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.
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Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
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“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
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Additionally, each book published by IntechOpen contains original content and research findings.
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We 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.
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.
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Simba 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.
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IntechOpen, 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.
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Since the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\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\n
Our 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\n
Additionally, each book published by IntechOpen contains original content and research findings.
\n\n
We 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.
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\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"7144",leadTitle:null,fullTitle:"Veterinary Anatomy and Physiology",title:"Veterinary Anatomy and Physiology",subtitle:null,reviewType:"peer-reviewed",abstract:"Knowledge of veterinary anatomy and physiology is essential for veterinary professionals and researchers. The chapters reflect the diverse and dynamic research being undertaken in a variety of different species throughout the world. Whether the animals have roles in food security, agriculture, or as companion, wild, or working animals, the lessons we learn impact on many areas of the profession. This book highlights research ranging from the cardiovascular and musculoskeletal systems, prostate and hoof, through to histopathology, imaging, and molecular techniques. It investigates both healthy and pathological conditions at differing stages of life. The importance of each cell and tissue through to the whole organism is explored alongside the methodologies used to understand these vital structures and functions.",isbn:"978-1-78985-706-1",printIsbn:"978-1-78985-705-4",pdfIsbn:"978-1-83962-072-0",doi:"10.5772/intechopen.73942",price:119,priceEur:129,priceUsd:155,slug:"veterinary-anatomy-and-physiology",numberOfPages:168,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"75cdacb570e0e6d15a5f6e69640d87c9",bookSignature:"Catrin Sian Rutland and Valentina Kubale",publishedDate:"March 13th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7144.jpg",numberOfDownloads:14024,numberOfWosCitations:13,numberOfCrossrefCitations:13,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:21,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:47,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 28th 2018",dateEndSecondStepPublish:"June 18th 2018",dateEndThirdStepPublish:"August 17th 2018",dateEndFourthStepPublish:"November 5th 2018",dateEndFifthStepPublish:"January 4th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"10",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Ljubljana",institutionURL:null,country:{name:"Slovenia"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"25",title:"Veterinary Medicine and Science",slug:"veterinary-medicine-and-science"}],chapters:[{id:"65366",title:"Introductory Chapter: Veterinary Anatomy and Physiology",doi:"10.5772/intechopen.82412",slug:"introductory-chapter-veterinary-anatomy-and-physiology",totalDownloads:1879,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:null,signatures:"Valentina Kubale, Emma Cousins, Clara Bailey, Samir A.A. El-Gendy\nand Catrin Sian Rutland",downloadPdfUrl:"/chapter/pdf-download/65366",previewPdfUrl:"/chapter/pdf-preview/65366",authors:[{id:"202192",title:"Dr.",name:"Catrin",surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland"},{id:"246149",title:"Dr.",name:"Valentina",surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale"},{id:"283315",title:"Prof.",name:"Samir",surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy"},{id:"283317",title:"BSc.",name:"Emma",surname:"Cousins",slug:"emma-cousins",fullName:"Emma Cousins"},{id:"283318",title:"BSc.",name:"Clara",surname:"Bailey",slug:"clara-bailey",fullName:"Clara Bailey"}],corrections:null},{id:"65570",title:"The Anatomy, Histology and Physiology of the Healthy and Lame Equine Hoof",doi:"10.5772/intechopen.84514",slug:"the-anatomy-histology-and-physiology-of-the-healthy-and-lame-equine-hoof",totalDownloads:2124,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:1,abstract:"Satisfactory investigations of the equine foot appear to be limited by the histo-morphological complexity of internal hoof structures. Foot lameness is considered to be one of the most debilitating pathological disorders of the equine foot. In most species, foot lameness is traditionally linked to hoof deformity, and a set of molecular events have been defined in relation to the disease. So far, there is controversy regarding the incidence of foot lameness in horses, as it is unclear whether it is foot lameness that triggers hoof distortions or vice-versa. In order to develop a better understanding of foot lameness, we review both the healthy and lame foot anatomy, cell biology and vascularisation and using micro-computed tomography show new methods of visualising internal structures within the equine foot.",signatures:"Ramzi Al-Agele, Emily Paul, Valentina Kubale Dvojmoc, Craig J. Sturrock,\nCyril Rauch and Catrin Sian Rutland",downloadPdfUrl:"/chapter/pdf-download/65570",previewPdfUrl:"/chapter/pdf-preview/65570",authors:[{id:"202192",title:"Dr.",name:"Catrin",surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland"},{id:"246149",title:"Dr.",name:"Valentina",surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale"},{id:"261698",title:"Dr.",name:"Ramzi",surname:"Al-Agele",slug:"ramzi-al-agele",fullName:"Ramzi Al-Agele"},{id:"261699",title:"MSc.",name:"Emily",surname:"Paul",slug:"emily-paul",fullName:"Emily Paul"},{id:"261701",title:"Prof.",name:"Cyril",surname:"Rauch",slug:"cyril-rauch",fullName:"Cyril Rauch"},{id:"276603",title:"Mr.",name:"Craig",surname:"Sturrock",slug:"craig-sturrock",fullName:"Craig Sturrock"}],corrections:null},{id:"63901",title:"Macroscopic, Radiographic and Histopathologic Changes of Claws with Laminitis and Laminitis-Related Disorders in Zero-Grazed Dairy Cows",doi:"10.5772/intechopen.81255",slug:"macroscopic-radiographic-and-histopathologic-changes-of-claws-with-laminitis-and-laminitis-related-d",totalDownloads:1020,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Laminitis and laminitis-related claw disorders are prevalent in zero-grazed dairy cows. Confinement and limited movement influences claw size and shape. Abnormal claw size and shape causes imbalanced body weight distribution on the claws. Claw horn growth and wear is impaired, further aggravating laminitis disorders. The objective of this study was to determine: macroscopic disorders on the claws, as well as radiographic features and histopathologic changes on the claws with laminitis/laminitis-related disorders. A total of 159 dairy cow forelimb and hind limb feet (318 claws) were collected from an abattoir and a slaughter slab around Nairobi, Kenya. The claws were examined for macroscopic abnormalities, dorso-palmar or dorso-plantar radiography done, sagittal claw sections done, corium gross changes observed and corium tissues harvested for histopathology. Macroscopic disorders observed were: sole bruising, claw deformities, heel erosion, subclinical laminitis sole haemorrhages, double soles, chronic laminitis and white line separation. Radiographic changes observed mainly on distal phalanges were dilated vascular channels, irregular margins, exostoses/periostitis, distal phalangeal narrowing and lysis. Histopathologic changes in the corium included arterio-venous shunts, vascular wall rupture and thickening, vascular proliferation and thrombosis, corium and connective tissue oedema, degeneration, haemorrhages and spongiosis. Hence macroscopic, radiographic and histopathologic changes in laminitis claws affect locomotion.",signatures:"James Nguhiu-Mwangi and Peter M.F. Mbithi",downloadPdfUrl:"/chapter/pdf-download/63901",previewPdfUrl:"/chapter/pdf-preview/63901",authors:[{id:"262330",title:"Prof.",name:"James",surname:"Nguhiu-Mwangi",slug:"james-nguhiu-mwangi",fullName:"James Nguhiu-Mwangi"},{id:"271483",title:"Prof.",name:"Peter",surname:"Mbithi",slug:"peter-mbithi",fullName:"Peter Mbithi"}],corrections:null},{id:"63726",title:"Myocardial Metabolism",doi:"10.5772/intechopen.80870",slug:"myocardial-metabolism",totalDownloads:1499,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Myocardial metabolism alterations are associated with myocardial dystrophy and lead to the heart chambers dilatation, decreased contractility, organs perfusion and depended on symptoms. Nowadays heart failure treatment in veterinary medicine includes neurohormonal, circulatory and contractile aspects of this pathological state. Unfortunately, energy supplying component not presented in modern recommendations. Most of the used medications changing contractile ability, through the control of myocardial filaments sensibility to the different ions, but don’t affect the ability of cardiomyocytes to produce enough energy for this work. In order to understand the heart failure syndrome more completely, we should elucidate features, characteristics, and interactions between components of myocardial energy supply.",signatures:"Dmitrii Oleinikov",downloadPdfUrl:"/chapter/pdf-download/63726",previewPdfUrl:"/chapter/pdf-preview/63726",authors:[{id:"260411",title:"Dr.",name:"Dmitrii",surname:"Oleinikov",slug:"dmitrii-oleinikov",fullName:"Dmitrii Oleinikov"}],corrections:null},{id:"63889",title:"Anatomy, Histology, and Physiology of the Canine Prostate Gland",doi:"10.5772/intechopen.81410",slug:"anatomy-histology-and-physiology-of-the-canine-prostate-gland",totalDownloads:2051,totalCrossrefCites:5,totalDimensionsCites:7,hasAltmetrics:0,abstract:"The prostate gland is the only male accessory gland in dogs and is responsible for secreting the prostatic fluid. Morphologically, the canine prostate gland lacks differentiation into zones, presenting a uniform parenchyma along the longitudinal axis. The luminal epithelial cells secrete a liquid rich in calcium, citric acid, simple sugars, and different enzymes as a component of the seminal plasma. Since the prostatic diseases are very common in small animal practice, there are many information regarding mechanisms of the different prostatic conditions and lack of information regarding the anatomy, histology, and physiology of the canine prostate gland. Thus, this chapter aims to meticulously describe the anatomy, histology, and physiology of the canine prostate gland.",signatures:"Antonio Fernando Leis-Filho and Carlos E. Fonseca-Alves",downloadPdfUrl:"/chapter/pdf-download/63889",previewPdfUrl:"/chapter/pdf-preview/63889",authors:[{id:"258334",title:"Dr.",name:"Carlos Eduardo",surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves"},{id:"266102",title:"MSc.",name:"Antonio Fernando",surname:"Leis Filho",slug:"antonio-fernando-leis-filho",fullName:"Antonio Fernando Leis Filho"}],corrections:null},{id:"64559",title:"Major Health Constraints and Ethno-Vet Practices of Small-Scale and Backyard Chicken Production in Some Selected Regions of Ethiopia",doi:"10.5772/intechopen.81302",slug:"major-health-constraints-and-ethno-vet-practices-of-small-scale-and-backyard-chicken-production-in-s",totalDownloads:1013,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"A study was conducted with the aim of assessing the major health constraints facing the small-scale and backyard chicken producers and ethno-vet practices exercised in five regions of the country: Amhara, Benishangul-Gumuz, Oromia, Southern region, and Tigray. Household respondents were purposively selected and interviewed. Data were collected through pretesting, semi-structural questionnaires, and field observation. The overall frequency of diseases reported as the main health constraint was Newcastle disease (64%) followed by gastrointestinal infection (34%), respiratory syndrome (22%), internal and external parasites (16%), coccidiosis (15%), and fowl pox (5%). They had no awareness how to manage chicken diseases (91.5%), and their flocks were not vaccinated (84%). High disease occurrence is reported in long rainy season (59%). Ethno-vet practice was experienced by the majority of the interviewed households (51.9%). A total of 19 medicinal plants were reported as being used as a traditional medicine. The main causes of losses were identified as disease (67%) and predator attack (32%). Poor disease prevention and control and the lack of knowledge and management skills were the major constraints of poultry production in the study areas. Research and extension efforts should be directed at the identified constraints. Farmer training and improvement of veterinary services are important.",signatures:"Meskerem Adamu Chere",downloadPdfUrl:"/chapter/pdf-download/64559",previewPdfUrl:"/chapter/pdf-preview/64559",authors:[{id:"265422",title:"Dr.",name:"Meskerem",surname:"Adamu",slug:"meskerem-adamu",fullName:"Meskerem Adamu"}],corrections:null},{id:"65450",title:"Veterinarian’s Role in Conservation Medicine and Animal Welfare",doi:"10.5772/intechopen.84173",slug:"veterinarian-s-role-in-conservation-medicine-and-animal-welfare",totalDownloads:1423,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"The enhanced role of human actions brings new escalating conservation challenges and emerging diseases, which pressure impaired long-term survival of threatened free-ranging and captive wildlife species, while having hazardous effects on ecosystems and public health. Veterinarians have not only a broad education in comparative medicine (not a single-species focus) but also are also highly trained in recognizing, diagnosing and understanding disease impact on public health as well as on individuals, populations and whole ecosystems. Their skills and expertise turns them into valuable key players in planning, implementing and effectively assisting both in-situ and ex-situ conservation projects. In parks and zoological gardens, major goals have now won priority: the conservation of worldwide fauna and flora and the protection of animal welfare. Today, animal welfare can be scientifically assessed to determine the quality of life of individuals, in which behavioral assessment and behavioral enrichment are fundamental tools.",signatures:"Diana Raquel Neves Fernandes and Maria de Lurdes Ribeiro Pinto",downloadPdfUrl:"/chapter/pdf-download/65450",previewPdfUrl:"/chapter/pdf-preview/65450",authors:[{id:"161692",title:"Prof.",name:"Maria De Lurdes",surname:"Pinto",slug:"maria-de-lurdes-pinto",fullName:"Maria De Lurdes Pinto"},{id:"279598",title:"Dr.",name:"Diana",surname:"Fernandes",slug:"diana-fernandes",fullName:"Diana Fernandes"}],corrections:null},{id:"65535",title:"Reptilian Skin and Its Special Histological Structures",doi:"10.5772/intechopen.84212",slug:"reptilian-skin-and-its-special-histological-structures",totalDownloads:3019,totalCrossrefCites:5,totalDimensionsCites:9,hasAltmetrics:1,abstract:"Reptilian skin is covered with scales forming armor that makes it watertight and enables reptiles to live on land in contrast to amphibians. An important part of the skin is the horny epidermis, with thick stratum corneum in which waxes are arranged in membrane-like layers. In lizards and snakes, the whole skin is covered in overlapping epidermal scales and in turtles and crocodiles in dermal scutes. The cornified part of the epidermis is strengthened by β-keratin and sometimes α-keratin. In crocodiles and many turtles, the outer scale surface consists of β-keratin and the hinge region containing α-keratin. In lizards and snakes, both keratins form continuous layers with the α-keratin below the β-keratin. Some reptiles have developed a sensitive mechanosensory system in the skin. The colors of reptile skin are produced by melanocytes and three types of chromatophores: melanophores, xanthophores, and iridophores. The color patterns may be fixed or the chromatophores may provide rapid color change. Skin from different species of reptiles, turtles (red-eared slider (Trachemys scripta elegans)), snakes (Emerald tree boa (Corallus caninus) and Burmese python (Python bivittatus)), Cuvier’s dwarf caiman (Paleosuchus palpebrosus), lizards (Leopard Gecko (Eublepharis macularius)), and Green iguana (Iguana iguana), were examined with histology techniques and compared.",signatures:"Catrin Sian Rutland, Pia Cigler and Valentina Kubale",downloadPdfUrl:"/chapter/pdf-download/65535",previewPdfUrl:"/chapter/pdf-preview/65535",authors:[{id:"246149",title:"Dr.",name:"Valentina",surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:{id:"19",series:{id:"13",title:"Veterinary Medicine and Science",issn:"2632-0517",editor:{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}}}},tags:[{id:"23",label:"women in science book program"}]},relatedBooks:[{type:"book",id:"9081",title:"Equine Science",subtitle:null,isOpenForSubmission:!1,hash:"ac415ef2f5450fa80fdb9cf6cf32cd2d",slug:"equine-science",bookSignature:"Catrin Rutland and Albert Rizvanov",coverURL:"https://cdn.intechopen.com/books/images_new/9081.jpg",editedByType:"Edited by",editors:[{id:"202192",title:"Dr.",name:"Catrin",surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10497",title:"Canine Genetics, Health and Medicine",subtitle:null,isOpenForSubmission:!1,hash:"b91512e31ce34032e560362e6cbccc1c",slug:"canine-genetics-health-and-medicine",bookSignature:"Catrin Rutland",coverURL:"https://cdn.intechopen.com/books/images_new/10497.jpg",editedByType:"Edited by",editors:[{id:"202192",title:"Dr.",name:"Catrin",surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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\r\n\tThe bottom-up approach for the self-assembly of molecules, macromolecules, and particles into well-defined superstructures provides superior structural control of materials compared to top-down methods. Nature largely utilizes macromolecules to construct supramolecular materials, which ultimately contribute to the great array of forms and functions of life. Thus, the self-assembly of materials and the formation of superstructures have been of great interest in the fields of materials science, nanoscience, and nanoengineering.
