Types of vaccines.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"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:"3391",leadTitle:null,fullTitle:"Hot Topics in Echocardiography",title:"Hot Topics in Echocardiography",subtitle:null,reviewType:"peer-reviewed",abstract:"Echocardiography is still the most used imaging technique for the evaluation of cardiac anatomy and function and today it plays an essential role in daily decision making.\nThe echocardiographic technology and its applications have widely developed in the last years leading to a better diagnostic accuracy. 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\r\n\tCOVID-19 pandemic has caused shifts in consumer life and consumer behavior all around the world. Consumers face many situations that they have to overcome during the pandemic crises, affecting not only consumers’ current and future lives, but also companies’ business strategies and future survivals as well. Traditional consumer behavior has started to become a threat for the consumers, so their buying behavior has moved to Internet-centered online platforms with the use of technological advancements. This book aims to focus on consumer behavior during pandemic crises situations with the use of e-commerce. The technological advances and consumer expectations during the pandemic and post-pandemic periods lead to some shifts in consumer behavior and business operations as well.
\r\n\r\n\tThe book also hopes to cover crises management and handling of communication with situational factors which cause sharp transformations on both sides economically, socially, technologically, psychologically, and so on. Theoretical and practical chapters contributing to the mentioned context are highly appreciated and welcomed.
",isbn:"978-1-80356-183-7",printIsbn:"978-1-80356-182-0",pdfIsbn:"978-1-80356-184-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"0f4b358c85333ef0ec1148654c1ff90d",bookSignature:"Dr. Umut Ayman",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11581.jpg",keywords:"Consumer Behavior, Crises Situation, Pandemic, E-commerce, Post-pandemic, COVID-19, Buying Behavior, Digital Marketing, Consumer Engagement, Crises Management, Business Strategy, Behavior Model",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 3rd 2022",dateEndSecondStepPublish:"March 3rd 2022",dateEndThirdStepPublish:"May 2nd 2022",dateEndFourthStepPublish:"July 21st 2022",dateEndFifthStepPublish:"September 19th 2022",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Umut Ayman is an academician also working on campaign designs and launches for products/services for various sectors, and is involved in A to Z integrated marketing communication models including luxury consumption, branding, and fashion marketing communication issues. She also provides consultancy services for social responsibility projects.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"210632",title:"Dr.",name:"Umut",middleName:null,surname:"Ayman",slug:"umut-ayman",fullName:"Umut Ayman",profilePictureURL:"https://mts.intechopen.com/storage/users/210632/images/system/210632.jpeg",biography:"Umut Ayman completed her Bachelor’s degree in Business and her MBA in 1999 at the Eastern Mediterranean University (EMU). She completed her Communication and Media studies PhD in 2015 focusing in her thesis on consumption patterns in branded apparel products and consumers’ decision-making styles from a marketing communication perspective. Within the EMU Community Involvement Center, she provides consultancy services for social responsibility projects. She also works on campaign designs and launches for products/services for various sectors, and is involved in A to Z integrated marketing communication models including luxury consumption, branding, and fashion marketing communication issues. She holds introduction lectures on marketing communication, integrated marketing communication, marketing oriented public relations, marketing communication for social responsibility, IMC research methods, fashion marketing communication, branding and brand management, IMC campaign, and senior project courses. She is working as an Assistant Professor and Vice-chair at EMU, Faculty of Communication, Public Relations and Advertisement Department.",institutionString:"Eastern Mediterranean University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Eastern Mediterranean University",institutionURL:null,country:{name:"Cyprus"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"7",title:"Business, Management and Economics",slug:"business-management-and-economics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"185543",firstName:"Maja",lastName:"Bozicevic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/185543/images/4748_n.jpeg",email:"maja.b@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"9044",title:"Promotion and Marketing Communications",subtitle:null,isOpenForSubmission:!1,hash:"89b0a14e5fbc99691e93e210da34ea27",slug:"promotion-and-marketing-communications",bookSignature:"Umut Ayman and Anıl Kemal Kaya",coverURL:"https://cdn.intechopen.com/books/images_new/9044.jpg",editedByType:"Edited by",editors:[{id:"210632",title:"Dr.",name:"Umut",surname:"Ayman",slug:"umut-ayman",fullName:"Umut Ayman"}],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"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"54354",title:"A Review of Possible Triggering or Therapeutic Effects of Antimicrobial Vaccines on Psoriasis",doi:"10.5772/67691",slug:"a-review-of-possible-triggering-or-therapeutic-effects-of-antimicrobial-vaccines-on-psoriasis",body:'\nPsoriasis is a chronic, immune-mediated disease with a prevalence of 2–3% in adult population. Psoriatic arthritis affects approximately 11% of psoriasis patients, and cardiovascular disease is increased [1]. Psoriasis disease is caused by the interactions of genetic background with various environmental triggering factors. HLA-Cw6 allele in PSORS1, the most associated gene with psoriasis, encodes a major histocompatibility complex I allele that is the major factor for antigen presentation of intracellular peptides to the immune system [2].
\nSeveral environmental factors, such as trauma (Koebner effect), infections, obesity, smoking and some medications, play a role in the onset of psoriasis. Guttate psoriasis is related to streptococcal throat infections as two-thirds of patients have a history of throat infection nearly 2 weeks before the eruption [3, 4]. A homology between streptococcal M protein and human keratin 17, which is upregulated in the skin of psoriasis, has been reported. In the basis of this finding, T-cells cross-reacting with human keratin and streptococci have been detected in HLA-CW6-positive psoriasis patients, raising the possibility that psoriasis is an autoimmune disease [5].
\nIn the initial phase of the disease, certain dendritic cell (DC) populations such as plasmacytoid DCs (pDC) and dermal myeloid DCs are activated and produce the key psoriasis effector cytokines IL-12 and IL-23. Self-DNA or self-RNA from damaged keratinocytes and the antimicrobial peptide LL37 stimulate pDCs, through Toll-like receptor (TLR) 9 or TLR7/8 and IFN-alpha production is triggered. The stimulation of pDCs is followed by differentiation and activation of myeloid DCs, which express cytokines IL-12, tumor necrosis factor (TNF)-alpha, TGF-beta and IL-6. These cytokines induce T-cells to polarize into Th1 and Th17 subtypes, with suppressing of regulatory T-cells [1, 2, 6, 7]. CD4+ T-cells secreting IL-17 are classified as a different T-helper population called Th17 cells, which are critical in psoriasis pathogenesis. Th17 cells produce IL-17A and IL-17F, and Th1 cells produce TNF-alpha, IFN-gamma, IL-12, IL-22 and IL-23 that promote the pathological changes in psoriasis skin lesions [2, 8].
\nFor psoriasis patients with localized disease, topical treatments including corticosteroids, vitamin D derivatives, tazarotene, anthralin, tar, calcineurin inhibitors, keratolytic agents and urea are the first-line therapy [9]. Phototherapy is a mainstay option particularly for patients resistant to topical treatments with widespread disease [10]. In cases with moderate-to-severe psoriasis resistant to any of these treatments, conventional systemic therapy is done with methotrexate (MTX), cyclosporine, fumaric acid esters and acitretin. In patients who have failed to respond to conventional systemic therapies and phototherapy or the person is intolerant to, or has a contraindication to these treatments, biologic immunotherapy is used. There are several agents such as TNF-alpha inhibitors (etanercept, infliximab and adalimumab) and ustekinumab that are available in the treatment of psoriasis [11].
\nVaccination is a proven way of reducing the incidence of serious or life-threatening infectious disease in general population and in patients with immune-mediated inflammatory disease. Vaccines are recommended for psoriasis patients due to their susceptibility to infections [12]. The data emphasize that especially some types of vaccines may trigger an exacerbation of psoriatic skin lesions or induce improvement in psoriasis [1, 13].
\nIn this review, we aim to summarize the vaccines in psoriasis in terms of their both triggering and therapeutic effects.
\nPatients diagnosed with psoriasis are at risk of infections owing to the nature of disease and immunosuppressive therapies [12, 14]. Therefore, the medical board of the National Psoriasis Foundation recommends vaccinations in compliance with recommendations of the Advisory Committee for Immunization Practices to prevent infections [12]. Types of vaccines can be categorized as live and inactivated vaccines (Table 1) [12, 14].
\nInactivated or inert vaccines | \nLive vaccines |
---|---|
Salk poliomyelitis vaccine | \nVaccinia/smallpox | \n
Most influenza vaccines (injectable) | \nRotavirus | \n
Hepatitis A | \nMeasles-mumps-rubella | \n
Hepatitis B | \nYellow fever | \n
Human papillomavirus | \nOral poliomyelitis | \n
Diphtheria-tetanus-pertussis | \nVaricella zoster vaccine | \n
Haemophilus influenza type b conjugate vaccine | \nHerpes zoster | \n
Pneumococcal | \nIntranazal influenza virus | \n
Meningococcal | \nBCG | \n
Rabies | \nOral typhoid | \n
Parenteral typhoid | \n\n |
Anthrax | \n\n |
Japanese encephalitis | \n\n |
Types of vaccines.
Live vaccines, which contain attenuated natural pathogens, are contraindicated in immunocompromised patients and should be given 2 or 4 weeks before the immunosuppressive therapy. Additionally, immunosuppressive medications should be stopped generally 3 months before the immunization with live vaccines [12, 14]. However, a few reports suggest that some live vaccines such as yellow fever vaccine in patients receiving MTX may be safe [15]. More research is needed for safety of live vaccines in immunocompromised patients [12, 15]. Inactivated vaccines are safe for patients on immunomodulatory therapy due to their noninfectious content but vaccine response may be suboptimal [12, 14, 16]. It has been reported that the antibody response ratio following seven-valent conjugate pneumococcal vaccination was significantly higher in controls when compared to patients treated with MTX or MTX combined with TNF inhibitors. On the other hand, in the same study, patients treated with TNF inhibitors as monotherapy had numerically lower but not significantly different antibody levels, compared to controls [17]. In a study, ustekinumab did not impair the immune response to pneumococcal and tetanus toxoid vaccines in psoriasis patients [18]. In another study, efalizumab caused a nearly threefold decrease in the antibody response to tetanus toxoid vaccine while not changing the immune response to pneumococcal polysaccharide vaccine [19]. Immune responses to pneumococcal polysaccharide vaccine in patients with chronic plaque psoriasis treated with alefacept were similar to those seen in healthy subjects [20].
