrons and protons), but also energetic electrons. These particles, particularly at energies in the MeV range, induce displacement cascades in the detecting crystalline material and therefore produce defects of various nature, point-like or clusters. The temperature of operation and irradiation has a great influence on the outcome [25]. The result is a degradation of the energy resolution, which can be observed as a broadening of the photo-peaks, with a tail at low energy giving them an asymmetric aspect. As the detector can be compared to an ionization chamber with two electrodes polarized at different potentials, the current integrated by the readout electronics is a displacement current. The total charge collection is achieved when all holes and electrons are collected by the n+ (positively biased) and p+ (negatively biased) electrodes (cathode and anode). If carriers become trapped during the transport process, a loss of charge occurs leading to a peak tail at low energy. The collected charge is lower than the photo generated charge. Statistically, there is a certain charge deficit in the signal corresponding to one event, so the high-energy side of the peaks is not much affected [30], contrary to the low energy side. This leads to a loss of energy resolution. The charge loss is often followed by charge reemission with a large time constant, which has no real influence of the spectrum. An analytical model of radiation-induced defects has been proposed in Ref. [25] and developed in later papers.
\nThe radiation-induced effects have been widely studied in HPGe detectors [30, 25, 31], and, in the beginning, without a quantitative relation to crystalline defects introduced by irradiation in HPGe. Since these effects result in resolution degradation, their characterization is of utmost importance. We can cite a few extensive works on this subject, mostly using electrical measurements [12, 13]. A powerful characterization technique called photoelectric spectroscopy [32] or alternatively photo-thermal ionization spectroscopy (PTIS) has been successfully applied to HPGe, but this technique is limited to shallow hydrogenoid levels with low concentration and not operation-detrimental deep levels. It applies a two-step process, phonon + photon (far infrared) and requires low temperature operation (LHe) below the ionization temperature of impurities and dopants. No overlapping of the bound electron wavefunction is required, so it can only be used when the impurities have a low concentration. For deep-defects, deep level transient spectroscopy (DLTS) became the technique of choice. In particular, it helped to establish that deep traps that are created by a temperature increase above 77 K are more detrimental to detector operation than the primary defects that are created by irradiation at low temperature [3]. Neutron-induced defects are thought to be vacancy and interstitial related at 77 K. After annealing above this temperature, divacancies and impurity-vacancy defects are the most numerous centers observed that are electrically active. They give rise to numerous deep hole-traps with capture cross sections of the order of 10−13 cm−2. They only anneal out above 420–470 K, where less electrically active defects are created. The stable defects at 100 K and less are disordered regions containing a large concentration of vacancies and interstitials. These act as hole-traps but are less effective in degrading resolution than secondary defects observed at room temperature. Numerous studies have been devoted to the degradation of the resolution, and most of them identify the causes as being related to the defects with capture cross sections of the order of 10−11 cm−2 [2]. We know from experiments and simulations that these are due to zones with a high local defect density, which enhances capture probability [33] through an electrostatic effect.
\nStreet [34] has found that the presence of disorders in amorphous silicon enhances the cross section for the capture of carriers by the defects. Later, an analytical model has been developed that clearly explains this effect using simple assumptions [33]. This mitigates the direct role of disordered regions as being the sole origin of carrier capture at 77 K. The sizes of these disordered regions areof the order of the range of primary recoil atoms (\nFigure 1\n). Isolated defects should contribute greatly to the trapping process. The recoil of an atom is induced by the collision with the impinging particle. SRIM simulations show that its range is of the order of 10 nm at 10–30 keV, with around a few hundred vacancies being created on its trajectory. The recoil energy has been computed for neutrons in the MeV energy range, see \nFigure 1\n. In most cases, a thermal treatment above room temperature is used to remove radiation damage. In Ref. [31], recombination-enhanced annealing using minority-carrier injection was applied but with no significant results, at least at room temperature. At low temperature, when the defects are not stable, no improvement could be observed with this method. However, a strong dependence of the annealing stages on the material type (p or n) was observed in Refs. [3, 25] and other detector studies.
\nSRIM simulation showing the vacancy distribution for a Ge recoil of 30 keV.
For a long time, materials alternative to HPGe have been proposed, and corresponding detectors were fabricated. GaAs is one example (mostly for X-ray detection), and, more importantly, CdTe. The goal was to eliminate the need for cryogenic operation by the use of large band gap semi-insulating material (diamond is also considered). Many difficulties still exist, mostly related to the defect density that is much higher in binary materials [9]. The other drawback is the possibility to grow large crystals, which proves to be more difficult for alternative materials. Large diamond single crystals with a low nitrogen content are difficult to grow as they need high-pressure processing. However, some CdTe photon detectors using segmented crystals for photon identification have been successfully implemented on space missions (INTEGRAL) [24]. Segmentation allows reducing drift length and therefore trapping, so that the resolution can be maintained at an acceptable level.