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\r\n\t \r\n\tThis book will describe the self-assembly of materials and supramolecular chemistry design principles for a broad spectrum of materials, including bio-inspired amphiphiles, metal oxides, metal nanoparticles, and organic-inorganic hybrid materials. It will provide fundamental concepts of self-assembly design approaches and supramolecular chemistry principles for research ideas in nanotechnology applications. The book will focus on three main themes, which include: the self-assembly and supramolecular chemistry of amphiplies by coordination programming, the supramolecular structures and devices of inorganic materials, and the assembly-disassembly of organic-inorganic hybrid materials. The contributing chapters will be written by leading scientists in their field, with the hope that this book will provide a foundation on supramolecular chemistry principles to students and active researchers who are interested in nanoscience and nanoengineering fields.
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1. Introduction
The communication traffic volume handled by trunk optical transport networks has been increasing year by year [1]. Meeting the increasing demand not only requires a quantitative increase in total traffic volume, but also ideally requires an increase in the speed of individual clients to maintain the balance between cost and reliability. This is particularly appropriate for shorter links across the network, where the relatively high optical signal-to-noise ratio (OSNR) would allow the use of a higher capacity, but is less appropriate for the longest links, where products are already close to the theoretical limits [2]. In such circumstances, it is necessary to maximize resource utilization and in a static network one approach to achieve this is the deployment of spectrally efficient higher-order modulation formats enabled by digital coherent detection. As attested by the rapid growth in reported constellation size [3,4], the optical hardware for a wide variety of coherently detected modulation formats is identical [5]. This has led to the suggestion that a common transponder may be deployed and the format adjusted on a link by link basis to either maximize the link capacity given the achieved OSNR, or if lower, match the required client interface rate [6] such that the number of wavelength channels allocated to a given route is minimized. It is believed that such dynamic, potentially self-adjusting, networks will enable graceful capacity growth, ready resource re-allocation and cost reductions associated with improved transponder volumes and sparing strategies. However additional trade-offs and challenges associated with such networks are presented to system designers and network planners. One such challenge is associated with the nonlinear transmission impairments which strongly link the achievable channel reach for a given set of modulation formats, symbol-rates [6,7] across a number of channels.
Various methods of compensating fiber transmission impairments have been proposed, both in optical and electronic domain. Traditionally, dispersion management was used to suppress the impact of fiber nonlinearities [8,9]. Although dispersion management is appreciably beneficial, the benefit is specific to a limited range of transmission formats and rates and it enforces severe limitations on link design. Similarly, compensation of fiber impairments based on spectral inversion (SI) [10], has been considered attractive because of the removal of in-line dispersion compensation modules (DCM), transparency to modulation formats and compensation of nonlinearity. However, although SI has large bandwidth capabilities, it often necessitates precise positioning and customized link design (e.g., distributed Raman amplification, etc.). Alternatively, with the availability of high speed digital signal processing (DSP), electronic mitigation of transmission impairments has emerged as a promising solution. As linear compensation methods have matured in past few years [11], the research has intensified on compensation of nonlinear impairments. In particular, electronic signal processing using digital back-propagation (DBP) with time inversion has been applied to the compensation of channel nonlinearities [12,13]. Back-propagation may be located at the transmitter [14] or receiver [15], places no constraints on the transmission line and is thus compatible with the demands of an optical network comprising multiple routes over a common fiber platform. In principle this approach allows for significant improvements in signal-to-noise ratios until the system performance becomes limited only by non-deterministic effects [16] or the power handling capabilities of individual components. Although the future potential of nonlinear impairment compensation using DBP in a dynamic optical network is unclear due to its significant computational burden, simplification of nonlinear DBP using single-channel processing at the receiver suggest that the additional processing required for intra-channel nonlinearity compensation may be significantly lower than is widely anticipated [17,18]. Studies of the benefits of DBP have largely been verified for systems employing homogenous network traffic, where all the channels have the same launch power [19]. However, as network upgrades are carried out, it is likely that channels employing different multi-level formats will become operational. In such circumstances, it has been demonstrated that the overall network capacity may be increased if the network traffic will become inhomogeneous, not only in terms of modulation format, but also in terms of signal launch power [6,7,20]. In particular, if each channel operates at the minimum power required for error free propagation (after error correction) rather than a global average power or the optimum power for the individual channel, the overall level of cross phase modulation in the network is reduced [20].
In this chapter we demonstrate the application of electronic compensation schemes in a dynamic optical network, focusing on adjustable signal constellations with non identical launch powers, and discuss the impact of periodic addition of 28-Gbaud polarization multiplexed m-ary quadrature amplitude modulation (PM-mQAM) channels on existing traffic. We also discuss the impact of cascaded reconfigurable optical add-drop multiplexerson networks operating close to the maximum permissible capacity in the presence of electronic compensation techniques for a range of higher-order modulation formats and filter shapes.
2. Simulation conditions
Figure 1 illustrates the simulation setup. The optical link comprised nine (unless mentioned otherwise) 28-Gbaud WDM channels, employing PM-mQAM with a channel spacing of 50 GHz. For all the carriers, both the polarization states were modulated independently using de-correlated 215 and 216 pseudo-random bit sequences (PRBS), for x- and y-polarization states, respectively. Each PRBS was de-multiplexed separately into two multi-level output symbol streams which were used to modulate an in-phase and a quadrature-phase carrier. The optical transmitters consisted of continuous wave laser sources, followed by two nested Mach-Zehnder Modulator structures for x- and y-polarization states, and the two polarization states were combined using an ideal polarization beam combiner. The simulation conditions ensured 16 samples per symbol with 213 total simulated symbols per polarization. The signals were propagated over standard single mode fiber (SSMF) transmission link with 80 km spans, no inline dispersion compensation and single-stage erbium doped fiber amplifiers (EDFAs). The fiber had attenuation of 0.2 dB/km, dispersion of 20 ps/nm/km, and a nonlinearity coefficient (γ) of 1.5/W/km(unless mentioned otherwise). Each amplifier stage was modeled with a 4.5 dB noise figure and the total amplification gain was set to be equal to the total loss in each span.
Figure 1.
Simulation setup for 28-Gbaud PM-mQAM (m= 4, 16, 64, 256) transmission system with L wavelengths and M spans per node (total spans is given by N).
At the coherent receiver the signals were pre-amplified (to a fixed power of 0 dBm per channel), filtered with a 50 GHz 3rd order Gaussian de-multiplexing filter, coherently-detected and sampled at 2 samples per symbol. Transmission impairments were digitally compensated in two scenarios. Firstly by using electronic dispersion compensation (EDC) alone, employing finite impulse response (FIR) filters (T/2-spaced taps) adapted using a least mean square algorithm. In the second case, electronic compensation was applied via single-channel digital back-propagation (SC-DBP), which was numerically implemented by split-step Fourier method based solution of nonlinear Schrödinger equation. In order to establish the maximum potential benefit of DBP, the signals were up sampled to 16 samples per bit and an upper bound on the step-size was set to be 1 km with the step length chosen adaptively based on the condition that in each step the nonlinear effects must change the phase of the optical field by no more than 0.05 degrees. To determine the practically achievable benefit, in line with recent simplification of DBP algorithms, e.g. [17,18,21], we also employed a simplified DBP algorithm similar to [21], with number of steps varying from 0.5 step/span to 2 steps/span. Following one of these stages (EDC or SC-DBP) polarization de-multiplexing, frequency response compensation and residual dispersion compensation was then performed using FIR filters, followed by carrier phase recovery [22]. Finally, the symbol decisions were made, and the performance assessed by direct error counting (converted into an effective Q-factor (Qeff)). All the numerical simulations were carried out using VPItransmissionMaker®v8.5, and the digital signal processing was performed in MATLAB®v7.10.
3. Analysis of trade-offs in hybrid networks
3.1. Constraints on transmission reach
In a dynamic network, there are a large range of options to provide the desired flexibility including symbol rate [23], sub-carrier multiplexing [24], network configuration [25] signal constellation and various combinations of these techniques. In this section we focus on the signal constellation and discuss the impact of periodic addition of PM-mQAM (m= 4, 16, 64, 256) transmission schemes on existing PM-4QAM traffic in a 28-Gbaud WDM optical network with a total transparent optical path of 9,600 km. We demonstrate that the periodic addition of traffic at reconfigurable optical add-drop multiplexer (ROADM) sites degrades through traffic, and that this degradation increases with the constellation size of the added traffic. In particular, we demonstrate that undistorted PM-mQAM signals have the greatest impact on the through traffic, despite such signals having lower peak-to-average power ratio (PAPR) than dispersed signals, although the degradation strongly correlated to the total PAPR of the added traffic at the launch point itself. Using this observation, we propose the use of linear pre-distortion of the added channels to reduce the impact of the cross-channel impairments [26,27].
Note that the total optical path was fixed to be 9,600 km and after every M spans, a ROADM stage was employed and the channels to the left and right of the central channel were dropped and new channels with independent data patterns were added, as shown in Figure 2. in order to analyze the system performance, the dropped channels were coherently-detected after first ROADM and the central channel after the last ROADM link.
Figure 2.
Network topology for flexible optical network, employing PM-4QAM traffic as a through channel, and PM-mQAM traffic as neighboring channels, getting added/dropped at each ROADM site. Note that in this schematic only right-hand wavelength is shown to be added/dropped, however in the simulations both right and left wavelengths were add/dropped. The total path length was fixed to 9,600 km, and the number of ROADMs was varied.