\nIn a study assessing the seasonal 2012 influenza vaccination among patients with psoriatic arthritis and psoriasis, usage of TNF-alpha blockers or disease-modifying antirheumatic drugs did not affect the response rate [21]. Annual immunization with inactivated influenza vaccine is recommended for psoriasis patients on immunosuppressive treatment due to high mortality rates of seasonal influenza [12, 22]. In a French study on 1308 psoriasis patients, Sbidian et al. reported that 19% of patients received the 2009 monovalent H1N1 vaccine. Only 33% of the patients treated with biologics were vaccinated [23]. The vaccination rate of influenza vaccine in 2010/2011 was found 28% among 1299 patients with psoriasis or psoriatic arthritis in Germany. Thirty-eight percent of the patients were on biological therapy at the time of vaccination [22]. Despite the recommendations, the vaccination coverage was low in psoriasis patients in both studies [22, 23].
\nZoster vaccine, a live attenuated vaccine, is recommended for use in immunocompetent individuals 60 years of age or older to reduce the risk and severity of herpes zoster (HZ) [12]. Increased incidence of HZ has been reported in psoriasis patients receiving combination treatment with biologic medications and MTX while biologic or systemic agents as monotherapy did not increase the risk of HZ [24]. Zhang et al. reported that zoster vaccination was not related to increased risk of HZ in patients with immune-mediated disease including psoriasis under biological therapy [25, 26]. However, it was emphasized that infliximab increases the risk of HZ in most of the cohort studies while the risk of HZ in patients receiving etanercept, adalimumab or ustekinumab therapy is not clear [27]. Yun et al. indicated that the use of biologic agents and systemic steroids in patients with autoimmune and inflammatory diseases increased the risk of HZ [28]. Consequently, HZ vaccination should be considered for patients who are going to receive biological agents especially infliximab and combination treatment with MTX therapy. Additionally, the vaccine should be administered before initiation of the immunosuppressive therapy [24, 27].
\nAs a conclusion, it has been reported that immunization status, including
Type of vaccine | \nBefore therapy | \nOn therapy |
---|---|---|
\n | ||
Influenza | \nVaccinate with inactivated or live attenuated vaccine | \nAnnual inactivated influenza |
Human papillomavirus | \nRecommended for male and female < age 26 years | \nSame |
Hepatitis A | \nFor selected individuals at high risk (diabetes, liver disease, injecting drug users, homosexual men, employees or residents in institutional settings) | \nSame, test for serology after vaccination |
Hepatitis B | \nFor individuals at high risk and without evidence of disease and immunity | \nUse high-dose vaccine, test for serology after vaccination |
Pneumococcal | \nImmunization with 23-valent pneumococcal polysaccharide vaccine | \nImmunization with 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine if not given prior |
Haemophilus influenza type b | \nUnvaccinated individuals can be vaccinated | \nSame |
Diphtheria-tetanus-pertussis | \nBooster is recommended every 10 years and for high-risk wounds, offer before therapy | \nSame |
Meningococcal | \nFor selected individuals at high risk (asplenia, complement deficiency, group living situation) | \nSame |
Poliomyelitis | \nFor selected individuals at high risk (healthcare workers or laboratory personnel) | \nSame |
\n | ||
Varicella zoster | \nTest for serology before initiation of therapy, if negative, offer vaccination | \nContraindicated |
Herpes zoster | \n1 dose for adults ≥50 years | \nContraindicated |
Measles-mumps-rubella | \nAssessment of immunization by history and serology before initiation of therapy, if negative, offer vaccination | \nContraindicated |
Recommendations for vaccination of patients diagnosed with psoriasis before or on systemic immunosuppressants.
As mentioned above, basis on a genetic predisposition, various environmental factors may cause development of psoriasis in patients who are in latent period. Physical or chemical factors, infections and various types of medications are the most important among these, and they may affect the course of psoriasis by many different mechanisms [13]. Triggering vaccines on psoriasis and psoriatic arthritis are summarized below.
\nVarious types of skin trauma with subsequent development of new psoriasis lesions about 10 days later are known as ‘Koebner-phenomenon’ [29]. In a study evaluating the relation between ‘Koebner-phenomenon’ and intradermal antigens, 30 psoriasis patients and 20 control subjects were firstly determined for Koebner status and then were tested with intradermal injections of purified protein derivative, Candida, mumps, mixed respiratory vaccine and saline control solutions. Two psoriasis patients were Koebner positive and developed psoriasis at all five injection sites. Besides, in five Koebner negative patients, local psoriasis lesions were observed in at least one injection site of different antigens. These findings were interpreted that some psoriatic patients may have individually specific sensitivity to different antigens to trigger the cellular immune response in psoriasis [30].
\nAdditionally, in a recent placebo-controlled study, evaluating the ‘nontypeable Haemophilus influenza protein vaccine’, a psoriasis case was reported to be associated with injection of saline placebo at 114 days post-dose 3 in the placebo group indicating the Koebner effect [31].
\nBCG is a live attenuated strain of
A case of 50-year-old psoriasis patient in remission was described as guttate psoriasis 1 week after the Td vaccination [37]. Td vaccine has shown to induce IL-6 production, which stimulates Th17 cells, having a key role in psoriasis pathogenesis [37, 38]. It was suggested that this mechanism was the triggering cause in this case [37]. In a case-control study evaluating the potential risk factors for the onset of psoriatic arthritis, exposure to rubella (OR = 12.4, 95% CI = 1.2–122.14) and tetanus (OR = 1.9, 95% CI = 1.0–3.7) vaccines was reported at a higher frequency in psoriatic arthritis group as compared to the psoriasis group without arthritis [39].
\nShin et al. described a 26-year-old woman with multiple erythematous scaly macules scattered on the extremities and trunk compatible with guttate psoriasis following injection of an inactivated split-virus influenza A/H1N1 vaccine without adjuvant [40]. Güneş et al. reported 43 patients suffering from psoriasis in that 36 of them had exacerbation of pre-existing psoriasis while disease first appeared in the remaining seven patients after influenza vaccination in the 2009–2010 season. Thirty-seven of these patients had mixed plaque type and guttate psoriasis, three of them suffered from palmoplantar psoriasis, and another three of them had scalp psoriasis. Although there is the lack of control group and follow-up evaluations in that study, they suggested that their observations may support the association between influenza vaccination and the development of psoriasis due to the short-time onset of psoriasis after vaccination and the lack of other possible triggers [13].
\nThere is also a cross-sectional study investigating a total of 1125 cases for the onset or flare of psoriasis occurring within 3 months following the 2009 monovalent H1N1/seasonal vaccination through a national survey in France. The overall influenza vaccine coverage was found 19% in this population. Ten patients were reported with a psoriasis of new onset (
In another study, the effects of seasonal influenza vaccination in psoriatic arthritis patients under anti-TNF-alpha therapy were evaluated. 1 month after the vaccination (T1), patients (
In a retrospective study, which evaluated the possible side effects related to adenovirus types 4 and 7 in military recruits, psoriasis (21 versus 7 cases) was found more frequently (RR = 2.44, 95% CI = 1.13–5.31) in the vaccinated group (
Both conventional systemic treatments and biologic agents are related to serious side effects. The biologic immunotherapy agents act by inhibiting over-expressed T-cell activity by reducing T-cell numbers, T-cell trafficking or immune deviation and blocking the activities of proinflammatory cytokines, which may lead to severe infections, myelodegenerative and autoimmune disorders [29]. Additionally, over the past few years, various John Cunningham virus (JCV) associated brain syndromes have been reported as a result of increased usage of the immunomodulatory medications [44]. The progression in the enlightenment of the immunopathogenesis of psoriasis may provide new therapeutic options that do not have immunosuppressive side effects. Vaccination is a progressing therapy option for psoriasis and the other chronic inflammatory disorders such as multiple sclerosis, rheumatoid arthritis and atherosclerosis, which are termed as noncommunicable diseases [1, 45, 46]. It has clearly demonstrated that vaccines have the ability to activate effectors such as dendritic cells and T lymphocytes, which are also involved in psoriasis pathogenesis [41]. Noncommunicable disease vaccines target cells, proteins or other molecules that are related to these disorders and modulate the immune system, similar to traditional vaccines [45].
\nApproximately two-thirds of guttate psoriasis patients and a quarter of chronic psoriasis patients have an association with streptococcal throat infections. Fry et al. claimed that vaccination against Streptococcus pyogenes as well as the other possible microorganisms that trigger psoriasis may be a new way to prevent psoriasis [3, 4]. It has also been suggested that psoriasis may benefit from development of a T-cell receptor peptide vaccine [47].
\nAs we mentioned before, IL-17 has been shown to play an important role as a proinflammatory cytokine in psoriasis. IL-17 is demonstrated as a ‘target antigen’ for the treatment of autoimmune disorders and psoriasis in preclinical experiments in animal models and in clinical trials [48]. Dallenbach et al. showed that immunization with Qβ-IL-17, a virus-like particle-based vaccine, generated IL-17-specific IgG in mice. In order to evaluate the role of hypermutation and affinity maturation, they mutated the hypermutated antibody back to germline sequence, producing a set of two antibodies with VH regions differing in three aminoacids, but recognizing the same epitope. They showed that both the hypermutated and the germline antibody significantly neutralized IL-17 and blocked its biological activity
Over-expression of ß-defensin 2, known as a skin antimicrobial peptide, has been reported to be associated with psoriasis [50]. In a recent study, serum ß-defensin 2 levels have been found to correlate with IL-17A levels and psoriasis area severity index (PASI) scores in psoriatic patients [51]. Additionally, García-Valtanen et al. demonstrated that ß-defensin 2 improves the DNA vaccine efficacy due to its adjuvant-like effects besides its antiviral and immunomodulatory properties in a study of zebrafish. They claimed that this psoriasis-related peptide might be used as an adjuvant in DNA vaccination to improve the efficacy of viral vaccines [50].
\nThe TNF-alpha-induced protein 3 (TNFAIP3) is an anti-inflammatory factor that inhibits NF-κB activation in T-cells. In a few studies, it was reported that expression of TNFAIP3 mRNA was significantly higher in patients with mild psoriasis than in the patients with severe psoriasis, suggesting that TNFAIP3 gene may be a ‘target’ molecule for psoriasis therapy [52, 53]. There are also reported studies, which are mentioned below, about the usage of vaccines on psoriasis.
