\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"6351",leadTitle:null,fullTitle:"Vasculitis In Practice - An Update on Special Situations - Clinical and Therapeutic Considerations",title:"Vasculitis In Practice",subtitle:"An Update on Special Situations - Clinical and Therapeutic Considerations",reviewType:"peer-reviewed",abstract:'"Vasculitis" describes an inflammatory process that involves the blood vessels and contributes to vascular damage. Autoimmunity, infections, drugs, and malignancies have been considered among potential etio-pathogenic factors. In vasculitis, the inflammation might develop in either a systemic or an organ-specific form and might exist as an independent pathology "primary vasculitis" or as a presentation of an existing primary pathology, that is, "secondary vasculitis". This book Vasculitis In Practice-An Update on Special Situations - Clinical and Therapeutic Considerations unlike many publications in the field, uses a different evidence-based approach to organ-specific vascular inflammatory diseases. The authors highlighted the unmet needs from the 1994 Chapel Hill Consensus Conference introducing the latest clinically relevant definitions for the different forms of vasculitis revised in 2012. The identification, classification, and management of kidney disease with different types of vasculitis with an evidence-based update on proposed therapeutic strategies are presented in this publication.',isbn:"978-1-78923-699-6",printIsbn:"978-1-78923-698-9",pdfIsbn:"978-1-83881-423-6",doi:"10.5772/intechopen.69793",price:119,priceEur:129,priceUsd:155,slug:"vasculitis-in-practice-an-update-on-special-situations-clinical-and-therapeutic-considerations",numberOfPages:112,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"9213792932243386d6a3875223e8f474",bookSignature:"Reem Hamdy Abdellatif Mohammed",publishedDate:"September 19th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6351.jpg",numberOfDownloads:5348,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:2,numberOfDimensionsCitationsByBook:1,hasAltmetrics:0,numberOfTotalCitations:3,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 20th 2017",dateEndSecondStepPublish:"July 11th 2017",dateEndThirdStepPublish:"October 21st 2017",dateEndFourthStepPublish:"January 5th 2018",dateEndFifthStepPublish:"March 6th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"36290",title:"Prof.",name:"Reem Hamdy A.",middleName:null,surname:"Mohammed",slug:"reem-hamdy-a.-mohammed",fullName:"Reem Hamdy A. Mohammed",profilePictureURL:"https://mts.intechopen.com/storage/users/36290/images/system/36290.png",biography:'Professor Reem Hamdy Abdellatif Mohammed graduated from the School of Medicine, Cairo University, Egypt, where she is currently a Professor of Rheumatology and Clinical Immunology. She is a fellow of the Royal College of Physicians and a Certified International Professional Trainer (CIPT) at the Faculty and Leadership Development Center (FLDC), Cairo University, and at the Management Development Institute, Missouri State University, USA, carrying on teaching and training on the \\"Establishment of the Evidence-Based Strategy in Medical Research and Practice.\\" Dr. Mohammed is a verified editor, reviewer, and advisory board member for several reputable international journals. She is also a member of the “Capacity Building Team\\" at Cairo University. She is the author and co-author of several books and an international speaker in the field of rheumatology and immunology. \n\nScopus Author ID: 35280107100\n\nORCID ID: ORCID logohttps://orcid.org/0000-0003-4994-7687\n\nCU Scholar account: https://scholar.cu.edu.eg/?q=reemhamdy/publications',institutionString:"Cairo University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Cairo University",institutionURL:null,country:{name:"Egypt"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1035",title:"Clinical Immunology",slug:"immunology-allergology-and-rheumatology-clinical-immunology"}],chapters:[{id:"63077",title:"Introductory Chapter: Vasculitis",doi:"10.5772/intechopen.79560",slug:"introductory-chapter-vasculitis",totalDownloads:955,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Reem Hamdy A. Mohammed",downloadPdfUrl:"/chapter/pdf-download/63077",previewPdfUrl:"/chapter/pdf-preview/63077",authors:[{id:"36290",title:"Prof.",name:"Reem Hamdy A.",surname:"Mohammed",slug:"reem-hamdy-a.-mohammed",fullName:"Reem Hamdy A. Mohammed"}],corrections:null},{id:"62722",title:"Pauci-Immune Vasculitides with Kidney Involvement",doi:"10.5772/intechopen.76175",slug:"pauci-immune-vasculitides-with-kidney-involvement",totalDownloads:1201,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The clinical entity of pauci-immune vasculitis encompasses a group of diseases that may involve any organ system of the body and may be fatal if left untreated. This chapter will review these diseases, with a special interest in the clinical setting of kidney involvement. Small vessel vasculitides associated with the presence of antineutrophil cytoplasmic autoantibodies in the circulation will be the main part, since the vast majority of patients with histopathological proof of pauci-immune vasculitis are positive for these antibodies. Pauci-immune glomerulonephritis often manifests with rapidly deteriorating kidney function, while it may be accompanied by systemic necrotizing small vessel vasculitis such as microscopic polyangiitis, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis. Importantly, antineutrophil cytoplasmic autoantibody specificity has been shown to be associated with distinct clinical syndromes and different prognostic profiles among patients with pauci-immune vasculitis allowing easier recognition of the disease and long-term prognosis. Each of the clinical phenotypes will be described thoroughly with respect to the criteria required for establishment of diagnosis, the specific characteristics of renal and extrarenal histopathology, the clinical picture, the therapeutic management, and prognosis in short and long terms.",signatures:"Sophia Lionaki, Chrysanthi Skalioti, Smaragdi Marinaki and John N.\nBoletis",downloadPdfUrl:"/chapter/pdf-download/62722",previewPdfUrl:"/chapter/pdf-preview/62722",authors:[{id:"213115",title:"M.D.",name:"Sophia",surname:"Lionaki",slug:"sophia-lionaki",fullName:"Sophia Lionaki"}],corrections:null},{id:"62193",title:"Immune Complex Small-Vessel Vasculitis with Kidney Involvement",doi:"10.5772/intechopen.77226",slug:"immune-complex-small-vessel-vasculitis-with-kidney-involvement",totalDownloads:1028,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The term immune complex small-vessel vasculitis encompasses anti-glomerular basement membrane disease, cryoglobulinemic vasculitis, IgA vasculitis and hypocomplementemic urticarial vasculitis. These disorders affect predominantly small vessels, and renal involvement is frequent. In this chapter, we shall discuss thoroughly anti-GBM disease, cryoglobulinemic and IgA vasculitis with respect to the criteria required for the establishment of diagnosis, the specific characteristics of renal histopathology, the clinical picture, prognosis, and therapeutic management.",signatures:"Smaragdi Marinaki, Chrysanthi Skalioti, Sophia Lionaki and John N.\nBoletis",downloadPdfUrl:"/chapter/pdf-download/62193",previewPdfUrl:"/chapter/pdf-preview/62193",authors:[{id:"189888",title:"Prof.",name:"John",surname:"Boletis",slug:"john-boletis",fullName:"John Boletis"}],corrections:null},{id:"60045",title:"p53 and Vascular Dysfunction: MicroRNA in Endothelial Cells",doi:"10.5772/intechopen.75461",slug:"p53-and-vascular-dysfunction-microrna-in-endothelial-cells",totalDownloads:1075,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"In many cancer cells, p53 gene is mutated and accumulated, which is considered as a mechanistical target of tumorigenesis. The role of p53 in non-cancerous cells has been focused on, since p53 activation diversely affects as human diseases, including vascular dysfunctions. p53 regulates vascular events, including vascular inflammation and senescence as well as cardiac dysfunction. Many researchers also have paid attention to the role of noncoding RNAs (ncRNAs), especially small-sized microRNAs (miRNAs) for the last decade and their noble biological cellular functions have been discovered. miRNAs expressed in endothelial cells (endothelial miRNAs) have been shown to control vascular events. Firstly, the importance of p53 in a variety of vascular events, such as vascular inflammation and senescence, are summarized. Secondly, the way to regulate miRNAs by p53 and the involvement of miRNAs on p53 function are demonstrated. Finally, several endothelial miRNAs that have important roles are focused on. The aim of this chapter is to understand the role of p53 in vascular diseases in the view of endothelial cell biology and the contribution of miRNAs related to p53.",signatures:"Munekazu Yamakuchi, Sushil Panta and Teruto Hashiguchi",downloadPdfUrl:"/chapter/pdf-download/60045",previewPdfUrl:"/chapter/pdf-preview/60045",authors:[{id:"217082",title:"Associate Prof.",name:"Munekazu",surname:"Yamakuchi",slug:"munekazu-yamakuchi",fullName:"Munekazu Yamakuchi"},{id:"243041",title:"Dr.",name:"Sushil",surname:"Panta",slug:"sushil-panta",fullName:"Sushil Panta"},{id:"243042",title:"Prof.",name:"Teruto",surname:"Hashiguchi",slug:"teruto-hashiguchi",fullName:"Teruto Hashiguchi"}],corrections:null},{id:"59613",title:"Buerger’s Disease: Clinical Aspects and Evidence-Based Treatments",doi:"10.5772/intechopen.74603",slug:"buerger-s-disease-clinical-aspects-and-evidence-based-treatments",totalDownloads:1090,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Buerger’s disease (thromboangiitis obliterans) is a nonatherosclerotic, segmental, occlusive, and recurring progressive inflammatory form of vasculitis that most commonly affects the small- and medium-sized arteries, veins, and nerves in the upper and lower extremities. The cause is unknown, but it is most common in young men with a history of tobacco abuse. It is responsible for ischemic ulcers and extreme pain in the hands and feet. In many cases, notably in patients with the most severe presentations, there is no possibility of improving the condition with surgery (limb revascularization), and therefore, alternative therapies (e.g., sympathectomy, pharmacological agents, and many others) are used. This chapter discusses clinical aspects of Buerger’s disease and evidence-based treatment available currently.",signatures:"Daniel Guimarães Cacione",downloadPdfUrl:"/chapter/pdf-download/59613",previewPdfUrl:"/chapter/pdf-preview/59613",authors:[{id:"216255",title:"Ph.D.",name:"Daniel",surname:"Cacione",slug:"daniel-cacione",fullName:"Daniel Cacione"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"9104",title:"Lupus",subtitle:"Need to Know",isOpenForSubmission:!1,hash:"3bf7e412a25b5e723ece6658aaf36917",slug:"lupus-need-to-know",bookSignature:"Reem Hamdy A. Mohammed",coverURL:"https://cdn.intechopen.com/books/images_new/9104.jpg",editedByType:"Edited by",editors:[{id:"36290",title:"Prof.",name:"Reem Hamdy A.",surname:"Mohammed",slug:"reem-hamdy-a.-mohammed",fullName:"Reem Hamdy A. 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El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/10356.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"217045",title:"Dr.",name:"Arnold Forkuo",middleName:null,surname:"Donkor",fullName:"Arnold Forkuo Donkor",slug:"arnold-forkuo-donkor",email:"forkuo3@gmail.com",position:null,institution:{name:"Kwame Nkrumah University of Science and Technology",institutionURL:null,country:{name:"Ghana"}}},{id:"303360",title:"Dr.",name:"Evelyn",middleName:null,surname:"Asante-Kwatia",fullName:"Evelyn Asante-Kwatia",slug:"evelyn-asante-kwatia",email:"emireku@yahoo.com",position:null,institution:null},{id:"309974",title:"Prof.",name:"Abraham Yeboah",middleName:null,surname:"Mensah",fullName:"Abraham Yeboah Mensah",slug:"abraham-yeboah-mensah",email:"aymensah@yahoo.com",position:null,institution:{name:"Kwame Nkrumah University of Science and Technology",institutionURL:null,country:{name:"Ghana"}}},{id:"347910",title:"Mr.",name:"Lord",middleName:null,surname:"Gyimah",fullName:"Lord Gyimah",slug:"lord-gyimah",email:"lordgyimah36@gmail.com",position:null,institution:{name:"Kwame Nkrumah University of Science and Technology",institutionURL:null,country:{name:"Ghana"}}}]},book:{id:"10356",title:"Natural Medicinal Plants",subtitle:null,fullTitle:"Natural Medicinal Plants",slug:"natural-medicinal-plants",publishedDate:"May 11th 2022",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/10356.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"10264",leadTitle:null,title:"Click Chemistry",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThe goal of the book is to give the reader an overview of a field related to click chemistry. This book aims to provide information about click chemistry to the synthesis nano/microstructures, click chemistry for drug delivery nanosystems, and applications of click reactions in environmental technologies. The book welcomes submissions written by authors in the field of experimental methods and critical reviews from multi-disciplines such as chemistry, environmental chemistry, pharmacy and materials science.
\r\n\r\n\tAmong others, welcome topics are in situ click chemistry, classification of click chemistry, click chemistry in polymer science, click chemistry in materials science, click chemistry reactions in medicinal chemistry and pharmaceutical applications, click chemistry in environmental chemistry applications and pollutants, chemical sensors sensor based on click chemistry, photoelectrochemical sensor based on click chemistry, wastewater treatment, nanoadsorbent, hydrogel networks.
\r\n\r\n\tAll interested authors are welcome to focus on recent studies, industrial applications, and new technological developments on click chemistry in nanotechnology.
\r\n\t
Pemphigus is a distinct organ-specific autoimmune blistering disorder involving skin and mucous membranes associated with autoantibodies directed against desmosomes-intercellular adhesive molecule complex localized on the keratinocyte cell surface [1, 2, 3, 4].
Pemphigus has three major variants, which are classified depending on the basis of the clinical, histological features, immunofluorescence staining pattern and autoantibody profile of the disease including
The term “pemphigus” origins from the Greek word “pemphix”, which has a meaning of “blister” [1]. It is a chronic potentially life-threating bullous disorder if not treated on time [4, 7, 8]. The phenotypes of pemphigus represent a complex spectrum with multiple genetic and environmental factors playing a role in disease pathogenesis [9, 10].
Together with clinical manifestations, the histopathological and immunopathological data support the diagnosis of the disease. The best site for the cutaneous biopsy for the appropriate histopathological examination is a fresh (< 24 h) small vesicle or 1/3 of the peripheral portion of the blister including the perilesional normal appearing skin. For direct immunofluorescence microscopic (DIF) examination, a perilesional normal appearing skin area up to 1 cm from a fresh vesicle should be taken and should be transformed in saline or in a cylinder of liquid nitrogen in a period lesser than 36 h [11, 12, 13].
