Standards or guidance related to cord blood and umbilical cord-derived cells.
\r\n\t
\r\n\tWith the development of the modern industry and society, the requirement of multifunctional, time effective, more reliable devices has become one of the most serious global challenges. Accordingly, around the globe, many researchers are working to meet the increasing demands in the fields of aircraft, aerospace, automobile, marine, electronic and allied industries and many other non-engineering areas which include medical and bio-medical fields.
\r\n\tIn line with the current global challenges, this book aims to incorporate topics from all the emerging Smart Material technologies covering application, synthesis, self-assembly, manipulation, simulation and theoretical modeling of smart materials. The book focus is envisioned on the Synthesis/ Simulation and Application of Smart Materials and Smart Hybrid Composites; Smart Sensing Materials; Smart Bioactive/ Nanostructured Materials for Health; Smart Photonic Materials; Shape Memory Alloys & Polymers and Smart Polymers.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"139621c1c59461cc2dd2fa3632449513",bookSignature:"Dr. Prasanta Kumar Ghosh, Dr. Arti Rushi and Dr. Kunal Datta",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9297.jpg",keywords:"Aircraft Applications, Civil Engineering Applications, Defence Applications, Mechanical Engineering Applications, Smart Sensing Materials, Nanowires, Nanocomposites, Drug Delivery Systems, Artificial Organs, Smart Photonic Materials, Orthopedic Surgery, Smart Polymers",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 24th 2019",dateEndSecondStepPublish:"March 2nd 2020",dateEndThirdStepPublish:"May 1st 2020",dateEndFourthStepPublish:"July 20th 2020",dateEndFifthStepPublish:"September 18th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"294687",title:"Dr.",name:"Prasanta",middleName:"Kumar",surname:"Ghosh",slug:"prasanta-ghosh",fullName:"Prasanta Ghosh",profilePictureURL:"https://mts.intechopen.com/storage/users/294687/images/system/294687.jpg",biography:"Dr. Prasanta Kumar Ghosh currently working as Assistant Professor at School of Physics, MIT-World Peace University (MIT-WPU) Pune (MS) India.\n\nHe has received his Ph.D. (Physics) degree in 2013 from the Department of Physics, Dr. B. A. M. University, Aurangabad (MS) India. Dr. Ghosh is an applied physicist and passionate in designing specialized solutions for industrial problems. \n\nHe is a researcher in the field of functional nanomaterials, soft matters and instrumentation. An Advisory Board Member at Materials Research Express (SCOPUS Indexed journal), IOP publishing, UK and Reviewer of several International Physics (material science) journals. He has been awarded as \\'Top Peer Reviewer in Materials Science” in Global Peer Review Awards 2019, by Publons. Dr. Ghosh has published 54 research papers in various international journals, books and conferences.",institutionString:"School of Physics, MIT-World Peace University (MIT-WPU)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:{id:"272217",title:"Dr.",name:"Arti",middleName:null,surname:"Rushi",slug:"arti-rushi",fullName:"Arti Rushi",profilePictureURL:"https://mts.intechopen.com/storage/users/272217/images/system/272217.jpg",biography:"Dr. Arti Dinkarrao Rushi is currently working as an assistant professor in the Department of Basic Sciences and Humanities, Maharashtra Institute of Technology, Aurangabad (MS) India. She has received her M. Sc. and a Ph.D. degree in 2012 and 2016 respectively, from the Department of Physics, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad (MS), India. Her area of interest includes nanotechnology, electrochemical sensors, functionalized materials, macrocyclic compounds, application of sensors for environment protection. Dr. Rushi has been published 39 research papers in various international journals, books, and conferences.",institutionString:"Maharashtra Institute of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:{id:"294686",title:"Dr.",name:"Kunal",middleName:null,surname:"Datta",slug:"kunal-datta",fullName:"Kunal Datta",profilePictureURL:"https://mts.intechopen.com/storage/users/294686/images/system/294686.jpg",biography:"Dr. Kunal Prasanta Datta currently working as Head, Industrial Automation Division in Deen Dayal Upadhayay Kaushal Kendra, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad (MS) India. He has received his Ph.D. (Physics) degree in 2013 from the Department of Physics, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad (MS) India. His area of interest includes instrumentation, electrochemical sensors (based on SWNTs, porphyrins, organic conducting polymers, nanoparticles). Mainly his research work concentrated on real-time measurement of inorganic/organic air pollutants from the environment. Dr. Datta has published 54 research papers in various international journals, books, and conferences.",institutionString:"Dr. Babasaheb Ambedkar Marathwada University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Dr. Babasaheb Ambedkar Marathwada University",institutionURL:null,country:{name:"India"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"71407",title:"Umbilical Cord Blood and Cord Tissue Bank as a Source for Allogeneic Use",doi:"10.5772/intechopen.91649",slug:"umbilical-cord-blood-and-cord-tissue-bank-as-a-source-for-allogeneic-use",body:'\nUmbilical cord blood (CB) has been utilized as a source of hematopoietic stem cells for three decades. It could potentially also serve as the optimum source of immune cells, such as mononuclear cells (MNC), regulatory T cells, NK cells, and mesenchymal stromal cells (MSCs) with or without genetic modifications, for immunotherapy and neurogenic regeneration in some cases. In addition, UB could be prepared as readily available products [1].