\nA placebo-controlled study in patients with chronic plaque psoriasis evaluated the potential beneficial effects of
A study performed on 36 patients with psoriatic arthritis randomized the patients to receive two intradermal injections of 50 µg delipidated, deglycolipidated
Mycobacterium w is a nonpathogenic, rapidly growing, cultivable strain of atypical mycobacteria and has been used as an adjuvant immunotherapy for leprosy, tuberculosis and human immunodeficiency virus, like
The mechanism of mycobacterium immunotherapy leads to improvement in psoriasis is not known exactly. Lehrer et al. suggested that the decreasing effect of TNF-alpha might cause clinical improvement in psoriasis patients treated with
In a trial about a vaccine for cutaneous leishmaniasis, O’Daly et al. observed 100% clinical remission of a psoriatic lesion in one patient after third vaccination. After this discovery, they performed an open-label, single-center study to evaluate the leishmaniasis vaccine (AS100®) in 2770 psoriasis patients. When baseline PASI values were compared with the post-treatment values, PASI 100 was achieved in 23%, PASI 75 in 45%, PASI 50 in 13%, PASI 10 in 9% and <PASI 10 was determined in 3% of patients. The most common adverse effects were pain and nodule formation, which were injection side related. The other systemic adverse effects were considered as mild and moderate in severity. Similar results were observed in a second, double-blind, placebo-controlled study, performed by the same group [60]. In a subsequent study, O’Daly et al. evaluated further purified vaccines, resulting in seven chromatography fractions per four Leishmania species. They suggested that three fractions from
A placebo-controlled study was conducted by El-Darouti et al. to evaluate the adjuvant effect of live attenuated varicella vaccine (Varilrix®) in patients with resistant severe psoriasis after their observation of improvement in one patient with severe psoriasis following a chickenpox infection. Study group received four doses of Varilrix® once every 3 weeks before low-dose cyclosporine (2.5 mg/kg/day) while control group received four doses of subcutaneous saline as placebo. Study group demonstrated significantly higher improvement in their PASI values. According to El-Darouti et al., the hypotheses explaining the mechanism of live attenuated varicella vaccine on psoriasis are given as below [64]:
\nThe stimulating effect of varicella zoster virus on the humoral response by Th-2 cells and subsequent downregulation of the Th-1 response,
The inhibitory effect of IFN-alpha on Th-17 cells by peripheral blood cells exposed to varicella zoster virus antigen,
The upregulation of regulatory T-cells that have inhibitory effects on psoriasis after receiving varicella vaccine.
Subsequently, El-Darouti et al. reported that live attenuated varicella vaccine is effective in psoriasis when used with low-dose cyclosporine by acting possibly on the Th17/ regulatory T-cells balance [65].
\nVaccination is an effective tool for reducing the incidence of serious or life-threatening infectious disease [45]. Patients diagnosed with psoriasis are at risk of infections due to the nature of disease and immunosuppressive therapies [12, 14]. For this reason, the medical board of the National Psoriasis Foundation recommends vaccination for patients diagnosed with psoriasis in compliance with recommendations of the Advisory Committee for Immunization Practices [12]. Besides, vaccines such as
The liver is the largest organ in the body, and while it only accounts for about 3% of the total body weight it receives 25% [1, 2] of the cardiac output via the hepatic artery and portal vein. This is due to its multifunctionality in regulating glucose and amino acid homeostasis, detoxifying the blood, processing of lipoproteins and their fats, synthesis of bile and proteins, storage of glycogen and vitamins and filtering of bacteria, etc.
Hepatocytes produce many of the proteins involved in normal regulation of the clotting cascade and fibrinolytic system. These, with platelets, achieve a balanced haemostasis system with fine controls and checks at many levels to maintain free flow of blood within the circulation, prevent uncontrolled clotting of the blood and quickly plug blood vessel wall breaches to limit blood loss. Toxins and pathogens can not only cause hepatocyte injury but also damage hepatic sinusoidal cells and endothelial cells (ECs) throughout the circulation. The injury results in reduced synthesis of clotting factors but due to compensating changes in additional factors that regulate the clotting and fibrinolytic cascades, haemostasis and thrombin generation remain in balance [3] and any bleeding is usually due to the presence of varices. This new haemostasis balance is more sensitive to perturbation because synthesis and release of proteins and proteases responsible for its fine tuning, that come not only from hepatocytes but also sinusoidal cells and ECs, are also disrupted. The initial result is more likely to be a procoagulant state, but if hepatic dysfunction worsens the balance may tip the other way with predomination of fibrinolysis, thrombocytopenia and worsening platelet dysfunction causing bleeding.
The haemostasis disruption may lead to macro-vascular thromboses involving the complex circulation around the liver, i.e. the portal venous system (PVS) that includes the intra-hepatic portal vein branches, the splenic and superior mesenteric veins. Portal vein thrombosis (PVT) commonly occurs in patients with hepatic cirrhosis and/or carcinoma, while splenic vein thrombosis may also be found as an extension of a PVT or develop as a complication of splenectomy [4, 5]. PVT may also develop in the absence of primary liver disease [6] and has recently been described in patients with COVID-19 [7, 8] and in patients suffering vaccine-induced immune thrombocytopenic thrombosis (VITT) following COVID-19 vaccination [9].
In patients with cirrhosis the frequency of PVT increases with disease severity [10] from about 3%–25% [11]. In post-splenectomy patients with cirrhosis the frequency may reach 36% in the absence of anticoagulation and rates as high as 70%–5% have been found in the presence of malignancy (hepatoma, lymphomas, solid tumours, myeloproliferative neoplasms). Although at first PVT may be almost symptomless and many spontaneously disappear, persistence and recurrence result in significant or complete obstruction of one or more vessels of the PVS and portal hypertension with increasing morbidity. Formation of collateral circulations and varices are prone to rupture with often major blood loss. PVT can present either acutely with abdominal pain, diarrhoea and ileus—occasionally as an acute abdomen or chronically often with signs of portal hypertension.
Persistent/recurrent PVS thrombosis (PVST) may eventually be fatal, hence there is frequently a need for effective antithrombotic management. Especially if acute non-occlusive PVST or a thrombotic risk factor is present, e.g. sepsis, cancer, antiphospholipid antibody or an acquired or hereditary thrombotic risk (factor V Leiden, prothrombin mutation G20210A, protein C and/or S deficiency, etc.) then anticoagulation should be considered [12, 13] The aims of anticoagulation are thrombus recanalisation, reduction of portal hypertension to lower the bleeding risk and prevention of PVST recurrence. The use of anticoagulants has been reviewed and several meta-analyses of the results are available [5, 14]. Despite the heterogeneity of the included studies, there appears to be a growing consensus that use of anticoagulants for the treatment of PVT increases the rate of recanalisation compared with non-anticoagulated patients, but there is too little evidence concerning their benefit to risk balance with emphasis on bleeding complications.
The sinusoidal cells, which share many features of ECs, are particularly at risk of toxic injury. Both hepatic sinusoidal obstruction syndrome (SOS) and transplant associated thrombotic microangiopathy (TA-TMA) are examples of sinusoidal cell and EC injury. Detoxification of chemotherapeutic drugs and other toxins, including pathogen induced endotoxins, is mediated by the hepatic cytochrome P450 complex and any toxic side-products produced are neutralised by the glutathione enzymatic system (GSH). The centrilobular cells of the sinusoids have the least GSH and the lowest oxygen supply thus they are at most risk of toxic injury. If the activity of the P450 and/or GSH is impaired or overwhelmed, e.g. in hepatic disorders and/or the presence of high intensity chemotherapy, then toxic side-products accumulate leading to sinusoidal and EC injury. The resultant disruption of local haemostasis and immune system control result in microvascular thromboses the development of SOS [15] (formerly known as veno occlusive disease or VOD). The injury may extend beyond the sinusoids allowing toxic chemotherapeutic drugs and their side products to access ECs in the general circulation and other organs. If these are already injured by prior total body radiation and/or infections or by graft v host disease (GvHD) following haematogenous stem cell transplantation (HSCT), then further endothelial damage will develop with gradual or sudden emergence of the clinical and pathological picture of TA-TMA. Both SOS and TA-TMA occur most frequently as complications of HSCT as a result of the chemotherapy used to prepare for the transplant, the use of allogeneic in place of autologous transplants and post-transplant use of further chemotherapy and a cocktail of drugs to prevent or control infection, transplant rejection and GvHD. Both SOS and TA-TMA are associated with a high mortality. Table 1 shows risk factor associated with one or both complications.
Risk factor cited for occurrence and severity | SOS | TA-TMA |
---|---|---|
Gender (F > M) | (+) | |
Age at HSCT <10 years | + | |
Use of: alkylating cytostatic agents, platinum complexed agents, pyrrolizidine plant alkaloids | + | + |
Immunotherapies for acute leukaemias: gemtuzumab, inotuzumab, ozogamicin, | + | + |
Donor mismatch | + | |
Platelet transfusion mismatch | + | |
Number of prior stem-cell transplants | + | |
Fungal or viral infections/sepsis | + | |
Pre-existing hepatic injury (viral, cancer) | + | |
Active co-morbidity | + | |
Prior abdominal radiotherapy | + | + |
Immunodeficiency syndrome | + | |
Presence of an autoimmune disorder | + | |
The interval between malignancy diagnosis and the HSCT | + | |
Presence of acute GvHD | + | |
Inherited thrombophilia (FVL, G20210A) | + | |
Post HSCT cyclosporine, tacrolimus, serolimus | + | |
After autologous as well as allogeneic BMT | (+) | (+) |
Liver transplantation | + |
Risk factors for SOS and TA-TMA.
Complement cascade proteins also originate in the liver. In health the immunological/anti-inflammatory and haemostatic systems are finely tuned and, because of their cross-talk via various interacting pathways, maintain a finely balanced vascular homeostasis ready to repel ‘foreign’ invasion and seal damaged vessels to limit blood loss and procoagulant products (including PAI-1, thrombomodulin, vWF and microparticles). However, sinusoidal cell and EC injury related to HSCT injury leads to release of a cocktail of cytokines and mitogens, the so-called ‘cytokine storm’. Unregulated complement activation [16, 17, 18, 19, 20] ensues and the balance and cross-talk between haemostasis and the immune systems is disturbed. The result is further EC damage with fibrin deposition and thrombi feeding into the pathogenesis of both SOS and TA-TMA.
SOS usually manifests within 21 days but may present late, with thrombocytopenia and signs of portal hypertension due to fibrous obliteration of the sinusoids and central venules. Endothelial injury underlies both disorders but for some [21] this is insufficient to consider SOS as a vascular endothelial syndrome. However, others [22] disagree since TA-TMA, with its mixed endothelial/immune origin is included [21]. Furthermore, immunological involvement in the pathogenesis of SOS is also very likely since injured ECs release cytokines and mitogens and these are capable of complement cascade activation and disruption [23]. These can also activate the coagulation cascade via the intrinsic pathway further increasing thrombin production. Observations that the frequency of SOS increases with the use of mis-matched and unrelated donor cells and is redusced in T-cell depleted HSCT also point to an immunological connection. The overall frequency of SOS development after bone-marrow transplantation (BMT) is about 14% (range 5%–50%), depending upon the chemotherapeutic drug and/or conditioning regimen used for cancer treatment and transplantation, and the clinical diagnostic criteria used [24, 25]. Children appear to be more prone to SOS but the wide range is greatly influenced by diagnostic imprecision, clinical status of the patient at BMT, and the conditions of the transplant, particularly the type of conditioning used. SOS is associated with a 40% mortality but in the presence of organ disfunction this may rise to 80%.