As though some pemphigus variants, particularly PV and PNP, are potentially life-threatening diseases, early diagnosis is necessary and early onset of immunosuppressive treatment should be promptly initiated [14]. Moreover, some variants of pemphigus may indicate the presence of an underlying malignancy [15].
In this chapter, after the classification of pemphigus, firstly, pathogenetic properties and mechanism of acantholysis are discussed. After then, the review of pemphigus including the epidemiology, clinical features, histopathological and immunopathological findings, target antigens, and comorbidities of each pemphigus variant is discussed briefly.
Pemphigus is classified into two major types according to the level of intraepidermal separation by the most authors: PV and PF [2, 16, 17]. In the last decades, rarer and newer variants of pemphigus have taken part in classification [1, 4, 6], which is described in the following sections.
The evidence outlines that pemphigus is mediated by pathogenic circulating anti-Desmoglein 1/3 (Dsg) antibodies, which mediate blister formation [1, 2, 3, 4, 5, 6, 16, 17, 18, 19, 20, 21]. Previously, it was accepted that the presence of anti-Dsg antibodies alone is sufficient for the development of pemphigus [22]. According to the compensation hypothesis, the development of pemphigus is based on the normal epidermal distribution of Dsg1 and 3 molecules and Dsg1 and 3 antibody profiles [2, 16]. However, several reports have been reported pointing the discrepancy between clinical phenotype and autoantibody profile that contradicts with this theory [22, 23, 24, 25, 26].
While the production of pathogenic autoantibodies (Abs) is the key for the development of the disease, today it is obvious that many immunological steps are also required prior to the antibody induction [3, 22, 27]. Recent studies investigating the role of lymphocytes have demonstrated the role of T cells and B cells in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity [28].
Today, it is obvious that some HLA class II alleles are involved in the activation of Dsg3-specific CD4+ T cells, which drives the pathogenetic pathways. The epidermal loss of adhesion is induced by pathogenic IgG Abs, which are produced by B cells. HLA-DRB1*04:02 is highly prevalent in PV, which provides the recognition of Dsg3 by CD4+ T cells. T cell-dependent B cell activation is critical for the induction of pathogenic IgG Abs [28, 29, 30, 31].
Recent studies have also emphasized the important role of T regulatory (reg) cells in the development of pemphigus, and it has been concluded that a balance between self-reactive lymphocytes and T reg cells may be a key element in determining whether individuals produce pathogenic Abs and develop pemphigus or not [9, 32, 33].
PV is the most commonly seen and representative clinical form of pemphigus with an incidence of 0.1–0.5/100.000 population [1, 2, 7, 13]. The average age at onset is usually at fourth and fifth decades, but may occur in the elderly or children. The incidence rate is higher among patients with Jewish and Mediterranean ancestry [1, 2, 5, 7, 13]. Various environmental factors such as drugs (captopril, penicillamine), infections (herpes simplex virus, Epstein–Barr virus, etc.), pesticides, ultraviolet radiation (UVR), ionizan radiation, thermal burns, stress and food containing an allium, phenol, thiol, or urushiol have been reported to trigger PV [10, 13, 34].
Patients with PV may present with only mucosal involvement and some with both mucosal and skin involvement [2, 4, 5]. In majority of the patients, oral mucosa is the site of onset, while cutaneous involvement usually occurs subsequently. It is most commonly characterized by painful erosions, erosions with whitish exudate and erythematous patches usually localized on gingiva and buccal mucosa [1, 2, 4, 5, 13] (Figures 1 and 2). The other mucosal areas, nasal cavity, larynx (epiglottis, vocal cords), oropharynx, esophagus, vagina, vulva, penis, and anus may also be affected [1, 13]. Epistaxis and hoarseness are present owing to the involvement of the nose, pharynx, and larynx [1, 13, 35, 36, 37]. Genital mucosa is one of the frequent sites involved in PV after the oral mucosa [37].
The eroded lesions are seen on the palate, right and left sides of the lower lip.
The erosions with whitish exudates are seen on the left posterior side of the buccal mucosa.
Cutaneous involvement usually follows mucosal lesions by 3 or 4 months [1, 4, 5]. The skin lesions cause burning and painful sensation. Cutaneous lesions are characterized by flaccid bullae evolving into painful extensive erosive areas (Figure 3). These blisters appear on the normal or erythematous skin, which are fragile, break rapidly, and it is hard to find an unruptured bullae. The Nikolsky sign is present. The bullae in PV can be localized or generalized, and any area of the skin may be involved. The most frequent areas affected are: face, axilla, and scalp, and this may be due to the fact that Dsg3 has its highest expression in these areas [1, 2]. Umbilicus and/or nail involvement are the other sites that may be affected [2, 4, 5, 13, 38, 39, 40]. The presence of the nail lesions may be the sign of relapse or recurrence of the disease [40]. Apart from these, cases of PV with the involvement of only cutaneous lesions have also been reported [41, 42, 43].
The extensive erosions localized on the back of the patient.
Intraepidermal suprabasal acantholysis and infiltration with predominantly neutrophils and eosinophils are observed (tombstone pattern) [2, 5, 13].
DIF examination shows lace-like IgG deposition with or without C3 on the surface of the keratinocytes in the mid-lower or entire epidermis [2, 5, 12, 13, 16]. Indirect immunofluorescence (IIF) examination, using a substrate of normal human skin or monkey esophagus, shows circulating antiepithelial IgG and lace-like deposition [2, 4, 5, 12]. Enzyme-linked immunosorbent assay (ELISA) is also available in detecting antigens of PV and serves as a tool for assessing the disease severity [44, 45]. Target antigens identified in PV are Dsg1 (with a molecular weight (MW) of 165 kD) and Dsg3 (MW-130 kD) [2, 3, 4, 5, 9]. Desmocollin (Dcs) is another antigen that is thought to be responsible in some pemphigus patients [46, 47].
Myasthenia gravis (MG) and abnormalities of thymus including benign or malignant thymoma and thymic hyperplasia have been reported to be associated with PV [2, 5, 48, 49]. Thymic abnormalities may precede or follow the onset of pemphigus. The other common disorders that have been reported to be associated with PV are systemic lupus erythematosus (SLE), bullous pemphigoid (BP), and PF [48].
Pemphigus vegetans (P veg) is accepted as the rarest variety of PV comprising of only 1–2% of all pemphigus patients. P veg has been reported to occur in all age groups, affecting primarily middle-aged females (sex ratio: F/M = 14/3) [50].
P veg is characterized by vegetative lesions preferentially affecting intertriginous (axillary, inframammarial areas) and periorificial regions [2, 5, 50, 51, 52]. The initial course of the disease is similar to PV. In the later stages, tumid vegetating, hypertrophic and verrucous lesions occur specifically between skin folds [5, 50, 53]. Two subtypes of P veg are recognized. The first one is Neumann P veg, which usually begins like PV with easily rupturing vesicles and bullae that evolve to form hypertrophic granulating erosions and then vegetating exuding masses. The second type is Hallopeau P veg, which is initially characterized by pustular lesions that break and gradually evolve into vegetating erosions [5, 50]. Mucosal involvement may not always be seen. Involvement of the vermillion border of the lips is the clinical hallmark of oral involvement [54]. Nail involvement is rarely described [50]. In P veg, the course of the disease is long, with remission and recurrence periods. Hallopeau P veg has a relatively benign course, while the Neumann type is often refractory to therapy. One of the frequent complications is the development of secondary bacterial infections, and also malnutrition and cachexia may coexist to the condition [5, 50].
Suprabasal acantholysis is present in the earlier stages of P veg similar to PV. In the following periods, irregular epidermal hyperplasia, papillomatosis, microabscess composed of eosinophils and neutrophils are also seen [2, 5, 50].
DIF and IIF examination results are indistinguishable from the findings of PV. As P veg is a subtype of PV, it is expected to react with the same antigens, Dsg1 and Dsg3 [2, 5, 50]. The presence of auto-Abs targeting additional desmosomal proteins including Dsc1, Dsc2, Dsc3 and periplakin have also been reported [51, 55].
PF (foliaceus originates from the Latin word folium with a meaning of “leaf”) is the superficial form of pemphigus [1, 2, 4, 5]. PF has a universal occurrence and occurs sporadically, while the endemic form of PF, called as fogo selvagem (FS) or wild fire (WF), is predominantly seen in the rural and tropical regions of Brazil [5, 7, 16, 58, 59]. Another variant of PF, a localized form, is called as pemphigus erythematosus (PE) [16, 59]. Sporadic form of PF is most common in Europe and USA [16].The average age of PF ranges between 40 and 60 years, while FS is very often in children, adolescents and young adults. It is usually seen equally in both females and males with a female preponderancy [59, 60]. FS occurs in genetically related family members. It has been reported that black fly (Simulium nigrimanum) bites were more frequent in patients with FS than in control patients [61, 62]. The authors suggested this vector or other infectious agents carry a molecule-triggering anti-Dsg1 response through antigen mimicry or cross-reactivity [58, 61].
PF is considered as a more benign form of the disease generally presenting with only cutaneous involvement [2, 5, 16, 59]. However, transition from PV to PF or vice versa may be observed [63, 64, 65]. More rarely, transition to BP has been reported [65]. The primary clinical feature of PF is fragile, superficial bullae evolving rapidly to erosive lesions. Nikolsky sign is positive. PF usually begins on the trunk, but may also be localized on the face and scalp. Sometimes yellowish crusted and scaly erythematous plaques on face and trunk predominate the clinical findings resembling the clinical picture of seborrheic dermatitis [2, 5, 16, 59, 66]. In FS, the disease usually begins on the head, neck, and seborrheic regions of the skin. The oral mucosa, palms of the hands, and plant of the feet are usually spared [59, 66]. In both PF and FS, lesions may become confluent and can transform to exfoliative erythroderma [67]. These patients should be hospitalized due to the risk of metabolic instability and mortality [1, 16, 59]. Pain and/or burning sensation may be noted. Unlike PV, there is no oral or other mucosal involvement [2, 5, 16, 59]. Mildest form of PF may be misdiagnosed for years [61].
Histological separation is more superficial than PV and exists along the granular layer. Eosinophilic spongiosis may also be seen in very early forms of PF [2, 5, 16, 59].
PE, also known as Senear-Usher syndrome, is a localized form of PF [2, 5, 16, 59]. It affects most frequently elderly population. Clinical and immunological features of PE resemble both PF and cutaneous lupus erythematosus (LE) [16, 75]. Clinically erythematous plaques, scaly to crusted lesions, occur across the malar areas of the face in a butterfly distribution mimicking the clinical appearance of LE [16]. The lesions are usually induced by UVR [75]. In 80% of the patients, antinuclear antibodies (ANA) without the presence of anti-ds-DNA antibodies may be detected [1, 2, 5, 16, 59]. DIF examination of the lesions may show both intercellular (IC) deposition IgG/C3 and granular deposition of IgG and C3 at the dermoepidermal junction (lupus band test) [5, 16, 59, 75].
PNP is a rare disease that manifests with clinically distinct painful mucosal erosions and polymorphic cutaneous lesions [1, 4, 15, 76]. The incidence of PNP is thought to be less common than PV or PF. PNP presents most often in older patients aged between 45 and 70 years [77, 78]. In almost all cases, PNP is associated with neoplasms mostly with lymphoproliferative diseases [4, 15, 66, 76, 77, 78].
The onset of the lesions usually presents with initially limited cheilitis and/or ulcerative stomatitis, which then progresses to severe, intractable, hemorrhagical stomatitis with persistent painful mucosal ulcerations in the oropharynx and esophagus [4, 5, 15, 16, 77]. Oral lesions usually extend to the vermillion border of the lips [15, 77]. Eye involvement especially includes conjunctival erosions and occurs in 70% of patients [79, 80, 81, 82]. Cutaneous lesions are usually seen after the onset of mucosal involvement with a duration of days to months [77, 83, 84]. Cutaneous lesions are widespread and are usually polymorphic including lichenoid lesions, erythema multiforme-like lesions, vesiculobullous and erosive lesions. The palmar involvement is usually observed [4]. Lichen planus-like lesions localized on skin, nails and/or mucosa resemble lichen planus, target-like lesions resemble erythema multiforme, and bullous lesions and erosive lesions resemble PV and bullous pemphigoid [4, 15, 66, 76, 77, 83, 84, 85, 86, 87]. Cutaneous lesions mimicking graft versus host disease or Stevens-Johnson syndrome may also be observed [86, 87].
As though most of the patients with PNP are associated with malignancies, the prognosis of PNP is severe with a high mortality rate [15, 77, 83, 84, 88, 89]. Internal organ involvement including lungs (Bronchiolitis obliterans), thyroid, kidney and gastrointestinal system has been documented [15, 88, 89]. Most authors have reported that the term “paraneoplastic pemphigus” is too restrictive to describe the developing multiorgan syndrome involvement and have suggested a new nomenclature named as paraneoplastic autoimmune multiorgan syndrome (PAMS) [15, 88].
Several biopsies are often required to achieve the diagnosis [77, 81]. The histopathological features of PNP reveal variability according to the type of the morphology of the cutaneous lesion [15, 77, 84, 90]. Intraepidermal suprabasal acantholysis (resembling PV), keratinocyte necrosis and vacuolar interface changes (resembling erythema multiforme/lichen planus) may be observed [77, 90].
DIF examination is characterized by the deposition of immunoreactants (IgG deposits with or without compleman) in IC region of epidermis and deposition of IgG/IgM and/or C3 along the basal zone membrane (BZM) [15, 17, 77, 84]. IIF using rat bladder epithelium as substrate shows an IC pattern that appears to be highly specific but less sensitive for PNP/PAMPS (including monkey esophagus (86% sensitivity) and murine tongue (100% sensitivity). A variety of antigens including Dsg1, Dsg3, envoplakin, periplakin, bullous pemphigoid antigen1 (BPAG1), plectin, desmoplakin 1, and desmoplakin 2 can be detected by immunoprecipitation [15, 17, 77, 84].