\nParticle identification through pulse shape discrimination is one of the developments that are used mainly in nuclear physics [35]. These techniques can be adequately used to determine the region of the detector where the interaction took place. There have been early reports for methods of particle identification in germanium and silicon detectors [36, 37]. The detection of photons is basically through ionization, and there is no important interaction with the nucleus, which could transfer momentum to the nucleus. If we consider other particles with a significant mass, their interaction with the nucleus may induce the recoil, which in turn is slowed down in the detector material. The slowing-down process results in ionization (electron-hole pair generation), defect creation (vacancies and interstitials), and phonon creation. One should note that according to SRIM simulations, in the typical energy range for the recoil (20–30 keV), the most important contribution (73%) is from phonon emission. The energy used for vacancy creation is of the order of 3%, which indicates that defect monitoring [38] could provide an alternative way to estimate the total integrated flux of interacting particles, since when stable defects are created, their concentration is proportional to the total number of interacting particles in a given time interval, which can be very long. The rest of the energy is used for ionization (25%). This result is close to the experimental result obtained for cryogenic detectors, as it will be discussed in the paragraph on dark matter detection.
\nSimulations of the interaction of photons with matter have been given a certain attention. Monte Carlo codes have been developed. Recently, the NWEGRIM code [18] from Pacific Northwest laboratories has been used to simulate the interaction of photons in silicon, but these simulations could also be applied to germanium. GEANT4 has been used for simulation of charged particles interacting with germanium [39].
\nHigh-purity germanium γ-ray tracking arrays, such as AGATA (Advanced GAmma Tracking Array) [40] and GRETINA/GRETA (Gamma Ray Energy Tracking Array) [41] represent the state-of-the-art in high-resolution γ-ray spectroscopy for nuclear physics experiments. These spectrometers are composed of highly segmented large-volume HPGe crystals. Pulse-shape analysis, applied to the recorded signals from the segments, yields three-dimensional interaction positions with a typical precision of about 2 mm [40, 41]. Subsequently, a γ-ray tracking algorithm is applied to the determined interaction points in order to group and order them in sequences corresponding to individual γ-rays. In this procedure, the geometrical criteria and the Compton scattering formula are used, and the full energy of a γ-ray is determined as the sum of the energies of the interactions ascribed to the same trajectory.
\nThe γ-ray tracking arrays provide improved energy resolution for in-beam nuclear physics studies, thanks to much reduced Doppler broadening as compared to standard γ-ray spectrometers. The use of γ-ray tracking also eliminates the need for Compton-suppression shields, commonly used with HPGe crystals in order to improve the peak-to-total ratio. Consequently, the entire 4π solid angle can be surrounded with Ge crystals, which leads to significantly increased detection efficiency. The resolving power of a 4π γ-ray tracking array is estimated to be up to two orders of magnitude better than that of the existing conventional γ-ray spectrometers, depending on the physics case [41]. This is particularly important for studies of very exotic nuclei far from stability, employing weak radioactive-ion beams at intermediate energies (up to several hundred MeV/u), which leads to recoil velocities that may exceed 30% of the speed of light [42].
\nThe last two decades have seen an important effort devoted to search for dark matter, using underground direct detection apparatus [36, 37, 43, 44, 45, 46, 47]. The first stage was to design a detector that is able to discriminate between particles in order to identify the so-called weakly interacting massive particles that are thought to be a constituent of dark matter. The developed detectors include two channels: a “thermal” channel which is based on the thermalization of phonons and a ionization channel which is proportional to the number of carriers collected. In reality, the so-called Luke-Neganov effect [48, 49] affects the properties of the detector. The Luke-Neganov effect consists in the amplification of the phonon signal by the electron (carrier) drift [50].
\nThe charge signal may be expressed as:
\nwhere E is the average energy for electron-hole pair creation, and
\nThe ST term is proportional to the charge multiplied by the voltage drop, so we can write that if t is the time necessary for the charge to be collected,
\nFirst term: \n
These relations indicate the need to operate at weak field to achieve a reduction in the contribution of the phonon signal. At high fields, the phonon signal tends to grow linearly with the applied voltage. Of course, the heat signal can only be detected if the calorific capacity is low enough, and so the operating temperature should be very low. Germanium detectors are also good cryogenic (mK range) bolometers. Another reason for the choice germanium is that its nucleus is nucleon rich (for instance compared with silicon). This should enhance interaction cross sections of WIMPS with the detecting medium. If we consider the interaction of fast neutrons with germanium (in the MeV range) as an example, the elastic-scattering cross section is much higher than the inelastic cross section [31] and is of the order of 3 barns [5]. Hence, the mean free path of these fast neutrons is close to a few centimeters. The recoil nucleus with an energy of a few tens of keV dissipates 25% of its energy into ionization, which amounts to a few keV (5 keV). The ionization channel monitors this fraction of energy. A similar phenomenon was observed, but not published, in planar HPGe 77 K detectors, exposed to neutrons, in the MeV range [51]. The heat channel monitors almost entire energy deposited by the recoils, except for the fraction needed for vacancy-interstitial (defect) creation. If a neutron is fully absorbed in the bolometer following multiple scattering, the total energy of all recoils matches the initial energy of the impinging neutron, and therefore the heat channel signal reflects the total energy deposited.