\nIt is well-known that human mesenchymal stromal cells (MSCs) can be harvested from various tissues that include the bone marrow (BM) [2], cord blood (CB) [3], adipose tissue [4], placenta [5], and umbilical cord (UC) [6]. Recently, clinical trials using MSCs for various diseases have been conducted, and some of them were approved. The BM is considered the traditional source of MSCs, and the characteristics and applications of BM-derived MSCs (BM-MSCs) have been studied in detail. However, the harvesting of these cells is associated with an invasive procedure, and it may cause hemorrhage, infection, and chronic pain. In addition, BM-MSCs exhibit accelerated senescence as the donors’ age [7].
\nOn the other hand, both CB and UC are routinely discarded as medical waste. The harvesting of CB and UC-derived MSCs (UC-MSCs) is therefore noninvasive and painless. The CB drawn from the UC and placenta is well-known as the source of hematopoietic stem cells for CB transplantations. However, in this article, we focus on the CB as the source for immune cells and regenerative medicine, such as regulatory T cells (Treg), NK cells, MSCs, and so on. The UC is the conduit between the developing embryo and placenta and consists of two umbilical arteries and one umbilical vein buried in the Wharton’s jelly. UC-MSCs have the abilities of multipotency and self-renewal properties comparable or superior to MSCs derived from other tissues in some papers. For this reason, several private CB banks have begun to collect CB and UC. We have thus established the cord blood/cord bank, “IMSUT CORD”, as a new type of biobank, to supply both frozen UC tissues and master cells for research and clinical uses.
\nIn this chapter, we will introduce the overall flow from collection to shipment as taking the example of IMSUT CORD and discuss several issues that need to be resolved in unrelated allogeneic off-the-shelf stable supply system at present.
\nThere are many public and private CB banks in the world, in which procedures are nearly standardized intended for hematopoietic stem cell transplantation (HSCT) as shown in Section 5. The procedures include informed consent acquisition from the mother, collection of CB, processing, storage, to shipment, which have been already established. In the case of UC bank for unrelated allogeneic uses, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) which issued ICH Q5A as the regulation of materials for biological products requires the second blood test from the baby’s mother, to deny viral infection in window period at delivery. Figure 1 shows the overall process of banking in the mother’s side. We deal with both CB and UC. In the CB and UC collection hospitals, the purpose, overall process, private information policy, the right to withdrawal, 6-month health check, and second blood test for the mother to confirm the negative study of infection are explained to the mother, and she gives written consent as the guardian of the baby. In addition to obtaining informed consent, questionnaires about medical history, genetic history of the baby donor’s family, and history for the mother’s communicable disease risk behavior are conducted to survey their health. The CB and UC are then collected, and the mother’s blood is tested for infections. These documentations and tests in CB bank can be referred to UC banking as well, although additional safety tests for UC banking shall be required strictly. UC-MSCs from one donor can be delivered and administered to many patients. Especially when the CB and UC passed the safety and some quality tests at clinical grade, the mother is asked to receive the blood test to make sure that all infection tests are negative in 6 months after delivery. These second tests are demanded by the Pharmaceuticals and Medical Devised Agency (PMDA) like the FDA and EMA, because it should be proven that the donor’s mother and baby were not in the window period of viral infections at delivery. On the other hand, bacterial contamination is also taken care because the baby and placenta with UC come out from nonsterile vagina. We collect UC in the case of a scheduled cesarean section to reduce the possibility of contamination due to the exposure to the vaginal bacterial/fungal flora.
\nOverall flow from informed consent acquisition to shipment.
CB and UC are then transported from the collection hospitals to the CB/UC bank under controlled and validated temperature. CB is transported at validated temperature range (2–25°C) to protect cell viability, and the UC is cooled at 2–10°C in our facility.
\nAmong the processing methods to obtain nucleated cells from CB for hematopoietic stem cell transplantation, the hydroxyethyl starch (HES) centrifugation method (HES method) is the most efficient and common. The HES method originated from the New York Blood Center CB bank [8]. Recently, automated CB processing SEPAX® (GE Healthcare Life Sciences) [9] and AutoXpress Platform® (Cesca Therapeutics, Inc.) [10] have been developed. For CB cryopreservation, DMSO and Dextran 40 together with CB-plasma are used worldwide [8].
\nOn the other hand, no processing method of fresh or frozen CB not for hematopoietic stem cell transplantation has been settled as standard. The use of mononuclear cells (MNCs) obtained by the Ficoll-Paque centrifugation method (Ficoll method) or cell sorting with antibody-conjugated magnetic beads might be a new candidate for further processing and culture method. CB processed by HES method resulted in whole nucleated cells including neutrophils, monocytes, lymphocytes, and nucleated red blood cells with some amount of red blood cells (RBC). The recovery rate of hematopoietic stem cells and mononuclear cells processed by HES method is superior to those by Ficoll method. That is why HES method is introduced by CB banks in the world [8]. However, neutrophils in the nucleated cells and residual RBC may cause the aggregation resulting in the difficulty of further processing, when the frozen and thawed cells are diluted with large volume of isotonic solutions such as medium. Only frozen-thawed CB nucleated cells can be diluted with dextran and albumin/saline solution [8]. On the other hand, frozen-thawed MNCs processed by Ficoll method does not require such a special solution and can be diluted with medium and PBS, although the recovery rate of MNCs from the fresh CB by Ficoll method is less than that by HES methods.
\nMSCs derived from fresh CB are difficult to expand. Only one company, Medipost Co., Ltd., in Korea, has succeeded in expanding CB-derived MSCs. Their product, Cartistem®, has been approved by the Ministry of Food and Drug Safety in Korea for the treatment of osteoarthritis [11].