PNP usually precedes the diagnosis of the underlying malignancy. In 1/3 of the cases, the underlying malignancy has not been diagnosed at the time of diagnosis. Therefore, when a diagnosis of PNP is made, a comprehensive workup for an underlying malignancy is mandatory [4, 15, 76, 77]. Hematological malignancies are associated with 84% of the patients of PNP. The most common reported hematological malignancies are non-Hodgkin lymphoma (38.6%), chronic lymphocytic leukemia (18.4%), Castleman disease (18.4%), and thymoma (5.5%) [15, 48, 77, 84].
PH is a rare and distinct entity of pemhigus [6, 11]. It has been first described in patients who had clinical features that resemble dermatitis herpetiformis, but showed the features of pemphigus histopathologically and immunologically [6, 11, 91, 92]. It usually accounts 6–7% of cases and affects females and males equally [11, 92].
Patients usually have erythematous, gyrate, annular and polycyclic lesions with clusters of pustules, vesicles, in herpetiform pattern. The clinical presentation of PH may be atypical and may mimic various other bullous diseases [6, 92]. Pruritus is usually present [6, 11, 92, 93]. Mucous involvement is not a usual finding [6, 11]. PH usually has a good psis, although some cases may progress into classic pemphigus [11, 94].
The histopathological examination shows eosinophilic or neutrophilic spongiosis and microabscesses (neutrophils and/or eosinophils) in the mid or subcorneal epidermis mostly without acantholysis. Acantholysis may be seen in the later stages of the disease process and may be minimal [6, 11, 92, 93].
DIF examination shows IC deposits of IgG and C3 in epidermis, while IIF examination shows circulating IgG auto-Abs. The target antigen is usually Dsg 1 (or less frequently Dsg3) [6, 11, 95]. Recent studies have demonstrated DSc1, Dsc3 and unknown protein 178-kDa protein [11, 92, 96] by immunoblotting.
IGAP is a rare entity of pemphigus [6, 11]. It has two clinical types: intraepidermal neutrophilic type (IEN) and subcorneal pustular dermatosis (SPD) [6, 11, 66]. It is usually observed in the middle-aged or the elderly with an average age at 48 years, but also has been reported in childhood [6, 11]. There is a slight predominance of females [6].
Patients with both types of IGAP present with flaccid vesicles or pustules on either erythematous or normal skin mostly localized on axillary and groin areas, but trunk, proximal extremities and abdominal regions are also involved. The pustules tend to coalesce to form annular or circinate pattern. SPD is clinically indistinguishable from the disease subcorneal pustular dermatosis. In IEN type, pustules coalesce to form a sunflower-like configuration [2, 6, 11, 102, 103]. Pruritus is severe and affects patients’ daily activities. Mucosal involvement is rare [2, 6, 11].
There is slight acantholysis and neutrophilic infiltration in epidermis. In SPD type, neutrophilic infiltration is localized subcorneally in the upper epidermis, while in IEN type in lower epidermis or entire epidermis [5, 6, 11].
In DIF examination, deposition of IgA in IC space of epidermis is detected. IgG and/or C3 is sometimes deposited but is weaker than IgA. In the SPD type, deposition is limited to upper epidermis, while in IEN type, it is deposited in lower epidermis or in whole epidermis [6, 11]. Using healthy human skin and monkey esophagus, circulating IgA auto-Abs have been demonstrated in 50% of the patients [5, 11]. The antigens in IGAP are Dsg1, Dsg3, Dsc1, and Dsc3 [3, 4]
In SPD type, the most frequently reported association is monoclonal IgA gammopathy [11, 48, 103].
Pemphigus, especially some types, is a life-threatening disease and has a mortality risk. Therefore, the diagnosis should be made as soon as possible, and the treatment should be started. Today, a better understanding of the role of immunological dysregulation in the pathogenesis will also cause offering newly targeted therapeutical agents in the treatment of pemphigus.
Abs | Antibodies |
ACE | Angiotensin-converting enzyme |
ANA | Antinuclear antibody |
Anti-ds DNA | Double-stranded DNA antibody |
BO | Bronchiolitis obliterans |
BZM | Bazal zone membrane |
C3 | Compleman 3 |
DIF | Direct immunofluorescence |
Dsc | Desmocollin |
Dsg | Desmoglein |
ELISA | Enzyme-linked immunosorbent assay |
FS | FogoSelvagem |
HLA | Human leucocyte antigen |
IC | Intercellular |
IEN | Intraepidermal neutrophilic type |
Ig | Immunoglobulin |
IGAP | IgA Pemphigus |
IIF | Indirect immunofluorescence |
MG | Myasthenia gravis |
MW | Molecular weight |
P veg | Pemphigus vegetans |
PAMPS | Paraneoplastic autoimmune multi-organ syndrome |
PE | Pemphigus erythematosus |
PF | Pemphigus foliaceus |
PH | Pemphigus herpetiformis |
PNP | Paraneoplastic pemphigus |
PV | Pemphigus vulgaris |
Reg | Regulatory |
SLE | Systemic lupus erythematosus |
UVR | Ultraviolet radiation |
WF | Wild fire |
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease of unknown etiology, progressive and irreversible interstitial lung disease (ILD). IPF is the most common form of idiopathic interstitial pneumonia. It affects around 3 million people worldwide [1]. The increasing count of IPF cases is evident. The prognosis for patients with IPF is poor, with a median survival of 3–5 years if untreated [1]. IPF generally affects adults over 50 years, mainly in their sixth or seventh decade, but the earlier onset was noted in familial IPF. According to the epidemiological data, the incidence rates in Europe and North America are between 2.8 and 19 cases per 100,000 people per year [2]. The number of cases older than 65 years of age is about 400 per 100,000. The IPF has a prevalence of 8.2 cases per 100,000 and belongs to the rare diseases group [3]. The first IPF manifestation is shortness of breath (up to 85% of cases), chronic non-productive cough (up to 75%), tiredness, loss of appetite, and progressive exertional dyspnea, followed by an impaired quality of life [4]. More rarely, it can be an acute exacerbation (AE), acute episodes of sudden, rapid worsening of the disease of dyspnea over just a few weeks, and a consequent significant increase in mortality risk [5].
The pathogenesis of IPF is not completely understood. For many years, IPF was principally an inflammatory disease, given the increase in inflammatory cells in the lungs. Dramatic advances in the understanding of IPF pathogenesis mechanisms over the past decade were based on proteomics data. It discovered proteins in terms of prognosis, diagnosis, and IPF progression. Today, we think about IPF as an epithelial-driven disease. IPF originates from unknown microinjuries resulting from recurrent exposures of the lung epithelium to stimuli or predisposition, followed by initiation of alveolar epithelial cells (AECs) dysfunction, fibroblast recruitment, and proliferation and progression of fibrosis through fibroblast differentiation, myofibroblasts proliferation, and accumulation of extracellular matrix and remodeling [6].
Usually, pulmonary function tests reveal reduced total lung capacity, low carbon monoxide diffusing capacity, and arterial hypoxemia. Although the course of the disease is variable, IPF has a poor prognosis, mortality is high, and reported median survival is from 2.5 to 5 years from the time of diagnosis [7, 8].
The most frequent cause of death is respiratory failure. Although there is no identified cause for the IPF, men are more frequently affected than women. Genetic and environmental factors may contribute to the development or worsen the prognosis of IPF. A history of smoking increases the risk of developing IPF. Occupational and environmental risk factors for IPF are agricultural exposure, dusts from metal, asbestos, wood, chemicals, air pollution, etc. Although IPF is a disease that is limited to the lungs, numerous comorbidities have been increasingly recognized in patients with IPF, such as cardiovascular, pulmonary hypertension and ischemic heart disease, gastroesophageal reflux, lung cancer, chronic obstructive pulmonary disease/pulmonary emphysema, depression, sleep apnea, and diabetes [9].
Diagnosis of IPF is challenging because the initial symptoms are vague, non-specific, often mild, and may be attributed to advancing age or other diseases. Frequently the diagnosis is complex, requiring a multidisciplinary evaluation as recommended by international guidelines. The diagnosis of IPF continues to be a diagnosis of exclusion of other known causes for pulmonary fibrosis. High-resolution computed tomography (HRCT) plays a central role in the diagnosis of IPF. The presence of the HRCT pattern of usual interstitial pneumonitis is the hallmark of IPF diagnosis. In the case of the inconsistent pattern of UIP, significant inter-observer variability, surgical lung biopsy is necessary despite possible complications: triggering of the pneumothorax, pulmonary collapse, etc. Specific combinations of HRCT patterns and histopathology patterns in patients subjected to lung tissue sampling (transbronchial lung cryobiopsy or surgical lung biopsy) are an important part of the diagnosis.
In summary, the required criteria for diagnosing IPF is the combination of exclusion of known causes of ILD and presence of UIP pattern on chest HRCT or exclusion of known causes of ILD and specific HRCT/histology combinations. In the case of atypical HRCT presentation, lung biopsy is recommended. However, not all patients are eligible due to age and comorbidity limits. The average time from the symptoms’ onset to the correct diagnosis is approximately 1.5 years [10, 11, 12].
Current guidelines also support the use of clinical, radiological, and physiologic evaluations to estimate IPF disease severity and predict disease progression [12]. These include quality of life questionnaires and quantitation of IPF exacerbation frequency; serial measurements of forced vital capacity (FVC), diffusing capacity for the lungs for carbon monoxide (DLCO), and 6-min walk test (6MWT) distances; and sequential HRCT scans when indicated. Composite scoring systems such as the Composite-Physiologic Index (CPI) and Gender Age Physiology (GAP) index, which incorporate demographic and physiological data, may represent more accurate prognostic models [13, 14].
IPF patients usually respond poorly to therapy. The treatment is based on the use of antifibrotic drugs (nintedanib or pirfenidone), which slow down the disease progression, but they do not significantly improve the survival of these patients. Lung transplantation is the only treatment option that increases survival in IPF. Early intervention may help improve clinical outcomes [15].
A growing body of knowledge highlights IPF diagnosis, and providing accurate prognostic information is difficult using the currently available clinical, radiological, and physiologic findings. Furthermore, pulmonary function tests, clinical assessments, and imaging are very good for some cases, but not good for others. For example, lung biopsy is often not feasible in an elderly population with co-morbidities, etc. [16].
With the development of new treatments for IPF, it is critical to identify patients at an earlier stage of disease and rapidly identify those patients who will progress to worse clinical outcomes. That’s why there has been an emergence of molecular biomarkers. Compared to today’s diagnostic methods, an optimal biomarker for discriminating patients with IPF from healthy subjects or non-IPF patients should be less invasive, more rapid, and reproducible, easier to obtain from patients.
At the same time, we are the witnesses that non-invasive biomarkers can provide very important information for the clinical assessment of patients. Although considerable advances have been made in the last decade in revealing IPF pathogenesis, this is not the case with IPF biomarkers. Similar to the previous guidelines, current existing guidelines such as 2021 German Respiratory Society (DGP), 2018 American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), American Latin Thoracic Association (ALAT) guidelines strongly recommend not to measure any serum biomarker for IPF diagnosis and distinguishing IPF from other interstitial lung diseases in patients with newly detected ILD of apparently unknown cause who are clinically suspected of having IPF. Also, no guidelines on prognostic biomarkers are available [12, 17, 18, 19, 20].
Although there is no molecular biomarker in widespread clinical use for IPF, advancements in this field have been achieved; a growing body of literatures indicates a fascinating field of IPF biomarkers has reported changes in the level of various biomarkers in IPF patients, which implies the potential to become a new tool for clinical practice of IPF.
IPF biomarkers include:
predisposition biomarkers for identification of patients at risk for developing IPF
diagnostic biomarkers for identification of IPF patients and differentiation of IPF patients from healthy controls or patients with other ILD or another lung disease
prognostic biomarkers for staging disease severity, monitoring disease progression, herald worsening of IPF or the onset of an acute exacerbation or more accurate prediction of mortality
therapeutic biomarkers that are a reliable measure of efficacy and safety during treatment
biomarkers used as a surrogate endpoint in clinical trials helping predict clinical benefit based on epidemiologic/therapeutic/pathophysiologic evidence [21, 22, 23].
It is very well known that the ideal biomarker should be noninvasive, easily measured by a single, readily available test, to have high sensitivity/specificity, to be reproducible, accurate, widely available, and cost/effective [24].
Before considering the clinical implementation of the biomarker candidate, it must be evaluated critically with respect to key analytical and clinical characteristics. Criteria to be satisfied for definitive clinical implementation of biomarker related to the test such as adequate assays for its measurement, its predictive value defined in specific clinical contexts, optimal cut-off(s), and known timing of measurement (release kinetics) [25, 26].
Biomarkers should be measured from body fluids or tissues (serum, urine, exhaled breath condensates bronchoalveolar lavage fluid (BALF) transbronchial biopsy, surgical lung biopsy, etc.) with a recommendation to use easily obtainable body fluids or tissues. Although airway biomarkers could be obtained non-invasively via exhaled breath, is simple to collect and unlimited in quantity, most studies used bronchoscopy to obtain these biomarkers via BALF [27].
Additionally, incremental marker value should be examined, and the data about the effect on patient management and outcome and cost-effectiveness should be available. Also, validation across sexes, ages, ethnicities, and disease severity to assure generalizability is very welcome.
This chapter will summarize our current knowledge about IPF biomarkers associated with alveolar epithelial cell damage and dysfunction, biomarkers related to extracellular matrix remodeling and fibroproliferation, as well as biomarkers related to immune dysfunction.
Markers that belong to this group are the most studied biomarkers and offer the most convincing data. The increase in serum levels of these markers can be attributed to an increase in the production of these proteins by regenerating alveolar type II cells and/or to an enhanced permeability following the destruction of the alveolar-capillary barrier [28].
Krebs von den Lungen-6 (KL-6) antigen is a high molecular weight glycoprotein belonging to the group of human transmembrane mucins, expressed on type II pneumocytes, bronchial epithelium, as well as in glandular epithelium, including breast and pancreatic epithelium [22].
It was originally studied as a potential tumor marker in adenocarcinoma, whereas today’s research is mainly based on KL-6 as a diagnostic and prognostic biomarker in ILD [22]. It shows marked inter-individual variability in serum levels.
Although few studies have revealed the KL-6 role as a diagnostic marker for IPF and found a higher value of KL-6 in patients IPF compared to controls. KL-6 was approved in Japan more than twenty years ago as a diagnostic biomarker in ILD [29].