TA-TMA usually presents at any time within the first 3 months of transplantation but may appear up to several years after the HSCT. The overall frequency of TA-TMA is about 5% but up to 76% [26] has been reported (see Table 1). Mortality may reach 80% and is related to the number of risk factors present, e.g. the type of cytotoxic agent, particularly methotrexate, cyclophosphamide, etc., used in the conditioning regimens for transplantation, presence of active infection, use of matched unrelated donors, transplant mismatches, presence of GvHD and previous BMT. Survivors may suffer long term morbidity due to chronic organ damage.
Perhaps TA-TMA represents a vascular form of GvHD since it may precede the appearance of GvHD and its frequency increases with the severity of GvHD [21] and they share similarities in pathophysiology [27, 28, 29]. These considerations may explain the overlaps and differences between SOS and TA-TMA in their risk factors (see Table 1) and their distribution, clinical presentation and sequelae (see Table 2). In addition, it may account for their presence together in some patients and the continuing controversy over their diagnostic criteria that confounds early recognition and treatment of both disorders.
Reported disease characteristics1 | SOS | TA-TMA |
---|---|---|
Frequency | 2%–60% | 5%–20% |
Post HSCT onset: | ||
Adults acute | <21 days | No limit (1–3 months) |
Adults chronic | ≥21 days | |
Paediatric | No limit | |
Frequency: | ||
Adults | ≥40% | About 8% |
Paediatrics | ≥17% | |
Organ dysfunction: | ||
Liver | + | + |
Kidney | + | + |
Lung | + | + |
GI tract | − | + |
CNS problems | + | Late |
Cardiac | − | + |
Polyserositis | − | + |
MOD | early | + |
Fluid retention | + | + |
Hypertension | — | + |
Laboratory: | ||
Thrombocytopenia | + | + |
Haemolytic anaemia | − | + |
Schistocytes | − | + |
Lactate dehydrogenase | − | + |
Indirect and direct Coomb’s tests | — | + |
Complement activation | (+) | + |
Pro-inflammatory markers | TNFα, ICAM-1 | TNFα, VCAM-1 |
Haemostasis impairment | vWF, TM, PAI-1 | vWF, TM |
Mortality | 5% (1–>60%)1 | 40–>80% |
Some characteristics of SOS and TA-TMA after HSCT compared.
Depending upon the rapidity with which the clinical status worsens and time of assessment.
It is possible that SOS and TA-TMA are different clinical presentations of the same problem. Their pathogenesis is similar and the resulting sinusoidal and EC injury triggers release of many factors resulting in disruption of both haemostasis and immune systems. In this respect both SOS and TA-TMA are similar to the general group of microangiopathies [22, 30].
It is clear that both antithrombotic and immune modulating drugs are indicated to prevent or treat both conditions. However, prevention is always better than cure if the right product is available. The ability of a single product to attenuate the effects of both systems without causing further damage would be a desirable bonus especially if this can be done safely and relatively cheaply.
Danaparoid sodium is a mixture of linear glycosaminoglycuronans (GAGs) with a MWave of 4500 Da (range 2500–10,000 Da). It is extracted from porcine mucosa after heparin removal and ultrafiltration. The final product consists of heparan sulphate (HS) 85% with about 12% dermatan sulphate (DS) and traces of chondroitin sulphates 4 and 6 (CS). The HS appears to be more concentrated in the lower MWave chains and the DS and CS in the longer chains. The main structural difference between danaparoid and the heparins is the presence of glucuronic acid in place of iduronic acid. Enzyme degradation of danaparoid GAG chains produces disaccharides (see Figure 1) with a low degree of sulphation and acidification. Hence the GAG chains in danaparoid a low overall negative charge density compared with the heparins [unfractionated (UFH) and the fractionated low molecular weight heparins (LMWHs)]. However, about 5% by weight of the HS fraction of danaparoid [the so-called high affinity HS (HA-HS)] consists of more highly sulphated chains because like those of UFH they contain an antithrombin (AT) binding pentasaccharide sequence that includes a triple sulphated glucosamine residue. Only this specific AT binding site possesses a higher overall negative surface charge density than the rest of danaparoid chains that do not bind AT.
Comparison of heparin and danaparoid disaccharide structures.
Danaparoid is an antithrombotic that inhibits thrombin generation by both AT mediated inhibition of factor Xa by the HA-HS subfraction and direct inhibition of thrombin activation of factor IX by the major non AT binding HS. In addition, a minor inhibition of thrombin activity is produced by the HA-HS, mediated via AT, and by the DS fraction mediated via heparin-cofactor II.
Danaparoid is not a heparin but a heparinoid and further, unlike the heparins, it is not an anticoagulant because the recommended therapeutic dose regimen hardly affects the routine clotting tests (aPTT, PT, ACT and TT). A lack of spontaneous platelet activation and the weak inhibition of thrombin-induced platelet activation is associated with virtually normal primary haemostasis and hence low bleeding risk.
Three biological effects of danaparoid can be assayed—its anti-Xa activity, anti-thrombin activity and TGI. These have plasma half-lives of 24.7, 2.0 and 6.7 h respectively. However, the anti-thrombin activity is too weak for monitoring and at the time of its clinical development (1980s) there was no simple TGI assay. Hence the pharmacokinetics of danaparoid was based on the effect of the smallest subfraction of danaparoid (HA-HS) that represents only 5% by weight of the total product and is responsible for only half of its anti-thrombotic activity.
Plasma anti-Xa activity measurements have shown that at least the HA-HS subfraction is cleared via the kidneys and that the liver plays no role in its elimination from the blood. In the absence of overall labelling studies it is assumed that the remaining fractions of danaparoid undergo a similar fate. Although useful for estimating plasma levels of danaparoid the anti-Xa activity shows poor correlation with bleeding or thrombotic events reflecting the fact that this assay, unlike thrombin generation inhibition (TGI), does not measure all actions contributing to danaparoid’s effect on haemostasis.
Only 5% of the HS chains in danaparoid contain the trisulphated disaccharide required for AT binding. The remaining chains are low in both sulphate and acidic groups hence the overall negative charge density of danaparoid is low compared with the heparins (see Figure 1). Thus danaparoid is unable to bind to the many positively charged ‘heparin-binding’ proteins in the circulation and without this ‘neutralising effect’ danaparoid is 100% bioavailable for antithrombotic activity compared with 30% for UFH and about 80% for the LMWHs. This is also the reason why the anti-Xa activity units (U) of danaparoid are not equivalent to the IU of the heparins.
Clinical development of danaparoid led to widespread approval for deep venous thrombosis (DVT) prophylaxis hip following hip orthopaedic and general cancer surgery and in Japan for the treatment of disseminated intravascular thrombosis (DIC). The absence of heparin making it unlikely to cross-react with the specific antiplatelet antibody led to its approval for the treatment of heparin-induced thrombocytopenia (HIT), including the prevention or treatment of thrombosis in patients with renal failure requiring use of an extracorporeal circuits, in children and in pregnancy, if these patients also have HIT or other forms of heparin intolerance. Table 3 compares some PK and PD aspects of danaparoid with those of the heparins.
Apart from its antithrombotic activity, animal and isolated tissue experiments revealed that like heparin danaparoid has both immune-modulatory and anti-inflammatory activities [32], with both similarities and differences from the heparins (see Table 4).
The first indication of this came when danaparoid prevented heparin from activating platelets in the presence of plasma from patients with HIT [33]. In addition, it was found that while the isolated HA-HS subfraction (4% by weight of danaparoid) showed 100% cross reactivity with the specific HIT antibody this was totally prevented by addition of the remaining 96% of danaparoid with no affinity for AT [34]. Finally it was shown that danaparoid is unique among currently available antithrombotics in interfering with the interactions of the specific HIT antibody with heparin and its platelet and monocyte targets [35]. In addition, it was shown that danaparoid is unable complex with platelet factor 4 (PF4, a platelet derived cytokine to which heparin binds to induce HIT) to form the ultra-high molecular weight complexes with neo-antigenic sites [36] required to induce the specific antiplatelet antibody underlying the pathogenesis of HIT. Other experiments [37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49] (summarised in Table 4, where it is compared with the effects of the heparins) have shown that danaparoid inhibits or attenuates anti-inflammatory effects induced by various triggers, including endotoxin, ischaemia, reduction of ischaemia/reperfusion-induced hepatic injury in animals and a pilot endotoxin study in volunteers. Many of these actions occurred at the equivalent of its usual therapeutic dosing intensities. They appear to be independent of danaparoid’s antithrombotic activity, since they occur in the absence of AT or other clotting cascade constituents. From independent studies of synthetic GAGs or chemically modified heparin the resultant chemical structure of its oligosaccharide chains is of great importance. The low degree of sulphation with fewer acid groups and the absence of the 2-O sulphate group on the glucosamine (see Figure 1) appear to be responsible for many of the immune-modulatory/anti-inflammatory activities summarised in Table 4 [31, 32, 50, 51, 52, 53].
Thus fine structural differences between the many HSs within the body are responsible for myriad interactions that are site-specific with roles in haemostasis, inflammation, leukocyte transmigration, immune homeostasis, lipid metabolism, cell attachment, angiogenesis, migration, invasion and cell differentiation.
Based on the combination of antithrombotic activity and immune/modulatory actions danaparoid has been successfully used to treat patients with sepsis, DIC and HIT. In addition its low bleeding inducing capacity has led to off label use to prevent post-HSCT SOS and TA-TMA and to treat patients with PVT.
Danaparoid exposure in relation to PVT is available for 559 patients. Five retrospective comparative studies treated 177 patients with danaparoid only v UFH [54], v danaparoid + AT [55, 56] or v danaparoid + AT and AT only [57] and danaparoid + AT v AT only [58]. In addition, 383 patients received danaparoid in reports of retrospective case series and single case reports [57, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91] in which danaparoid was used alone or combined with AT and finally 2 single case reports of danaparoid administered with UFH [92] or urokinase [93]. Danaparoid was given to treat the PVT in 41 of the 43 reports. In the remaining 2 it was given for PVT prophylaxis. Table 5 shows some patient characteristics that could be identified with the treatment given.