\nThere are diverse procedures and culture methods for the isolation of MSCs from the various compartments of UC, such as Wharton’s jelly, veins, arteries, UC lining membrane, subamnion, and perivascular regions [12]. The isolation methods of MSCs from the Wharton’s jelly, vein, and arteries of UC are reported previously, although the marked differences were not found as far as the 10% fetal bovine serum (FBS) and α minimum essential medium (MEM) [13]. There are several papers to obtain MSCs from whole UC versus Wharton’s jelly [14] or different parts of the same UC [15], but we suggest that to process from whole UC seems sufficient and simple for further processing [15]. Despite the wide range of isolation and culture procedures, the different groups seem to agree on the cryopreservation of UC tissue [16] and explant method [17] followed by the harvest of migrating cells from tissue. However, large-scale culture methods remain to be determined. Figure 2 shows the example of scheme of CB and UC collection and process and shipping to clinical use.
\nIMSUT CORD scheme of CB and UC from collection to shipping for clinical use.
It is known that the UC tissue can be frozen in a cryoprotectant. This possibility of cryopreservation is the advantages of UC tissue for both clinical and research uses. The reasons of the advantages are:
UC tissue processing can be started after the donor’s health and infection statuses are confirmed well. This leads to initial cost-effectiveness because unnecessary works using inappropriate materials are eliminated. In addition, we can thaw a small amount of the UC to survey, before culturing MSCs in a large scale.
Storage of the tissues of origin allows us to keep traceability and to check the quality as the biological resources at a later date.
When new reagents or techniques were developed in the future, we can isolate novel cells from the cryopreserved UC tissues.
If the donor, the baby, has diseases that can be treated with autologous cells, including iPS cells or gene-modified cells, or autologous UC-MSCs, the cryopreserved UC tissues would be the appropriate source.
Several animal serum-free cryoprotectants containing 5–10% dimethyl sulfoxide (DMSO) are available. Whether the use of serum originating from animals, such as fetal bovine serum (FBS), is required, is critical, because it adds the risk of the transmission of zoonotic infections, immunological reactions, and additional regulatory issues [18]. There are several reports of cryopreservation of the UC tissue, using serum-free and xenogeneic animal-free (xeno-free) cryoprotectants. Ennis et al. introduced CryoStor CS10® (BioLife Solutions Inc., WA) for isolating human UC perivascular cells (HUPVCs). However, they did not show the comparative test results to those of fresh UC [19]. Roy et al. reported the cryopreservation of the UC tissue in 10% DMSO and 0.2 M sucrose solution, but the cumulative cell yield derived from the frozen-thawed UC-MSCs in their solution was inferior to that of fresh UC-MSCs [20]. We previously reported the cryopreservation of UC tissue, with no impact on viability, using a serum- and animal origin-free cryoprotectant, STEM-CELLBANKER® [16]. We demonstrated that cells derived from UC cryopreserved in this manner retained the phenotypic characteristics of MSCs, including the immunosuppressive activity in allogeneic mixed lymphocyte reactions, as well as differentiation potential. As shown in Figure 2, with the cryopreservation of UC tissue, UC processing might be altered.
\nThere are two major approaches after frozen-thawed UC tissue: explant and enzymatic digestion methods. Frozen-thawed UC tissue is manually minced into small fragments approximately 1–2 mm3 in size. Mincing is preferred to using a surgical scalpel or the use of an autologous mixer. These fragments are aligned and seeded regularly on a tissue culture-treated dish. After the tissue fragments attach to the bottom of the dish, culture media is added, slowly and gently in order not to detach the fragments [21, 22, 23, 24]. Media is then refreshed every 3–7 days for 2–4 weeks until the fibroblast-like adherent cells reach 80–90% confluence. Subsequently, adherent cells and tissue fragments are rinsed once with PBS, detached using trypsin, and washed with media. The culture is then filtered to remove tissue fragments. The disadvantage in the explant method is that tissue fragments often float in media, resulting in the poor recovery of cells. To protect the exfoliation of tissue fragments from the bottom of the culture dish, we introduced stainless steel mesh (Cellamigo®; Tsubakimoto Chain Co.) shown in Figure 2, No. 8. In this manner, we can plate source tissue more quickly and harvest more MSCs. In addition, the incubation time required to reach 80–90% confluence is reduced [17].
\nIn the enzymatic digestion method, UC is minced into small pieces and immersed in the media containing enzymes such as collagenase, or a combination of collagenase and hyaluronidase with or without trypsin [21, 24, 25, 26]. The cells dissociated by the enzymes are then cultured until they reach full confluence. However, the digestion method is costly and time-consuming and may result in decreased cell viability due to lytic activity and varying sensitivity of the cells to collagenase. In addition, the initial harvested cells include more of the other types of cells compared with that harvested using the explant method.
\nIt is critical to consider how much we can expand the UC-MSCs to allow allogeneic “off-the-shelf” industrial availability, because the proliferation of adherent cells needs a large surface area. The conventional method uses multilayered flasks, and the cells are cultured in incubators installed in cleanrooms. These multilayer flasks can consistently support the expansion of UC-MSCs, and the state of cell confluence can be examined under the microscope. However, this method requires the considerable involvement of operators because the processes of seeding, refreshment, passage, and harvest require individual and manual works. Several companies have introduced the spinner bioreactor with a microcarrier made of plastic, dextran, denatured collagen-coated beads, and other components. The bioreactor system may reduce the number of operators required and may allow to reduce the clean levels of facility since it is a closed system. On the contrary, several critical problems of the bioreactor system exist. The cost of equipment is high and it is difficult to evaluate cell proliferation environment such as pH, lactate, and so on. When some microcarriers are torn off by spinner, or undigested microcarriers are residual in the final products, we have no ideas to remove the residual microcarriers completely. Recently, a plastic bag bioreactor system with a microcarrier in gentle locking was reported [27]. The most critical problem is that the cells produced by the flask-based culture method may be different from those by bioreactors. Harvesting cells on a large scale is still not easy. Recently, filter-based cell concentration and washing systems were introduced (https://www.kaneka.co.jp/en/business/healthcare/med_006.html, KANEKA, Japan). Automatic cell packaging may be also required in large-scale expansion.