The optimum performance of the central PM-4QAM channel at 9,600 km occurred for a launch power of -1 dBm. In this study, the launch power of all the added channels was also fixed at -1 dBm, such that all channels had equal launch powers. Figure 3 illustrates the performance of the central test channel after the last node (solid), along with the performance of co-propagating channel employing various modulation formats after the first ROADM node (open) for a number of ROADM spacing’s, using both single-channel DBP (Figure 3a) and EDC (Figure 3b). It can be seen that single-channel DBP offers a Qeff improvement of ~1.5 dB compared to EDC based system. This performance improvement is strongly constrained by inter-channel nonlinearities, such that intra-channel effects are not dominant. Moreover, the figure shows that as the number of ROADM nodes are increased, or the distance between ROADMs decreases, the performance of higher-order neighboring channels improves significantly due to the improved OSNR.
It can also be seen from Figure 3 that added channels with higher-order formats induce greater degradation of the through channel. In particular if there are 30 ROADM sites (320 km ROADM spacing) allocated to transmit PM-64QAM, whilst this traffic operates with significant margin, the through traffic falls below the BER of 3.8x10-3. This increased penalty is due to the increased nonlinear degradation encountered in the first span after the ROADM node, where higher formats induce greater cross phase modulation(XPM) than PM-4QAM by virtue of their increased PAPR. However, even when the add drop traffic is PM-4QAM, the performance of the through channel degrades slightly as the number of ROADM nodes is increased, despite the reduction in PAPR due to the randomization of the nonlinear crosstalk.
The estimated PAPR evolutions for the various formats are shown in Figure 4. Asymptotic values are reached after the first span, and reach a slightly higher value for m ≥ 16. The PAPR is reduced at the ROADM site itself, particularly for PM-4QAM. Figure 4 implies that harmful increases in the instantaneous amplitude of the interfering channels are not the entire cause of the penalty experienced by the through channel; we can therefore only conclude that the additional distortion results from interplay between channel walk off and nonlinear effects. Given that walk-off is known to induce short and medium range correlation in crosstalk between subsequent bits, effectively low pass filtering the crosstalk [28]. We thus believe that the penalty experienced by the through channel is not only because of variation in PAPR, but also due to the randomization of the crosstalk by the periodic replacement of the interfering data pattern.
Figure 3.
Qeff as a function of number of ROADMs (and distance between ROADM nodes) for 28-Gbaud PM-mQAM showing performance of central PM-4QAM (solid, after total length), and neighboring PM-mQAM (open, after first node). a) with single-channel DBP, b) with electronic dispersion compensation. Square: 4QAM, circle: 16QAM, up triangle: 64QAM, diamond:256QAM. Up arrows indicate that no errors were detected, implying that the Qeff was likely to be above 12.59 dB. Total link length is 9,600 km.
Figure 4.
Variation in PAPR, for 4QAM (black), 16QAM (red), 64QAM (green) and 256QAM (blue) for a loss-less linear fiber with 20 ps/nm/km dispersion.
Figure 5.
Qeff of the PM-4QAM through channel for 28-Gbaud PM-mQAM add/drop traffic after 9,600 km as a function of a figure of merit (FOM) defined in the text for various add drop configurations. Solid: with single-channel DBP, open: with EDC.
This is confirmed by Figure 5, which plots the Qeff of PM-4QAM after last node, for both EDC and single-channel DBP, in terms of a figure of merit (FOM) related to the increased amplitude modulation experienced by the test channel in the spans immediately following the ROADM node, defined as,
FOMPM−mQAM(m)=(ROADMN)×[Imax(m)/Iall(m)¯]E1
wherem represents the modulation order, ROADMN represents number of add-drop nodes, Imax and Iallare the maximum and mean intensity of the given modulation format at the ROADM site. A strong correlation between the penalty and change in PAPR is observed. For instance, for a high number of ROADMs the system would be mostly influenced by relatively un-dispersed signals and the difference between peak-to-average fluctuations for multi-order QAM varies significantly. This leads to higher-order modulation formats impinging worse cross-channel effects on existing traffic for shorter routes.
Having observed that the nonlinear penalty is determined by the reduction in the correlation of nonlinear phase shift between bits arising from changing bit patterns, and to changes in PAPR arising from undistorted signals, it is possible to design a mitigation strategy to minimize these penalties. Figure 6 illustrates, for both EDC and single-channel DBP systems, that if the co-propagating higher-order QAM channels are linearly pre-dispersed, the performance of the PM-4QAM through traffic can be improved. The figure shows that when positive pre-dispersion is applied, such that the neighboring channel constellation is never, along its entire inter node transmission length, restored to a well-formed shape, the impact of cross-channel impairments on existing traffic is reduced significantly.
Figure 6.
Qeff of the PM-4QAM through channel with 30 ROADM sites, when the neighboring PM-64QAM channel is linearly pre-dispersed. Solid: with single-channel DBP, open: with EDC.
On the other hand, when negative pre-dispersion of less than the node-length (distance per node) is employed, the central test channel is initially degraded further. This behavior can be attributed to the increased impact of the PAPR of the un-dispersed constellation which is restored in the middle of the link. However, if negative pre-dispersion of more than the node-length is employed, the penalty is reduced due to lower PAPR induced XPM, and the performance saturates for higher values of pre-dispersion, similar to the case of positive pre-dispersion. Note that avoiding well formed signals along the entire link corresponds to maximizing the path averaged PAPR of the signals. The benefits of this strategy have subsequently been predicted from a theoretical standpoint [27].
3.2. Constraints on transmitted power
In this section, we demonstrate that independent optimization of the transmitted launch power enhances the performance of higher modulation order add-drop channels but severely degrades the performance of through traffic due to strong inter-channel nonlinearities. However, if an altruistic launch power policy is employed such that the higher-order add-drop traffic still meets the BER of 3.8x10-3, a trade-off can be recognized between the performance of higher-order channels and existing network traffic enabling higher overall network capacity with minimal crosstalk [19].
As a baseline for this study, we initially consider transmission distances up to 9,600km with the same 80km spans, suitable to enable a suitable performance margin (at bit-error rate of 3.8x10-3) for the network traffic given various modulation schemes at a fixed launch power of -1 dBm, (optimum power as determined in previous section. For a dynamic network with N ROADMs and mth order PM-QAM, the overall results are summarized in Table 1. The table shows under which conditions the central PM-4QAM channel (right-hand symbol), and the periodically added traffic (left-hand symbol) are simultaneously able to achieve error-free operation after FEC. Two ticks indicate that both types of traffic is operational, whilst a cross indicates that at least one channel produces severely errorred signals. As expected, with decreasing ROADM spacing, the operability of higher-order neighboring channels increases due to the improved OSNR. However, it can also be seen that as a consequence, added channels with higher-order formats induce greater degradation of the through channel through nonlinear crosstalk as shown in Section 3.1. In particular, if the ROADM spacing is 320 km, allocated to transmit PM-64QAM, whilst this traffic is operable, the through traffic falls below the BER threshold. Conversely for large ROADM spacing, there is little change in nonlinear crosstalk, since the m-QAM signals are highly dispersed, but the higher order format traffic has insufficient OSNR for error free operation. We refer to this approach as “fixed network power”.
\n\t\t
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\n\t\t
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\n\t\t
\n\t\t
\n\t\t\t
mQAM/ ROADM spacing
\n\t\t\t
4800 km
\n\t\t\t
2400 km
\n\t\t\t
1200 km
\n\t\t\t
640 km
\n\t\t\t
320 km
\n\t\t\t
160 km
\n\t\t\t
80 km
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\t4QAM\n\t\t\t
\n\t\t\t
\n\t\t\t\t++\n\t\t\t
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\n\t\t\t\t++\n\t\t\t
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\n\t\t\t\t++\n\t\t\t
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\n\t\t\t\t++\n\t\t\t
\n\t\t\t
\n\t\t\t\t++\n\t\t\t
\n\t\t\t
\n\t\t\t\t++\n\t\t\t
\n\t\t\t
\n\t\t\t\t++\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\t16QAM\n\t\t\t
\n\t\t\t
\n\t\t\t\tx+\n\t\t\t
\n\t\t\t
\n\t\t\t\t++\n\t\t\t
\n\t\t\t
\n\t\t\t\t++\n\t\t\t
\n\t\t\t
\n\t\t\t\t++\n\t\t\t
\n\t\t\t
\n\t\t\t\t++\n\t\t\t
\n\t\t\t
\n\t\t\t\t+x\n\t\t\t
\n\t\t\t
\n\t\t\t\t+x\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\t64QAM\n\t\t\t
\n\t\t\t
\n\t\t\t\tx+\n\t\t\t
\n\t\t\t
\n\t\t\t\tx+\n\t\t\t
\n\t\t\t
\n\t\t\t\tx+\n\t\t\t
\n\t\t\t
\n\t\t\t\t++\n\t\t\t
\n\t\t\t
\n\t\t\t\t+x\n\t\t\t
\n\t\t\t
\n\t\t\t\t+x\n\t\t\t
\n\t\t\t
\n\t\t\t\t+x\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\t256QAM\n\t\t\t
\n\t\t\t
x+
\n\t\t\t
\n\t\t\t\tx+\n\t\t\t
\n\t\t\t
\n\t\t\t\tx+\n\t\t\t
\n\t\t\t
\n\t\t\t\tx+\n\t\t\t
\n\t\t\t
\n\t\t\t\txx\n\t\t\t
\n\t\t\t
\n\t\t\t\txx\n\t\t\t
\n\t\t\t
\n\t\t\t\t+x\n\t\t\t
\n\t\t
\n\t
Table 1.
Operability of PM-mQAM/4QAM above BER threshold of 3.8x10-3for a total trnamsission distance of 9,600km. Tick/Cross (Left) represents performance of mQAM, Tick/Cross (Right) represents corresponding performance of central 4QAM. Tick: Operational, Cross: Non-operational
Since higher-order modulation formats have higher required OSNR, we expect the optimum launch power for those channels to be different than those used in the fixed network power scenario which was operated at a launch power of -1 dBm. Thus, for example, for large ROADM spacing, we improved performance might be expected if the add-drop traffic operates with increased launch power. Figure 7 illustrates the performance of through channel and the higher-order add-drop channels as a function of launch power of the add-drop traffic (through channel operates with a fixed, previously optimized, launch power of -1 dBm). For clarity we report two ROADM spacings, selected to give zero margin (Figure 7a) or ~2 dB margin (Figure 7b) for 256QAM add drop traffic. The ROADM spacing for 16 and 64QAM signals were scaled in proportion (approximately) to their required OSNR levels under linear transmission. The exact ROADM spacing is reported in the figure captions.
Figure 7 clearly illustrates that the higher-order formats operating over a longer (shorter) reach enable lower (higher) Qeff, but also that the nonlinear effects increase in severity as the modulation order is increased. In particular, the long distance through traffic is strongly degraded before the nonlinear threshold is reached for such formats. Comparing Figure 7a and\n\t\t\t\t\tFigure 7b, we can see that the reduced ROADM spacing in Figure 7b enables improved performance of the add-drop channels; however the degradation of the through channel is increasingly severe. This change in behavior between formats can be attributed to the increased amplitude modulation imposed by un-dispersed signals added at each ROADM site, as discussed previously.
Figure 7.
Qeff as a function of launch power of two neighboring channels for 28-Gbaud PM-mQAM, showing performance of central PM-4QAM (Solid), and neighboring PM-mQAM (Half Solid). Triangle: 16QAM, Circle: 64QAM, Square:256QAM. The launch power per channel for PM-4QAM is fixed to -1 dBm. ROADM spacing of, a) 2400, 640, 160 km, b) 1200, 320, 80 km for 16, 64, 256 QAM, respectively.
We can use the results of Figure 7 to analyze the impact of various power allocation strategies. Clearly if we allow each transponder to adjust its launch power to optimize its own performance autonomously, a high launch power will be selected and the degradation to the traffic from other transponders increases in severity, and in all six scenarios in Figure 7 the through channel fails if the performance of the add drop traffic is optimized independently. This suggests that launch power should be centrally controlled. Howevercentrally controlled optimization of individual launch powers for each transponder is complex; so a more promising approach would be a fixed launch power irrespective of add-drop format or reach to minimize the complexity of this control. We have already seen (Table 1) that if the launch power is set to favor the performance of PM-4QAM (-1 dBm) the flexibility in transmitted format for the add/drop transponders is low, and to confirm this in Figure 7 four of the scenarios fail. The best performance for these two scenarios is achieved at a fixed launch power of -3 dBm, but we still find that 3 scenarios fail to establish error free connections. However, if the transponders are altruistically operated at the minimum launch power required for the desired connection (not centrally controlled), the majority of the scenarios studied result in successful connections. The one exception is the add-drop of 256QAM channels with a ROADM spacing of 160 km, which is close to the maximum possible reach of the format. Note that shorter through paths would tend to use higher-order formats for all the routes, where nonlinear sensitivity is higher [29], and therefore we expect similar conclusions.