\nThe calibration runs yielded the ratio of the ionization signal to the phonon energy equal to 30%. This is very close to the value of 25%/73% = 0.35 determined in a SRIM simulation. When the particle interacts with matter purely via ionization, as it is the case for photons, the ratio of ionizing energy to the total energy is close to one, if no Luke-Neganov amplifying occurs. Therefore, this configuration can be used for particle discrimination [46]. For the WIMPS experiments, if we consider that these particles interact with the nuclei of the detecting media, this provides a way of discriminating the photons from other events. At this cryogenic energy (a few mK), the shallow and deep levels may disturb the charge transport through the detector (\nFigure 2\n). This is the reason why the detector is saturated with photo-generated carriers prior to data acquisition. In spite of this, more detailed defect studies on the starting material should be made [52]. In particular, as very shallow levels may have an impact, the nonthermal carrier emission or capture should be studied. Additionally, a method using alternately biased electrodes on each surface of the detectors, including the sides, has enabled the measurement of volume-only events, eliminating near-surface events related to low-energy particles strongly interacting with the medium [46]. Other techniques have been developed [53] to solve this problem.
\nDiagram showing the energy of the trapping level in Ge band gap versus temperature, using a simple Boltzmann factor. This is valid at high temperature for thermal emission with a time constant Tau. The region investigated by DLTS is delimited by the upper square on the right. The purple arrow shows the operation of DM cryogenic experiments such as EDELWEISS.
As many particle detectors, HPGe detectors are now also used for other purposes than fundamental research. HPGe detectors can now be found in different industries such as environment control, medical imaging, and of course radioactive material control.
\nOne of the most common uses of HPGe is the monitoring of atmospheric radiations. Stations around the world check the air quality and collect air content samples or solid samples, such as rocks, water, or plants. The samples are then analyzed in a laboratory. Thanks to their excellent resolution and low background once placed in a suitable environment, and the radio-elements contained in the samples can be determined. It is, for example, possible to detect radio-elements with concentrations down to 0.1–1 Bq/kg in solids and 0.1 Bq/L in water. The system can be improved by adding scintillator array around the germanium detectors to eliminate signals from cosmic rays. Such system is, for example, used to obtain a sensitivity of millibecquerels per cubic meter of an air sample.
\nAnother practical example of use of HPGe to study radioactivity of liquids can be found in the study of old wines. Take a 1928 vintage bottle of Bordeaux wine; its cost can approach $10,000. However, how sure is the buyer that this bottle is really from 1928? To check this, the bottle was placed in an array of germanium detectors. The analysis immediately showed that the bottle contained traces of Cs137. Cs137 is a radioactive element presents in the atmosphere due to nuclear bombs…, which means that it cannot be found in a bottle of 1928. The quantification of Cs137 is now used to date wine produced after 1950 without opening the bottle.
\nSo far, HPGe detectors for medical purposes were mainly used for nuclear waste control produced by hospital. Here, the procedure is the same than for any nuclear waste collected from a nuclear power plant for example. The contaminated volume is placed near the detector. The analysis of the spectrum will reveal radioactive elements present and their quantity. The cost and mechanical constraints related to the use of liquid nitrogen limited the deployment of HPGe in hospitals for medical imaging. However, novel imaging methods, combining HPGe and silicon detectors are envisioned for future scanners such as ProSPECTus. Such system could reduce the dose to the patient, improve image quality, and be faster to acquire.
\nThe list of industrial applications of HPGe will become longer as we progress toward more reliable, easier to use, and cheaper detectors. Originally only pushed by fundamental research, the development of new HPGe is now also driven by the needs of companies using them. New applications, not yet considered, will then emerge.
\nThe future of HPGe detectors depends on the availability of other materials that would match the resolution performance of HPGe at 77 K, while operating at room temperature. Segmentation of the detectors provides a way to reduce carrier collection lengths and hence to mitigate the effects of electrically active deep defects. With integrated microelectronics, the noise can be as low as a few tens of electrons. With on detectors CMOS chips and low capacitance detectors, the electronic noise can be reduced to less than 100 e-h pairs. With ε equal to 4.5 eV (GaAs, CdTe), this corresponds to a resolution of the order of 450 eV. This could also be applied to HPGe detectors that are being used for double beta decay or dark matter experiments. The multielectrode scheme that is implemented in EDELWEISS III [46] is a first step toward a time-projection chamber HPGe detector, allowing an improved discrimination ability. Each electrode could be a separate channel, which would be easy for the detector operated at low field and low voltage. It seems clear that the use in more routine applications such as, for instance, high-precision radioactive material characterization and radioactive material tracing to avoid nuclear dissemination will remain a field where HPGe is the most competitive despite the need for LN2 cryogenic installations. Development of cryogenic cooling fridges will eliminate this specific constraint. In scientific applications, HPGe, being one of the chemically purest materials ever fabricated, will remain needed.
\nThe contribution of researchers from IRFU and other institutions, with whom the first author had fruitful discussions while working on dark matter instrumentation, is gratefully acknowledged.
\nThe authors declare having no conflict of interest.
IntechOpen publishes different types of publications
",metaTitle:"Types of publications",metaDescription:"IntechOpen publishes different types of publications",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"IntechOpen Edited Volumes are integrated collections of chapters about particular topics that present new areas of research or novel syntheses of existing research and, as such, represent perspectives from various authors.
\\n\\nEdited Volumes can be comprised of different types of chapters:
\\n\\nRESEARCH CHAPTER – A research chapter reports the results of original research thus contributing to the body of knowledge in a particular area of study.