Serum concentrations of KL-6 depend on the polymorphism of the MUC1 gene encoding its synthesis, which accounts for the different values in people of different ethnicities [29]. For these reasons, validation in the non-Asian population is necessary for this biomarker to be internationally used in patients with IPF [30].
However, KL-6 has been mostly studied as a prognostic biomarker. KL-6 values are predominantly increased in ILD, characterized by damage to AECs and progressive thinning of the interstitium, including IPF. A serum cut-off value of ≥1000 U/ml is associated with a poorer prognosis of patients with ILD and a higher risk of death [30].
KL-6 fluctuations in the follow-up of IPF patients have also been reported to be potentially useful in predicting functional disease progression [31]. Few studies examined the prognostic significance of serial measurements of KL-6 levels in IPF. Sokai et al. [32] found that serial measurements of serum KL-6 may provide additional prognostic information than physiological parameters in patients with IPF. Wakamatsu et al. [33] found that patients with both initial serum KL-6 values <1000 U/mL and no serial increase in KL-6 had more favorable prognoses than those with serial increases in KL-6 or initial serum KL-6 values ≥1000 U/mL. Bennett et al. [34] revealed that higher KL-6 levels in BALF are related to the more severe and extended disease.
As previously discussed, the course of IPF varies widely, and some patients experiencing acute exacerbations of IPF, but the risk factors contributing to AE are unclear. It was noticed that basal values of KL-6 are significantly higher in patients who develop AE compared to patients with stable IPF [30]. Qui et al. [35], in systematic review and meta-analysis, investigated the risk factors for AE in IPF patients. The meta-analysis included seven articles involving 14 risk factors for AE in IPF patients, and poor pulmonary function, mechanical procedures, higher serum KL-6, and secondary pulmonary hypertension were associated with increased risks of AE in IPF patients.
Meta-analysis of 10 studies in IPF found that KL-6 had the strongest association with diagnosis of lung fibrosis compared with the three other examined markers (SP-D, SP-A, and MMP7) until for prognostic studies (decline in forced vital capacity and/or mortality) in IPF, KL-6 showed significant prognostic value [36].
Recently published systematic review and meta-analysis [37] was evaluated the robustness of available evidence for the use of KL-6 measurements in blood to predict prognosis in IPF patients. Twenty-six studies were included in the systematic review, and 14 studies were mainly performed on Asian patients in meta-analysis. The meta-analysis found that IPF patients with increased KL-6 concentrations had a significantly increased risk of developing AE, but the relation of KL-6 concentrations with mortality was not found.
Secreted mucins are the most abundant glycoprotein component of mucus. Secreted mucins (MUC2, MUC5AC, MUC5B, MUC6–8, and MUC19) are secreted into the extracellular space [38] MUC5B is among the major best-described, secreted gel-forming mucins. The main tissues expression of MUC 5B is; respiratory tract, submandibular glands, endocervix. Mucin 5B is one of the main components of respiratory secretions, and it participates in defense of the respiratory system from infections [39, 40]. However, the accumulation of this gel-forming glycoprotein further contributes to impaired gas exchange and complicates the clinical features of IPF patients [41]. The over-expression of mucin 5B in a study in mice showed a negative effect on mucociliary clearance, so inhaled harmful substances remain in the airways longer and initiate damage, and consequently tissue repair with fibrotic changes [42].
In 2011, a genome-wide linkage study identified a locus on chromosome 11 that was significantly associated with IPF risk. A common single nucleotide polymorphism (SNP) (rs35705950) in the promoter of the gene encoding for Mucin 5B (MUC5B) is associated with an increased risk for IPF [43, 44]. Meta-analysis of Zhu et al. [45] revealed a strong association between the MUC5B promoter rs35705950 polymorphism and the risk of IPF, and confirmed that the minor T allele is significantly associated with an increased risk of IPF compared.
The same polymorphism has been associated with higher concentrations of MUC5B and its distribution, predominantly in the epithelial cells of small airways [46]. Mutations in this gene are not the only cause of increased mucin expression. Recent data indicate that increased DNA methylation is also associated with increased MUC5B expression [47]. This association has not been clarified yet and is certainly a topic for future research.
It was also shown that mucin 5B could be a good prognostic marker. Namely, the mutation in the promoter region of the MUC5B gene is associated with a lower risk of lethal outcome [48]. It has not yet been found how the same mutation leads simultaneously to an increased risk of disease. Yet, it is associated with a better prognosis and a higher degree of survival.
Certain similarities between IPF and lung cancer have already been identified. Both diseases primarily affect the lower parts of the lung lobes; risk factors such as smoking, exposure to harmful substances in the living and work environment, viral infections, and others are also common. There are also certain similarities in pathogenetic mechanisms, such as genetic and epigenetic changes, dysfunctions at the molecular and cellular levels, and activation of certain signaling pathways [49]. All the above indicates the possibility of using certain tumor markers in IPF when assessing the severity of the disease and predicting the outcome [50].
Carbohydrate antigen 19-9 (CA 19-9) is a marker of epithelial damage, widely used as a serum tumor marker of carcinoma of the pancreas and digestive system [51]. An increase in the concentration of this marker has been observed in patients with IPF, but the significance of determining it is still speculative.
Another widely used tumor marker that indicates the severity of the disease in IPF is CA 15-3. This glycoprotein, or the most significant tumor marker of breast cancer, is elevated in patients with pulmonary fibrosis. It is useful in predicting the severity of the disease, and after lung transplantation, there is a decrease in its concentration [50].
Carcinoembryonic antigen (CEA), a glycoprotein used as a serum tumor marker of colon, rectum, stomach, pancreas, lung, and breast cancer, also stands out as a useful marker in IPF [52]. The values of this analyte are elevated in IPF and are associated with the severity of the disease [52].
Yin and Lloyd [53] recently identified MUC16 as a transmembrane mucin corresponding to the CA125 antigen, long known as a marker for ovarian cancer. Recently, CA125 was identified as a serum biomarker for disease progression and death in IPF patients.
In the analysis from the PROFILE study, examining 123 serum proteins in IPF patients, Maher et al. [54] singled out primarily CA19-9, CA125, and SP-D as three markers with the greatest potential for routine use in clinical practice. Although these three biomarkers are all secreted in small amounts by the pulmonary epithelium in states of health, SP-D being secreted by alveolar type 2 cells and CA19-9 and CA-125 by the bronchial epithelium, they are secreted abundantly by the metaplastic epithelium of IPF patients. Mahler et al. [54] indicate that the potential of these parameters is reflected precisely in their ability to distinguish patients from healthy people (SP-D) reliably, predict disease progression (CA 19-9), and dynamically reflect disease progression and overall mortality (CA 125) [54]. By examining the concentrations of CA19-9 in the final stage of IPF, Balestro et al. [55] got results consistent with previous research. Namely, most patients at this stage of the disease had CA19-9 values above the threshold (37kU/L). As confirmed by the results of several studies on different populations, CA19-9 is a reliable marker of disease progression [50, 54, 55].
The direct mechanisms of the increase in the concentration of tumor markers in idiopathic pulmonary fibrosis remain unclear. Nevertheless, research results are consistent in that these already widely used markers are useful in assessing the severity and progression of IPF [49, 50]. The great potential of these molecules is reflected, among other things, in the fact that they are already in routine use, as well as that there are commercial tests for their determination, unlike many of the aforementioned potential markers of the IPF.
Surfactant proteins are lipoprotein complexes synthesized and then secreted exclusively by alveolar epithelial cells, bronchial epithelial cells, as well as Clara cells [56]. They are encoded by SFTPA, SFTPB, SFTPC, and SFTPD genes [57]. Their role is to reduce surface tension in the alveoli and prevent their collapse [58].
Surfactant proteins themselves, as well as mutations in the genes encoding these proteins, have been described as potential biomarkers in IPF [22]. Mutations in the genes for surfactant proteins (SP) C and A2 have been associated with the development of oxidative stress and damage to the endoplasmic reticulum, but an additional profibrotic stimulus is necessary to induce the development of pulmonary fibrosis [59, 60, 61].
However, SP-A and SP-D are the most studied surfactants in IPF, as well as surfactants studied for the longest time. The mechanisms by which SP-A and SP-D from pneumocytes enter the circulation are hyperplasia of AECs and thus increased synthesis of these proteins, and loss of AEC integrity i.e., increased permeability of the basement membrane of the pulmonary epithelium to the interstitium [58].
In the serum of patients with IPF, there was a significant increase in the concentration of SP-A and D, while in contrast, their concentration in BAL was lower compared to healthy, control subjects [58]. In addition, an increase in SP-D has been found in patients with acute exacerbations of the disease [62]. This surfactant protein may be useful in detecting patients who are more prone to disease progression and poorer outcomes [54]. There is evidence that SP-D is a biomarker that can be used for differential diagnosis of interstitial lung disease, as its level is higher in IPF than in other ILDs [63].
Wang et al. [64], in a meta-analysis of 21 articles, evaluated the use of serum SP-A and SP-D for differential diagnosis and prognosis of IPF. Serum SP-A levels were significantly higher in patients with IPF than in patients with non-IPF ILD. In the AE of IPF, serum SP-A/D was higher than those in the stable stage.
Studies, therefore, show that these proteins, as well as KL-6 and matrix metalloproteinase-7 (MMP-7), are predictive markers; however, in some studies, only SP-A and SP-D are independent predictors of mortality [65]. In addition, SP-D has proved to be a more sensitive marker than SP-A, with a sensitivity of 77% (SP-A sensitivity is 33%). However, these markers are not specific to IPF, but their increase is also observed in other interstitial lung diseases. Also, a study conducted in South Korea has shown that the application of these biomarkers in IPF, combined with clinical parameters, does not significantly contribute to the assessment of outcome compared to the application of clinical parameters alone. However, if KL-6 is included in the assessment, the contribution of biomarkers to clinical parameters becomes significant [65].
Compared with SP-A and SP-D in the serum of patients with IPF, the data for SP-B are limited. SP-B is a component of pulmonary surfactant, produced by alveolar epithelial cells, which is synthesized as a preproprotein [66]. The maturation process of this protein involves primarily the removal of the signal peptide, followed by the glycosylation of the C-terminal region, and finally, the cleavage of the N- and C-terminal propeptides [67]. Mature surfactant protein B is hydrophobic and strongly associated with phospholipids rich in surfactants. At the same time, its precursors, proSP-B, and C-proSP-B are more hydrophilic so that they can be found in the supernatant of bronchoalveolar lavage [68]. In healthy subjects, concentrations of both mature and SP-B precursors are almost undetectable in serum [69]. The study of Khan et al. [68] has been studied SP-B precursor, C-pro-SP-B, as a new biomarker in serum of patients with different chronic lung diseases, including ILDs. The highest C-proSP-B levels were detected in the serum IPF patients. In a multivariate analysis, C-proSP-B levels were able to discriminate IPF patients from patients with all other pulmonary diseases (p < 0.0001). SP-B pre-proteins might serve as a biomarker in pulmonary diseases with alveolar or interstitial damage in IPF.
Clara cells are exocrine bronchiolar cells with several different physiological functions, including a protective and regenerative role, as well as a role in maintaining pulmonary homeostasis [70]. These cells’ protective and regulatory function is achieved through the secretion of various surfactants, glycosaminoglycans, enzymes, and other proteins [70]. In addition, these cells are involved in the biotransformation of many harmful substances that enter the lungs through the inhaled air [71].
CC16 is a 16 kDa homodimeric secretory protein of Clara cells with anti-inflammatory and antioxidant properties and has been studied as a potential therapeutic agent in various lung diseases [70]. It is encoded by the SCGB1A1 gene. Low serum CC16 values are associated with decreased lung function in children, accelerated decline in lung function in adults, and an increased risk of death, primarily in lung cancer [72].
In contrast, significantly high values of CC16 have been observed in the serum and bronchoalveolar lavage of patients with IPF [72]. Also, CC16 values are high in other interstitial lung diseases, such as sarcoidosis, although the values are significantly higher in IPF [72]. It is assumed that the activation of Clara cells after the alveolar epithelium damage leads to elevated serum concentrations of CC16. However, the exact role of CC16 in the alveolar repair process has not been thoroughly tested [70]. Although CC16 is a potential biomarker in various lung diseases, further studies are needed since CC16 values do not correlate with disease severity; there are no reference values, nor can it be used independently in diagnostics since it is a non-specific marker [70].
Telomeres are repetitive nucleotide sequences at the ends of chromosomes, whose role is to protect chromosomes from degradation [73]. As DNA polymerase cannot completely replicate the DNA strand, wherein a sequence of about 50 nucleotides is lost during each replication, the importance of telomeres is reflected in the fact that during replication, these non-coding parts of chromosomes are lost. The loss of telomere parts is compensated by the telomerase enzyme, which incorporates guanine-rich sequences at the ends of chromosomes during cell replication. However telomeres become shorter during repeated replications, resulting in cell aging and apoptosis [74].
It has been found that approximately one-third of patients with familial IPF have shortened telomeres, and/or mutations in the gene encoding telomerases [75]. When examining telomere length in peripheral blood leukocytes in patients with IPF, it was found that 40% of patients with familial IPF and a quarter of patients with sporadic IPF have shortened telomeres, below the 10th percentile [76]. In a 2014 cohort study involving over three hundred patients with IPF, it was found that telomere length in peripheral blood leukocytes was an independent predictor of mortality [77]. It was also found that telomere shortening in peripheral blood leukocytes as a surrogate marker for telomere mutations, so telomere length in peripheral blood may be examined in the family of a carrier of these mutations, instead of carrying out genetic analysis, which would indicate a risk factor for familial IPF [78].
Integrins are receptors found on the surface of cells, and they have a role in their binding to the extracellular matrix, in the interconnection of cells, and their migration, proliferation, and innate immune response [79]. Structurally they are heterodimers, made of different α and β subunits, and the αvβ6 integrin itself consists of αv and β6 subunits. The β6 subunit is expressed only in epithelial cells, so the whole integrin is present only. This integrin is extremely important for the pathogenesis of IPF, as it can activate transforming growth factor beta (TGF-β), which is involved in the interaction of lung epithelial cells and fibroblasts [80]. In patients with IPF, higher concentrations of this integrin have been found in lung tissue [81]. Also, higher concentrations of integrin are associated with a poorer prognosis [82].