4. Application in meshed networks
In the previous section, we identified that optimum performance for a given predetermined modulation format was obtained by using the minimum launch power. However, this arbitrary selection of transmitted format fails to take into account the ability of a given link to operate with different formats, leading to a rich diversity of connections. In this section, we focus on the impact of flexibility in the signal constellation, allowing for evolution of the existing ROADM based static networks. We consider a configuration where network capacity is increased by allowing higher-order modulation traffic to be transmitted on according to predetermined rules based on homogenous network transmission performance. In particular we consider a 50 GHz channel grid with coherently-detected 28-Gbaud PM-mQAMand 20 wavelength channels. We demonstrate that even if modulation formats are chosen based on knowledge of the maximum transmission reach aftersingle-channel digital back-propagation, for the network studied, the majority of the network connections (75%) are operable with significant optical signal-to-noise ratio margin when operated with electronic dispersion compensation alone. However, 23% of the links require the use of single-channel DBP for error free operation. Furthermore, we demonstrate that in this network higher-order modulation formats are more prone to impairments due to channel nonlinearities and filter crosstalk; however they are less affected by the bandwidth constrictions associated with ROADM cascades due to shorter operating distances. Finally, we show that, for any given modulation order, a minimum filter Gaussian order of ~3 or bandwidth of ~35 GHz enables the performance with approximately less than 1 dB penalty with respect to ideal rectangular filters [30].
4.1. Network design
To establish a preliminary estimate of maximum potential transmission distance of each available format, we employed the transmission reaches identified in Section 3. These are suitable to enable a BER of 3.8x10-3 at a fixed launch power of -1 dBm assuming the availability of single-channel DBP. These conditions gave maximum reaches of 2,400 km for PM-16QAM, 640 km for PM-64QAM and 160 km for 256 QAM. Note that only single-channel DBP was considered in this study since in a realistic mesh network access to neighboring traffic might be impractical. WDM based DBP solution may be suitable for a point to point submarine link or for a network connection where wavelengths linking the same nodes co-propagate using adjacent wavelengths. Implementation of this condition would require DBP aware routing and wavelength assignment algorithms. This approach could enable significant Qeff improvements or reach increases. For 64QAM, up to 7 dBQeffimprovements were shown in [29], although the benefit depends on the number of processed channels [31].
We then applied this link capacity rule to an 8-node route from a Pan-European network topology (see highlighted link in Figure 8). To generate a representative traffic matrix, for each node, commencing with London, we allocated traffic demand from the node under consideration to all of the subsequent nodes, operating the link at the highest order constellation permissible for the associated transmission distance, and selecting the next wavelength. We note that none of the links in this chosen route were suitable for 256QAM, indeed only the Strasberg to Zurich and Vienna to Prague links are expected to be suitable for this format.
Figure 8.
node Pan-European network topology. Link 1: London-to-Amsterdam: 7 spans, Link 2: Amsterdam-to-Brussels: 3 spans, Link 3: Brussels-to-Frankfurt: 6 spans. Link 4: Frankfurt-to-Munich: 6 spans, Link 5: Munich-to-Milan: 7 spans, Link 6: Milan-to-Rome: 9 spans, Link 7: Rome-to-Athens: 19 spans. (80 km/span).
Once all nodes were connected by a single link, this process was repeated (in the same order), adding additional capacity between nodes where an unblocked route was available until all 20 wavelengths were allocated, and no more traffic could be assigned without blockage.
Table 2 illustrates the resultant traffic matrix showing the location where traffic was added and dropped (gray highlighting) and the order of the modulation format (numbers) carried wavelength (horizontal index) on each link (vertical index). For example, emerging from node 6 are nine wavelengths carrying PM-4QAM and 5 wavelengths carrying PM-16QAM whilst on the center wavelength, PM-16QAM data is transmitted from node 1 (London) to node 5 (Munich) where this traffic is dropped and replaced with PM-64QAM traffic destined for node 6 (Milan). This ensured that various nodes were connected by multiple wavelengths. As it can be seen, the adopted procedure allowed for a reasonably meshed optical network (36 connections) with shortest route of 3 spans and longest path of 57 spans, emulating a quasi-real traffic scenario with highly heterogeneous traffic. At each node, add-drop functionality was enabled using a channelized ROADM architecture where all the wavelengths were de-multiplexed and channels were added/dropped, before re-multiplexing the data signals again. We considered Rectangular and Gaussian-shaped filters for ROADM stages, and the order of the Gaussian filters was varied from 1 through 6.
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Table 2.
Traffic matrix (Each element represents the modulation order, Grayed: Traffic dropped and added at nodes highlighted in gray.
4.2. Results and discussions
4.2.1. Nonlinear transmission with ideal ROADMs
Figure 9 depicts the required OSNR of each connection as a function of transmission distance, after electronic dispersion compensation. Note that in this case we employed rectangular ROADM filters to isolate the impact of inter-channel nonlinear impairments from filtering crosstalk (no cascade penalties were observed with ideal filters).
Numerous conclusions can be ascertained from this figure. First, these results confirm that with mixed-format traffic and active ROADMs, as the transmission distance is increased the required OSNR increases irrespective of the modulation order due to channel nonlinearities. Second, as observed by the greater rate of increase in required OSNR with distance, the higher-order channels are most degraded by channel nonlinearities, even at the shortest distance traversed. Furthermore, even for the shortest distances the offset between the theoretical OSNR for a linear system and the simulated values are greater for higher order formats. These two effectsare attributed to the significantly reduced minimum Euclidian distance which leads to increased sensitivity to nonlinear effects. However, for a system designed according to single-channel DBP propagation limits, as the one studied here, one can observe that majority of the links operate using EDC alone (except the ones highlighted by up-arrows). Note that managing the PAPR for such formats through linear pre-dispersion could further improve the transmission performance, as shown in Section 1.3. Additionally, in order to examine the available system margin, Figure 9 also shows the received OSNR for various configurations, where it can be seen that majority of the links (except 3) have more than 2 dB available margins, and that our numerical results show an excellent match to the theoretical predictions.
Figure 9.
Nonlinear tolerance of PM-mQAM in a dynamic mesh network after EDC. a) Colored: OSNR at BER of 3.8x10-3 vs. Distance (Links traversed: 1(square), 2(circle), 3(up-tri), 4(down-tri), 5(left-tri), 6(right-tri), 7(diamond), horizontal lines (theoretical required OSNR)), open: intermediate nodes, solid: destination nodes. Black: Received OSNR (black spheres), Line (theoretical received OSNR), Dotted Line (theoretical received OSNR with 5 dB margin). Up arrows indicate failed connections (corresponding to drop nodes).
As discussed, the results presented in Figure 9 exclude 9 network connections classified as failed (25% of the total traffic), where the calculated BER was always found to be higher than the 3.8x10-3. In order to address the failed routes, we employed single-channel DBP, as shown in [21], on such channels, as shown in Figure 10 (red: simplified, blue: full-precision 40 steps per span).It can be seen that all but one of the links can be restored by using single-channel DBP, with the Qeffincreasing by an average of ~1 dB, consistent with the improvements observed for heterogeneous traffic in Section 1.3. The link which continues to give a BER even after after single-channel DBP is operated with the highest order modulation format studied, and its two nearest neighbors are both highly dispersed. Note that even though the maximum node lengths are chosen based on nonlinear transmission employing single-channel DBP, most of the network traffic also abide by the EDC constraints (64QAM: ≥ 1 span, 16QAM: ≥ 6 spans, 4QAM ≥ 24 spans). The failed links have one-to-one correlation with violation of these EDC constraints, allowing for prediction of DBP requirements with a quarter of the total network traffic requiring the implementation of single-channel DBP. Also, note that all but two of the links are operable with less than 15 DBP steps for the whole link.
Figure 10.
Qeff as a function of network nodes for failed routes, shown by up-arrows in Fig. 5, for PM-mQAM in a dynamic mesh network. After EDC (black) and single-channel DBP (red: simplified, blue: full-precision 40 steps per span). Table shows the network parameters for each scenario and number of steps for single-channel simplified DBP.
These results give some indication of the benefit of flexible formats and DBP. For particular network studied (assuming one of the two failed links works with high precision DBP), if homogeneous traffic, employing 4QAM, is considered, a total network capacity of 4-Tb/scould be achieved. On the other hand, flexible m-ary QAM employing bandwidth allocation based on EDC performance limits only (not shown) enables ~60% increase in transmission capacity (6.8-Tb/s), while designs accounting for SC-DBP add a further 12% increase in capacity (7.7-Tb/s). Note that for traffic calculations based on EDC constraints, we assumed that the routes of Figure 10 would operate satisfactorily for the next format down and that there would be no increase in the nonlinear penalty experienced by any other channel. Further increase in capacity can be attained if pre-dispersion or limited WDM DBP are used, or if more format granularity is introduced (e.g. 8QAM and 32QAM) to exploit the remaining margin. In this example, 25% of transponders operating in single-channel DBP mode enable a 12% increase in capacity. One may therefore argue that in order to provide a the same increase in capacity without employing DBP, approximately 12% more channels would be required, consuming 12% more energy (assuming that the energy consumption is dominated by the transponders). In the case studied, since a ¼ of transponders require DBP, breakeven would occur if the energy consumption of a DBP transponder was 50% greater than a conventional transponder. Given that commercial systems allocate approximately 3-5% of their power to the EDC chipset [32], this suggests that the DBP unit used could be up to 16 times the complexity of the EDC chip. The results reported in Figure 10 with simplified DBP fall within this bound and highlight the practicality of simplified DBP algorithms.
Figure 11.
Qeff as a function of Gaussian filter order (35 GHz bandwidth) for a 6 dB margin from theoretical achievable OSNR. a) 4QAM; b) 16QAM; c) 64QAM. (up-arrows indicate that no errors were detected).
4.2.2. Filter order and BW dependence
Figure 11 shows the performance of a selection of links with less than 6 dB margin from the theoretical achievable OSNR (see Figure 9 for links used, we show only the links with the worst required OSNR in the case of 16QAM for clarity), as a function of the Gaussian filter order within each ROADM. As it is well-known, the transmission penalty decreases as filter order increases [33]. However, it can be seen that for higher-order modulation formats, the transmission performance saturates at lower filter orders, compared to lower-order formats. This trend is related to the fact that modulation formats traversing through greater number of nodes are more strongly dependent on the Gaussian order (attributed to known penalties from filter cascades [34,35]). For instance, the performance of 4QAM traffic is severely degraded as a function of Gaussian order, due to the higher number of nodes traversed by such format. 16QAM channels show relatively good tolerance to filter order due to reduced number of hops, however when greater than 3 nodes are employed, the performance again becomes a strong function of filter order. 64QAM is least dependent on filter order since no intermediate ROADMs are traversed. For any given modulation order, a minimum Gaussian order of ~3 enables the optimum performance to be within 1 dB of the performance for an ideal rectangular filter.
Figure 12.
Qeff as a function of Gaussian filter bandwidth (and filter order) for worst-case OSNR margin seen in Figure 6.8. a) 4QAM; b) 16QAM; c) 64QAM.
The simulated Qeff versus 3 dB bandwidth of the ROADM stages and filter order is shown in Figure 12, again for the worst-case required OSNR observed in Figure 9 for each modulation format. For lower bandwidths, the Qeff is degraded due to bandwidth constraints. With the exception of second order filters, bandwidths down to 35 GHz are sufficient for all the formats studied. However, consistent with previous analysis (in Figure 10), the impact of filter order on 64QAM is minimal and lower-order filters seem to have better performance than higher-order ones at 25GHz bandwidth. This is because when the signal bandwidth (28-GHz) exceeds the filter bandwidth, the lower order filters capture more of the signal spectra. However, this effect is visible in the case of 64QAM only since no nodes were traversed in this case, thereby avoiding the penalty from ROADM stages with lower filter orders.
5. Summary and future work
In this chapter we explored the network aspect of advanced physical layer technologies, including multi-level formats employing varying DSP, and solutions were proposed to enhance the capacity of static transport networks. It was demonstrated that that if the order of QAM is adjusted to maximize the capacity of a given route, there may be a significant degradation in the transmission performance of existing traffic for a given dynamic network architecture. Such degradations were shown to be correlated to the accumulated peak-to-average power ratio of the added traffic along a given path, and that management of this ratio through pre-distortion was proposed to reduce the impact of adjusting the constellation size on through traffic. Apart from distance constraints, we also explored limitations in the operational power range of network traffic. The transponders which autonomously select a modulation order and launch power to optimize their own performance were reported to have a severe impact on co-propagating network traffic. A solution was proposed to operate the transponders altruistically, offering lower penalties than network controlled fixed power approach. In the final part of our analysis, the interplay between different higher-ordermodulation channels and the effect of filter shapes and bandwidth of(de)multiplexers on the transmission performance, in a segment of pan-European optical network was explored. It was verified that if the link capacities are assigned assuming that digital back propagation is available, 25% of the network connections fail using electronic dispersion compensation alone. However, majority of such links can indeed be restored by employing single-channel digital back-propagation. Our results indicated some benefit of flexible formats and DBP in realistic mesh networks. We showed that for particular network studied, if homogeneous traffic, employing 4QAM is considered, a total network capacity of 4 Tb/s can be achieved. On the other hand, flexible m-ary QAM employing bandwidth allocation based on EDC performance limits enable ~60% increase in transmission capacity (6.8 Tb/s), while designs accounting for SC-DBP add a further 12% increase in capacity (7.7 Tb/s). Further enhancement in network capacity may be obtained through the use of intermediate modulation order, dispersion pre-compensation for nonlinearity control and the use of altruistic launch powers.