\\n\\nREVIEW CHAPTER – A review chapter analyzes or examines research previously published by other scientists, rather than reporting new findings thus summarizing the current state of understanding on a topic.
\\n\\nCASE STUDY – A case study involves an in-depth, and detailed examination of a particular topic.
\\n\\nPERSPECTIVE CHAPTER – A perspective chapter offers a new point of view on existing problems, fundamental concepts, or common opinions on a specific topic. Perspective chapters can propose or support new hypotheses, or discuss the significance of newly achieved innovations. Perspective chapters can focus on current advances and future directions on a topic and include both original data and personal opinion.
\\n\\nINTRODUCTORY CHAPTER – An introductory chapter states the purpose and goals of the book. The introductory chapter is written by the Academic Editor.
\\n\\nMonographs is a self-contained work on a particular subject, or an aspect of it, written by one or more authors. Monographs usually have between 130 and 500 pages.
\\n\\nTYPES OF MONOGRAPHS:
\\n\\nSingle or multiple author manuscript
\\n\\nCompacts provide a mid-length publishing format that bridges the gap between journal articles, book chapters, and monographs, and cover content across all scientific disciplines.
\\n\\nCompacts are the preferred publishing option for brief research reports on new topics, in-depth case studies, dissertations, or essays exploring new ideas, issues, or broader topics on the research subject. Compacts usually have between 50 and 130 pages.
\\n\\nCollection of papers presented at conferences, workshops, symposiums, or scientific courses, published in book format
\\n"}]'},components:[{type:"htmlEditorComponent",content:"IntechOpen Edited Volumes are integrated collections of chapters about particular topics that present new areas of research or novel syntheses of existing research and, as such, represent perspectives from various authors.
\n\nEdited Volumes can be comprised of different types of chapters:
\n\nRESEARCH CHAPTER – A research chapter reports the results of original research thus contributing to the body of knowledge in a particular area of study.
\n\nREVIEW CHAPTER – A review chapter analyzes or examines research previously published by other scientists, rather than reporting new findings thus summarizing the current state of understanding on a topic.
\n\nCASE STUDY – A case study involves an in-depth, and detailed examination of a particular topic.
\n\nPERSPECTIVE CHAPTER – A perspective chapter offers a new point of view on existing problems, fundamental concepts, or common opinions on a specific topic. Perspective chapters can propose or support new hypotheses, or discuss the significance of newly achieved innovations. Perspective chapters can focus on current advances and future directions on a topic and include both original data and personal opinion.
\n\nINTRODUCTORY CHAPTER – An introductory chapter states the purpose and goals of the book. The introductory chapter is written by the Academic Editor.
\n\nMonographs is a self-contained work on a particular subject, or an aspect of it, written by one or more authors. Monographs usually have between 130 and 500 pages.
\n\nTYPES OF MONOGRAPHS:
\n\nSingle or multiple author manuscript
\n\nCompacts provide a mid-length publishing format that bridges the gap between journal articles, book chapters, and monographs, and cover content across all scientific disciplines.
\n\nCompacts are the preferred publishing option for brief research reports on new topics, in-depth case studies, dissertations, or essays exploring new ideas, issues, or broader topics on the research subject. Compacts usually have between 50 and 130 pages.
\n\nCollection of papers presented at conferences, workshops, symposiums, or scientific courses, published in book format
\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5774},{group:"region",caption:"Middle and South America",value:2,count:5240},{group:"region",caption:"Africa",value:3,count:1721},{group:"region",caption:"Asia",value:4,count:10411},{group:"region",caption:"Australia and Oceania",value:5,count:897},{group:"region",caption:"Europe",value:6,count:15812}],offset:12,limit:12,total:118381},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"0",sort:"dateEndThirdStepPublish",topicId:"6,5"},books:[{type:"book",id:"9662",title:"Vegetation Index and Dynamics",subtitle:null,isOpenForSubmission:!0,hash:"0abf2a59ee63fc1ba4fb64d77c9b1be7",slug:null,bookSignature:"Dr. Eusebio Cano Carmona, Dr. Ricardo Quinto Canas, Dr. Ana Cano Ortiz and Dr. Carmelo Maria Musarella",coverURL:"https://cdn.intechopen.com/books/images_new/9662.jpg",editedByType:null,editors:[{id:"87846",title:"Dr.",name:"Eusebio",surname:"Cano Carmona",slug:"eusebio-cano-carmona",fullName:"Eusebio Cano Carmona"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9659",title:"Fibroblasts - Advances in Cancer, Autoimmunity and