\nThe academic culture level such as IMSUT CORD is at small to middle scale. Only the company may have the ability to expand the cells at extra-large scale and maintain to control and supply the cell product for clinic constantly.
\nMaster and product cells of UC-MSCs for clinical use are usually required for long-term cryopreservation, together with records on the donor infant and the mother. There are several cryoprotectants for long-term cryopreservation. The most popular cryoprotectant consists of 5–10% dimethyl sulfoxide with human albumin. Recently, serum-free cryoprotectants, described in Section 4.1, have been commercialized and are thought to be more ideal compared to those containing human-derived serum. In addition to cryoprotectants, it is important to build an adequate record preservation system. Those who manage the long-term cryopreservation should preserve the records that include the documentation relating to the collection including donors, processing, results of quality tests, and instruments directly related to the products. The kinds of records and the length to be preserved are in accordance with the bank policies and standards and the corresponding domestic laws and regulations. It is necessary to discuss how long we should or we can cryopreserve CB and UC tissue, UC master cells, and product cells, in the technical and ethical aspects. In the technical aspect, the cell-preserving vessel to accommodate the cell suspension for long-term freezing should be durable in a liquid nitrogen. In the ethical aspect, we do not expect whether the babies can recapture their ownership of CB and UC even though their mother waived the ownership of them, when they grow up to be adult.
\nThe Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposed the minimal criteria for defining human MSCs [28, 29]. First, MSCs must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73, and CD90 but not CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR surface molecules. Third, MSCs must differentiate into adipocytes, chondroblasts, and osteoblasts in vitro [30, 31, 32]. Immunosuppressive effects have now become the most popular property of MSCs for potential clinical use [12]. Defect in HLA-class II expression with negative CD80 and CD86in UC-MSCs even in the presence of inflammatory cytokines such as IFN-γ can theoretically rescue them from immune recognition by CD4+ T cells [33]. MSCs can also inhibit proliferation of and cytokine secretion by immune cells, as well as alter subtypes of macrophage from M1 to M2 in vitro [34, 35, 36, 37]. This immunomodulation is linked mainly to soluble factors such as indoleamine 2,3-dioxygenase (IDO), PGE2, and HLA-G5 [38], hepatocyte growth factor, and transforming growth factor-β1 released from MSCs [39]. Further quality tests are dependent on clinical applications and characteristics of MSCs.
\nThe safety tests required differ according to the risks of clinical applications. For example, the tests of CB banking for hematopoietic stem cell transplantation are different from those of UC-MSCs. Donor-recipient relation of the former is one-to-one, and the risk is limited to one patient. On the other hand, that relationship of the latter, as UC-MSCs master cells and product cells, is one-to-many, so hundreds of patients may suffer health injuries by one donor. Thus, the vials of UC-MSCs are tested thoroughly at a designated time not only known viruses but also unknown viruses. Those tests should follow the local, national or international applicable laws and regulations. More precise safety tests for CB and UC shall be described elsewhere for the respective products for clinical application.
\nThere are international standards/guidance for CB collection, banking, and release of hematopoietic stem cell transplantation, such as the Foundation for the Accreditation of Cellular Therapy (FACT)/NETCORD [40], American association of Blood Banks (AABB), US Food and Drug Administration (FDA) shown in Table 1, and local standards or regulations under the applicable laws in respective countries. A CB/UC bank, facility, or individual should implement if the standard of practice in the community or applicable law establish additional requirements. International standards/guidance for biobanking process for UC collection, processing, culture, and release has not been settled, but collection and banking protocols can follow the CB banking standards and good tissue practice. Each CB/UC bank, facility, and individual should analyze its practices and procedures to determine whether additional standards apply. Compliance with the standards is not an exclusive means of complying with the standard of care in the industry or community or with local, national, or international laws or regulations [40]. Allogeneic public CB banks requested US FDA accreditation with FACT/NETCORD or AABB in the USA, while the CB banks in Europe (EU) required FACT/NetCord with additional requirements like FACT/JACIE standards, when it is requested by the respective national regulation affairs. There are many private or private-public combined CB banks in the world, which tend to follow the AABB standards and have the inspection and accreditation (http://www.aabb.org/sa/facilities/celltherapy/Documents/AABB-Accredited-Cord-Blood-Facilities.pdf).