UFH | LMWH | Danaparoid | |
---|---|---|---|
Coagulation cascade inhibition1: | |||
Co-factor dependent | IXa, Xa, XIa, IIa | Xa, IIa | Xa, [IIa] |
Co-factor independent | IXa | IXa | IXa |
Potency in buffer: | |||
Anti-Xa | 193 IU/mg | 80–120 IU/mg | 18 U/mg |
Anti-IIa | 193 IU/mg | 35–45 IU/mg | <1.0 U/mg |
Bioavailability (IV) | 20%–30% | 85%–95% | ~100% |
Elimination half-life IV (hours) | 1.5 (a-Xa) | 4.0 (a-Xa) | 6.7 (TGI) |
Elimination route | RE system | Renal 10%–40% | Renal >50% |
Administration route | IV, SC | IV, SC | IV, SC |
Clotting test prolongation2 | aPTT,PT,TT,HepT | aPTT,PT,TT,HepT | HepT only |
Thrombin inhibition | Yes | Yes | Very weak |
TGI | Yes | Yes | Yes |
Platelet activation | Yes | Yes | No |
Increase fibrinolysis | Yes | Yes | No |
Increases clot permeability3 | Yes | No | Yes |
Plasma protein binding | Very high | Moderately high | [no]4 |
Bleeding inducing capacity | At high doses | Low | Low |
AT concentration sensitive | Yes | Yes | [no]5 |
Effect on APC production | Reduces | [reduces] | Maintains |
Inhibition of clot bound IIa | At very high doses | No | No |
The heparins and danaparoid, modes of action, pharmacokinetics and pharmacodynamics compared.
Roman numerals refer to clotting factors.
aPTT, PT and TT measure residual thrombin activity, the HepT (Heptest) measures anti-Xa and anti-IIa activities.
Increases plasmin access.
Only to its specific targets: AT and HCoII.
One study of PVT treatment [31] found less efficacy of dan if AT <50%.
[ ] square brackets indicates action greatly reduced or virtually absent, APC = activated protein C.
Inhibition or reduces: | Heparin | LMWHs | Danaparoid |
---|---|---|---|
Endotoxin lung injury1: | |||
Local | Yes | Yes | Yes |
Coagulopathy Inflammation | No | nd | No |
Fibrinolysis systemic | No | nd | No |
Coagulopathy | Yes | Yes | Yes |
Reperfusion injury | Yes | Yes | Yes |
Anti-inflammatory | Yes | Yes | Yes |
Endothelial glycocalyx damage | (yes) | (yes) | Yes |
Growth factor production | Yes | Yes | Yes |
Interferon | Yes | Yes | Yes |
Burn/smoke inhalation injury | Yes | Yes | Yes |
Endothelial injury | Yes | Yes | Yes |
Intimal hyperplasia | Yes | (yes) | (yes) |
Cell proliferation | Yes | Yes | Yes |
Angiogenesis | Yes | Yes | Yes |
Annexin binding2 | Yes | Yes | Yes |
Tissue and/or organ damage | Yes | (yes) | nd |
Leucocyte activation and adhesion | Yes | Yes | Yes |
NET formation | Yes | Yes | nd |
Effects of HMGB-1 | Yes | Yes | Yes |
Immunogenic binding with PF4 | Yes | Yes | No |
Virus transduction | Yes | (yes) | weak4 |
Spontaneous ‘HIT’ induction | No | No | Yes |
HIT antibody interactions | No | No | Yes |
GAG immune-modulatory effects at therapeutic dose levels.
However highly dependent on the specific annexin and degree of sulphation of the GAG involved.
Single report using recombinant adeno-associated virus- type 24.
HIT = heparin-induced thrombocytopenia, HMGB-1 is a chromatin protein and cytokine mediator of inflammation, NET = neutrophil extracellular trap, PF4 = platelet factor 4.
nd—no data, brackets indicate action is weaker or only occurs under certain circumstances.
Parameter1 | Danaparoid use in comparative studies | Danaparoid use in case reports2 | |||
---|---|---|---|---|---|
Alone | With AT | Controls | Alone | With AT | |
N2 | 75 | 64 | 118 | 390 | |
Age (range in years) | 23–85 | ||||
M/F distribution (%) | 35.1/64.9 | ||||
Cirrhosis | 67/67 | 7/7 | 329/355 | ||
Varices | 105/107 | 197/283 | |||
Hepatocellular cancer | 65/107 | 113/274 |
General characteristics of PVT of danaparoid treated patients and non-danaparoid controls.
Not all studies had complete information hence the different denominator.
Danaparoid was compared in most studies with danaparoid + AT. In Ref. [31] the number receiving dan alone or + AT is only specified in an interim analysis for 28 of the final 55 patients. Three additional case reports of dan + UK, dan + UFH and dan + warfarin are not included in table but are discussed in text.
AT = Antithrombin.
Hepatic PVT was present in 524 of the 558 patients exposed to danaparoid (including those receiving AT and the 3 receiving concomitant antithrombotics—UFH, warfarin or a thrombolytic). In 33 patients thrombus was also present in the splenic vein and in 33 in the superior mesenteric vein, but only 11 single case reports stated the exact distributions when 2 or more sites were implicated, i.e. PV + SMV 6 cases, PV + SV 1 case, PV + SV and SMV 3 cases and PV + B-Ch 1 case and one publication mentioned that in 16 of 41 patients the PVT was present in more than 1 site.
The frequencies of some relevant presenting parameters were inconsistently provided in the study reports, e.g. hepatic failure was hardly mentioned but one study [60] reported a mean MELD score of 8.6, encephalopathy was only mentioned in four reports, the Child-Pugh status was provided for 10 comparative studies and 6 case reports as either scores (range 5–12) or classes A, B and C—118, 166 and 49 respectively, bleeding (in all cases gastrointestinal, 3 due to varices) was only mentioned in 6 single case reports and severe infection in only 3 reports, mean plasma AT levels available in only 8 publications were low normal or <60% of normal levels in 7 and platelet counts provided in only 5 single case reports and 4 comparative studies or case series were a median 80 G/L (range 17–655). It is not known if these parameters were therefore normal, absent or not considered, hence their absence from the pooled overview shown in Table 5.
Patients were followed-up after danaparoid discontinuation for at least 3 months and in some studies events up to 2 or 3 years were recorded. During this follow-up period at least 210 patients had been transitioned to a warfarin to continue anticoagulation. One study [66] found that long-term edoxaban succeeded but warfarin failed to sustain successful initial danaparoid treatment of PVT.
All studies, apart from three single cases [72, 81, 94], were performed in Japan. In two cases, HIT [72, 81] was also present and in three cases the PVT was accompanied by hepatic vein thrombosis (HVT, Budd-Chiari syndrome) [72, 81, 87]. Because treatment and prevention of PVT is an off label indication for danaparoid the dosing regimen used in Japan was that approved for DIC treatment, i.e. 1250–2500 U/day as 1 or 2 i.v. bolus injections (or short infusions) respectively. For most patients the higher dose 1250 U b.d., i.v. was chosen. In the three non-Japanese single case reports [72, 81, 91] the danaparoid regimen was ‘therapeutic’ (i.e. >2250 U/day) to treat HIT resulting from initial use of a heparin for the PVT and/or the HVT. In one of these patients it was used safely up to and after orthotopic liver transplant and to anticoagulate the cell saver during surgery [81]. For the other HIT patient no precise dosing information is available and for the third non-Japanese patient [93], the dose was also not mentioned but it was administered with warfarin until the patient could be discharged on warfarin only. Danaparoid exposure lasted a median 14 days (range 4 days to 2 months). In addition, sporadic reports state its successful re-use when PVT recurred during long-term warfarin use [55, 59, 67, 70].
Fifteen reports showed that AT was used concomitantly with danaparoid in 180 patients and in 2 studies AT was used alone as a comparator in 93 patients. In some studies comparing danaparoid alone with danaparoid + AT the AT was only used in patients presenting with plasma levels below 60%. The AT regimen was usually 1500 U daily for 3 days, but in one comparative study [56] and one case report [88] it was administered for 5 days. Administration of AT was often dependent upon the patient’s AT status but in two studies danaparoid alone was compared with danaparoid + AT.
The efficacy of danaparoid treatment assessed as complete, ≥70%, 50%–70%, <50% recanalisation/no change or as a new/progressive thrombosis, are summarised in Table 6.
Treatment | Outcome of PVT treatment | |||||
---|---|---|---|---|---|---|
Degree of PVT resolution | New/progression of thrombus | |||||
Complete | ≥70% | 50%–70% | <50%/nc | |||
Danaparoid only all studies | 270 | 94 | 124 | 34 | 12 | 6 |
34.8% | 45.9% | 12.6% | 4.4% | 2.2% | ||
Danaparoid + AT all studies | 87 | 24 | 34 | 9 | 20 | 0 |
27.6% | 39.1% | 10.3% | 23.0% | |||
All danaparoid | 370 | 173 | 97 | 61 | 38 | 1 0.3% |
46.8% | 26.2% | 16.5% | 10.3% | |||
AT only | 24 | 11/24 | nd | nd | nd | nd |
45.8% |
Pooled outcomes of PVT treatment.
nc = no change, AT = antithrombin, nd = no data.
Danaparoid treatment was associated with complete recanalisation in 46% of the patients and clinically significant thrombosis management in 72.6% (i.e. ≥70% PVT resolution) of the patients (although some investigators considered >50% reduction as clinically significant). An ineffective outcome was recorded in 10.7% of the patients including one with progression of thrombosis. Two studies assessed vessel volume reduction as a measure of recanalisation. One [61], involving 41 patients treated with danaparoid only, expressed the result as the mean reduction of 55.1% ± 40.2% at 2 weeks, the other [66], involving 55 patients also treated with danaparoid only, found a reduction from median 3.43 cm3 to 1.42 cm3, also at 2 weeks. Incidental presenting thromboses were: SSST and ovarian vein in one patient and two PEs, all resolved during danaparoid treatment, but only one of the three concomitant hepatic vein thromboses responded favourably to danaparoid. In all reports providing data on coagulation markers d-dimer, TAT and fibrinogen the plasma levels normalised by 2 weeks. All platelet counts (including the two patients with HIT) also increased to normal except for one patient, but no reason was given. In addition, plasma AT levels, whether above 60% before danaparoid treatment initiation or supplemented with injected AT, did not deteriorate during danaparoid use. The only study with a group of non-anticoagulated controls showed.
Three bleeding events (0.8%) developed, one each in three patients, during danaparoid treatment initiation: two from varices (one following endoscopic ligation), and one peritoneal haemorrhage. Danaparoid was restarted in one. No problem was recorded during the transition from danaparoid to warfarin.
No patient death was reported within 3 months of stopping danaparoid treatment. Other adverse events reported were the development of ascites in two patients (one with diarrhoea) and one case of thrombocytopenia that was not considered serious but no other details were provided. Despite one investigator [56] calculating that warfarin doubled the time of PVT recurrence from 1 to 2 years, eight others [55, 56, 57, 58, 59, 61, 66, 67] reported that follow-up treatment with warfarin failed to maintain PVT reductions achieved when danaparoid was discontinued.