Inflammation",subtitle:null,isOpenForSubmission:!0,hash:"926fa6446f6befbd363fc74971a56de2",slug:null,bookSignature:"Ph.D. Mojca Frank Bertoncelj and Ms. Katja Lakota",coverURL:"https://cdn.intechopen.com/books/images_new/9659.jpg",editedByType:null,editors:[{id:"328755",title:"Ph.D.",name:"Mojca",surname:"Frank Bertoncelj",slug:"mojca-frank-bertoncelj",fullName:"Mojca Frank Bertoncelj"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8977",title:"Protein Kinase - New Opportunities, Challenges and Future Perspectives",subtitle:null,isOpenForSubmission:!0,hash:"6d200cc031706a565b554fdb1c478901",slug:null,bookSignature:"Dr. Rajesh Kumar Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8977.jpg",editedByType:null,editors:[{id:"329385",title:"Dr.",name:"Rajesh",surname:"Singh",slug:"rajesh-singh",fullName:"Rajesh Singh"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10557",title:"Elaeis guineensis",subtitle:null,isOpenForSubmission:!0,hash:"79500ab1930271876b4e0575e2ed3966",slug:null,bookSignature:"Dr. Hesam Kamyab",coverURL:"https://cdn.intechopen.com/books/images_new/10557.jpg",editedByType:null,editors:[{id:"225957",title:"Dr.",name:"Hesam",surname:"Kamyab",slug:"hesam-kamyab",fullName:"Hesam Kamyab"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10218",title:"Flagellar Motility in Cells",subtitle:null,isOpenForSubmission:!0,hash:"5fcc15570365a82d9f2c4816f4e0ee2e",slug:null,bookSignature:"Prof. Yusuf Bozkurt",coverURL:"https://cdn.intechopen.com/books/images_new/10218.jpg",editedByType:null,editors:[{id:"90846",title:"Prof.",name:"Yusuf",surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10750",title:"Solanum tuberosum - a Promising Crop for Starvation Problem",subtitle:null,isOpenForSubmission:!0,hash:"516eb729eadf0d1a9d1d2e6bf31e8e9c",slug:null,bookSignature:"Prof. Mustafa Yildiz and Dr. Yasin Ozgen",coverURL:"https://cdn.intechopen.com/books/images_new/10750.jpg",editedByType:null,editors:[{id:"141637",title:"Prof.",name:"Mustafa",surname:"Yildiz",slug:"mustafa-yildiz",fullName:"Mustafa Yildiz"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10797",title:"Cell Culture",subtitle:null,isOpenForSubmission:!0,hash:"2c628f4757f9639a4450728d839a7842",slug:null,bookSignature:"Prof. Xianquan Zhan",coverURL:"https://cdn.intechopen.com/books/images_new/10797.jpg",editedByType:null,editors:[{id:"223233",title:"Prof.",name:"Xianquan",surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10772",title:"Parasitic Plants",subtitle:null,isOpenForSubmission:!0,hash:"31abd439b5674c91d18ad77dbc52500f",slug:null,bookSignature:"Dr. Ana Maria Gonzalez and Dr. Hector Sato",coverURL:"https://cdn.intechopen.com/books/images_new/10772.jpg",editedByType:null,editors:[{id:"281854",title:"Dr.",name:"Ana Maria",surname:"Gonzalez",slug:"ana-maria-gonzalez",fullName:"Ana Maria Gonzalez"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10737",title:"Equus",subtitle:null,isOpenForSubmission:!0,hash:"258ffafc92a7c9550bb85f004d7402e7",slug:null,bookSignature:"Associate Prof. Adriana Pires Neves",coverURL:"https://cdn.intechopen.com/books/images_new/10737.jpg",editedByType:null,editors:[{id:"188768",title:"Associate Prof.",name:"Adriana",surname:"Pires Neves",slug:"adriana-pires-neves",fullName:"Adriana Pires Neves"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10777",title:"Plant Reproductive Ecology - Recent Advances",subtitle:null,isOpenForSubmission:!0,hash:"3fbf391f2093649bcf3bd674f7e32189",slug:null,bookSignature:"Dr. Balkrishna Ghimire",coverURL:"https://cdn.intechopen.com/books/images_new/10777.jpg",editedByType:null,editors:[{id:"206647",title:"Dr.",name:"Balkrishna",surname:"Ghimire",slug:"balkrishna-ghimire",fullName:"Balkrishna Ghimire"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10749",title:"Legumes",subtitle:null,isOpenForSubmission:!0,hash:"49d3123cde96adbe706adadebebc5ebb",slug:null,bookSignature:"Dr. Jose Carlos Jimenez-Lopez",coverURL:"https://cdn.intechopen.com/books/images_new/10749.jpg",editedByType:null,editors:[{id:"33993",title:"Dr.",name:"Jose Carlos",surname:"Jimenez-Lopez",slug:"jose-carlos-jimenez-lopez",fullName:"Jose Carlos Jimenez-Lopez"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10751",title:"Bovine Science",subtitle:null,isOpenForSubmission:!0,hash:"9e3eb325f9fce20e6cefbce1c26d647a",slug:null,bookSignature:"Dr. Muhammad Abubakar",coverURL:"https://cdn.intechopen.com/books/images_new/10751.jpg",editedByType:null,editors:[{id:"112070",title:"Dr.",name:"Muhammad",surname:"Abubakar",slug:"muhammad-abubakar",fullName:"Muhammad Abubakar"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:19},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:5},{group:"topic",caption:"Business, Management and Economics",value:7,count:2},{group:"topic",caption:"Chemistry",value:8,count:8},{group:"topic",caption:"Computer and Information Science",value:9,count:6},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:7},{group:"topic",caption:"Engineering",value:11,count:21},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:4},{group:"topic",caption:"Materials