\nItems | \nAccreditation organization | \nStandards or guidance titles | \n
---|---|---|
Cord blood (CB) processing for hematopoietic stem cell transplantation | \nFACT/NETCORD FACT/JACIE | \nInternational Standards for Cord Blood Collection, Banking, and Release for Administration International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration \nhttp://www.factwebsite.org/cbstandards/\n | \n
FDA in the USA | \nGuidance for Industry: Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications Guidance for Industry and FDA Staff: Investigational New Drug Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System \nhttp://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. | \n|
AABB | \nStandards for Cellular Therapy Services \nhttp://www.aabb.org/sa/Pages/Standards-Portal.aspx\n | \n|
Umbilical cord-derived cells including mesenchymal stromal cells (UC-MSCs)/somatic cell or other derivative cells CB not intended for hematopoietic stem cell transplantation | \nFACT | \nCommon standards for Cellular Therapies \nhttp://www.factwebsite.org/cbstandards/\n | \n
FDA in the USA | \nGood Tissue Practice 21CFR 1271.210 Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products Guidance for FDA Reviewers and Sponsors Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) \nhttp://www.fda.gov/cber/guidelines.htm\n | \n|
AABB | \nStandards for Cellular Therapy Services \nhttp://www.aabb.org/sa/Pages/Standards-Portal.aspx\n | \n|
EMA in EU | \nTissues and Cells Directives: Guideline on human cell-based medicinal products (EMEA/CHMP/410896/2006) for ATMP | \n|
PMDA (Japan) | \nGood Gene, Cellular, and Tissue-based Products Manufacturing Practice (GCTP) | \n|
Quality management system | \nISO | \nISO9001 ISO/TC276 (Draft) \nhttps://www.iso.org/standard/62085.html\n | \n
Standards or guidance related to cord blood and umbilical cord-derived cells.
Foundation for the Accreditation of Cellular Therapy, FACT; US Food and Drug Administration, FDA; American Association of Blood Banks, AABB; advanced therapy medicinal products, Pharmaceutical and medical devices agency (PMDA). This table does not include the law defined in each country. These standards, guidance, guidelines, and practices are not intended to apply all cell therapies using CB and UC. The CB/UC bank carefully chooses and implements them for your intended products under the applicable law.
The number of clinical trials using CB and UC-MSCs in the fields of immune cell therapies and regenerative medicine has been increasing. On the other hand, CB as a source of hematopoietic stem cell transplantation is less used recently, because the cell number is limited, the engraftment of HSC is delayed, and HLA haplo-identical HSCT is induced and controlled. These clinical trials are aimed uses that include severe acute graft-versus-host disease (GVHD) treatment, rapid engraftment of HSCT, and the prevention of severe acute GVHD. Clinical trials using CB- and UC-MSCs are summarized in Tables 2 and 3, respectively. We started a sponsor-investigator clinical trial using UC-derived MSCs for patients with treatment-resistant severe acute GVHD supported by the research fund of the Japan Agency for Medical Research and Development (AMED). Consistent supply is the critical key to conduct clinical trials and for marketing. For the stable supply of frozen CB and UC, or UC-derived MSCs, we have established a CB and UC bank, named IMSUT CORD, in our institute. This bank also provides CB and UC-MSCs for immunotherapy and regenerative medicine products to hospitals and pharmaceutical companies shown in Figure 2. The bank also provides frozen CB, frozen UC, master cells, and the cells after master cells as an intermediate products requiring further processing or more culture in the companies.
\nAuthors | \nCell type | \nDisease | \nPatients number | \nAge (range) year | \nRoute and procedure of administration | \nCell number/kg or body | \nResults | \nAdverse events | \n
---|---|---|---|---|---|---|---|---|
Brunstein et al. [41] | \nCB-NC-derived Treg (CB from The New York Blood Center) | \nGrade II–IV acute GVHD | \nTreg: 11 | \n61 (45–68) | \nIV | \n3–100 × 106 Treg/kg | \naGVHD: Treg group 9%, control 45% cGVHD: Treg 0%, control 14% | \nNo dose-limiting infusion adverse events | \n
\n | \n | \n | Control: 22 | \n60 (34–69) | \n\n | — | \n\n | \n |
Kellner et al. [42] | \nFucosylated or non-fucosylated UCB-Tregs | \nHSCT | \n5 | \n\n | IV (−1 day of HSCT) | \n1 × 106/kg | \n\n | No infusion reactions | \n