In terms of network evolution, the ultimate goal is to enable software-defined transceivers, where each node would switch itself to just-right modulation scheme and associated DSP, based on various physical layer, distance, power, and etc. constraints. Modeling of real-time traffic employing the content covered in this chapter, should motivate and pave the way for high capacity upgrade of currently deployed networks. In addition, modulation/DSP aware routing and wavelength assignment algorithms (e.g. DBP bandwidth aware wavelength allocation) would further enhance the transmission capacity.
Acknowledgments
This work was supported by Science Foundation Ireland under Grant numbers 06/IN/I969 and 08/CE/11523.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/44295.pdf",chapterXML:"https://mts.intechopen.com/source/xml/44295.xml",downloadPdfUrl:"/chapter/pdf-download/44295",previewPdfUrl:"/chapter/pdf-preview/44295",totalDownloads:2063,totalViews:151,totalCrossrefCites:1,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:8,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"April 28th 2012",dateReviewed:"August 27th 2012",datePrePublished:null,datePublished:"June 13th 2013",dateFinished:"April 18th 2013",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/44295",risUrl:"/chapter/ris/44295",book:{id:"3360",slug:"current-developments-in-optical-fiber-technology"},signatures:"Danish Rafique and Andrew D. Ellis",authors:[{id:"99536",title:"Prof.",name:"Andrew D.",middleName:null,surname:"Ellis",fullName:"Andrew D. Ellis",slug:"andrew-d.-ellis",email:"andrew.ellis@tyndall.ie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University College Cork",institutionURL:null,country:{name:"Ireland"}}},{id:"157201",title:"Dr.",name:"Danish",middleName:null,surname:"Rafique",fullName:"Danish Rafique",slug:"danish-rafique",email:"danishrafique@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University College Cork",institutionURL:null,country:{name:"Ireland"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Simulation conditions",level:"1"},{id:"sec_3",title:"3. Analysis of trade-offs in hybrid networks",level:"1"},{id:"sec_3_2",title:"3.1. Constraints on transmission reach",level:"2"},{id:"sec_4_2",title:"3.2. Constraints on transmitted power",level:"2"},{id:"sec_6",title:"4. Application in meshed networks",level:"1"},{id:"sec_6_2",title:"4.1. Network design",level:"2"},{id:"sec_7_2",title:"4.2. Results and discussions",level:"2"},{id:"sec_7_3",title:"4.2.1. Nonlinear transmission with ideal ROADMs",level:"3"},{id:"sec_8_3",title:"4.2.2. Filter order and BW dependence",level:"3"},{id:"sec_11",title:"5. Summary and future work",level:"1"},{id:"sec_12",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'R.W. Tkach, "Scaling optical communications for the next decade and beyond," Bell Labs Technical Journal 14, 3-9 (2010).'},{id:"B2",body:'P. Winzer, “Beyond 100G Ethernet,” IEEE Communications Magazine 48, 26 (2010).'},{id:"B3",body:'S. Makovejsm, D. S. Millar, V. Mikhailov, G. Gavioli, R. I. Killey, S. J. Savory, and P. Bayvel, “Experimental Investigation of PDMQAM16 Transmission at 112 Gbit/s over 2400 km,” OFC/NFOEC, OMJ6 (2010).'},{id:"B4",body:'J. Yu, X. Zhou, Y. Huang, S. Gupta, M. Huang, T. Wang, and P. Magill, “112.8-Gb/s PM-RZ 64QAM Optical Signal Generation and Transmission on a 12.5GHz WDM Grid,” OFC/NFOEC, OThM1 (2010).'},{id:"B5",body:'M. Seimetz, Higher-order modulation for optical fiber transmission. Springer (2009).'},{id:"B6",body:'A. Nag, M. Tornatore, and B. Mukherjee, “Optical network design with mixed line rates and multiple modulation formats,” Journal of Lightwave Technology 28, 466–475 (2010).'},{id:"B7",body:'C. Meusburger, D. A. Schupke, and A. Lord, “Optimizing the migration of channels with higher bitrates,” Journal of Lightwave Technology 28, 608–615 (2010).'},{id:"B8",body:'M. Suzuki, I. Morita, N. Edagawa, S. Yamamoto, H. Taga, and S. Akiba, "Reduction of Gordon-Haus timing jitter by periodic dispersion compensation in soliton transmission," Electronics Letters 31, 2027-2029 (1995).'},{id:"B9",body:'C. Fürst, C. Scheerer, G. Mohs, J-P. Elbers, and C. Glingener, "Influence of the dispersion map on limitations due to cross-phase modulation in WDM multispan transmission systems," Optical Fiber Communication Conference, OFC ’01, MF4 (2001). '},{id:"B10",body:'D.D. Marcenac, D. Nesset, A. E. Kelly, M. Brierley, A. D. Ellis, D. G. Moodie, and C. W. Ford, "40 Gbit/s transmission over 406 km of NDSF using mid-span spectral inversion by four-wave-mixing in a 2 mm long semiconductor optical amplifier," Electronics Letters 33, 879 (1997).'},{id:"B11",body:'M. Kuschnerov, F. N. Hauske, K. Piyawanno, B. Spinnler, M. S. Alfiad, A. Napoli, and B. Lankl, “DSP for coherent single-carrier receivers,” Journal of Lightwave Technology 27, 3614-3622 (2009).'},{id:"B12",body:'X. Li, X. Chen, G. Goldfarb, Eduardo Mateo, I. Kim, F. Yaman, and G. Li, ‘‘Electronic post-compensation of WDM transmission impairments using coherent detection and digital signal processing,” Opt. Express, 16, 880 (2008).'},{id:"B13",body:'D. Rafique, J. Zhao, and A. D. Ellis, "Digital back-propagation for spectrally efficient WDM 112 Gbit/s PM m-ary QAM transmission," Opt. Express 19, 5219-5224 (2011).'},{id:"B14",body:'C. Weber, C.-A. Bunge, and K. Petermann, ‘‘Fiber nonlinearities in systems using electronic predistortion of dispersion at 10 and 40 Gbit/s,” Journal of Lightwave Technology 27, 3654-3661 (2009).'},{id:"B15",body:'G. Goldfarb, M.G. Taylor, and G. Li, ‘‘Experimental demonstration of fiber impairment compensation using the split step infinite impulse response method,” IEEE LEOS, ME3.1 (2008).'},{id:"B16",body:'D. Rafique and A. D. Ellis, "Impact of signal-ASE four-wave mixing on the effectiveness of digital back-propagation in 112 Gb/s PM-QPSK systems," Opt. Express 19, 3449-3454 (2011).'},{id:"B17",body:'L.B. Du, and A. J. Lowery, "Improved single channel backpropagation for intra-channel fiber nonlinearity compensation in long-haul optical communication systems," Opt. Express 18, 17075-17088 (2010).'},{id:"B18",body:'L. Lei, Z. Tao, L. Dou, W. Yan, S. Oda, T. Tanimura, T. Hoshida, and J. C. Rasmussen, "Implementation Efficient Nonlinear Equalizer Based on Correlated Digital Backpropagation," OFC/NFOEC, OWW3 (2011).'},{id:"B19",body:'S. J. Savory, G. Gavioli, E. Torrengo, and P. Poggiolini, "Impact of Interchannel Nonlinearities on a Split-Step Intrachannel Nonlinear Equalizer," Photonics Technology Letters, IEEE 22, 673-675 (2010).'},{id:"B20",body:'D. Rafique and A. D. Ellis, "Nonlinear Penalties in Dynamic Optical Networks Employing Autonomous Transponders," Photonics Technology Letters, IEEE 23, 1213-1215 (2011).'},{id:"B21",body:'D. Rafique, M. Mussolin, M. Forzati, J. Martensson, M.N. Chugtai, A.D. Ellis, “Compensation of intra-channel nonlinear fibre impairments using simplified digital backpropagation algorithm”, Optics Express, Opt. Express 19, 9453-9460 (2011). '},{id:"B22",body:'C. S. Fludger, T. Duthel, D. vanden Borne, C. Schulien, E.-D. Schmidt, T. Wuth, J. Geyer, E. DeMan, G.-D. Khoe, and H. de Waardt,, "Coherent Equalization and POLMUX-RZ-DQPSK for Robust 100-GE Transmission," J. Lightwave Technol. 26, 64-72 (2008).'},{id:"B23",body:'T. Wuth, M. W. Chbat, and V. F. Kamalov, “Multi-rate (100G/40G/10G) Transport over deployed optical networks,” OFC/NFOEC, NTuB3 (2008).'},{id:"B24",body:'W. Wei, Z. Lei, and Q. Dayou, “Wavelength-based sub-carrier multiplexing and grooming for optical networks bandwidth virtualization,” OFC/NFOEC, PDP35 (2008)'},{id:"B25",body:'R. Peter, and C. Brandon, “Evolution to colorless and directionless ROADM architectures,” OFC/NFOEC, NWE2 (2008).'},{id:"B26",body:'D. Rafique and A.D. Ellis “Nonlinear penalties in long-haul optical networks employing dynamic transponders,” Optics Express 19, 9044-9049, (2011).'},{id:"B27",body:'S. Turitsyn, M. Sorokina, and S. Derevyanko, "Dispersion-dominated nonlinear fiber-optic channel," OpticsLetters 37, 2931-2933 (2012) .'},{id:"B28",body:'L.E. Nelson, A. H. Gnauck, R. I. Jopson, and A. R. Chraplyvy, “Cross-phase modulation resonances in wavelength-division-multiplexed lightwave transmission,” ECOC, 309–310 (1998).'},{id:"B29",body:'D. Rafique, J. Zhao, and A. D. Ellis, "Digital back-propagation for spectrally efficient WDM 112 Gbit/s PM m-ary QAM transmission," Opt. Express 19, 5219-5224 (2011).'},{id:"B30",body:'D. Rafique and A.D. Ellis “Nonlinear and ROADM induced penalties in 28 Gbaud dynamic optical mesh networks employing electronic signal processing," Optics Express 19, 16739-16748, (2011).'},{id:"B31",body:'D. Rafique and A. D. Ellis, "Various Nonlinearity Mitigation Techniques Employing Optical and Electronic Approaches," Photonics Technology Letters, IEEE 23, 1838-1840 (2011).'},{id:"B32",body:'K. Roberts, “Digital signal processing for coherent optical communications: current state of the art and future challenges,” SPPCOM, SPWC1 (2011).'},{id:"B33",body:'F. Heismann, “System requirements for WSS filter shape in cascaded ROADM networks,” OFC/NFOEC, OThR1 (2010).'},{id:"B34",body:'T. Otani, N. Antoniades, I. Roudas, and T. E. Stern, “Cascadability of passband-flattened arrayed waveguidegrating filters in WDM optical networks,” Photonics Technology Letters 11, 1414-1416 (1999).'},{id:"B35",body:'M. Filer, and S. Tibuleac, “DWDM transmission at 10Gb/s and 40Gb/s using 25GHz grid and flexible-bandwidth ROADM,” OFC/NFOEC, NThB3 (2011).'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Danish Rafique",address:null,affiliation:'
Photonic Systems Group, Tyndall National Institute and Department of EE/Physics, University College Cork, Dyke Parade, Ireland
now with Nokia Siemens Networks, S.A., Lisbon, Portugal
'},{corresp:null,contributorFullName:"Andrew D. Ellis",address:null,affiliation:'
Photonic Systems Group, Tyndall National Institute and Department of EE/Physics, University College Cork, Dyke Parade, Ireland
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1. Introduction
Extracellular vesicles (EVs) are a varied group of cell-derived, microscopic, fluid-filled pouches that cells release into the neighboring microenvironment. Recent studies show that not only do EVs play an integral part in the development of cancer through intercellular communication, cell survival, and immune modulation but also may assist with the early diagnosis and improved treatment of diseases such as epithelial ovarian cancer (EOC) [1]. EVs are quickly gaining recognition as an important enabler of EOC propagation and may potentially serve as a powerful tool in inhibiting and even reversing the progression of this disease. Historically, EOC has been a frustrating gynecologic malignancy characterized by its furtive early course that leads to an advanced presentation at initial diagnosis with subsequent poor outcomes [1]. Public health entities are ineffective at screening for early disease, leaving patients with few warnings to herald a lurking predator that affects 1–3% of women throughout their lifetime [2]. Once an EOC has manifested, the primary treatment options are surgery in combination with chemotherapy. While initially effective, these treatments are often fruitless at abating the malignancy due to the persistence of microscopic disease and the development of chemoresistance [3]. EOC patients desperately need new treatments, and EVs may provide an opportunity to gain an improved understanding about EOC proliferation and metastasis while hopefully providing novel, effective treatments.