Matrix metalloproteinases (MMP) are zinc-dependent proteases, which degrade the extracellular matrix. They can modulate the proliferation, migration, and apoptosis of smooth muscle cells, endothelial cells, and some types of immune system cells. So far, 23 members of this family have been discovered, encoded by 24 genes, where two genes serve to encode the same matrix metalloproteinase - MMP-23 [83]. Under physiological conditions, the activity of these enzymes, collectively called matrixins, is regulated at the level of transcription, activation of their inactive zymogen precursors, interaction with extracellular matrix components, and finally inhibition by endogenous inhibitors [84]. Matrixins are divided into seven categories: collagenases, gelatinases, stromelysins, membrane-type MMP, matrilysins, metalloelastases, and other types of matrixins [85].
Although MMPs are expected to prevent fibrotic changes due to their many functions and role in ECM degradation, these enzymes can have both a profibrotic and an antifibrotic role [85]. More details on members of the MMP-7 and MMP-1 matrix families, specifically elevated in the serum of patients with IPF, will be provided below.
This metalloproteinase is expressed in alveolar epithelial cells, phagocytes, and fibrocytes. An increase in MMP-7 levels has been observed in patients with IPF, and this enzyme has been confirmed as a biomarker of IPF [86]. The expression of this matrixin in the lung epithelium in IPF is further increased by osteopontin, a marker that will be discussed later [87]. Two SNPs have been identified in the promoter of the MMP-7 gene, which causes increased transcription, and are associated with the development of idiopathic pulmonary fibrosis [88]. In addition, as an enzyme that effectively removes tissue pathway factor inhibitor (TPFI), MMP-7 creates a procoagulant environment in the alveolar space, which has been observed in many fibrotic diseases, including IPF. Although this enzyme is also involved in the regeneration of lung epithelium after damage, in studies in mice lacking the MMP-7 gene, it was not possible to induce pulmonary fibrosis (PF) with bleomycin, suggesting that this metalloproteinase nevertheless promotes the development of PF [89]. This fact singles out MMP-7 as a potential new therapeutic target.
White et al. study tested the differentiation of IPF from a heterogeneous comparator group that included various other ILDs [63]. In another study, the serum MMP7 levels of IPF patients were compared to a group of patients with other ILD. Serum MMP7 values had a median sensitivity, specificity, accuracy, and diagnostic odds ratio of 71.7, 64.4, 68.4, and 4.7%, respectively [90]. MMP7 indicates a correct IPF diagnosis in more than half of the patients, suggesting an incorrect classification in about one-third of patients. Based on these data, the diagnostic value of these serum biomarkers is currently considered insufficient to support clinical use [17].
The Bosentan Use in Interstitial Lung Disease (BUILD)-3 trial that assessed potential prognostic capabilities of few biomarkers showed that MMP-7 is higher than healthy controls. Baseline MMP-7 levels were good predictors of worsening and could predict changes in FVC as early as month 4. MMP-7 shows the potential to be a reliable predictor of lung function decline and disease progression [91].
Despite the promising data regarding MMP-7 as a prognostic biomarker of IPF, it is not included in clinical practice due to the lack of reproducible, uniform cut-off values in different studies. There are major discrepancies between different studies about collection matrices; for example, EDTA collection tubes suppress MMP activity while PBMC layers are sometimes [10% of cases) contaminated by neutrophils, therefore significantly affecting predictive cut-off thresholds [92].
This type of matrixin degrades the extracellular matrix collagen; it is not expressed in healthy tissue but during physiological and pathophysiological processes [87]. Along with MMP-7, MMP-1 is the most studied matrixin in IPF. The combination of these two matrixins in the diagnosis of IPF has a positive predictive value of up to 91% (for concentrations of MMP-7 > 2.6 ng/mL and MMP-1 > 8.9 ng/ mL). Additionally, elevated values of these two MMPs can reliably distinguish IPF from other ILDs [86].
Osteopontin (OPN) is an acidic phosphorylated glycoprotein secreted by various cells, including osteoclasts, activated T-lymphocytes, and activated macrophages [93]. Osteopontin is a multifunctional cytokine involved in various biological processes, including cell adhesion, chemotaxis, and reparative processes [87]. In this regard, the biological role of osteopontin in the pathogenesis of cardiovascular diseases, diabetes, glomerulonephritis, and several types of cancer is suggested [93, 94].
The function of osteopontin in the occurrence of pulmonary fibrosis was tested in experimental mouse models, where the role in promoting the migration, adhesion, and proliferation of fibroblasts in the bleomycin-induced pulmonary fibrosis was demonstrated [93, 94]. In addition, analysis of lung biopsy samples of patients with IPF showed that osteopontin is a cytokine with the highest expression [93].
Osteopontin serum values are significantly higher in AE of IPF, compared to values in stable IPF, which is associated with a poorer prognosis [87, 95]. Although OPN is increased in serum and BALF of IPF patients [96], it is not specific in differentiating IPF from other ILDs [93].
The studies did not show the correlation between OPN concentration and SP-A and KL-6 concentrations, which can be explained by the different origins of these markers. Serum values of KL-6 and SP-A better reflect a later phase of the fibrosis process, i.e., the remodeling phase [93]. Although OPN values are highest in patients with IPF, no significant differences were observed compared to the values in patients with other ILD subtypes, indicating the limited use of this biomarker in differential diagnosis [94].
Periostin is an extracellular matrix protein from the fascicline family, and it is involved in the pathogenesis of various diseases accompanied by increased levels of inflammation and fibrosis [97]. Studies have shown that periostin is a protein that is highly expressed in the lungs of patients with IPF [97, 98]. The highest level of periostin expression in the lungs is in fibroblasts, in the areas of active fibrosis [97]. Stimulation of periostin synthesis in fibroblasts is influenced by various factors, including TGF-β and IL-4/IL-13 [98]. Experimental mouse models have shown that suppression of the periostin gene or administration of neutralizing antibodies protects to a large extent against bleomycin-induced pulmonary fibrosis [99]. Also, periostin acts in cooperation with inflammatory cytokines, such as TNF-α, by activating NF-κB, which is accompanied by the production of inflammatory cytokines and chemokines, leading further to the development of pulmonary fibrosis [97].
All this indicates the importance of the biological role of periostin in the pathogenesis of PF. However, elevated serum levels of periostin are also observed in other inflammatory diseases, which is why there is a need to develop a test that will enable greater diagnostic specificity [98]. There is a test designed to determine specifically periostin monomers, which is a better diagnostic marker compared to total periostin [98]. In addition, both total and monomeric periostin are better predictive markers of short-term deterioration of IPF compared to conventional markers KL-6, SP-D, and LDH [98]. The potential role of periostin in the treatment of patients with IPF should also be noted since experimental mouse models have shown that suppression of periostin expression or administration of neutralizing antibodies may result in improvement in the fibroproliferative phase [99].
Lysyl oxidase (LOX) and lysyl oxidase-like proteins (LOXL) represent a group of enzymes with important roles in extracellular matrix remodeling, including covalent binding of elastin and collagen [100]. The LOXL proteins promote collagen accumulation and deposition, participating in ECM stabilization. In addition to the enzymatic function, LOX also has a function in regulating the transcription of elastin and collagen III genes [101].
Four LOX isoenzymes (LOX1-LOX4) encoded by genes located on different chromosomes have been identified [101]. Changes in LOX expression, i.e., increased LOX activity, have been associated with the mechanisms of fibrotic changes in certain lung, liver, and kidney diseases [101]. Increased LOX expression was observed in experimental mouse models in bleomycin-induced pulmonary fibrosis [101].
Also, elevated serum concentrations of LOXL2 in patients with IPF have been associated with a higher risk of disease progression but cannot be correlated with disease severity [101, 102]. Given its role in the pathogenesis of pulmonary fibrosis, the applicability of LOXL2 as a potential therapeutic target was examined. However, the study of the use of a monoclonal anti-LOXL2 antibody (simtuzumab) in the treatment of patients with IPF was discontinued in the second phase of the clinical trials due to the lack of efficiency [101]. One of the potential reasons for failure is the impossibility of adequate penetration into the lung tissue, but there were not enough data for a complete evaluation [101]. In any case, further testing of the diagnostic, predictive and prognostic value of LOXL2 as a biomarker in IPF is necessary.
IGFs are hormones or growth factors primarily synthesized in the liver. For the most part, they are bound to some of their binding proteins (IGF-BP), which modulate their effects and bioavailability [103]. The IGF binding protein family consists of six members, which also originate primarily from the liver. IGF and IGF-BP are synthesized locally in many tissues to achieve their autocrine and paracrine effects, respectively [104].
Studies have shown a significant increase in circulating concentrations of these binding proteins in newly diagnosed IPF patients. In contrast, in those patients who started using antifibrotic drugs, lower levels of GFBP-2 were found than in patients who do not receive this type of therapy [105]. IGFBP-2 values do not return to the levels of healthy subjects, even with the use of antifibrotic therapy [105].
As IGFs are very strong growth factors, their significant increase in the process of fibrosis, and even lung fibrosis, is expected. However, Guiot et al. [105] found a decrease in the concentration of these analytes in the serum of IPF patients. These surprising results can be explained in several ways. It is possible that IGF-BP, by binding to the extracellular matrix in the lungs with fibrotic changes, locally releases IGF and thus enables its effects in such an environment. On the other hand, an increase in the concentration of binding proteins to insulin-like growth factors means that these factors bind to a greater extent, thus reducing their effectiveness, which can also have a protective role in IPF [106, 107, 108].
Fibulin 1 (Fbln1) is a secretory glycoprotein with a significant role in embryonic morphogenesis and alveolar septal formation [109]. Four isoforms of this protein (Fbln1a/b/c/d) have been isolated, differing from each other in C-terminal sequences [110]. However, the identification of individual variants is difficult due to the unavailability of antibodies specific to certain isoforms [111]. Fbln1 has an important role in tissue repair and has been associated with several different respiratory diseases [111]. The importance of the Fbln1c form in the pathogenesis of various respiratory diseases is especially emphasized, which is achieved through the stimulation of fibroblast proliferation and remodeling of the extracellular matrix [110, 111]. Experimental mouse models have shown that the inhibition of Fbln1c expression reduces the proliferation of smooth muscle cells and fibroblasts and collagen deposition around the small airways [111]. In addition, mouse models have shown a significant role of Fbln1c in chronic inflammation, where the inhibition of Fbln1c expression reduces the influx of inflammatory cells into the bronchoalveolar lavage and the synthesis of cytokines and chemokines in the lungs [111]. Accordingly, Fbln1 is mentioned as a potential biomarker and therapeutic target in respiratory and other diseases involving inflammation and remodeling [111].
Elevated values of Fbln1 in the serum and lungs of patients with IPF compared to healthy subjects suggest a role of Fbln1 in the pathogenesis of this disease [109]. High values of Fbln1 in the lungs are a consequence of increased production in smooth muscle cells and fibroblasts; apart from that, under the influence of TGF-β, exogenously synthesized Fbln1 is incorporated into the extracellular matrix [111]. The high serum concentration of Fbln1 correlates with decreased lung function and is associated with acute exacerbation of the disease [109, 112]. Fbln1 values are higher in patients with IPF compared to other ILDs. Still, they are in correlation with pulmonary function in other types of disease, suggesting that Fbln1 may be a predictive marker of disease progression in other ILDs, such as idiopathic nonspecific pneumonia [109].
Excessive deposition of the extracellular matrix is critical to the pathogenesis of IPF. Collagen is the main component of the extracellular matrix, whose synthesis and degradation take place in a balanced way in healthy lungs, while in IPF, this balance is disturbed [113, 114]. During synthesis, the procollagen is cleaved, and during the degradation of collagen molecules, MMPs cut parts of this molecule, which reveals different neoepitopes in all these processes [115].
Peptides formed during synthesis and newly formed neoepitopes are released into the circulation and detected in the blood. Studies have shown that serum concentrations of neoepitopes of collagen synthesis PRO-C3 and PRO-C6 (collagen type 3 and type 6) are higher in patients with IPF compared to healthy subjects of the same age. Their elevated concentration is associated with IPF progression [115]. The concentration of collagen degradation markers (C1M, C3M, C6M, and CRPM) is also elevated in IPF. Longitudinal changes in serum concentrations of these neoepitopes follow the progression of fibrosis and can predict mortality in individuals with IPF in three months [116]. Biomarkers of collagen synthesis and degradation have the potential to improve clinical trials in IPF, prognostic evaluation, and make decisions on therapy [115].
HSP47 is a protein necessary for the synthesis and secretion of collagen molecules. Increased expression of HSP40 is closely related to excessive production and accumulation of collagen, so these data indicate a significant role of this molecule in fibrotic processes and its correlation with the activity of such diseases. It has been shown that a significant increase in the concentration of HSP47 occurs during the acute exacerbation of the disease, compared to the stable form of IPF. Additionally, this biomarker has been found to be superior to better known and studied markers of pulmonary fibrosis, such as KL-6 and SP-A and D [117]. It was assumed that, as HSP47 concentrations in the exacerbation phase of the disease are higher than during stable disease, this distinction would also exist between patients with a stable form of the disease and healthy subjects. However, these assumptions have been refuted in the research conducted [117, 118].
The precise role of HSP47 in the pathogenesis of IPF has not been determined, but this molecule is likely responsible for the additional effect of pirfenidone in the inhibition of fibrotic processes. In addition to direct suppression of type I collagen expression, it is possible that pirfenidone partially achieves its anti-fibrotic effect by suppressing the expression of HSP47 depending on TGF-β1 [119].
The lungs are characteristic of IPF patients in the regions of the so-called fibroblast foci, where ECM production is most active. In these foci, the predominant cells are myofibroblasts, where under the effect of various cell mediators, the proliferation of these cells takes place, with the inhibition of their apoptosis [120]. Myofibroblasts are cells that phenotypically correspond to the stage between fibroblasts and smooth muscle cells [121].
There are two hypotheses on the origin of myofibroblasts: traditional – that they are formed from fibroblasts after their activation by inflammatory stimuli and more recent – that they are formed by differentiation of alveolar epithelial cells [122].