Due to the lack of adequate non danaparoid and or AT controls an indirect comparison of pooled PVT treatment outcomes with various other drug treatment strategies has been made in Table 7. These data [95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107], however, lack consistency in describing PVT treatment outcomes. Hence it was necessary to express the results as complete and ≥50%. Despite this restriction it appears that clinically relevant PVT resolution, i.e. complete or ≥70% recanalisation, occurred in 73% of danaparoid treated patients compared with <42% for no treatment, <62% for sulodexide and <67% for the LMWH. It is not possible to calculate for warfarin but it is also in likely to be in the region of 70%. Thus the efficacy of danaparoid is at least as good as warfarin and the LMWH. However the frequencies of no change or progression of the PVT and bleeding was much lower with danaparoid.
Antithrombotic treatment | Outcome of PVT treatment1 | Bleeding events | |||||
---|---|---|---|---|---|---|---|
Extent of PVT resolution | New or TE extension | ||||||
Complete | ≥70% | 50%–70% | <50% or nc | ||||
LMWHs2 | 298 | 86 | 97 | 67 | 22 | 26 | |
31.6% | 35.7%3 | 24.6% | 8.1% | 9.6% | |||
Warfarin | 121 | 82 83.7% | 12 | 4 | 23 | ||
12.2% | 4.1% | 23.5% | |||||
Sulodexide | 32 | 5 | 8 | 8 | 0 | 11 | |
23.8% | 38.1% | 38.1% | 52.4% | ||||
None | 209 | 7 | 103 | 45 | 49 | 5 | |
2.6% | 38.6% | 20.3%4 | 22.1%4 | 1.9% | |||
Danaparoid | 357 | 118 | 158 | 43 | 32 | 6 | 3 |
33.1% | 44.3% | 12.0% | 9.0% | 1.7% | 0.8% |
Comparison of pooled published non-danaparoid PVT outcomes with pooled danaparoid outcomes.
in many reports PVT resolution expressed only as complete or ≥50%.
LMWH unspecified, enoxaparin and nadroparin.
only >50% resolution data for all studies.
in one study of 20 patients data for <50% resolution and recurrence were combined (12 = 60.0%) hence the study has been excluded from the calculation.
nc = no change, TE = thrombi, LMWHs = low molecular weight heparins.
Comparison with non-danaparoid controls other than AT is confounded by: the fact that only two small studies [54, 58] used such controls. One study tested danaparoid prophylaxis and found that no PVTs in the 11 danaparoid treated patients but 2 in the 32 patients receiving AT only. The two PVTs and seven from a prior ‘testing’ cohort in this study were successfully treated with danaparoid. In a study of cirrhosis related PVT [54] danaparoid successfully managed all eight PVTs in its treatment group but of the seven UFH + Urokinase controls only five (71.4%) responded favourably and the two non-responders died of liver failure within 3 months of treatment. While there is little evidence from non-danaparoid controls in the danaparoid studies there is evidence based on the use of the heparins and VKA that anticoagulation increases the chance of recanalisation of PVT. However if recurrences are to be prevented it is also necessary to follow-up with long term outpatient anticoagulation. This has largely been left to the VKAs but more recently the oral direct oral anticoagulants (DOACs) have also become available.
The diagnosis of SOS is usually based on the Baltimore or Seattle criteria, and not every publication
Danaparoid has been evaluated in at least 524 patients for the prevention of SOS and/or TA-TMA after HSCT. All eight reports [108, 109, 110, 111, 112, 113, 114, 115] come from Japan. Malignancies, particularly haematogenous cancers, formed about 80% of the reasons for HSCT. The non-malignant reasons were mainly aplastic anaemia, adrenoleukodystrophy and mucopolysaccharidoses. The subjects presented with a wide spectrum of underlying clinical disorders and had followed a course of chemotherapy (the conditioning regimen) or radiotherapy. In addition they had or were still receiving prophylaxis against GvHD and a cocktail of prophylactic medication to prevent BMT rejection and infection. Many of these drugs cause SOS or TA-TMA because of their hepato- and renal toxicity.
Japanese investigators have compared danaparoid use in both indications with standard prophylaxis using AT and/or ursodeoxycholic acid (UDCA) with or without antithrombotic co-medication. Defibrotide (DF) the standard therapy for SOS/TA-TMA treatment is also increasingly used for their prevention but there has not been a direct comparison with danaparoid.
The 197 patients in 2 comparative studies were adults [108] or mostly adults (median age 48 years, range 16–70 years) [109], as was one of the single cases reported [115]. The remaining studies and case reports of 326 patients were performed exclusively or mostly in children (age range < 1–18 years). In the only two studies with data males appeared to predominate (64.2%).
The dosing regimens for danaparoid (provided in all but one case series and a single case report), dalteparin and UDCA in adults and children in the remaining reports are shown in Table 8. For danaparoid the adult regimen 2500 U/day follows that approved for DIC treatment in Japan and is close to the lower limit of the recommended dosing range for thrombosis treatment. This has been adapted for use in children and the 60–70 U/Kg/day is similar to that used for paediatric (V)TE treatment [116]. However this is equivalent to 4200–4900 U/day for a 70 kg adult, twice the dosing intensity received by adults for SOS/TA-TMA prevention.
SOS/TA-TMA prophylaxis regimen | Dosing regimens of danaparoid and active controls used for SOS/TA-TMA prophylaxis1 | |||
---|---|---|---|---|
Adults | Children | |||
Dosing regimen | Dosing regimen | |||
Danaparoid used alone | 164 | 1250 U b.d., i.v. | 0 | — |
Danaparoid (+ UDCA) | 33 | 1250 U o.d.,i.v. | 223 | 30 U/kg b.d.,i.v. |
Dalteparin used alone | 59 | 3000 IU/day as i.v. infusion | 0 | — |
Dalteparin (+ UDCA) | 52 | 2500–3500 IU/day | 96 | 70 IU/Kg/day |
UDCA used alone | 195 | 600 mg/day | 0 | — |
UDCA + antithrombotic | 85 | 300–600 mg/day | 210 | 10 mg/kg/day |
Dosing regimens used for danaparoid and controls for SOS/TA-TMA prophylaxis.
for 1 adult and 103 children no dosing regimen is available.
b.d. twice daily, o.d. once daily, i.v. = intravenous, UDCA = ursodeoxycholic acid.
Many studies concentrated on SOS without mention of TMA, hence it is not known if TA-TMA was absent or not considered. The efficacy outcomes of these prophylactic studies with danaparoid were usually mainly expressed as outcome survival (OS) and treatment related mortality (TRM). All efficacy and bleeding outcomes are summarised in Table 9.
Antithrombotic and/or UDCA | SOS | TA-TMA | TRM | OS | GvHD | MB | |
---|---|---|---|---|---|---|---|
Danaparoid only | 255 | 23/255 | 11/255 | 14/255 | 191/255 | 51/164 | 4/164 |
9.0% | 4.3% | 5.5% | 74.9% | 31.1%3 | 2.4% | ||
Danaparoid + UDCA | 268 | 24/202 | nd | 2/114 | 188/235 | 5/77 | 6/211 |
11.9% | 1.8% | 80.0% | 6.5%4 | 2.8% | |||
Dalteparin only | 59 | 13/59 | nd | 12/59 | 29/59 | 24/59 | 6/59 |
22.0% | 20.3% | 49.2% | 40.7%3 | 10.2% | |||
Dalteparin + UDCA | 148 | 22/148 | nd | 17/86 | 56/96 | 13/86 | 4/47 |
14.9% | 19.8% | 58.3% | 15.1%4 | 8.5% | |||
UDCA only | 195 | 28/195 | nd | 16/195 | nd | nd | 10/195 |
14.4% | 8.2% | 5.1% |
Pooled treatment outcomes of SOS/TA-TMA prevention in danaparoid studies.
early and late refer only to TA-TMA <2 weeks or ≥ 4 weeks respectively, and to TRM ≤3 months or 2–5 years respectively, according to the publications with data on either or both.
nd = no data or in some cases insufficient clarity of data (mortality rate compared in terms of p values or cumulative frequency charts).
total is for only acute GvHD (grade II–IV) at 3 months.
total is for acute GvHD (grade II-IV) at 3 months plus chronic GvHD.
Dan = danaparoid, (LMW)H = low and unfractionated heparins, MB = major bleeding, nd = no or unclear data, OS = outcome survival, SOS = sinusoidal obstruction syndrome, TA-TMA transplant associated thrombotic microangiopathy, TRM = treatment related mortality, UDCA = urso-deoxycholic acid.
Not all parameters were addressed in each of the seven studies therefore % frequency calculations have been corrected by the available data. This indirect comparison suggests that danaparoid reduces SOS/TA-TMA frequency in patients undergoing HSCT at least as well as a LMWH and UDCA with a lower frequency of bleeding at the dosing regimen used. More importantly it appears that danaparoid ± UDCA reduced TRM. Unfortunately the study with a UDCA treatment only control [99] did not provide information on TRM or OS development and for an unexplained reason halved the dose of danaparoid to 1250 U o.d.
The frequency of major bleeding events was lowest in patients receiving danaparoid. The development of GvHD was only mentioned in two study reports with grossly disparate results (see Table 9) between anticoagulant alone or combined with UDCA. One dalteparin treated subject developed HIT [105] but there is no record of how this was treated. Two danaparoid treated patients developed DIC. Of the 16 patients undergoing allogenic SCT for Adrenoleukodystrophy [108] transient haemolytic anaemia (2), engraftment syndrome (9) and viral reactivation developed all of which improved with specific treatment or supportive care while danaparoid treatment continued.
Of the 5 specifically paediatric studies three [110, 111, 114] reported no post-BMT complications and two [112, 113] reported 27 patients (8.3%) with SOS, TA-TMA or DIC associated with sepsis or engraftment syndrome. All were successfully treated with recombinant thrombomodulin.
Currently while several drugs for SOS prophylaxis are available there is no clear treatment to prevent TA-TMA.
Despite some reports of successful prophylaxis with UFH and LMWHs a meta- analysis and systematic review of their use [117] found no significant reduction in risk of SOS. Safety also appeared to be an issue when used in patients with gastro-intestinal varices or thrombocytopenia or renal dysfunction, especially when they were combined with lipo-prostaglandin E1 or UDCA. Hence heparin is no longer recommended for SOS prophylaxis [20].
UDCA, currently the most widely used drug for SOS prevention, is a natural bile acid that is capable of reducing the toxicity of its companion bile acids in cholestatic liver diseases. In inflammatory disorders it can ‘attenuate the pro-inflammatory cytokine environment through decreased expression of TNF-α, interleukins 1 and 2, and interferon-γ, thereby minimising endothelial injury occurring in HSCT associated with the cytokine storm [117]. UDCA is safe and not only lowers the frequency of SOS but also of TRM and appears to have a small effect in reducing the development of GvHD [118]. It is occasionally used in combination with UFH and LMWHs but there is little evidence that they improve its efficacy. Outcomes of UDCA use shown in Table 10 are derived from several studies and reviews [117, 118, 119, 120, 122].