Science",value:14,count:6},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:25},{group:"topic",caption:"Neuroscience",value:18,count:2},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:3},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Robotics",value:22,count:1},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:1}],offset:12,limit:12,total:24},popularBooks:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5252},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editedByType:"Edited by",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editedByType:"Edited by",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editedByType:"Edited by",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editedByType:"Edited by",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9669",title:"Recent Advances in Rice Research",subtitle:null,isOpenForSubmission:!1,hash:"12b06cc73e89af1e104399321cc16a75",slug:"recent-advances-in-rice-research",bookSignature:"Mahmood-ur- Rahman Ansari",coverURL:"https://cdn.intechopen.com/books/images_new/9669.jpg",editedByType:"Edited by",editors:[{id:"185476",title:"Dr.",name:"Mahmood-Ur-",middleName:null,surname:"Rahman Ansari",slug:"mahmood-ur-rahman-ansari",fullName:"Mahmood-Ur- Rahman Ansari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editedByType:"Edited by",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editedByType:"Edited by",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editedByType:"Edited by",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editedByType:"Edited by",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"16",title:"Medicine",slug:"medicine",parent:{title:"Health Sciences",slug:"health-sciences"},numberOfBooks:1511,numberOfAuthorsAndEditors:39573,numberOfWosCitations:21767,numberOfCrossrefCitations:11544,numberOfDimensionsCitations:29307,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"medicine",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editedByType:"Edited by",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editedByType:"Edited by",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9406",title:"Clinical Implementation of Bone Regeneration and Maintenance",subtitle:null,isOpenForSubmission:!1,hash:"875a140c01518fa7a9bceebd688b0147",slug:"clinical-implementation-of-bone-regeneration-and-maintenance",bookSignature:"Mike Barbeck, Nahum Rosenberg, Patrick Rider, Željka Perić Kačarević and Ole Jung",coverURL:"https://cdn.intechopen.com/books/images_new/9406.jpg",editedByType:"Edited by",editors:[{id:"204918",title:"Dr.",name:"Mike",middleName:null,surname:"Barbeck",slug:"mike-barbeck",fullName:"Mike Barbeck"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9122",title:"Cosmetic Surgery",subtitle:null,isOpenForSubmission:!1,hash:"207026ca4a4125e17038e770d00ee152",slug:"cosmetic-surgery",bookSignature:"Yueh-Bih Tang",coverURL:"https://cdn.intechopen.com/books/images_new/9122.jpg",editedByType:"Edited by",editors:[{id:"202122",title:"Prof.",name:"Yueh-Bih",middleName:null,surname:"Tang",slug:"yueh-bih-tang",fullName:"Yueh-Bih Tang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9134",title:"Recent Advances in Digital System Diagnosis and Management of Healthcare",subtitle:null,isOpenForSubmission:!1,hash:"ff00a5718f23cb880b7337b1c36b5434",slug:"recent-advances-in-digital-system-diagnosis-and-management-of-healthcare",bookSignature:"Kamran Sartipi and Thierry Edoh",coverURL:"https://cdn.intechopen.com/books/images_new/9134.jpg",editedByType:"Edited by",editors:[{id:"29601",title:"Dr.",name:"Kamran",middleName:null,surname:"Sartipi",slug:"kamran-sartipi",fullName:"Kamran Sartipi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9569",title:"Methods in Molecular Medicine",subtitle:null,isOpenForSubmission:!1,hash:"691d3f3c4ac25a8093414e9b270d2843",slug:"methods-in-molecular-medicine",bookSignature:"Yusuf Tutar",coverURL:"https://cdn.intechopen.com/books/images_new/9569.jpg",editedByType:"Edited by",editors:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editedByType:"Edited by",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9839",title:"Outdoor Recreation",subtitle:"Physiological and Psychological Effects on Health",isOpenForSubmission:!1,hash:"5f5a0d64267e32567daffa5b0c6a6972",slug:"outdoor-recreation-physiological-and-psychological-effects-on-health",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/9839.jpg",editedByType:"Edited by",editors:[{id:"158692",title:"Ph.D.",name:"Hilde G.",middleName:null,surname:"Nielsen",slug:"hilde-g.