Zhu et al. [43] | \nCB-MNC | \nChronic complete spinal cord injury | \n8 in Hong Kong | \n42.6 ± 2.7 | \nIT (dorsal entry zone) | \n1.6–3.2 × 106\n | \nWalk 10 m, 15/20 pts. (p = 0.001), no necessity of assistance for bladder management, 12/20 (p = 0.001) and bowel management (p = 0.002) | \n1 neuropathic pain;1 subarachnoid hematoma and pneumocephalus due to cerebrospinal loss;1 arachnoid hemorrhage I HK group, | \n
Phase I–II | \n20 in Kunming | \n36.9 ± 2.4 | \n68 AEs including postoperative wound swelling; 9 pain Overall 5 severe AE in 28 patients | \n|||||
Shah et al. [44] | \nCB-MNC-derived NK cells (CB from MD Anderson Cord Blood Bank) | \nMultiple myeloma undergoing autologous PBSCT | \n12 | \n48–70 | \n\n | 5 × 106, 1 × 107, 5 × 107 and 1 × 108 CB-NK cells/kg | \n10 achieved VGPR (8 near CR) as the best response | \nNo infusional toxicities and no GVHD | \n
Lv et al. [45] | \nCB-MSC + UC-MSCs | \nAutism | \n14 CB-MNC9 CB-MNC and UC-MSCs14 no cells therapy | \nCB-MNC: 7.08 (3.29–12.01) CB-MNC + UC-MSCs: 6.51 (3.98–9.83)Control: 5.02 (3.51–10.02) | \nIV | \nProximately 2 × 106/kg CB-MNCs1 × 106/kg of UC-MSCs 4 times in 5–7 day | \nImprovement of CARS, ABC scores, and CGI evaluation at 24 weeks in CB-MNCs with UC-MSCs | \nNo treatment-related and no severe adverse effects | \n
Dolstra et al. [46] | \nCB-CD34-derived NK cells (CB from Cord Blood Bank Nijmegen) | \nAML in old patients | \n10 | \n68–76 | \nIV | \n3 and 30 × 106/kg | \nNK cell maturation in vivo, MRD become negative in 2/4 with MRD before IV | \nNo GVHD, no toxicity | \n
Park et al. [47] | \nCB-derived MSCs | \nRheumatoid arthritis | \n9 | \n57.4 ± 10.0 | \nIV | \n2.5 × 107, 5 × 107, or 1 × 108\n | \nDAS2/-ESR decreased, inflammatory cytokine levels are reduced | \nNo DLT, no major toxicity | \n
Laskowitz et al. [48] | \nCB-NC (CB from Carolinas Cord Blood Bank or MD Anderson Cord Blood Bank) | \nCerebral stroke | \n10 | \n65.5 (45–79) | \nIV on 3–9 days poststroke | \nCell dose 1.54 (0.84–3.34) × 107/kg, CD34+ 2.03 (0.10–6.80) × 105/kg | \nAll improved by at least one grade in Modified Rankin Score | \nAE tolerated no serious AE | \n
Huang et al. [49] | \nCB-MSCs | \nCerebral palsy (age: 3–12) | \n27 (CB-MSCs) | \nCB-MSCs: 7 (3–12) | \nIV | \n27:4 CB-MSCs IV at 5 × 107 with basic rehabilitation treatment | \nSignificant improved of GMFM-88 evaluation | \nNo serious AE | \n
27 (control) | \nControl: 7 (3–12) | \n|||||||
Kim et al. [50] | \nCB-MSCs | \nModerate-to-severe atopic dermatitis | \n34 (7 in phase I, 27 in phase IIa) | \n29.07 ± 2.03 (n = 14) | \nSC | \n2.5 × 107\n | \nImproved atopic dermatitis scores, pruritus score, serum IgE and eosinophil number | \nNo serious AE | \n
28.08 ± 1.07 (n = 11) | \n5.0 × 107\n | \n
Clinical trials using allogeneic cord blood.
AE, adverse event; AML, acute myeloid leukemia; CB, cord blood; UC, umbilical cord; MSCs, mesenchymal stromal cells; MNCs, mononuclear cells; NK cells, natural killer cells; Treg, regulatory T cells; GVHD, graft-versus-host disease; PBSCT, peripheral blood stem cell transplantation; IV, intravenous injection; SC, subcutaneous injection.
Authors | \nDisease | \nPatients number | \nAge (range) year | \nRoute and procedure of administration | \nCell number/kg or body | \nFrequency interval | \nResults | \nAdverse events | \n
---|---|---|---|---|---|---|---|---|
Engraftment facilitation and graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation | \n||||||||
Wu et al. [51] | \nSevere steroid-resistant aGVHD | \n2 | \nPt 1:4 | \nIV | \nPt 1: 3.3, 7.2, 8.0 × 106/kg | \n3 | \nImproved | \nNo | \n
Pt 2:6 | \nIV | \nPt 2: 4.1 × 106/kg | \n1 | \n|||||
Si et al. [52] | \nSevere aplastic anemia | \n37 | \n5 | \nIV (7–10 days after HSCT) | \n1 × 106/kg | \n1 | \naGVHD II–IV; 17 of 37 (45.9%) | \nNo | \n
(0.75–11.58) | \ncGVHD, 7 of 37 (18.9%) | \n|||||||
Wu et al. [53] | \nRefractory/relapsed hematologic malignancy | \n50 | \n26 (9–58) | \nIV (4 h before haploidentical HSCT) | \n5 × 105/kg | \n1 | \naGVHD II–IV, 12 of 50 (24.0%) cGVHD, 17 of 45 (37.7%) (3 extended) | \nNo | \n
Wu et al. [54] | \nSevere AA | \n21 | \n18 (4–31) | \nIV (4 h before HSCT) | \n5 × 105/kg | \n1 | \naGVHD II-IV;12 of 21 (57.1%) 3 of 9 extended cGVHD | \nNo | \n
Fu et al. [55] | \nRefractory severe AA | \n5 | \n15.2 (9–22) | \nIV (2 days after PBSCT) | \n1 × 106/kg | \n1 | \nNo severe aGVHD or cGVHD | \nNo | \n
Gao et al. [56] | \nProphylaxis of chronic GVHD after HLA-haploidentical stem cell transplantation | \n62 | \nAge < 8, 15 pts.; 18–40, 39; >40, 8 | \nIV | \n3 × 107 cells | \nUntil cGVHD occurred, leukemia relapsed, or 4 cycles | \ncGVHD at 2 yr.: MSCs group 27.4%, control 49.0% (P = .021). Severe lung cGVHD: MSCs group 0, control 7 (P = .047) | \nNo | \n