Antithrombotic and/or UDCA | SOS | TRM | OS | GvHD | MB | |
---|---|---|---|---|---|---|
Danaparoid only | ||||||
All | 255 | 9.0% | 5.5% | 74.9% | 31.1% | 2.4% |
Adults | 164 | 10.4% | 8.6% | 65.2% | 31.1% | 3.7% |
Children | 91 | 6.8% | 0.0% | 92.3% | nd | 0.0% |
Danaparoid + UDCA | ||||||
All | 268 | 11.9% | nd | 74.6% | 6.5% | 2.8% |
Adults | 33 | 15.2% | nd | 65.2% | nd | 3.0% |
Children | 235 | 4.1% | 1.8% | 80.0% | 9.1% | 1.5% |
UDCA only | 1441 | 14.4% | 8.2% | nd | nd | 5.1% |
DF ‘only’5 | 1371 | 4.9% | 19.0% | 72.3% | 22.2% | 22% |
DF + UDCA6 | 56 | 1.9% | 1.9% | nd | nd | nd |
Pooled results of SOS prophylaxis studies.
From Table 9
From Table 9 and additional data from non-danaparoid studies.
Assessed at either D + 100 and/or 2–5 years after HSCT, OS was 100% for danaparoid + UDCA.
Assessed at D + 100 after HSCT.
From Ref. [121]
Dan = danaparoid, DF = defibrotide, GvHD = graft v host disease, (LMW)H = low and unfractionated heparins, MB = major bleeding, nd = no or unclear data, OS = outcome survival, SOS = sinusoidal obstruction syndrome, TA-TMA transplant associated thrombotic microangiopathy, TRM = treatment related mortality, UDCA = urso-deoxycholic acid.
This oligodesoxyribonucleotide extracted from porcine intestinal mucosa has numerous antithrombotic, EC protective, fibrinolytic, anti-ischaemic and angiogenic activities. Its clear benefits for the treatment of SOS have led to approval by the FDA for this indication. More recently DF has been investigated for SOS prevention with mixed results [121, 123, 124, 125, 126, 127]. The inter-study variance may be due to the different dosing regimens used (including occasional co-medication with UDCA) and different intervals between diagnosis and DF treatment initiation. Greater success has been reported using initiating DF earlier [128] after SOS diagnosis or combining it with UDCA [129].
The outcomes of non-danaparoid studies with UDCA and DF for the prevention of SOS (and where mentioned TA-TMA) are summarised and compared with danaparoid in Table 10. The data for danaparoid only and in combination with UDCA have been separated because of the apparent greater. Impact of comedication with UDCA on the frequencies of TRM and GvHD. For many studies it is unclear to what extent TA-TMA might have been present and therefore contributed to caused morbidity or death since it was mentioned. In addition not all parameters were assessed in all studies hence percentages are based only on the available data. The frequency of haemorrhages with DF in several studies [130, 131] has been as high as 22%, but in one study [130] was the same as the unspecified controls. So there remains some confusion regarding its safety.
Interestingly the danaparoid efficacy appears to be better in children than in adults, perhaps related to the use of a higher dosing intensity/kg body weight.
Danaparoid dosed at 1250 U b.d., i.v. in adults and 30 U/kg body weight b.d., i.v. in children, appears to be effective and safe for the treatment of PVT or prevention of SOS and TA-TMA. Despite the relatively high danaparoid dosing intensity used in children there were no reports of bleeding complications in any of the studies and case reports supporting its safety in these vulnerable subjects.
Nevertheless, the intermittent dosing regimen based on DIC treatment used for both adults and children is unlikely to be optimal since it takes 2–3 days to reach steady state drug levels, produces post-injection peak levels of drug that could cause bleeding in high risk patients and pre-injection troughs with insufficient thrombosis protection. The antithrombotic action of danaparoid is shared between the 5% by weight HA-HS and the 80% by weight NA-HS subfractions of danaparoid with greatly different half-lives—25 and 7 h respectively. Hence by the time the next 12 hourly danaparoid injection is due there is much less of the NA-HS left in the circulation even at steady-state pharmacokinetics. This subfraction is largely responsible for the anti-inflammatory and immunosuppressive actions of danaparoid [34]. Hence for TE treatment PK modelling was used to determine a dosing regimen that provided circulating therapeutic danaparoid levels as quickly as possible and maintained the natural ratios of the HS-HS and NA-HS constituents continuously. The ideal regimen was found to be an i.v. loading dose of 2250 U (body weight adjusted—1250 U if <55 kg and 3000 U if >90 kg), followed by a continuous i.v. infusion of 400 U/h × 4 hours, followed by 300 U/h × 4 hours, followed by the maintenance infusion rate of 150–200 U/h for as long as considered necessary. This regimen immediately attains and maintains the target plasma anti-Xa activity range of 0.4 and 0.8 U/mL and outside Japan is approved for patients with thrombosis. This can be important for increasing the efficacy of danaparoid not only for PVT treatment but also for SOS/TA-TMA prevention since the inflammatory disturbances should respond better to the continuous presence of the NA-HS subfraction of danaparoid. If a bleeding risk is present then the daily danaparoid dosing intensity, can be lowered by reducing the loading dose size by 25%–50% and the maintenance infusion rate to 100–125 U/h.
Due to differences in detail between guidelines for the management of PVT, some confusion remains surrounding attempts to evaluate and compare its alternative treatment strategies. Many clinical factors such as the distribution of Child-Pugh status, the cause of cirrhosis, the frequency of cirrhosis, varices or hepatocellular carcinoma, the distribution of PVST and grade of vessel obstruction at the time of antithrombotic initiation, the age of the thrombus, the presence of infection, the inclusion of different antithrombotics and their combination with either AT or UDCA. Furthermore there is a need to standardise what is considered a ‘good clinical treatment outcome’ for PVT. Is it complete recanalisation only [94], or ≥70% partial recanalisation [58] or is ≥50% [95] sufficient. What assessment criteria for an effect on PVT is best
The pooled results of danaparoid treatment suggest that it possesses at least the same efficacy as AT and its performance does not seem to be enhanced by the addition of AT. Danaparoid appears to be safe even in patients with moderate to severe hepatic dysfunction and extensive varices. A Japan-wide survey performed in 2018 [132], revealed that 46% of the 539 patients included in the responses were treated with danaparoid alone or + AT. A comparison of the outcomes of the six most common treatment regimens i.e. heparin, warfarin, danaparoid, heparin + warfarin, danaparoid + antithrombin and no anticoagulant, showed that warfarin produced the highest complete PVT disappearance rate (about 50% compared with danaparoid at 30%). However, the rate of PVT disappearance plus reduction (not defined) was highest for danaparoid about 80% compared with just over 70% for warfarin. The rates of no change and PVT extension were both lowest for danaparoid at about 18% and 2% respectively. Furthermore, PVT disappearance rates with danaparoid + AT while better than those of heparin were inferior to those achieved with danaparoid alone.
Apart from one study [108] there appears to be agreement on the prophylactic dosing regimens of danaparoid used for adults or children to prevent SOS/TMA. Children above 2 years appear to require almost double the dosing intensity used in adults to achieve the same plasma anti-Xa levels [116], but it does not appear to have compromised safety in terms of bleeding and side-effects.
The study [109] that did not use UDCA co-medication recorded a higher rate of acute GvHD (grades II–IV) for both danaparoid alone and dalteparin alone compared with the much lower rates recorded for both drugs when combined with UCDA in the other major comparative study [110]. Whether this reveals a true effect of UDCA or a centre/patient cohort treatment bias requires further investigation. Acute GvHD is a risk factor for TA-TMA, thus it is unfortunate that the investigators [109] comparing a low intensity danaparoid + UDCA with dalteparin + UDCA and UDCA alone, although detailing measures taken to prevent GvHD, did not refer to it again.
Two comparative studies concluded that danaparoid: ‘reduces the incidence of transplant associated microangiopathies’ in adults [105] or ‘lowers TRM after stem-cell transplantation in children’ [110] since in both studies danaparoid was superior to dalteparin with or without UDCA. Whether or not these results are due to the antithrombotic action of danaparoid alone or a combination with its anti-inflammatory effects has not been investigated. The latter is likely in view of the positive results of danaparoid use in HIT [133], sepsis [134], APS [135, 136] and paroxysmal nocturnal haemoglobinuria [137].
Although one patient exposed to danaparoid developed thrombocytopenia it was not reported to be due to HIT. However, of 214 control patients receiving UFH or a LMWH in the danaparoid studies a case of HIT was recorded [109].
Long term antithrombotic treatment appears to be crucial for preventing PVT recurrences and the VKAs have until recently been the method of choice. However, despite one investigator [56] calculating that warfarin doubled the time of PVT recurrence from 1 to 2 years, eight others [55, 56, 57, 58, 59, 61, 62, 67] reported that follow-up treatment with warfarin after initial danaparoid failed to maintain PVT reductions achieved when danaparoid was discontinued. A comparison of warfarin v edoxaban following danaparoid PVT reduction showed that only edoxaban maintained or reduced the already achieved vessel volume reduction.
Whether any pharmaceutical prophylaxis for SOS/TATMA is effective remains controversial, but it appears possible with current therapy options and UDCA is now recommended by the EBMT Handbook and the British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines. It is unclear if UDCA improves the efficacy of danaparoid but it appears to improve the safety of DF in patients with a high risk of developing SOS. It is also unclear who should receive prophylaxis and which treatment is most likely to offer the best risk–benefit ratio so it is interesting that danaparoid is especially effective in reducing both SOS and TRM in children and increases their OS.
DF appears to be efficacious in preventing SOS but at the expense of a high bleeding rate (perhaps related to its pro-fibrinolytic activity). A large prospective Phase III controlled trial of DF v best management without DF was discontinued in 2018. The manufacturers report of the interim analysis of that study concluded ‘it would be highly unlikely to reach statistical significance for the primary end-point of SOS survival at Day +30 post HSCT in the final analysis if the study were to complete enrolment’ [138]. So that there remains confusion around the evidence for DFG suitability for SOS prophylaxis. Danaparoid however, appears to be safe even when compared with UDCA.