-nielsen",fullName:"Hilde G. Nielsen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editedByType:"Edited by",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editedByType:"Edited by",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9018",title:"Some RNA Viruses",subtitle:null,isOpenForSubmission:!1,hash:"a5cae846dbe3692495fc4add2f60fd84",slug:"some-rna-viruses",bookSignature:"Yogendra Shah and Eltayb Abuelzein",coverURL:"https://cdn.intechopen.com/books/images_new/9018.jpg",editedByType:"Edited by",editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9523",title:"Oral and Maxillofacial Surgery",subtitle:null,isOpenForSubmission:!1,hash:"5eb6ec2db961a6c8965d11180a58d5c1",slug:"oral-and-maxillofacial-surgery",bookSignature:"Gokul Sridharan",coverURL:"https://cdn.intechopen.com/books/images_new/9523.jpg",editedByType:"Edited by",editors:[{id:"82453",title:"Dr.",name:"Gokul",middleName:null,surname:"Sridharan",slug:"gokul-sridharan",fullName:"Gokul Sridharan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1511,mostCitedChapters:[{id:"19013",doi:"10.5772/21983",title:"Cell Responses to Surface and Architecture of Tissue Engineering Scaffolds",slug:"cell-responses-to-surface-and-architecture-of-tissue-engineering-scaffolds",totalDownloads:9697,totalCrossrefCites:109,totalDimensionsCites:230,book:{slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",title:"Regenerative Medicine and Tissue Engineering",fullTitle:"Regenerative Medicine and Tissue Engineering - Cells and Biomaterials"},signatures:"Hsin-I Chang and Yiwei Wang",authors:[{id:"45747",title:"Dr.",name:"Hsin-I",middleName:null,surname:"Chang",slug:"hsin-i-chang",fullName:"Hsin-I Chang"},{id:"53659",title:"Ms.",name:"Yiwei",middleName:null,surname:"Wang",slug:"yiwei-wang",fullName:"Yiwei Wang"}]},{id:"46479",doi:"10.5772/57353",title:"Floating Drug Delivery Systems for Eradication of Helicobacter pylori in Treatment of Peptic Ulcer Disease",slug:"floating-drug-delivery-systems-for-eradication-of-helicobacter-pylori-in-treatment-of-peptic-ulcer-d",totalDownloads:1995,totalCrossrefCites:79,totalDimensionsCites:180,book:{slug:"trends-in-helicobacter-pylori-infection",title:"Trends in Helicobacter pylori Infection",fullTitle:"Trends in Helicobacter pylori Infection"},signatures:"Yousef Javadzadeh and Sanaz Hamedeyazdan",authors:[{id:"94276",title:"Prof.",name:"Yousef",middleName:null,surname:"Javadzadeh",slug:"yousef-javadzadeh",fullName:"Yousef Javadzadeh"},{id:"98229",title:"Dr.",name:"Sanaz",middleName:null,surname:"Hamedeyazdan",slug:"sanaz-hamedeyazdan",fullName:"Sanaz Hamedeyazdan"}]},{id:"25512",doi:"10.5772/30872",title:"Epidemiology of Psychological Distress",slug:"epidemiology-of-psychological-distress",totalDownloads:8066,totalCrossrefCites:57,totalDimensionsCites:145,book:{slug:"mental-illnesses-understanding-prediction-and-control",title:"Mental Illnesses",fullTitle:"Mental Illnesses - Understanding, Prediction and Control"},signatures:"Aline Drapeau, Alain Marchand and Dominic Beaulieu-Prévost",authors:[{id:"84582",title:"Dr.",name:"Aline",middleName:null,surname:"Drapeau",slug:"aline-drapeau",fullName:"Aline Drapeau"},{id:"84605",title:"Dr.",name:"Alain",middleName:null,surname:"Marchand",slug:"alain-marchand",fullName:"Alain Marchand"},{id:"84606",title:"Dr.",name:"Dominic",middleName:null,surname:"Beaulieu-Prévost",slug:"dominic-beaulieu-prevost",fullName:"Dominic Beaulieu-Prévost"}]}],mostDownloadedChaptersLast30Days:[{id:"43758",title:"Anxiety Disorders in Pregnancy and the Postpartum Period",slug:"anxiety-disorders-in-pregnancy-and-the-postpartum-period",totalDownloads:39763,totalCrossrefCites:11,totalDimensionsCites:20,book:{slug:"new-insights-into-anxiety-disorders",title:"New Insights into Anxiety Disorders",fullTitle:"New Insights into Anxiety Disorders"},signatures:"Roberta Anniverno, Alessandra Bramante, Claudio Mencacci and Federico Durbano",authors:[{id:"157077",title:"Dr.",name:"Federico",middleName:null,surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"},{id:"166382",title:"Dr.",name:"Roberta",middleName:null,surname:"Anniverno",slug:"roberta-anniverno",fullName:"Roberta Anniverno"}]},{id:"70711",title:"Fetal Growth Restriction",slug:"fetal-growth-restriction",totalDownloads:1706,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"growth-disorders-and-acromegaly",title:"Growth Disorders and Acromegaly",fullTitle:"Growth Disorders and Acromegaly"},signatures:"Edurne Mazarico Gallego, Ariadna Torrecillas Pujol, Alex Joan Cahuana Bartra and Maria Dolores Gómez Roig",authors:[{id:"202446",title:"Ph.D.",name:"Maria Dolores",middleName:null,surname:"Gómez Roig",slug:"maria-dolores-gomez-roig",fullName:"Maria Dolores Gómez Roig"},{id:"311835",title:"Dr.",name:"Edurne",middleName:null,surname:"Mazarico",slug:"edurne-mazarico",fullName:"Edurne Mazarico"}]},{id:"70405",title:"Hemostasis in Cardiac Surgery: How We Do it with Limited Resources",slug:"hemostasis-in-cardiac-surgery-how-we-do-it-with-limited-resources",totalDownloads:2694,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:null,title:"Contemporary Applications of Biologic Hemostatic Agents across Surgical Specialties - Volume 1",fullTitle:"Contemporary Applications of Biologic Hemostatic Agents across Surgical Specialties - Volume 1"},signatures:"Fevzi Sarper