Fibrocytes are cells originating from the monocytic lineage. In case of tissue damage, migrate to the site of damage attracted by chemotactic factors and then differentiate into fibroblast-like cells. They are present in the circulation and can produce ECM. Fibrocytes express different markers, and these are primarily CD45 leukocyte markers and type I collagen. During its differentiation, it has been found that CD45 expression gradually decreases while type I collagen expression remains unchanged. It has also been found that their differentiation is accelerated under the effect of TGF- β [123]. Although they have a protective role in the process of tissue remodeling and damage repair, it is considered that fibrocytes are involved in the progression of pulmonary fibrosis. Studies show that in the blood of IPF patients, an increased number of circulating fibrocytes is associated with a poor disease outcome [124, 125]. It has been found that, compared to healthy subjects, in patients with IPF, there is a significantly higher number of circulating fibrocytes, identified precisely as CD45+, collagen type I+ cells. In addition, in patients with AE of the disease, these cells are present in ten times greater numbers than in the case with a stable state [125].
Although IPF is primarily not an inflammatory disorder, inflammatory and immune-mediated pathways are activated in IPF patient’s lungs.
CC chemokine ligand 18 (CCL18) is a protein secreted by myeloid lineage cells: monocytes, macrophages, and dendritic cells. In patients with idiopathic pulmonary fibrosis, alveolar macrophages produce large amounts of CCL18 [126, 127]. Th2 cytokines lead to alternative activation of alveolar macrophages, which thus activated have a role in tissue and fibrosis healing [128, 129]. Alternatively, activated macrophages produce CCL18, which leads to increased collagen production by pulmonary fibroblasts, and collagen then stimulates alveolar macrophages to produce CCL18 by a positive feedback loop. In this way, the process of fibrosis is continuously maintained [126].
Increased serum concentrations of CCL18 in IPF are negatively correlated with pulmonary function tests and associated with disease progression [126, 127]. In a prospective study of 72 patients, significantly higher mortality was observed in the group of patients with a CCL 18 concentration above 150 ng/mL [130]. It was also found that pirfenidone used in the treatment of IPF significantly reduces the expression of CCL18 in macrophages [130].
Data obtained from meta-analysis Elhai et al. showed that CCL18 has a significant prognostic value [36]. Based on previous research, it can be concluded that CCL18 is a good prognostic marker in IPF.
In a posthoc analysis of phase 3 ASCEND and CAPACITY trials [131], concentrations of IPF biomarkers in IPF patients who received pirfenidone 2403 mg/day or placebo were investigated, and their associations with changes in FVC and disease progression over one year. CCL18 was consistently prognostic for absolute change in percentage of FVC% and was the most consistent predictor of disease progression across IPF cohorts.
CC chemokine ligand 2 (CCL2) is one of the chemokines involved in the recruitment of mononuclear phagocytes, thereby promoting inflammation and the development of tissue fibrosis [132]. Additionally, the recruitment of fibrocytes into the lungs most likely occurs because of interactions between chemokine ligands (including CCL-2) and their receptors [133]. More than 20 years ago, it was established that significantly higher serum concentrations of this chemoattractant are present in patients with idiopathic pulmonary fibrosis [134]. A recently published paper, which focused on examining the prognostic potential of various chemokines, found significantly higher concentrations of CCL-2 in patients with both acute exacerbations of IPF and a stable form of the disease, compared to a control group of subjects [135]. The same study concluded that CCL2 levels, among other chemokines, showed neither correlation with lung function nor patient survival [135].
CXC chemokine 13 (CXCL13) is a protein secreted by dendritic cells and the main mediator in attracting B lymphocytes to inflammatory lesions. Antigen-stimulated B lymphocytes undergo a process of gradual maturation, so these cells, as well as altered, differentiated B lymphocytes, are present in patients with IPF [136]. Increased CXCL13 mRNA has been isolated in the lungs of patients with IPF compared to control subjects, and serum levels of CXCL13 were increased in patients with IPF compared to control subjects. Elevated CXCL13 protein levels are associated with increased mortality in patients with IPF. The highest levels of CXCL13 were found in IPF patients with acute exacerbations or pulmonary hypertension [137].
The toll-like receptor is a transmembrane glycoprotein receptor expressed predominantly endosomal. Recent studies show an association between Toll-like receptors and aberrant fibrogenesis characteristic of idiopathic pulmonary fibrosis [138]. These receptors recognize molecular patterns that can be potentially dangerous and promote adequate immune response [138]. The Toll-like receptor 3 L412F polymorphism is associated with defective TLR3 activation, which causes mortality in IPF [139]. The association of this mutation with accelerated decline in lung function and consequent early death has been proven. This information can be critical in identifying patients with a rapidly progressive phenotype [140]. Toll-like receptor 3 belongs to the group of receptors that have a significant role in innate immunity. It mediates the innate immune response to tissue injury or infection by inducing NF-κB activation and type 1 interferon production [141]. Toll-like receptors recognize patterns from bacterial, viral, protozoal, and fungal pathogens, which are most important for their survival [141]. The Toll-like receptor 3 is a receptor that recognizes viral double-stranded RNA (dsRNA) and regulates the pro-inflammatory response and IFN-1 production [142]. In studies on fibroblasts in IPF, the unregulated proliferation of primary fibroblasts was observed and decreased production of IFN-β mediated by TLR3 receptors [139]. Activation of TLR3 receptors in primary fibroblasts has an antifibrotic effect and leads to a decrease in TGF-β production, increased collagen production, and increased metalloproteinase activity [143, 144].
The TLR signaling pathway during the reactive response to viruses acts as a blocker of fibroproliferation, so TLR3 signaling deficiency can cause an inadequate lung response to viral pathogens and expose them to chronic cycles of damage and repair considered the basis of IPF pathology [144].
Toll-interactin protein (TOLLIP) is a protein whose expression in the lungs has been observed in type II alveolar cells, macrophages, and basal cells. This protein has a role in important signaling pathways associated with lung diseases, including IL-1β, IL-13, TLR, and TGF-β [145].
It has been found that the rs111521887 and rs5743894 gene variants located in TOLLIP introns are associated with 40–50% reduced TOLLIP gene expression in the lungs and susceptibility to IPF [146]. Interestingly, the rs5743890_G allele is related to increased mortality in IPF, although it is associated with decreased IPF susceptibility, which suggests that the genetic basis is related to different clinical outcomes [39]. This indicates the heterogeneity and complexity of the pathogenesis of IPF [146]. TOLLIP is an important regulator of innate immune responses mediated by Toll-like receptors and the TGF-β1 signaling pathway through TGF-β1 receptor degradation [92]. It antagonizes the TGF-β signaling pathway by degrading the TGF-β1 receptor [147]. This TLR inhibitory protein is potentially useful for detecting various responses to the treatment of IPF in different genotypes [148].
Decreased TOLLIP expression increases proinflammatory cytokines IL-6 and TNF production in macrophages after TLR stimulation [149]. These data suggest that TOLLIP expression may be protective by reducing the proinflammatory and profibrotic cascade [144].
Defensins are small antimicrobial peptides mainly secreted by neutrophils and epithelial cells, which affect some gram-positive and gram-negative bacteria, as well as viruses [92]. Comparative analysis of gene expression from blood and lung tissue samples of patients with stable IPF and those with acute exacerbation of IPF revealed increased gene expression for alpha-defensins 3 and 4 in IPF with acute disease exacerbation [150].
Alpha-defensins are activated by MMP7, whose gene expression is also increased in the lungs of patients with IPF [22]. It has been found that serum levels of alpha defensin are higher in patients with IPF than in healthy subjects and are associated with the deterioration of the disease [150, 151].
S100 calcium-binding protein A4 (S100A4, fibroblast-specific protein-1) belongs to the S100 family containing calcium-binding motifs. S100A4 promotes lung fibrosis via proliferation and activation of fibroblasts and promotes the transition of fibroblasts to myofibroblasts [152].
Akiyama et al. [153] have shown the clinical significance of serum S100A4 in IPF patients. They revealed an independent association of higher S100A4 levels with a higher disease progression rate and a higher mortality rate, suggesting that S100A4 may be promising in the prognosis and management of IPF. The presence of higher levels of S100A4 in the serum of participants with IPF was linked with a significantly lower progression-free survival and higher 2-year mortality.
S100A8/A9 belongs to the S100 family of calcium-binding proteins derived from neutrophils and monocytes, which modulate the immune response [154]. In the pathogenesis of pulmonary fibrosis, the role of these proteins is based on the proliferation of fibroblasts, the influence on their differentiation, and the increase in collagen production by mentioned cells [155]. Concentrations of S100A8 and A9 are, as recent research results show, significantly higher in patients with acute disease exacerbation than in healthy patients, as well as in patients with confirmed IPF without acute exacerbation [156]. Patients with higher concentrations of these two biomarkers had a significantly poorer three-month survival rate, so S100A8 and S100A9 proved to be significant prognostic markers [156].
S100A12 is a member of the S100 family of calcium-binding proteins that has a significant role in regulating inflammatory processes and immune response. Its proinflammatory activity includes chemotaxis and activation of the intracellular signaling cascade, leading to cytokine and oxidative stress production [157]. In a study with a relatively large number of patients with IPF, serum concentrations of S100A12 in IPF were high and correlated with poor disease prognosis [158].
HSP production is regulated by various stress effects on cells, as well as their damage. They are located on the cell surface and have a role in transmitting information and modulation of the immune response [159]. Various autoantibodies to HSP have been found in patients with autoimmune diseases. What singled out HSP and autoantibodies to these proteins as potential biomarkers in IPF is, inter alia, the fact that cell cultures have been found to have the ability to activate monocytes and increase IL-8 production by these cells [158, 160]. IL-8, as a pro-inflammatory chemokine, further acts as a chemoattractant on neutrophils and activates them [161]. This interleukin is considered one of the major mediators in the pathogenesis of IPF, and its higher serum concentrations and BAL of these patients are associated with more extensive pulmonary fibrosis [162].
The results of a study conducted by Mills et al. indicate that IPF patients did not show a significant increase in serum antiHSP-72 antibodies compared to healthy subjects, nor did the concentration of the identical immunoglobulins differ between IPF and other interstitial lung diseases. However, in the bronchoalveolar lavage, an increase in the concentration of total antibodies (classes G, A, and M), but not of class G itself, is associated with a better disease outcome, i.e., it was observed in patients with slower disease progression [163]. These results contrast with the data from the previous study, which showed that the increase in the concentration of autoantibodies to HSP-70 in IPF patients was associated with a poor disease outcome [164]. This discrepancy in the conclusions can be justified by applying different methods, i.e., the antigens used to isolate antibodies and the non-homogeneous groups in the research of Kahloon et al. in terms of age, gender and ethnicity. It is undeniable that these proteins and autoantibodies directed at them have their place in the pathogenesis of IPF, but further research is needed to elucidate the role and potential use of these biomarkers in pulmonary fibrosis.
YKL-40 is a glycoprotein, a member of the chitinase and chitin-like protein family, expressed in many tissues, especially those characterized by high metabolic activity [165]. The exact biological role of YKL40 is not fully known, but it is involved in various pathophysiological processes as an inflammatory glycoprotein, including cell proliferation, migration, and tissue remodeling [166].
YKL-40 is mainly expressed in alveolar epithelial cells and macrophages, and its values are elevated in the serum and lungs of patients with IPF [165]. In addition, high concentrations of YKL-40 are detected in other diseases accompanied by high levels of fibrosis, such as liver cirrhosis, Crohn’s disease, and systemic sclerosis [165]. Elevated levels of YKL-40 in serum and bronchoalveolar lavage are associated with a higher risk of death in patients with IPF, although there is a weak correlation between these concentrations [104]. Also, YKL-40 values are inversely related to lung function in asthma, sarcoidosis, and IPF [165]. YKL-40 is not a marker specific for IPF, although the cut-off value of 79 ng/ml is mentioned in the literature and associated with a poorer prognosis [105]. Compared to the short-term prognostic markers SP-D and CCL18, YKL-40 has the highest predictive value 3–4 years after diagnosis, so a potential combination of these markers could allow a better assessment of survival [165].
Vimentin is a cytoskeleton protein in cells of mesenchymal origin which is considered responsible for increased cell invasiveness so that one can assume its importance in fibroblast invasion into the so-called fibrous foci in the lungs of IPF patients [167]. This filament is essential to the process of wound healing, so its overexpression results in increased cell invasiveness and excessive scar tissue formation [167, 168].
Immunochemical staining of tissue samples from IPF patients showed that vimentin was significantly more expressed in the cells at the periphery of the fibrous focus than in the center. In the same study, it was found that in the fasting state, as an inducer of the autophagy process, fibroblasts originating from IPF patients expressed vimentin more than control group fibroblasts, while the process of autophagy was lacking [169].
The defect of the autophagy process has already been associated with the development of idiopathic pulmonary fibrosis, where there is no removal of parts of the extracellular matrix by their implementation in autophagosomes and the destruction of these products after fusion with lysosomes [170, 171].
The antiangiogenetic, as well as the antitumor agent WFA (withaferin A), can bind to vimentin, covalently modify it, and cause its aggregation [172]. Treatment of IPF fibroblasts with this agent increased the number of autophagosomes in these cells, i.e., it stimulated autophagy. In addition, the expression of vimentin and type I collagen were reduced, and the inhibition of vimentin reduced the invasiveness of fibroblasts [169]. All these facts confirm the role of vimentin in pulmonary fibrosis and its importance in the progression of the disease.
Various cells involved in the development of pulmonary fibrosis secrete vimentin under the influence of TGF-β1 [173]. This secreted cytoskeletal protein was found in significantly higher IPF patients than in the healthy, control group [174]. Over-expression of otherwise immunologically inert molecules leads to their higher immunogenicity [175]. This is confirmed by the results of a 2017 study that proved anti-vimentin autoantibodies in IPF patients in a much higher concentration than is the case with other lung diseases and healthy subjects. Patients with poorer clinical and poor disease outcomes had higher circulating concentrations of anti-vimentin antibodies features [174].