Zhu et al. [57] | \nHigh-risk acute leukemia | \n25 | \n11.2 (4–17) | \nIV (before haploidentical HSCT) | \nMedian 1.14 × 106/kg (1.03–1.39 × 106/kg) | \n4 (over 7 days intervals) | \naGVHDI, 8 of 25 (32.0%) cytomegalovirus viremia, 23 of 25 (92.0%) | \nNo | \n
Pan et al. [58] | \nExtensive bone marrow necrosis of a chronic myeloid leukemia patient | \n1 | \n10 | \niBM | \niBM: 2 × 107/kg | \n1 | \nBM recovered | \nNo | \n
IV | \nIV: 2 pp. × 106/kg | \n|||||||
Neurogenic injuries | \n||||||||
Wang et al. [59] | \nTraumatic brain injury | \n20 | \n27.5 (5–48) | \nIntrathecal (IT) | \n1 × 107\n | \n4 (5–7 days intervals) | \nMotor functional recovery after 6 months | \nNo | \n
Jin et al. [60] | \nHereditary spinocerebellar ataxia | \n16 | \n39.9 (21–56) | \nIV + intrathecal | \nIV; 4 × 107\n | \n4 (over 7 days interval) | \nMotor functional recovery after 6 months | \nNo | \n
IT; 2 × 107 cells | \n||||||||
Wang et al. [61] | \nCerebral palsy | \n16 (8 twins) | \n6.29 (3–12) | \nIT | \n1–1.5 × 107 cells | \n4 (3–5 days intervals) | \nMotor functional recovery after 1 and 6 months | \nNo | \n
Diabetes mellitus | \n||||||||
Guan et al. [62] | \nDM (type 2) | \n6 | \n40.5 (27–51) | \nIV | \n1 × 106/kg | \n2 (2 weeks interval) | \nInsulin-independent for 25–43 Mo, 3 dose reduction of insulin, others | \nNo | \n
Hu et al. [63] | \nDM (type 1) | \n15 | \n17.6 | \nIV | \n2.6 ± 1.2 × 107/kg | \n2 (4 weeks interval) | \nHbA1c and C-peptide improvement in MSCs group | \nNo | \n
Cai et al. [64] | \nDM (type 1) | \n21 | \n18–29 (5–28) at onset | \nSupraselective pancreatic artery cannulation | \n1.1 × 106/kg, with autologous BM-MNC | \n1 | \nModerate improvement of metabolic measures | \n1 transient abdominal pain | \n
Kong et al. [65] | \nDM (type 2) | \n18 | \n\n | IV | \n1 × 106/kg | \nDay 0 and until Day 90 if effective | \nFBS reduced plasma C-peptide and regulatory T cells increased | \n4/18: slight fever | \n
Heart and angioplasty | \n||||||||
Cai et al. [66] | \nAvascular necrosis of the femoral head | \n30 | \n41.6 (19–63) | \nFemoral head artery (co transplant with autologous BM) | \nAutologous BM-BM-MNCs, 60.7 ± 11.5 × 106/kg UC-MSCs, 1 × 106/kg | \n1 | \nImproved | \nNo | \n
\n | \n | |||||||
Can et al. [67] | \nMyocardial ischemia | \n39 | \n30–80 | \nIntracoronary | \n2 × 107/kg | \n1 | \nOngoing | \nNo | \n
Zhao et al. [68] | \nSevere systolic heart failure | \n30 | \n52.9 (20–79) | \nIntracoronary | \nUnknown | \n1 | \nCardiac remodeling and function improved with reduced mortality rate | \nNo | \n
Li et al. [69] | \nCoronary chronic total occlusion | \n15 | \nUnknown | \nIntracoronary | \n3 × 106/4 × 106/5 × 106/kg | \n1 | \nInfarcted size reduced with improved left ventricular EF | \nNo | \n
Musialek et al. [70] | \nAcute myocardial infarction | \n10 | \n55.6 (32–65) | \nIntracoronary | \n3 × 107/body | \n1 | \nFeasible and procedural safe as off-the-shelf cellular therapy | \nTransient fever (38.9°C) | \n
Bartolucci [71] | \nHeart failure | \n15 | \n57.33 ± 10.05 | \nIV | \n1 × 106 cells/kg | \n1 | \nSignificant improvements in LVEF, NYHA functional class, Minnesota Living with Heart Failure Questionnaire | \nNo | \n
Liver | \n||||||||
Xue et al. [72] | \nDecompensated liver cirrhosis | \n50 | \nUnknown | \nIntrahepatic artery | \n3 × 107/body | \n1 | \nIncrease of serum albumin | \nNo | \n
Wang et al. [73] | \nPrimary biliary cirrhosis | \n7 | \n49 (33–58) | \nIV | \n5 × 105/kg at 4 weeks interval | \n3 | \nALP and γ-GTP | \nNo | \n
Shi et al. [74] | \nPrevention of acute liver allograft rejection | \n14 (13, single dose, 1 multiple dose) | \n57 ± 12 | \nIV | \n1 × 106 cells | \nSingle (13 pts), 3 times every 4w (1 pt) | \nDecreases of ALT, AST, T-BIL Histologic improvements, MSCs 6, control 0. | \nNo | \n
Liang et al. [75] | \nLiver cirrhosis caused by autoimmune diseases | \n23 (2 CB-MSC, 1 BM MSC) | \n53.4 (35–70) | \nIV | \n1 × 106 cells/kg | \n1 | \nNot statistically significant improvement | \n2, fever; 3, mild fidgetiness, suffered from insomnia | \n
Zhang et al. [76] | \nIschemic-type biliary lesions following liver transplantation | \n12 | \n47.3 ± 10.1 | \nIV | \n1 × 106 cells/kg | \n6 (1, 2, 4, 8, 12, 16 weeks) | \nSignificantly decreased need for interventional therapies. 1-, 2-yr graft survival rates: MSCs group (100%, 83.3%), control group (72.9%, 68.6%) | \nNo | \n
Xu et al. [77] | \nHepatitis B virus-related acute-on-chronic liver failure | \n30:UC-MSC | \nUC-MSC: 40.67 ± 9.89 | \nIV | \n105 cells/kg | \nUC-MSC, once a week, 4 times | \nNo significant improvement of short-term prognosis | \nFever, UC-MSC 11 pts., PE + UC-MSC 6 pts | \n
20, UC-MSC + plasma exchange | \nUC-MSC/plasma exchange, 42.00 ± 6.55 | \nIV | \n\n | UC-MSC/PE: first 2 UC-MSC: 2nd day after 1st, 3rd PE treatments | \n\n | |||