It is difficult to generalise about the cost effectiveness of different pharmacological strategies for SOS prevention due to the unclear duration of drug administration and inter-country differences in basic drug and hospitalisation costs. In Europe the current price of 10 × 750 U ampoules of danaparoid sodium varies between € 975 and € 1250 (price discounting not considered), having been much less when originally approved for DVT prophylaxis. Thus per patient treatment of PVT at 3 A/day for 2 weeks could cost about € 5250. For SOS/TA-TMA prophylaxis danaparoid administration at 3–4 A/day for the median 2 months treatment duration would cost between € 17,500 and € 30,000. This assumes long term follow-up treatment with a VKA or DOAC to prevent recurrence of the PVT. For DF dosed at 25 mg/kg/day divided into 4 doses the drug cost is about the same as danaparoid. DF is known to reduce hospital stay but this effect is somewhat offset by the fact that unlike danaparoid many patients do not complete their treatment due to adverse events, particularly bleeding and these events incur the costs of additional investigations and treatment. One single centre study [139] found an SOS incidence of 7.4% and a TRM of 19%. Their cost effectiveness analysis led to the conclusion that ‘prophylactic DF for children at risk of SOS was not cost-effective with respect to TRM and length of hospital stay’. By contrast the UDCA cost per patient (in 2013) was about € 400 for 2 months treatment [140]. UDCA can be a lifelong treatment but and its cost price may have risen since then. Which is the most cost-effective for the management of SOS/TA-TMA hinges on the desired outcome—mere prevention or reducing TRM and increasing OS.
Problems associated with study design, diagnostic criteria, end-point choice and evaluation, and use of single or several pharmacological agent, make it difficult to evaluate and compare the outcomes of different drug trials in hepatic thrombotic disorders.
Despite the absence of studies against placebo/no treatment to establish absolute efficacy, comparative studies versus a LMWH suggest that danaparoid is effective and safe for the treatment of PVT and not only prevents SOS and TA-TMA but reduces TRM and increases OS after HSCT. It is unclear if the efficacy of danaparoid is improved with the addition of AT or UDCA.
Danaparoid has a high cost of treatment but a cost-efficacy analysis has not been performed. Its safety, particularly the low haemorrhagic risk, may offset some of these costs.
Given the potentially fatal outcomes of hepatic thrombotic disorders, the ease of administration of danaparoid, its apparent efficacy and safety in patients with a high bleeding risk, danaparoid merits further investigation in the management of hepatic thrombotic disorders. However the dose of danaparoid needs to be optimised.
There remains a great need for sufficiently powered, double-blind, randomised controlled trials, with well defined end-points relevant for clinical practise, to evaluate the short and long-term effects of currently available antithrombotics used in the management of hepatic thrombotic disorders.
The author declares no conflict of interest.
Authors are listed below with their open access chapters linked via author name:
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\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nJocelyn Chanussot (chapter to be published soon...)
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\\n\\nAbdul Latif Ahmad 2016-18
\\n\\nKhalil Amine 2017, 2018
\\n\\nEwan Birney 2015-18
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\\n\\nGang Chen 2016-18
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\\n\\nZhigang Chen 2016, 2018
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\\n\\nFrancisco Herrera 2017, 2018
\\n\\nJaakko Kangasjärvi 2015-18
\\n\\nHamid Reza Karimi 2016-18
\\n\\nJunji Kido 2014-18
\\n\\nJose Luiszamorano 2015-18
\\n\\nYiqi Luo 2016-18
\\n\\nJoachim Maier 2014-18
\\n\\nAndrea Natale 2017, 2018
\\n\\nAlberto Mantovani 2014-18
\\n\\nMarjan Mernik 2017, 2018
\\n\\nSandra Orchard 2014, 2016-18
\\n\\nMohamed Oukka 2016-18
\\n\\nBiswajeet Pradhan 2016-18
\\n\\nDirk Raes 2017, 2018
\\n\\nUlrike Ravens-Sieberer 2016-18
\\n\\nYexiang Tong 2017, 2018
\\n\\nJim Van Os 2015-18
\\n\\nLong Wang 2017, 2018
\\n\\nFei Wei 2016-18
\\n\\nIoannis Xenarios 2017, 2018
\\n\\nQi Xie 2016-18
\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
\\n"}]'},components:[{type:"htmlEditorComponent",content:'New for 2018 (alphabetically by surname).
\n\n\n\n\n\n\n\n\n\nJocelyn Chanussot (chapter to be published soon...)
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nYuekun Lai
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nPrevious years (alphabetically by surname)
\n\nAbdul Latif Ahmad 2016-18
\n\nKhalil Amine 2017, 2018
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This is associated with increase in water demand over limited resources and poor quality water that adversely affects crop quality and yield and deteriorates soil properties. Even though soil salinity has been affectingagriculture for thousands of years, significant research has been conducted only in the past 100 years. Desalination, which is the process of reducing the salt content in water to an acceptable level, could be an alternative for improving water quality, thereby increasing water sources and reducing the competition among various users of water. Thus, desalination could lead to improved crop quality, improved crop yield, enhanced all‐year round crop production, and as such become an important tool for effective agricultural water management.",book:{id:"5768",slug:"desalination",title:"Desalination",fullTitle:"Desalination"},signatures:"OrevaOghene Aliku",authors:[{id:"176082",title:"Mr.",name:"OrevaOghene",middleName:null,surname:"Aliku",slug:"orevaoghene-aliku",fullName:"OrevaOghene Aliku"}]},{id:"39734",title:"Transition Metal Sulfide Catalysts for Petroleum Upgrading – Hydrodesulfurization Reactions",slug:"transition-metal-sulfide-catalysts-for-petroleum-upgrading-hydrodesulfurization-reactions",totalDownloads:3767,totalCrossrefCites:3,totalDimensionsCites:8,abstract:null,book:{id:"2874",slug:"hydrogenation",title:"Hydrogenation",fullTitle:"Hydrogenation"},signatures:"A. Infantes-Molina, A. Romero-Pérez, D. Eliche-Quesada, J. Mérida-Robles, A. Jiménez-López and E. Rodríguez- Castellón",authors:[{id:"126325",title:"Dr.",name:"Enrique",middleName:null,surname:"Rodríguez-Castellón",slug:"enrique-rodriguez-castellon",fullName:"Enrique Rodríguez-Castellón"}]},{id:"55122",title:"Low-Cost Multi-Effect Solar Still: Alternative Appropriate Technology for Personal Desalination",slug:"low-cost-multi-effect-solar-still-alternative-appropriate-technology-for-personal-desalination",totalDownloads:1724,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Multi effect solar still (MES) has a stack of multiple layers for evaporation and condensation. The latent heat dissipated during condensation at the front layers are repeatedly recycled for evaporation at the back layers to increase overall desalination productivity. Despite of high efficiency and long history, MES has not been widely used yet, because of relative high cost. In this chapter, newly designed MES is introduced. Since it has low cost, light weight material and simple structure, it could be easily mass even at less developed country. The cost of production for a 1 m2 unit is expected to be less than 300 USD. Structural features are introduced with experimental result which was outdoor tested with homemade lab prototype with 0.219 m2 effective area. 9kg/m2 per day of fresh water was obtained at sunny day (19.5MJ/m2) in Seoul, Korea, which is close to WHO’s recommended minimal daily water supply for individuals (7.5~15 liters). For more practical implementation, further development on prototype and production process should be made as well as long term outdoor test under actual climate it would be used. Worldwide collaboration would be necessary for speeding up implementation.",book:{id:"5768",slug:"desalination",title:"Desalination",fullTitle:"Desalination"},signatures:"Pak Hunkyun",authors:[{id:"197095",title:"Dr.",name:"Hunkyun",middleName:null,surname:"Pak",slug:"hunkyun-pak",fullName:"Hunkyun Pak"}]},{id:"39725",title:"Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones",slug:"asymmetric-hydrogenation-and-transfer-hydrogenation-of-ketones",totalDownloads:8389,totalCrossrefCites:3,totalDimensionsCites:7,abstract:null,book:{id:"2874",slug:"hydrogenation",title:"Hydrogenation",fullTitle:"Hydrogenation"},signatures:"Bogdan Štefane and Franc Požgan",authors:[{id:"146116",title:"Associate Prof.",name:"Bogdan",middleName:null,surname:"Stefane",slug:"bogdan-stefane",fullName:"Bogdan Stefane"},{id:"147826",title:"Prof.",name:"Franc",middleName:null,surname:"Požgan",slug:"franc-pozgan",fullName:"Franc Požgan"}]}],onlineFirstChaptersFilter:{topicId:"496",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:27,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:49,paginationItems:[{id:"80495",title:"Iron in Cell Metabolism and Disease",doi:"10.5772/intechopen.101908",signatures:"Eeka Prabhakar",slug:"iron-in-cell-metabolism-and-disease",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Iron Metabolism - Iron a Double‐Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81799",title:"Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases",doi:"10.5772/intechopen.104978",signatures:"Richa Rai",slug:"cross-talk-of-purinergic-and-immune-signaling-implication-in-inflammatory-and-pathogenic-diseases",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81764",title:"Involvement of the Purinergic System in Cell Death in Models of Retinopathies",doi:"10.5772/intechopen.103935",signatures:"Douglas Penaforte Cruz, Marinna Garcia Repossi and Lucianne Fragel Madeira",slug:"involvement-of-the-purinergic-system-in-cell-death-in-models-of-retinopathies",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81756",title:"Alteration of Cytokines Level and Oxidative Stress Parameters in COVID-19",doi:"10.5772/intechopen.104950",signatures:"Marija Petrusevska, Emilija Atanasovska, Dragica Zendelovska, Aleksandar Eftimov and Katerina Spasovska",slug:"alteration-of-cytokines-level-and-oxidative-stress-parameters-in-covid-19",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}}]},overviewPagePublishedBooks:{paginationCount:27,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science and Technology from the Department of Chemistry, National University of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013. She relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the National Institute of Fundamental Studies from April 2013 to October 2016. She was a senior lecturer on a temporary basis at the Department of Food Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is currently Deputy Principal of the Australian College of Business and Technology – Kandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI) Ambassador to Sri Lanka.",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"26",type:"subseries",title:"Machine Learning and Data Mining",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11422,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"43680",title:"Prof.",name:"Ciza",middleName:null,surname:"Thomas",slug:"ciza-thomas",fullName:"Ciza Thomas",profilePictureURL:"https://mts.intechopen.com/storage/users/43680/images/system/43680.jpeg",institutionString:null,institution:{name:"Government of Kerala",institutionURL:null,country:{name:"India"}}},{id:"16614",title:"Prof.",name:"Juan Ignacio",middleName:null,surname:"Guerrero Alonso",slug:"juan-ignacio-guerrero-alonso",fullName:"Juan Ignacio Guerrero Alonso",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6HB8QAM/Profile_Picture_1627901127555",institutionString:null,institution:{name:"University of Seville",institutionURL:null,country:{name:"Spain"}}},{id:"3095",title:"Prof.",name:"Kenji",middleName:null,surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki",profilePictureURL:"https://mts.intechopen.com/storage/users/3095/images/1592_n.jpg",institutionString:null,institution:{name:"University of Chicago",institutionURL:null,country:{name:"United States of America"}}},{id:"214067",title:"Dr.",name:"W. 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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. 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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. 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