As mentioned above, the central event in the development of IPF is an excessive reaction to repeated damage to alveolar epithelial cells with the formation of scar tissue that replaces the functional one [176]. Pulmonary fibrosis was considered a non-immune disease, but more and more evidence speak in favor of the role of the immune system in initiating the onset of fibrotic changes, as well as in the progression of fibrosis.
Regulatory T-lymphocytes are CD4+ T-cells that participate in immunosuppression and prevent the development of an immune response to the body’s antigens (autotolerance) [177]. These cells can produce various cytokines, including IL-10 and TGF-β1, and therefore may have the potential to both suppress and promote the onset of fibrotic changes [148].
Activation of these T-lymphocytes increases the expression of semaphorin seven, which has a chemotactic effect on macrophages, stimulates the production of proinflammatory cytokines, and regulates collagen production by fibrocytes [178]. Increased expression of semaphorin seven on regulatory T cells has been found in IPF [179].
The cell population of Th2 lymphocytes (T-helper cells) and their product IL-13, which have long been known to have a role in allergic diseases and the pathogenesis of asthma, are now also associated with the development of IPF. Namely, this interleukin affects the extracellular matrix production and induces tissue fibrosis, which has been shown in animal models, where increased expression of IL-13 had profibrotic effects [180]. Studies show an increased concentration of this cytokine in the blood of patients with IPF and the correlation of these concentrations with disease progression [181]. These claims are consistent with the results of studies performed on mice lacking the IL-13 gene in which the induction of pulmonary fibrosis by bleomycin was inhibited [182].
The soluble receptor for advanced glycation end-products (sRAGE) acts as a decoy for capturing advanced glycation end-products (AGEs) and inhibits the activation of the oxidative stress and apoptotic pathways. The study of Manichaikul et al. [183] found that adults with IPF have lower sRAGE levels. They were associated with greater disease severity and a higher death rate or lung transplant at one year compared with healthy controls. Additionally, lower plasma sRAGE levels in patients with IPF and other ILDs when compared with healthy controls Lower sRAGE levels were associated with disease severity. In their study, Cabrera Cesar et al. [184] provide evidence, for the first time, for the possible use of AGE as a differential diagnostic biomarker to distinguish between IPF and connective tissue disease-associated interstitial lung disease (CTD-ILD). The role of RAGE in human and experimental models of IPF did not fully understand [185].
Machahua et al. [186] evaluated the AGEs, and sRAGE levels in serum as a potential biomarker in IPF, demonstrate that the increase of AGE/sRAGE ratio is higher in IPF. AGE/sRAGE increase correlates with respiratory functional progression (FVC and DLCO values); changes in serum AGEs and sRAGE correlated with % change of FVC, DLCO, and TLC during the follow-up.
No difference in AGE or RAGE expression was observed in lungs with non-specific interstitial pneumonia compared to that in the controls. Levels of circulating AGEs also increased significantly in the lungs of patients with IPF compared to those with NSIP and normal control [187].
Aberrant angiogenesis is implicated in the pathogenesis of pulmonary fibrosis, and mediators of this process are VEGF, endothelin 1, interleukin 8.
Vascular endothelial growth factor-A (VEGF-A) is the predominantly expressed member of the VEGF family and is often denoted as VEGF. It is a tyrosine kinase glycoprotein and is one of the most potent factors that stimulate angiogenesis. VEGF is elevated in IPF compared with healthy controls [137, 188].
Barratt et al. [189] report that the levels of VEGF-A165b protein were found to be dramatically elevated in the lung tissue of patients with IPF, is produced mostly by the alveolar epithelium but also by macrophages, lymphocytes, and fibroblasts.
Ando et al. reported reduced VEGF-A in the BALF of IPF patients compared to controls [190]. VEGF-A levels in peripheral blood are associated with the severity and progression of IPF [191]. Enhanced expression of VEGF-A is correlated with increased alveolar-capillary density in non-fibrotic regions of IPF lungs [192].
Nintedanib, therapeutics for IPF, acts by targeting VEGF receptor signaling, slows IPF progression, but the utility of VEGF as a marker of treatment success is not determined [193, 194].
Endothelin-1 (ET-1) is a vasoactive peptide that plays a central role in lung fibrosis. ET-1 drives fibroblast activation, proliferation, differentiation into myofibroblast - processes that lead to excessive collagen deposition [195]. Barlo et al. [196] revealed that ET-1 in serum was significantly increased in IPF patients compared with healthy control subjects until it was significantly decreased in bronchoalveolar lavage fluid (BALF).
Interleukin-8 (IL-8) is produced by phagocytes when exposed to inflammatory stimuli and promotes angiogenesis [191]. IL-8 levels were significantly higher in IPF exacerbated patients, and an increase in IL-8 by one pg/ml increases the odds of death by 6.7% in IPF patients [197]. Schupp et al. [198] found significantly higher levels of IL-8 in BAL samples from IPF-AE patients compared to stable IPF patients. Xaubet et al. [199] found that the percentage of IL-8–positive bronchoalveolar lavage macrophages was significantly higher in areas of IPF lung with extensive fibrosis defined by HRCT scans compared with BALF from healthy volunteers.
The literature supports the concept of combining multiple markers and/or clinical parameters in clinical decision support. Biomarker panels consisting of two or more suspected biomarkers may potentially indicate a higher likelihood of IPF than any single biomarker, more effectively differentiate IPF patients from healthy volunteers and patients with other pulmonary diseases, define prognosis at the time of diagnosis, identify responses to therapy.
For example, the improved predictive value of the combination of biomarkers SP-A and SP-D in IPF was observed [200]. Rosas et al. [86] found that the combination of serum MMP1 and MMP7 levels distinguish IPF from other chronic lung diseases more than either protein on its own. Also, the combination of five proteins (MMP-7, MMP-1, MMP-8, Insulin-like Growth Factor Binding Protein 1(IGFBP1) and tumor necrosis factor receptor superfamily, member 1a (TNFRSF1A)) could distinguish with high sensitivity and specificity IPF patients from normal controls. White et al. [63] showed that a combined serum biomarker panel combining SP-D, MMP-7, and osteopontin differentiated IPF patients from other types of ILD (except for rheumatoid arthritis–associated ILD) more readily than each biomarker, and this biomarker index may improve diagnostic confidence in IPF. Hamai et al. [201] found that a combination of MMP-7 and KL-6 potentially support the diagnosis of IPF and might improve survival prediction in patients with IPF. Recently published study Xue et al. [202], found that KL-6, CCL3, and CXCL13 significantly improves the diagnosis of idiopathic interstitial pneumonia. IPF patients with a high level of SP-D but low KL-6 in their serum had a better prognosis [203]. A panel of mi-RNAs including miR-302c, miR-423, miR-210, miR-376C, and miR-185 has been shown to be associated with disease severity, differentiating fast from slow IPF progressors [204].
The next step was to examine the combination of clinical parameters and molecular biomarkers to achieve more accurate results regarding the prognosis of IPF. Kinder et al. [84] reported on a significant improvement in their prediction model of 1-year mortality in surgical lung biopsy-proven IPF, when serum levels of SP-A and SP-D were added to the clinical predictors of mortality alone [205]. Richards et al. [206] evaluated a panel of 92 proteins in a retrospective derivation cohort of IPF patients and tested significant findings in an independent validation cohort of IPF patients, and identified five biomarkers (MMP-7, intercellular adhesion molecule-1, Interleukin-8, vascular cell adhesion protein −1, S100A12) associated with disease progression or mortality. Combining clinical parameters and plasma protein concentrations (gender, FVC%, DLCO%, MMP-7), they constructed peripheral blood risk index-PCMI, distinguishing high and low mortality risk subgroups in the derivation was accurately predictive of mortality in the validation cohort. Song et al. [65] found that the predictive model of survival includes biomarkers (MMP7, SPA, KL6) and clinical variables (FVC%, DLCO%, age, change in FVC at six months) is better than the model based on clinical parameters.
Herazo-Maya et al. [207] have recently identified a 52-gene signature in peripheral blood mononuclear cells of patients with IPF, and y further validated in six different cohorts of patients with IPF. They developed a SAMS (Scoring Algorithm for Molecular Subphenotypes) risk scoring system based on the 52-gene signature. Applying SAMS, low risk and high-risk groups of IPF patients with significant differences in outcome (mortality or transplant-free survival). This 52-gene signature could be valuable in predicting response to therapy.
In testing the idea that a combination of clinical and biological parameters can improve IPF patients’ outcomes prediction, Adegunsoye et al. [208] derived a clinical-molecular risk (CMR) score (CA-125, MMP7, YKL-40, OPN, age, and percent predicted FVC) for treatment exposed patients. They found that a clinical-molecular signature of IPF transplant-free survival may provide a reliable predictor of outcome risk in anti-fibrotic treated patients. This risk score may help identify individuals at risk of poor outcomes despite antifibrotic initiation and open the discussion of the application of CMS risk score before initiation of antifibrotic therapy to identify patients warranting closer clinical monitoring or earlier lung transplant referral [209].
Within the last decade, a broad range of molecular biomarkers for IPF has been reported. Until now, despite a large number of publications about IPF biomarkers, their use in routine is not recommended in international clinical practice yet. The successful translation of molecular biomarkers into clinical practice requires validation in large, multi-center, prospective studies with long-term, longitudinal follow-up, standardization of assays, serial measurements of biomarkers, and interventional trials that show changes related to clinical IPF state.
However, most data about IPF biomarkers originate from small-sized, single-center studies of the retrospective design, cross-sectional with measurements at a single time-point, and often in Asiatic cohorts of patients where their use is more common. This raises questions about the generalizability of the results obtained in Asiatic cohorts as well as about the determination of an optimal cut-off. Their accuracy should also be confirmed in non/Asiatic, Caucasian cohorts to routinely apply them in the management of IPF.
Furthermore, diagnostic criteria for IPF have recently changed, and most of the studies published before did not systematically use HRCT or histology. However, using these stringent criteria, confident data regarding biomarkers value could be obtained. Also, the gold standard for measuring disease activity is missing.
The validation of useful and accurate diagnostic markers could reduce uncertainty and the use of the invasive procedure. Inter-assay disagreement can represent a confounding factor in the interpretation of test results in different studies, and the definition of an optimal cut-off is very important.
Finally, as already touched on in the chapter, investigators are resorting to panels of multiple biomarkers to differentiate IPF patients more effectively from healthy volunteers or patients with other pulmonary diseases. The use of a biomarker index composed of multiple biomarkers already studied separately, with the aim of improving diagnostic accuracy in distinguishing IPF from other ILDs or healthy controls, is promising.
There is evidence of extremely strong genetic association in IPF. Recent advances in genetic sequencing and bioinformatics have made it much easier to detect genetic variants rapidly. It seems that in the near future, we will be able to analyze genetic markers to gain prognostic information for IPF patients or help screen at-risk patients with a familial history that do not exhibit signs or symptoms of IPF.
The utilization of high-throughput sequencing to detect microbial and/or viral genetic material in bronchoalveolar lavage fluid or lung tissue samples has amplified the ability to identify and quantify specific microbial and viral populations [210].
Use of liquid biopsy, which allows the isolation of circulating cell-free DNA from blood, could be very important in the discrimination of patients affected by IPF from those with other ILDs [211].
Discovery, validation, and implementation of clinically useful molecular biomarkers discovered through omics (genomics, epigenomics, transcriptomics, proteomics, and metabolomics) will facilitate precision medicine in IPF [212, 213, 214].
Soon, we expect the results of many clinical trials evaluating as primary or secondary outcomes known and new biomarkers that will convince clinicians of the value of using biomarkers at multiple stages of the diagnosis and personalized management of IPF.
The authors declare no conflict of interest.