Türker",authors:null},{id:"64851",title:"Herbal Medicines in African Traditional Medicine",slug:"herbal-medicines-in-african-traditional-medicine",totalDownloads:9954,totalCrossrefCites:10,totalDimensionsCites:17,book:{slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Ezekwesili-Ofili Josephine Ozioma and Okaka Antoinette Nwamaka\nChinwe",authors:[{id:"191264",title:"Prof.",name:"Josephine",middleName:"Ozioma",surname:"Ezekwesili-Ofili",slug:"josephine-ezekwesili-ofili",fullName:"Josephine Ezekwesili-Ofili"},{id:"211585",title:"Prof.",name:"Antoinette",middleName:null,surname:"Okaka",slug:"antoinette-okaka",fullName:"Antoinette Okaka"}]},{id:"59779",title:"Effective Communication in Nursing",slug:"effective-communication-in-nursing",totalDownloads:6504,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"nursing",title:"Nursing",fullTitle:"Nursing"},signatures:"Maureen Nokuthula Sibiya",authors:[{id:"73330",title:"Dr.",name:"Nokuthula",middleName:null,surname:"Sibiya",slug:"nokuthula-sibiya",fullName:"Nokuthula Sibiya"}]},{id:"64858",title:"The Neurobiology of Anorexia Nervosa",slug:"the-neurobiology-of-anorexia-nervosa",totalDownloads:892,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"anorexia-and-bulimia-nervosa",title:"Anorexia and Bulimia Nervosa",fullTitle:"Anorexia and Bulimia Nervosa"},signatures:"Ashley Higgins",authors:null},{id:"63771",title:"The Role of Catheter Reshaping at the Angiographic Success",slug:"the-role-of-catheter-reshaping-at-the-angiographic-success",totalDownloads:536,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"angiography",title:"Angiography",fullTitle:"Angiography"},signatures:"Yakup Balaban",authors:[{id:"252647",title:"Associate Prof.",name:"Yakup",middleName:null,surname:"Balaban",slug:"yakup-balaban",fullName:"Yakup Balaban"}]},{id:"61866",title:"Plants Secondary Metabolites: The Key Drivers of the Pharmacological Actions of Medicinal Plants",slug:"plants-secondary-metabolites-the-key-drivers-of-the-pharmacological-actions-of-medicinal-plants",totalDownloads:5564,totalCrossrefCites:13,totalDimensionsCites:32,book:{slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Rehab A. Hussein and Amira A. El-Anssary",authors:[{id:"212117",title:"Dr.",name:"Rehab",middleName:null,surname:"Hussein",slug:"rehab-hussein",fullName:"Rehab Hussein"},{id:"221140",title:"Dr.",name:"Amira",middleName:null,surname:"El-Anssary",slug:"amira-el-anssary",fullName:"Amira El-Anssary"}]},{id:"17956",title:"Sexual and Reproductive Function in Chronic Kidney Disease and Effect of Kidney Transplantation",slug:"sexual-and-reproductive-function-in-chronic-kidney-disease-and-effect-of-kidney-transplantation",totalDownloads:11790,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"after-the-kidney-transplant-the-patients-and-their-allograft",title:"After the Kidney Transplant",fullTitle:"After the Kidney Transplant - The Patients and Their Allograft"},signatures:"Mahboob Lessan-Pezeshki and Shirin Ghazizadeh",authors:[{id:"26564",title:"Prof.",name:"Mahboob",middleName:null,surname:"Lessan Pezeshki",slug:"mahboob-lessan-pezeshki",fullName:"Mahboob Lessan Pezeshki"},{id:"26571",title:"Prof.",name:"Shirin",middleName:null,surname:"Ghazizadeh",slug:"shirin-ghazizadeh",fullName:"Shirin Ghazizadeh"}]},{id:"64747",title:"Bone Development and Growth",slug:"bone-development-and-growth",totalDownloads:3711,totalCrossrefCites:6,totalDimensionsCites:9,book:{slug:"osteogenesis-and-bone-regeneration",title:"Osteogenesis and Bone Regeneration",fullTitle:"Osteogenesis and Bone Regeneration"},signatures:"Rosy Setiawati and Paulus Rahardjo",authors:null}],onlineFirstChaptersFilter:{topicSlug:"medicine",limit:3,offset:0},onlineFirstChaptersCollection:[{id:"75604",title:"Normal Puerperium",slug:"normal-puerperium",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.96348",book:{title:"Midwifery"},signatures:"Subrat Panda, Ananya Das, Arindam Mallik and Surajit Ray Baruah"},{id:"75596",title:"The Use of a Dynamic Elastomeric Fabric Orthotic Intervention in Adolescents and Adults with Scoliosis",slug:"the-use-of-a-dynamic-elastomeric-fabric-orthotic-intervention-in-adolescents-and-adults-with-scolios",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.96391",book:{title:"Spinal Deformities in Adolescents, Adults and Older Adults"},signatures:"Martin Matthews and James Wynne"},{id:"75582",title:"Elimination of Plasmodium vivax Malaria: Problems and Solutions",slug:"elimination-of-plasmodium-vivax-malaria-problems-and-solutions",totalDownloads:1,totalDimensionsCites:null,doi:"10.5772/intechopen.96604",book:{title:"Current Topics and Emerging Issues in Malaria Elimination"},signatures:"Liwang Cui, Awtum Brashear, Lynette Menezes and John Adams"}],onlineFirstChaptersTotal:652},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/172885/pietro-romano",hash:"",query:{},params:{id:"172885",slug:"pietro-romano"},fullPath:"/profiles/172885/pietro-romano",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()