1.1 Why is epithelial ovarian cancer so hard to treat, and how can EVs help?
Worldwide, ovarian cancer is the seventh most common malignancy among women; and over 280,000 cases were diagnosed in 2012 alone [1, 4]. In the United States ovarian cancer is the fifth deadliest cancer among women and is the deadliest cancer originating in the female reproductive system [2]. The most common type of ovarian cancer is EOC, making up more than 90% of cases [5]. EOC encompasses numerous histologic subtypes, including serous, mucinous, endometrioid, and clear cell types; additionally, EOC can proliferate rapidly, known as high-grade disease, or have a more insidious course, known as low-grade disease [6]. Interestingly, in the past decade researchers discovered that high-grade serous EOC originates in the fallopian tubes and then migrates to the ovary; so clinicians treat EOC and fallopian tube cancer as the same entity [7]. Additionally, high-grade serous fallopian tube, ovarian, and primary peritoneal cancer are all considered the same clinical entity based on common behaviors and treatments [8]. The chapter will primarily discuss high-grade epithelial ovarian carcinoma of the ovary, fallopian tubes, and peritoneum because it is the predominant subtype of EOC and because publications prioritize this subtype when studying EVs.
EOC is a difficult disease. When testing detects this malignancy at an early stage, 80% of these patients are free of cancer at 5 years [8]. However, the early signs of EOC are nonspecific and insidious, ranging from abdominal discomfort or pain to bloating and early satiety [1]. Unfortunately, these vague symptoms lead to a late diagnosis for most patients, with about 80% of patients diagnosed with advanced disease that is more challenging to cure [9]. While surgery and chemotherapy are initially effective in treating advanced EOC, most patients experience a relapse of the cancer that is chemoresistant, with a five-year survival under 30% [5]. Based on these grim outcomes, patients need new diagnostic and therapeutic tools to improve detection and treatment of EOC.
1.2 Why are EVs so exciting?
EVs are generating excitement within the field of gynecologic oncology because they not only help researchers to better understand how cancers grow and spread but also because they can assist with the diagnosis and management of EOC at every step of the disease course. EOC EVs carry a wide array of information including microRNA (miRNA), non-coding RNA, messenger RNA, DNA, lipids, glycans, and proteins that play a role in the proliferation and metastasis of this disease. In fact, patients with EOC are known to have an upregulation in EV secretion, transforming the microenvironment surrounding the cancer and causing normal cells to secrete tumorigenic factors [10]. Researchers will someday be able to detect EOC EVs readily in blood or urine for early detection of the cancer so that clinicians can treat it at an earlier stage, preventing metastasis and resistance to chemotherapy from ever occurring. By understanding the information carried inside of EVs, patients will have access to personalized treatment regimens specifically tailored to their cancer. By exploring different ideas, scientists will be able to unlock the potential for EVs to provide dramatic breakthroughs in the diagnosis and treatment of EOC.
2. Extracellular vesicles and their role in epithelial ovarian cancer
2.1 What is an extracellular vesicle?
For the past decade the classification of EVs has been based on size, ranging from exosomes that are 30–100 nm, microvesicles (MVs) that are 100–1000 nm, and apoptotic bodies that are 0.1–5 μm [1]. Exosomes are the smallest EV and appear to originate within the lumen of multivesicular bodies [1]. Oncosomes, a subtype of MVs, are released by budding from malignant cells [1]. As cells undergo apoptosis, they release apoptotic bodies [1]. One factor that limits this classification system is that some EVs that function as oncosomes are larger than the typical 100–1000 nm and can be as large as 1–10 μm [1]. When trying to isolate and study EVs, it became apparent that size did not adequately capture the breadth of heterogeneity among EVs with their varied functions and content. In 2019 the International Society of Extracellular Vesicles published a recommendation for the use of the term extracellular vesicle to encompass all types of EVs while still including a subclassification system that incorporated size [11]. Therefore, in this chapter the term extracellular vesicle will be used. Eventually, the optimal method of classification for EVs will be based on the specific phenotype and content of an EV that would better describe its origin and function. However, current testing methods and understanding of this topic need to be further studied.
2.2 How do extracellular vesicles impact epithelial ovarian cancer?
EVs provide a pertinent target for research because EOC cells exploit EVs for intercellular messaging. By hijacking the EV communication system, cancer cells distort key biological processes that enhance cancer survival, including angiogenesis, immunity, apoptosis, inflammation, migration, invasion, and even activation of secretion of tumorigenic factors by stem cells [1]. Malignant cells dramatically increase EV synthesis, manipulating crucial intercellular communication, exerting control over the tumor’s surrounding environment, and transforming this microenvironment into a tumorigenic niche that facilitates chemoresistance and progression of disease [10]. Since EVs affect many aspects of EOC propagation and spread, they are suitable candidates for the development of new diagnostic and therapeutic management options.
3. Role of EVs in the diagnosis of epithelial ovarian cancer
3.1 How good are we at diagnosing epithelial ovarian cancer?
With the current tools available, clinicians are unable to reliably identify EOC early in its disease course, losing a valuable opportunity at early intervention and higher rates of cure. For patients who are diagnosed with EOC at stage I, disease that is confined to the ovaries, their five-year survival approaches 90% [2]. Survival drops precipitously for women with advanced stages of the disease, which is unfortunately the most common presentation. Attempts at establishing screening systems have certainly been investigated, with the United Kingdom famously conducting a randomized controlled study in which women were screened for EOC with a combination of serum markers and ultrasound [12]. When compared to women who underwent no screening, no impact was observed on overall survival from EOC [12]. Based on the results of this trial, no screening is currently recommended for the general population because modern diagnostic tests do not help patients that are diagnosed with EOC live longer and these same tests lead more women with benign ovarian diseases to have unnecessary procedures because the testing does not distinguish well between benign ovarian disease and cancer [12]. EVs present a promising new frontier for EOC screening because they are detectable in the serum and urine of patients, providing a potential novel method for diagnosing this cancer at an early stage when the patient can be cured more easily.
3.2 MicroRNA in EVs: how can they help to diagnose epithelial ovarian cancer?
One promising method for early cancer detection involves the analysis of EVs carrying microRNA, or miRNA, in the blood of patients. As strands of non-coding RNA that are 19–25 nucleotides in length, miRNAs are transcription products of DNA that regulate genes, a process that can activate or suppress the expression of different factors that can promote the growth and metastasis of EOC [1]. While most miRNA found in body fluids is cell-free and easily degradable, miRNA that is present in EVs is more stable, amplifying the role of this information in intercellular communication because it reaches cells more effectively [13]. When normal cells, such as stem cells, receive the miRNA from EVs, they produce tumorigenic factors that enhance the cancer’s ability to survive and promote invasion and dissemination [1].
When compared to healthy individuals, patients with EOC have levels of certain circulating miRNAs carried in EVs that are often elevated [13]. Numerous specific miRNAs have already been linked to EOC. For example, miR-222-3p, which Ying et al. showed promotes the conversion of normal macrophages into tumor-supporting macrophages through the activation of the SOCS3/STAT3 pathway, is elevated in patients with EOC. Once normal macrophages are transformed, they exert immunosuppressive effects that assist EOC cells in evading identification while also secreting factors that promote migration and growth. Since EV miR-222-3p levels are increased in this cancer, its detection in serum can serve as a diagnostic biomarker for early detection [14].
In another study Cappellesso et al. identified elevated levels of EVs with miR-21, a known regulator of the tumor suppressor gene programmed cell death 4 (PDCD4), in patients with EOC compared to patients with benign ovarian disease [15]. The gene PDCD4 typically prevents cancer through the regulation of apoptosis. However, in EOC, the increased expression of miR-21 directly inhibits PDCD4, allowing the cancer cell to further mutate and to invade other tissues. Similarly to miR-222-3p, EVs with miR-21 can enhance diagnostic testing and clinical staging of EOC.
While looking at individual EV miRNAs can provide clues for early detection of EOC, their true value will come from evaluating the miRNAs in large groups as diagnostic panels that together will provide screening with high sensitivity and specificity. In their study Taylor and Gercel-Taylor reviewed a panel of 8 miRNAs found in EVs—miR-141, miR-214, miR-200a, miR-200b, miR-200c, miR-21, miR-205—that displayed distinct biological profiles between patients with benign ovarian disease and those with EOC [16]. By utilizing this panel of EV miRNAs and including other EV miRNAs, a simple blood sample may serve as a powerful test that can be employed by clinicians to apprehend EOC in asymptomatic populations before it lethally spreads.
Proteins are also transported in EVs and can potentially serve as biomarkers for early diagnosis of EOC. One example of these EV proteins is EpCAM, which is recognized for its role in tumorigenesis and tumor proliferation and is elevated in patients with EOC. However, the diagnostic utility of EpCAM and other proteins is limited because the proteins can be elevated in patients with benign ovarian disease, decreasing the specificity of these markers [16]. If such proteins are then implemented into screening protocols, patients may have false-positive test results and may subsequently undergo invasive procedures with their associated complications without any benefit.
However, some proteins carried by EVs appear to be specific to EOC. CD24, a known poor prognostic marker for EOC, can be detected within EVs in malignant ascites of EOC patients [17]. Additionally, about half of the blood samples from a cohort of EOC patients contained EV claudin-4, another protein that can potentially serve as a diagnostic marker [18]. With the development of new diagnostic panels that combine EV proteins and miRNAs, patients will 1 day obtain testing that identifies EOC early and gives them a better chance at a cure.
Even easier to obtain than blood, urine is another potentially rich source for EOC EVs. Studies have identified numerous EV miRNAs such as miR-92a and miR-30a-5p that are elevated in the urinary samples of patients with EOC when compared to healthy controls [19, 20]. Specifically, miR-30a-5p is elevated in EOC but decreased in other malignancies such as gastric and colon cancer, making it a potentially unique biomarker [20]. While EV miRNAs found in urine are a potentially exciting biomarker for diagnosing EOC, more research is required to further take advantage of this easily accessible opportunity.
While these many EV factors provide appealing options for future diagnostic applications, some barriers hinder the utilization of EVs in the clinical setting. Current methods for isolation and purification of EVs are still constrained, relying on identification of these vesicles by size, a non-specific criterion that does not distinguish EVs from large proteins and other types of vesicular structures. The purification process involves ultracentrifugation, a process that is inefficient and cumbersome, especially for serum samples [21]. Also, current methods of molecular identification are limited by the small size of EVs as well as by the difficulty in detecting the EV content [21]. Once scientists solve these issues and answer other questions regarding the viability and concentration of EVs in blood and urine samples, the detection of EOC EVs will bolster the strength of diagnostic tools (Table 1).
Type of EV Content
Content
miRNA
miR-21
miR-30a-5p
miR-21
miR-92a
miR-141
miR-155
miR-181a
miR-200a
miR-200b
miR-200c
miR-205
miR-214
miR-222-3p
miR-223
miR-486
miR-1908
Protein
CD24
EpCam
Claudin-4
Table 1.
Potential panel of EV biomarkers for the diagnosis of epithelial ovarian cancer [1, 16, 17, 19, 20, 22].
4. Role of EVs in the prognosis of epithelial ovarian cancer
EVs are positioned to provide valuable prognostic information for EOC because current prognostic tools struggle to accurately predict an individual’s disease course and response to treatments. If there was a better understanding of how a patient’s particular cancer would grow and which medicines would be effective against it, providers would better optimize treatment strategies that would extend a patient’s life and even grant a better opportunity for cure. Currently, the prognosis for EOC is estimated based on generalized characteristics about this disease process within the context of the patient’s health status and medical history [8]. Some factors include age, stage of the cancer at the time of diagnosis, and performance status [8]. In recent years genetic research has played a significant role in patient prognosis. BRCA mutations, a pathologic process that affects the repair of double-strand DNA breaks, place patients at increased lifetime risk for EOC but also confer an improved prognosis for EOC especially with new therapies that are targeted toward patients with these mutations. While these factors provide some helpful guidance regarding a patient’s treatment outcomes, neither providers nor patients can accurately predict how an individual patient’s EOC will respond to therapies. However, with EVs new factors are being identified that can help in better understanding which patients will respond to certain therapies and what personalized treatment regimens will best address the cancer.