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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De",surname:"Nazaré",slug:"fabio-nazare",fullName:"Fábio Nazaré"}]},{id:"15098",doi:"10.5772/15736",title:"Silicon Carbide: Synthesis and Properties",slug:"silicon-carbide-synthesis-and-properties",totalDownloads:23099,totalCrossrefCites:29,totalDimensionsCites:68,abstract:null,book:{id:"83",slug:"properties-and-applications-of-silicon-carbide",title:"Properties and Applications of Silicon Carbide",fullTitle:"Properties and Applications of Silicon Carbide"},signatures:"Houyem Abderrazak and Emna Selmane Bel Hadj Hmida",authors:[{id:"18643",title:"Dr.",name:"Houyem",middleName:null,surname:"Abderrazak",slug:"houyem-abderrazak",fullName:"Houyem Abderrazak"},{id:"23082",title:"Dr.",name:"Emna Selmane",middleName:null,surname:"Bel Hadj Hmida",slug:"emna-selmane-bel-hadj-hmida",fullName:"Emna Selmane Bel Hadj Hmida"}]},{id:"47585",doi:"10.5772/58884",title:"Free Space Optical Communications — Theory and Practices",slug:"free-space-optical-communications-theory-and-practices",totalDownloads:9078,totalCrossrefCites:45,totalDimensionsCites:64,abstract:null,book:{id:"4473",slug:"contemporary-issues-in-wireless-communications",title:"Contemporary Issues in Wireless Communications",fullTitle:"Contemporary Issues in Wireless Communications"},signatures:"Abdulsalam Ghalib Alkholidi and Khaleel Saeed Altowij",authors:[{id:"100466",title:"Dr.",name:"Abdulsalam",middleName:null,surname:"Alkholidi",slug:"abdulsalam-alkholidi",fullName:"Abdulsalam Alkholidi"},{id:"131091",title:"MSc.",name:"Khalil",middleName:null,surname:"Altowij",slug:"khalil-altowij",fullName:"Khalil Altowij"}]}],mostDownloadedChaptersLast30Days:[{id:"70315",title:"Some Basic and Key Issues of Switched-Reluctance Machine Systems",slug:"some-basic-and-key-issues-of-switched-reluctance-machine-systems",totalDownloads:1264,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Although switched-reluctance machine (SRM) possesses many structural advantages and application potential, it is rather difficult to successfully control with high performance being comparable to other machines. Many critical affairs must be properly treated to obtain the improved operating characteristics. This chapter presents the basic and key technologies of switched-reluctance machine in motor and generator operations. The contents in this chapter include: (1) structures and governing equations of SRM; (2) some commonly used SRM converters; (3) estimation of key parameters and performance evaluation of SRM drive; (4) commutation scheme, current control scheme, and speed control scheme of SRM drive; (5) some commonly used front-end converters and their operation controls for SRM drive; (6) reversible and regenerative braking operation controls for SRM drive; (7) some tuning issues for SRM drive; (8) operation control and some tuning issues of switched-reluctance generators; and (9) experimental application exploration for SRM systems—(a) wind generator and microgrid and (b) EV SRM drive.",book:{id:"8899",slug:"modelling-and-control-of-switched-reluctance-machines",title:"Modelling and Control of Switched Reluctance Machines",fullTitle:"Modelling and Control of Switched Reluctance Machines"},signatures:"Chang-Ming Liaw, Min-Ze Lu, Ping-Hong Jhou and Kuan-Yu Chou",authors:[{id:"37616",title:"Prof.",name:"Chang-Ming",middleName:null,surname:"Liaw",slug:"chang-ming-liaw",fullName:"Chang-Ming Liaw"},{id:"306461",title:"Mr.",name:"Min-Ze",middleName:null,surname:"Lu",slug:"min-ze-lu",fullName:"Min-Ze Lu"},{id:"306463",title:"Mr.",name:"Ping-Hong",middleName:null,surname:"Jhou",slug:"ping-hong-jhou",fullName:"Ping-Hong Jhou"},{id:"306464",title:"Mr.",name:"Kuan-Yu",middleName:null,surname:"Chou",slug:"kuan-yu-chou",fullName:"Kuan-Yu Chou"}]},{id:"52822",title:"Non-Orthogonal Multiple Access (NOMA) for 5G Networks",slug:"non-orthogonal-multiple-access-noma-for-5g-networks",totalDownloads:14893,totalCrossrefCites:31,totalDimensionsCites:40,abstract:"In this chapter, we explore the concept of non-orthogonal multiple access (NOMA) scheme for the future radio access for 5G. We first provide the fundamentals of the technique for both downlink and uplink channels and then discuss optimizing the network capacity under fairness constraints. We further discuss the impacts of imperfect receivers on the performance of NOMA networks. Finally, we discuss the spectral efficiency (SE) of the networks that employ NOMA with its relations with energy efficiency (EE). We demonstrate that the networks with NOMA outperform other multiple access schemes in terms of sum capacity, EE and SE.",book:{id:"5480",slug:"towards-5g-wireless-networks-a-physical-layer-perspective",title:"Towards 5G Wireless Networks",fullTitle:"Towards 5G Wireless Networks - A Physical Layer Perspective"},signatures:"Refik Caglar Kizilirmak",authors:[{id:"188668",title:"Dr.",name:"Refik Caglar",middleName:null,surname:"Kizilirmak",slug:"refik-caglar-kizilirmak",fullName:"Refik Caglar Kizilirmak"}]},{id:"77871",title:"Protection of Microgrids",slug:"protection-of-microgrids",totalDownloads:301,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The concept of microgrids goes back to the early years of the electricity industry although the systems then were not formally called microgrids. Today, two types of microgrids can be seen: independent and grid connected. The protection requirement of these two types differs as the protection needs of an independent microgrid are intended for protecting components and systems within the microgrid, whereas a grid connected microgrid demands both internal and external protection. The first part of this chapter is dedicated to independent microgrids. How protection devices such as residual current circuit breakers, miniature and moulded case circuit breakers, and surge protective devices should be selected for an example microgrid is discussed while referring to the relevant standards. In the next section, the protection of a grid connected microgrid is discussed. Particularly, micro-source protection, microgrid protection, loss of mains protection and fault ride-through requirements are discussed while referring to two commonly used distributed generator connection codes. An example with simulations carried out in the IPSA simulation platform was used to explain different protection requirements and calculation procedures. Finally, grounding requirements are discussed while referring to different interfacing transformer connections and voltage source inverter connections.",book:{id:"10176",slug:"microgrids-and-local-energy-systems",title:"Microgrids and Local Energy Systems",fullTitle:"Microgrids and Local Energy Systems"},signatures:"Janaka Ekanayake",authors:[{id:"328170",title:"Prof.",name:"Janake",middleName:null,surname:"Ekanayake",slug:"janake-ekanayake",fullName:"Janake Ekanayake"}]},{id:"47585",title:"Free Space Optical Communications — Theory and Practices",slug:"free-space-optical-communications-theory-and-practices",totalDownloads:9076,totalCrossrefCites:45,totalDimensionsCites:64,abstract:null,book:{id:"4473",slug:"contemporary-issues-in-wireless-communications",title:"Contemporary Issues in Wireless Communications",fullTitle:"Contemporary Issues in Wireless Communications"},signatures:"Abdulsalam Ghalib Alkholidi and Khaleel Saeed Altowij",authors:[{id:"100466",title:"Dr.",name:"Abdulsalam",middleName:null,surname:"Alkholidi",slug:"abdulsalam-alkholidi",fullName:"Abdulsalam Alkholidi"},{id:"131091",title:"MSc.",name:"Khalil",middleName:null,surname:"Altowij",slug:"khalil-altowij",fullName:"Khalil Altowij"}]},{id:"41657",title:"Algorithms for Efficient Computation of Convolution",slug:"algorithms-for-efficient-computation-of-convolution",totalDownloads:10220,totalCrossrefCites:15,totalDimensionsCites:20,abstract:null,book:{id:"3158",slug:"design-and-architectures-for-digital-signal-processing",title:"Design and Architectures for Digital Signal Processing",fullTitle:"Design and Architectures for Digital Signal Processing"},signatures:"Karas Pavel and Svoboda David",authors:[{id:"154795",title:"Ph.D. Student",name:"Pavel",middleName:null,surname:"Karas",slug:"pavel-karas",fullName:"Pavel Karas"},{id:"155141",title:"Dr.",name:"David",middleName:null,surname:"Svoboda",slug:"david-svoboda",fullName:"David Svoboda"}]}],onlineFirstChaptersFilter:{topicId:"116",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82123",title:"Microwave-Assisted Pyrolysis Process: From a Laboratory Scale to an Industrial Plant",slug:"microwave-assisted-pyrolysis-process-from-a-laboratory-scale-to-an-industrial-plant",totalDownloads:36,totalDimensionsCites:0,doi:"10.5772/intechopen.104925",abstract:"One of the great challenges for the European Union (EU) is the “Circular Economy Package,” and to achieve this goal, materials at the end of their life cycle must be recycled using a sustainable process. In this way, as a thermochemical treatment, pyrolysis represents a significant opportunity so long it leads to the recovery of both energy and chemical content of mixed, contaminated, or deteriorated plastics. An excellent history of an academic-industrial adventure started in 2008 at the Department of Chemistry of the University of Florence demonstrates the possibility of employing microwaves to recycle plastics to preserve their energy and chemical content. After that, Techwave started industrialization of the process in 2019, realizing a small-scale prototype followed by a full-scale pilot plant using different plastic materials (e.g., polystyrene, acrylonitrile-butadiene-styrene (ABS), and polypropylene). Nowadays, the plant may process 90 kg/h of plastics with a low formation of char and gas and an interesting amount of liquid useful as a source of chemicals or fuel because it has an LHV of 35–43 kJ/kg. The Microwave-Assisted Pyrolysis (MAP) is an industrial novelty in plastic recycling, and it looks very promising for a much more modern and innovative plastic waste recovery system.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"Marco Frediani, Piero Frediani, Gianni Innocenti, Irene Mellone, Roberto Simoni and Gianpaolo Oteri"},{id:"82420",title:"Applications of Microwaves in Medicine and Biology",slug:"applications-of-microwaves-in-medicine-and-biology",totalDownloads:23,totalDimensionsCites:0,doi:"10.5772/intechopen.105492",abstract:"This chapter deals with the description of recent research activities oriented on the perspective of microwave technologies in medicine and biology. It brings new ideas about the possibilities of using microwaves in thermotherapy—above all toward hyperthermia in cancer treatment. Development of new types of hyperthermia applicators (based, e.g., on technologies such as metamaterials, evanescent modes in waveguides, and other types of transmission structures) will be discussed here. Furthermore, we would like to underline in this chapter perspectives of microwaves in medical diagnostics. It is possible to expect that, e.g., microwave differential tomography, UWB radar, and microwave radiometers (all three can be used both for medical diagnostic and for noninvasive temperature measurement) will soon play an important role in it. Finally, experimental equipment necessary for research on the biological effects of EM fields is presented.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"David Vrba, Jan Vrba, Ondrej Fiser, Jesus Cumana, Milan Babak and Jan Vrba Senior"},{id:"81917",title:"Fluidics for Reconfigurable Microwave Components",slug:"fluidics-for-reconfigurable-microwave-components",totalDownloads:15,totalDimensionsCites:0,doi:"10.5772/intechopen.104857",abstract:"Dielectric and conducting liquids with varying electromagnetic properties can offer novel alternatives for building tunable microwave passive components as well as antennas. Injecting these fluidics in or around microwave substrates alters their overall electrical characteristics, enabling circuit reconfigurability. Alternatively, changing the shapes and dimensions of conductors by using liquid metals can achieve similar reconfigurability. An overview of different liquids and their electromagnetic properties is first given. The principles behind the reconfigurability of the electrical characteristics of typical guiding structures based on mode shape variation in the presence of fluids are discussed. The realization of an N-bit programmable impedance tuner in 3D LTCC technology based on these principles is presented.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"Dorra Bahloul, Ines Amor and Ammar Kouki"},{id:"82105",title:"Vehicle-To-Anything: The Trend of Internet of Vehicles in Future Smart Cities",slug:"vehicle-to-anything-the-trend-of-internet-of-vehicles-in-future-smart-cities",totalDownloads:12,totalDimensionsCites:0,doi:"10.5772/intechopen.105043",abstract:"This chapter includes five parts—the concept of vehicle-to-anything (V2X), introduction of visible light communication (VLC), free-space optical communication (FSO), and terahertz (THz). The first part will present the concept of V2X. V2X is the basis and fundamental technology of future smart cars, autonomous driving, and smart transportation systems. Vehicle-to-network (V2N), vehicle-to-vehicle (V2V), vehicle-to-infrastructure (V2I), and vehicle-to-people (V2P) are included in V2X. V2X will lead to a high degree of interconnection of vehicles. The concept of VLC is presented in the second part. Intelligent reflecting surface (IRS) for nano-optics and FSO communication is introduced in the third part. At the same time, IRS keeps pace with the phase in communication links. Prospects of THz in glamorous cities are introduced in the fourth part. These new technologies will lead to trends in the future. A comparison of optical communication technology and applications in V2X is described in the fifth part.",book:{id:"10963",title:"Intelligent Electronics and Circuits - Terahertz, ITS, and Beyond",coverURL:"https://cdn.intechopen.com/books/images_new/10963.jpg"},signatures:"Mingbo Niu, Xiaoqiong Huang and Hucheng Wang"},{id:"82046",title:"One Model of Microwave Heating of Water Drop",slug:"one-model-of-microwave-heating-of-water-drop",totalDownloads:9,totalDimensionsCites:0,doi:"10.5772/intechopen.104949",abstract:"This work deals with the modeling of microwave heating of a water drop. A drop model is reduced to its electric dipoles, masses, and charges are constructed using the associating of COMSOL Multiphysics and Matlab software. The considered model proposes a microscopic point of view on microwave heating, which transforms electrical energy into heat.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"Serge Lefeuvre and Olga Gomonova"},{id:"82076",title:"Power Divider/Combiner",slug:"power-divider-combiner",totalDownloads:16,totalDimensionsCites:0,doi:"10.5772/intechopen.104911",abstract:"With the remarkable progress in the use of Internet of Things (IoT) and 5G, there is a demand for higher performance such as miniaturization, broadband/multiband, low loss, and high integration for several microwave circuits. This chapter treats microwave power dividers/combiners used in amplifiers, mixers, phase shifters, antenna feeding networks, and so on. Here, the treated circuits are composed of LC-ladder circuits and an absorption resistor. It shows that multiband (dual-band and tri-band) and broadband can be achieved by changing the number of stages of the LC-ladder circuit. In addition, the effectiveness of this design method is demonstrated by electromagnetic simulations and prototype experiments.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"Tadashi Kawai, Ayumu Tsuchiya and Akira Enokihara"}],onlineFirstChaptersTotal:41},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:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:140,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,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:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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"}}}}]},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:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,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. 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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. 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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. 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She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}]},{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. 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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. 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He previously worked as a post-doctoral fellow at the Ben-Gurion University of Negev, Israel; University of the Free State, South Africa; and Central University of Technology Bloemfontein, South Africa. He obtained his Ph.D. in Organic Chemistry from Nagaoka University of Technology, Japan. He has published more than seventy-four journal articles and attended several national and international conferences as speaker and chair. Dr. Kendrekar has received many international awards. He has several funded projects, namely, anti-malaria drug development, MRSA, and SARS-CoV-2 activity of curcumin and its formulations. He has filed four patents in collaboration with the University of Central Lancashire and Mayo Clinic Infectious Diseases. His present research includes organic synthesis, drug discovery and development, biochemistry, nanoscience, and nanotechnology.",institutionString:"Visiting Scientist at Lipid Nanostructures Laboratory, Centre for Smart Materials, School of Natural Sciences, University of Central Lancashire",institution:null},{id:"428125",title:"Dr.",name:"Vinayak",middleName:null,surname:"Adimule",slug:"vinayak-adimule",fullName:"Vinayak Adimule",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428125/images/system/428125.jpg",biography:"Dr. Vinayak Adimule, MSc, Ph.D., is a professor and dean of R&D, Angadi Institute of Technology and Management, India. He has 15 years of research experience as a senior research scientist and associate research scientist in R&D organizations. He has published more than fifty research articles as well as several book chapters. He has two Indian patents and two international patents to his credit. 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Since from August 2013 working as a Associate Professor, and in 2016 promoted to Profeesor in the School of Basic Sciences: Department of Chemistry and having 20 years of teaching and research experiences.",institutionString:null,institution:{name:"Rani Channamma University, Belagavi",country:{name:"India"}}},{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. 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He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"2",type:"subseries",title:"Prosthodontics and Implant Dentistry",keywords:"Osseointegration, Hard Tissue, Peri-implant Soft Tissue, Restorative Materials, Prosthesis Design, Prosthesis, Patient Satisfaction, Rehabilitation",scope:"