An important part of caring for patients with EOC is selecting the best treatment for their specific tumor. When determining a patient’s clinical management, the available prognostic information offers limited value in guiding clinicians about how to best care for their patients. However, novel therapeutic agents are demonstrating the need for refined prognostic tools that can identify a particular tumor’s sensitivity or resistance to certain treatments. For example, the breakthrough use of PARP inhibitors for the treatment of EOC over the past decade served as an important demonstration of the necessity to discover new patient factors that facilitate targeted treatments [23]. In cancer cells with impaired repair of double-stranded DNA breaks, also known as homologous recombination deficiency (HRD), PARP inhibitors promote double-stranded breaks through the inhibition of secondary single-stranded DNA repair that triggers apoptosis [23]. When EOC with HRD is treated with a PARP inhibitor, these patients experience a significant improvement in the management of their cancer. Therefore, patients with EOC are now tested for homologous recombination deficiency [23]. While PARP inhibitors are clearly a success, patients need new biomarkers for individualized treatments; and EVs can be these new targets.
EOC quickly becomes resistant to front-line chemotherapy regimens, but it is currently not possible to predict which patients will develop chemoresistance [16]. Evidence from multiple studies suggest that EVs can predict which patients will have a tumor that is sensitive to chemotherapy [1]. For example, Yan studied a cohort of 50 patients and demonstrated an increase in serum EV annexin A3 levels, a protein involved in exocytosis and vesicle trafficking, among patients with resistance against primary chemotherapy drugs when compared to patients that are still sensitive to those chemotherapies [24]. In a second study protein RAB7A functioned as a potential mediator of chemoresistance [25]. Functioning as a key regulator of the influx of chemotherapy agents into cells, RAB7A is downregulated in chemoresistant cells, potentially affecting drug sequestration [25]. Finally, some groups are studying serum panels of EV miRNAs that are associated with chemoresistance and include miR-181a, miR-1908, miR-21, miR-486, and miR-223 [22]. Together, these different EV molecular targets may serve as prognostic biomarkers to identify chemoresistance in patients with EOC and help tailor the appropriate medication combination for each patient.
5. Can extracellular vesicles inspire novel cancer therapies?
Based on its role in tumor invasion, chemoresistance, angiogenesis, cancer metastasis, and immunologic suppression, EVs present a promising opportunity to target important regulators of EOC progression and to mobilize the immunologic response to combat the malignancy. EVs and associated miRNAs are generating excitement as novel therapeutic targets for drug development.
5.1 EVs as a drug delivery system
EVs can be employed as a drug delivery system that targets cancer cells directly. Harboring packages of chemotherapeutic agents, the EVs can be manufactured to express cell surface antigens and receptors that target it toward cancer cells and spare normal cells, maximizing cytotoxic effect while sparing healthy tissue. In recent work Tang developed a model in which they incubated tumor cells with chemotherapy; and the tumor cells subsequently packaged the chemotherapy into EVs [26]. Tang’s group then took these EVs and demonstrated tumor-killing effect in mice with minimal side effects [26]. Therefore, if researchers translate this murine model into a therapy for EOC patients, EVs can be customized to carry the antitumor agents that are effective for a particular tumor. While chemotherapy affects tumor cells, it is also a treatment that damages healthy tissue, causing patients to experience a wide range of side effects. By having a treatment that can precisely target cancer cells while sparing normal tissues, clinicians could safely administer treatments to patients that could control or even cure EOC while avoiding harm.
5.2 Why are EVs so important in establishing the tumor microenvironment? Can the microenvironment become a target for new treatments?
In developing new therapeutic targets, one key area of focus is the immediate, small-scale environment surrounding cancer cells known as the microenvironment. The tumor microenvironment includes the extracellular matrix, neighboring blood vessels, stromal cells such as macrophages and fibroblasts, stem cells, signaling molecules, and immune cells [22]. For EOC the microenvironment becomes an integral component for drug targeting because of the role that it plays in protecting the tumor from chemotherapy and the immune system as well as in promoting proliferation, invasion, and metastasis. By targeting EOC EVs that transform healthy tissue into this tumorigenic niche, researchers will enhance the effectiveness of current treatments by reversing chemoresistance as well as limit the deadly growth and spread of this disease (Figure 1).
Figure 1.
The interaction between EOC cells and their microenvironment. Cancer cells release EVs that instruct normal cells to produce EVs that support cancer growth and invasion while also facilitating the development of chemoresistance and protection from the immune system [1, 2].
EVs derived from EOC cells promote the transformation from a normal microenvironment into a tumorigenic one through intercellular communication that stimulates angiogenesis, immune suppression, and stromal invasion [27]. Specifically, altered expression of miRNA such as miR-214, miR-31, and miR-155 has been linked to the conversion of fibroblasts, a support cell within the connective tissue, into cancer-associated fibroblasts (CAFs)— cells that participate in cancer propagation, support of the tumorigenic microenvironment, alteration of the extracellular matrix, and metastasis [1]. The CAFs then produce EVs enriched with TGFβ1 that then trigger the invasive properties of the tumor. With almost deliberate malintent, the cancer cells drive their own invasive potential by directing the formation of CAFs that provide the necessary growth factors that allow the malignancy to spread. Following treatment with cisplatin, a frontline chemotherapy agent, EOC cells release EVs that promote tumorigenic activity of mesenchymal stem cells that eventually stimulate cancer progression [28]. By developing therapies targeted at these factors that transform the healthy tissue surrounding cancer into the tumorigenic microenvironment, scientists can inhibit the cancer’s ability create its own protective environment that fuels its ability to grow and invade.
5.3 EVs and chemoresistance
Among the many challenges limiting the treatment of EOC, resistance to standard chemotherapy regimens exists as a frustrating inevitability in most patients with advanced disease; and EVs seem to play an integral role in this process. As the first-line regimen for EOC, platinum-based chemotherapy is the most effective treatment for EOC; yet 80% of patients with advanced EOC relapse, most within 2 years [3]. Following recurrence of the cancer, most people develop chemoresistance and succumb to the disease. An EOC that is platinum-resistant is defined as disease that recurs or progresses within 6 months of completion of the last treatment with a platinum-based regimen. Once a patient’s cancer reaches this state, expectations for disease control change, with low response rates to subsequent chemotherapies and a median survival falling below 12 months [3].
While platinum resistance is a complicated, multifactorial process that still needs further elucidation, EVs may help to better understanding this transformation. EOC EVs function as an intercellular communication system. Interestingly and frighteningly, EVs excreted by platinum-resistant tumor cells are capable of inducing resistance in other tumor cells [29]. While this mechanism is not well understood, once the EVs that mediate this process are better defined, they can become targets for possible therapeutic intervention. Furthermore, by understanding the EV content that conveys chemoresistance between cancer cells, scientists can alter the EVs to send information directly to tumor cells that reverses this resistance, allowing first-line treatments to again become effective.
The cytotoxic effect of platinum-based drugs such as cisplatin relies on the uptake of the chemotherapy into cells followed by DNA binding, leading to the formation of DNA crosslinks and breaks that result in apoptosis [3]. In patients that develop platinum resistance, some of their cancer cells exhibit reduced uptake or increased efflux of platinum agents, a process that EVs may facilitate [1, 3]. Transport proteins that have been implicated in this mechanism of drug resistance such as the lysosomal proteins ATPase copper-transporting alpha and beta have been found in EOC EVs, allowing cancer cells to survive against chemotherapy [22]. Is it possible to negate the effect of these EVs through targeted therapies? By disrupting this EV communication system with antibodies or other novel therapies, researchers can provide hope to these patients by overcoming chemoresistance and making their chemotherapy more effective.
5.4 EVs and immunosuppression
One important technique that allows EOC to proliferate and spread is the ability to suppress the immune system. By further understanding the elaborate underlying mechanisms through which EOC EVs dampen immunity, researchers will be able to block immune escape by the cancer cells, producing new treatments. By preventing immune suppression within the tumorigenic microenvironment, ovarian cells that were previously protected within this nurturing space would be freshly susceptible to immune cells that could find and eliminate the cancer cells [1].
Given the significant promise for novel treatments for EOC that reactivate the suppressed immune system, studies are already underway that target EOC EVs. One therapy utilizes dendritic cells as a map that directs the immune system toward the cancer. In one study these dendritic cells, known for presenting specific foreign antigens to the immune system for identification and targeting, were exposed to EVs isolated from the ascites of EOC patients [1]. The dendritic cells then presented tumor-specific antigens from the cancer EVs to resting T cells that subsequently differentiated and then killed EOC cells [30]. Dendritic cells may be harvested from a patient with EOC, cultured with isolated EOC EVs, and then reintroduced to the patient as an autologous injection that then directs the patient’s own T cells to eradicate the cancer. This concept elegantly demonstrates the potential for unleashing the immune system on cancer cells using EVs.
Another interesting avenue for treating EOC is through the utilization of immunoglobulins that directly target EVs. The serum of patients with EOC is more immunologically reactive when compared to the serum of healthy patients and patients with benign ovarian disease, indicating a robust immune response against the malignancy. As many studies have proven before, the natural immunoreactivity that the human body mounts against EOC is insufficient because the cancer employs tactics to evade the immune system, a process in which EVs play a significant role [22]. While immune evasion is a hallmark characteristic of EOC, the immune system may be mobilized against the cancer by findings ways to target EVs with immunoglobulins. Researchers can develop antibodies that specifically target EOC EVs, tagging them for the immune system so that they can be destroyed, effectively dismantling the vital EV communication system for the cancer cells and limiting the cancer’s ability to grow and spread. While this novel use of EVs is exciting, more research is needed to use this method. Mainly, scientists need to better characterize EVs to develop targets for immunoglobulins. Also, it is difficult for antibodies to target the content within EVs because it is protected by the vesicular walls, so proteins on the vesicle wall may provide a unique target for the antibodies. As scientists better understand the unique protein signatures of EOC EVs, immunity-based therapeutics may provide promising new avenues for treating these patients.
5.5 EVs and angiogenesis
Angiogenesis, a vital component of cancer proliferation and progression, has become an important focus in the care of patients with EOC. Ovarian cancers have previously been recognized for their role in promoting angiogenesis; so, by targeting these specific EVs in combination with other antitumor treatments, more effective regimens may be developed for combating this cancer. In the study GOG 218, Burger et al. conducted a clinical trial in which they incorporated a vascular endothelial growth factor (VEGF) inhibitor into the standard primary chemotherapy regimen for advanced EOC [31]. While patients on the VEGF inhibitor experienced a longer period of progression-free survival, they did not live any longer when compared to those who did not receive the treatment. While the inhibition of VEGF, a family of proteins recognized for stimulating the formation of blood vessels, clearly has some effect on tumor growth, other factors appear to be at play that limit the effectiveness of this therapy. One explanation is that EVs play a role in angiogenesis that circumvents the use of VEGF. Ovarian cancer-derived EVs that contain proteins such as CD147, metastasis-associated protein 1, and activating transcription factor 2 appear to have a key effect on angiogenesis that promotes cancer proliferation [32, 33]. A treatment for EOC could include antibodies or some other novel therapy that targets cancer EVs that carry these proteins that stimulate angiogenesis and then eliminate the ability for the cancer to develop its own blood supply.
Another appealing area of active research is the study of common dietary supplements that may have antiangiogenic properties through the production of antiangiogenic EVs. A promising supplement, Amla extract, derived from the Indian Gooseberry tree, has long been suspected to have cancer preventative properties [34]. One recent study tested the supplement on EOC cells and noted increased expression of EV miR-375 which appears to block the proangiogenic proteins SNAIL1 and IGF1R [34]. With a better understanding of the mechanism of this supplement and many others, scientists may 1 day provide dietary recommendations that can enhance a patient’s standard chemotherapy regimen or even derive a novel pharmacologic treatment that blocks blood vessel formation, helping to better destroy EOC cells [4].
6. Conclusion and clinical relevance
EOC remains a disease with a generally poor prognosis due to its asymptomatic early stages, ineffective screening mechanisms, and its predilection to develop chemoresistance with recurrence of disease. EVs are exciting within the field of EOC research because they provide the potential for many interventions that can save the lives of patients, ranging from diagnosing the cancer at earlier stages, identifying the optimal treatment for each individual patient, and even developing novel therapeutics that are more effective than the current regimens. With the ineffectiveness of screening tests, panels of EVs that can be detected in blood or urine provide hope for highly sensitive and specific tools that can give an accurate diagnosis of cancer in asymptomatic patients. Alternatively, by exploiting EVs to overcome chemoresistance, clinicians can redeploy existing treatments that typically become obsolete during a patient’s disease course. The demand for new diagnostic tools and therapies for patients with EOC is high, and EVs can be the next frontier for seemingly miraculous advancements in cancer care.
\n',keywords:"extracellular vesicles, exosomes, epithelial ovarian cancer, ovarian cancer, diagnosis, prognosis, novel therapy, gynecologic oncology",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/79698.pdf",chapterXML:"https://mts.intechopen.com/source/xml/79698.xml",downloadPdfUrl:"/chapter/pdf-download/79698",previewPdfUrl:"/chapter/pdf-preview/79698",totalDownloads:91,totalViews:0,totalCrossrefCites:1,dateSubmitted:"September 27th 2021",dateReviewed:"October 26th 2021",datePrePublished:"December 17th 2021",datePublished:null,dateFinished:"December 17th 2021",readingETA:"0",abstract:"Extracellular vesicles (EVs) are a varied group of cell-derived, microscopic, fluid-filled pouches released from cells into neighboring microenvironments that are quickly gaining recognition as a potentially powerful tool against epithelial ovarian cancer (EOC). Recent studies show that not only do EVs play an integral part in the development of cancer through intercellular communication, cell survival, and immune modulation but also may assist with early diagnosis and improved treatments. EOC currently has few effective screening options for early detection of this disease; and, therefore, it is detected at an advanced stage where it is more likely to recur, develop chemoresistance, and ultimately become fatal. Newer research has evaluated EVs as biomarkers for early screening and diagnosis and as novel targets for treatment of EOC. Moreover, EVs are possible targets for novel immunomodulatory therapies to directly target cancer cells or make cancer cells more susceptible to other treatment modalities. 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Role of EVs in the prognosis of epithelial ovarian cancer",level:"1"},{id:"sec_11",title:"5. Can extracellular vesicles inspire novel cancer therapies?",level:"1"},{id:"sec_11_2",title:"5.1 EVs as a drug delivery system",level:"2"},{id:"sec_12_2",title:"5.2 Why are EVs so important in establishing the tumor microenvironment? Can the microenvironment become a target for new treatments?",level:"2"},{id:"sec_13_2",title:"5.3 EVs and chemoresistance",level:"2"},{id:"sec_14_2",title:"5.4 EVs and immunosuppression",level:"2"},{id:"sec_15_2",title:"5.5 EVs and angiogenesis",level:"2"},{id:"sec_17",title:"6. Conclusion and clinical relevance",level:"1"}],chapterReferences:[{id:"B1",body:'Lucidi A, Buca D, Ronsini C, Tinari S, Bologna G, Buca D, et al. Role of extracellular vesicles in epithelial ovarian cancer: A systematic review. International Journal of Molecular Sciences. 2020;21(22):8762. DOI: 10.3390/ijms21228762'},{id:"B2",body:'Islami F, Ward EM, Sung H, et al. Annual Report to the Nation on the Status of Cancer, Part 1: National Cancer Statistics. J Natl Cancer Inst. 2021;113(12):1648-1669. DOI: 10.1093/jnci/djab131. [Published online ahead of print, 2021 Jul 8]'},{id:"B3",body:'Pokhriyal R, Hariprasad R, Kumar L, Hariprasad G. Chemotherapy resistance in advanced ovarian cancer patients. Biomark Cancer. 2019;11:1179299X19860815. Published 2019 July 5. DOI: 10.1177/1179299X19860815'},{id:"B4",body:'Zhang Y, Luo G, Li M, et al. Global patterns and trends in ovarian cancer incidence: age, period and birth cohort analysis. BMC Cancer. 2019;19(1):984. Published 2019 October 22. DOI: 10.1186/s12885-019-6139-6'},{id:"B5",body:'Li SS, Ma J, Wong AST. Chemoresistance in ovarian cancer: Exploiting cancer stem cell metabolism. Journal of Gynecologic Oncology. 2018;29(2):e32. DOI: 10.3802/jgo.2018.29.e32'},{id:"B6",body:'Mahmood RD, Morgan RD, Edmondson RJ, Clamp AR, Jayson GC. First-line management of advanced high-grade serous ovarian cancer. Current Oncology Reports. 2020;22(6):64. Published 2020 Jun 4. DOI: 10.1007/s11912-020-00933-8'},{id:"B7",body:'Perets R, Wyant GA, Muto KW, et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models. Cancer Cell. 2013;24(6):751-765. DOI: 10.1016/j.ccr.2013.10.013'},{id:"B8",body:'Stewart C, Ralyea C, Lockwood S. Ovarian Cancer: An Integrated Review. Seminars in Oncology Nursing. 2019;35(2):151-156. DOI: 10.1016/j.soncn.2019.02.001. Epub 2019 March 11'},{id:"B9",body:'Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA: a Cancer Journal for Clinicians. 2018;68(4):284-296'},{id:"B10",body:'Nakamura K, Sawada K, Kobayashi M, et al. Role of the exosome in ovarian cancer progression and its potential as a therapeutic target. Cancers (Basel). 2019;11(8):1147. Published 2019 August 10. DOI: 10.3390/cancers11081147'},{id:"B11",body:'Thery et al. 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BMC Cancer. 2009;9:244'},{id:"B19",body:'Zavesky L, Jandakova E, Turyna R, Langmeierova L, Weinberger V, Minar L. Supernatant versus exosomal urinary microRNAs. Two fractions with different outcomes in gynaecological cancers. Neoplasma. 2016;63(1):121-132'},{id:"B20",body:'Zhou J, Gong G, Tan H, Dai F, Zhu X, Chen Y, et al. Urinary microRNA30a-5p is a potential biomarker for ovarian serous adenocarcinoma. Oncology Reports. 2015;33(6):2915-2923'},{id:"B21",body:'Zhao Z, Yang Y, Zeng Y, He M. A microfluidic ExoSearch chip for multiplexed exosome detection towards blood-based ovarian cancer diagnosis. Lab on a Chip. 2016;16(3):489-496'},{id:"B22",body:'Li X, Wang X. The emerging roles and therapeutic potential of exosomes in epithelial ovarian cancer. Molecular Cancer. 2017;16:92. DOI: 10.1186/s12943-017-0659-y'},{id:"B23",body:'Mirza MR, Coleman RL, González-Martín A, Moore KN, Colombo N, Ray-Coquard I, et al. The forefront of ovarian cancer therapy: update on PARP inhibitors. Annals of Oncology. 2020;31(9):1148-1159. DOI: 10.1016/j.annonc.2020.06.004. Epub 2020 Jun 20. Erratum in: Ann Oncol. 2021 Aug;32(8):1066-1067'},{id:"B24",body:'Yan XD, Yin J, Yao H, et al. Increased expression of annexin A3 is a mechanism of platinum resistance in ovarian cancer. Cancer Research. 2010;70:1616-1624'},{id:"B25",body:'Guerra F, Paiano A, Migoni D, Girolimetti G, Perrone AM, De Iaco P, et al. Modulation of RAB7A protein expression determines resistance to cisplatin through late endocytic pathway impairment and extracellular vesicular secretion. Cancers (Basel). 2019;11(1):52. DOI: 10.3390/cancers11010052'},{id:"B26",body:'Tang K, Zhang Y, Zhang H, Xu P, Liu J, Ma J, et al. Delivery of chemotherapeutic drugs in tumour cell-derived microparticles. Nature Communications. 2012;3:1282'},{id:"B27",body:'Tang MK, Wong AS. Exosomes: Emerging biomarkers and targets for ovarian cancer. Cancer Letters. 2015;367(1):26-33'},{id:"B28",body:'Vera N, Acuña-Gallardo S, Grünenwald F, Caceres-Verschae A, Realini O, Acuña R, et al. Small extracellular vesicles released from ovarian cancer spheroids in response to cisplatin promote the pro-tumorigenic activity of mesenchymal stem cells. International Journal of Molecular Sciences. 2019;20(20):4972. DOI: 10.3390/ijms20204972'},{id:"B29",body:'Pink RC, Samuel P, Massa D, Caley DP, Brooks SA, Carter DR. The passenger strand, miR-21-3p, plays a role in mediating cisplatin resistance in ovarian cancer cells. Gynecologic Oncology. 2015;137(1):143-151'},{id:"B30",body:'Li QL, Bu N, Yu YC, Hua W, Xin XY. Exvivo experiments of human ovarian cancer ascites-derived exosomes presented by dendritic cells derived from umbilical cord blood for immunotherapy treatment. Clin Med Oncol. 2008;2:461-467. DOI: 10.4137/cmo.s776'},{id:"B31",body:'Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. The New England Journal of Medicine. 2011;365(26):2473-2483. DOI: 10.1056/NEJMoa1104390'},{id:"B32",body:'Millimaggi D, Mari M, D’Ascenzo S, Carosa E, Jannini EA, Zucker S, et al. Tumor vesicle-associated CD147 modulates the angiogenic capability of endothelial cells. Neoplasia. 2007;9(4):349-357'},{id:"B33",body:'Yi H, Ye J, Yang XM, Zhang LW, Zhang ZG, Chen YP. High-grade ovarian cancer secreting effective exosomes in tumor angiogenesis. Int J Clin Exp Pathol. 2015;8:5062-70 Shender VO, Pavlyukov MS, Ziganshin RH, Arapidi GP, Kovalchuk SI, Anikanov NA, Altukhov IA. Proteome-metabolome profiling of ovarian cancer ascites reveals novel components involved in intercellular communication. Molecular & Cellular Proteomics. 2014;13(12):3558-3571'},{id:"B34",body:'De A, Powers B, De A, et al. Emblica officinalis extract downregulates pro-angiogenic molecules via upregulation of cellular and exosomal miR-375 in human ovarian cancer cells. Oncotarget. 2016;7(21):31484-31500. DOI: 10.18632/oncotarget.8966'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Diego Aviles",address:null,affiliation:'
Department of Gynecologic Oncology, MD Anderson Cancer Center at Cooper, Cooper University Health Care, USA
Department of Surgery, Division of Surgical Research, Cooper University Health Care, USA
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Changes in mitochondrial Bcl‐2 family proteins were moderate and pro‐ and anti‐apoptotic proteins showed similar levels of regulation in both cell lines. 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Previous Dean of Faculty of Pharmacy at Sana\\'a University. Professor of Medicinal Chemistry Department. Member of Yemeni Medical Council. Member of many associations and international groups. Executive Editor in Universal Journal of Pharmaceutical Research. Editor and Associate Editor of some international journals. My interest is synthesis and biological activity of 4-oxopyrimidine and quinazolinone -4 derivatives, Structural biology and bioinformatics in drug design, study of Yemeni medicinal plants , development and validation of Spectrophotometric and HPLC methods for different drugs and antibiotics and antimicrobial resistance in Yemen.\nAuthor of more than 70 publications, 4 patents and 11 books.",institutionString:"Sana'a University",institution:{name:"Sana'a University",institutionURL:null,country:{name:"Yemen"}}},{id:"197828",title:"Associate Prof.",name:"Oya",surname:"Orun",slug:"oya-orun",fullName:"Oya Orun",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Marmara University",institutionURL:null,country:{name:"Turkey"}}},{id:"197833",title:"Dr.",name:"Pinar",surname:"Mega Tiber",slug:"pinar-mega-tiber",fullName:"Pinar Mega Tiber",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"198574",title:"Dr.",name:"Oliviu",surname:"Vostinaru",slug:"oliviu-vostinaru",fullName:"Oliviu Vostinaru",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"200773",title:"Ph.D.",name:"Giulia",surname:"Auriemma",slug:"giulia-auriemma",fullName:"Giulia Auriemma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Salerno",institutionURL:null,country:{name:"Italy"}}},{id:"200831",title:"Dr.",name:"Andrea",surname:"Cerciello",slug:"andrea-cerciello",fullName:"Andrea Cerciello",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"204549",title:"Dr.",name:"Pran Kishore",surname:"Deb",slug:"pran-kishore-deb",fullName:"Pran Kishore Deb",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204549/images/5256_n.jpg",biography:null,institutionString:null,institution:{name:"Philadelphia University",institutionURL:null,country:{name:"United States of America"}}},{id:"205616",title:"Prof.",name:"Raghuprasad",surname:"Mailabaram",slug:"raghuprasad-mailabaram",fullName:"Raghuprasad Mailabaram",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"205617",title:"Dr.",name:"Bilal",surname:"Al-Jaidi",slug:"bilal-al-jaidi",fullName:"Bilal Al-Jaidi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"WIS-cost",title:"What Does It Cost?",intro:"
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Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. 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Dr. Şentürk currently works as an professor of Biochemistry in the Department of Basic Pharmacy Sciences, Faculty of Pharmacy, Ağri Ibrahim Cecen University, Turkey. \nDr. Şentürk published over 120 scientific papers, reviews, and book chapters and presented several conferences to scientists. \nHis research interests span enzyme inhibitor or activator, protein expression, purification and characterization, drug design and synthesis, toxicology, and pharmacology. \nHis research work has focused on neurodegenerative diseases and cancer treatment. 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He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,series:{id:"11",title:"Biochemistry"}}},seriesLanding:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:318,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"14",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",fullName:"Abdulsamed Kükürt",profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",institutionString:null,institution:{name:"Kafkas University",institutionURL:null,country:{name:"Turkey"}}},{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"chapter.detail",path:"/chapters/44295",hash:"",query:{},params:{id:"44295"},fullPath:"/chapters/44295",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)}()