Gastrointestinal tract | \n||||||||
Zhang et al. [78] | \nCrohn’s disease | \n41 | \n32.7 (20–41) | \nIV | \n1 × 106 cells/kg | \nOnce a week, four times | \nDecreases of CDAI, HBI, corticosteroid dosage | \nFever 4, upper respiratory tract infection, 7 | \n
Hu et al. [79] | \nUlcerative colitis | \n34 | \n42.9 ± 23.1 | \nIV then IA | \n0.5 × 106 cells/kg | \n2, 7 days | \nDecreases of median Mayo score, histology score. Improvement of IBDQ scores | \nNo | \n
Skin | \n||||||||
Hashemi et al. [80] | \nChronic skin ulcer | \n5 | \n30–60 | \nCovered by acellular amniotic membrane seeded with WJSCs | \nAbout 2 × 106 cells were seeded | \nEpithelial surface of acellular amniotic membrane | \nSignificantly decreased wound healing time, wound size. Significantly declined wound size after 6, 9 days | \nNot stated | \n
Kidney | \n||||||||
Sun et al. [81] | \nPrevention of delayed graft function and acute rejection in renal transplantation | \n21 | \n41.0 ± 11.5 | \nIV | \n2 × 106 cells/kg (before transplantation), 5 × 106 (during surgery) | \n← | \nNo significant improvement | \nNo | \n
Deng et al. [82] | \nLupus nephritis | \n12 MSC, 6 placebo | \n29 ± 10 | \nIV | \n1 × 108 cells | \n2 times 1 wk. interval | \nNot statistically significant improvement | \n1: leucopenia, pneumonia, subcutaneous abscess, 1: severe pneumonia | \n
Autoimmune diseases | \n||||||||
Wang et al. [83] | \nActive and refractory SLE | \n40 | \n17–54 | \nIV | \n1 × 106 cells/kg on day 0 and 7 | \n2 | \nMCR (13 of 40, 32.5%), PCR (11 of 40, 27.5%) during 12 months, although several patients relapse after 6 months | \nNo | \n
Wang et al. [84] | \nRA | \n136 | \n46.1 | \nIV | \n4 × 107 cells, 2nd in 3 months later | \n1 (n = 112) | \nDecreases of serum TNF-α, IL-6, increase of regulatory T cells. Significant remission for 3–6 months | \nMild fever (<38.5°C) without treatment at injection, 6 patients | \n
2 (n = 24) | \n||||||||
Riordan et al. [85] | \nMultiple sclerosis | \n20 | \n41.2 (24–55) | \nIV | \n2 × 107 UC-MSC | \n7 (1–4 days) | \nSignificant improvements of various symptoms. Inactive lesions by MRI in 15/18 patients. (83.3%) after 1 year | \nHeadache, fatigue | \n
Others | \n||||||||
He et al. [86] | \nSevere sepsis | \n15 (3 cohorts) | \n56 (25–72) | \nIV | \n1 × 106 cells/kg | \n1 | \nSystem clinical outcomes are not changed | \nNo | \n
2 × 106 cells/kg | \n\n | |||||||
3 × 106 cells/kg | \n\n | |||||||
Cao et al. [87] | \nRecurrent intrauterine adhesions | \n27 | \n35.1 ± 3.8 (27–42) | \nLoaded onto a collagen scaffold | \n1 × 107\n | \n1 | \nPregnant, 10 of 26 patients | \nNo | \n
Clinical trials using allogeneic umbilical cord-derived mesenchymal stromal cells.
aGVHD, acute graft-versus-host disease; cGVHD, chronic GVHD; HSCT, hematopoietic stem cell transplantation; AA, aplastic anemia; BM, bone marrow; IT, intrathecal injection; AE, adverse event; AML, acute myeloid leukemia; CB, cord blood; UC, umbilical cord; BM, bone marrow; PE, plasma exchange; RA, rheumatoid arthritis; MSCs, mesenchymal stromal cells; DM, diabetes mellitus; FBS, fast blood sugar; ES, ejection fraction; IV, intravenous injection; SC, subcutaneous injection; DM, diabetes mellitus.
The following are also the major points for managing CB and UC banking.
\nFirst, to build an adequate quality management system to serve the resource of cell therapy products, we have introduced the concept of the ISO 9001 and obtained its certification, and as a result, we introduced the concept of PDCA cycle. Second, involvements of various kinds of specialists must be considered. There are many procedures, such as collection, obtaining informed consent, application to ethics review committee, and document management. Third, health check and infection test of the donor’s mother are required to ensure that no infection is detected after window period of infections. In this process, both traceability and personal information protection must be satisfied. Fourth, we respect the right of decision to donate, rejection, or withdrawal. Donor’s mother should be explained the policy of the bank that the consented withdrawal time is set at the initiation of processing for clinical use. Although the CB and UC belong to the baby, we obtain informed consent from the donor’s mother as guardianship and ownership are asked to be transferred to the bank. Fifth, there is also the issue of how long the UC tissue and UC-MSCs can be cryopreserved. For example, in the Japanese public CB bank for HSCT, the CB is cryopreserved for 10 years as a clinical grade of HSC source. After this period, they are used for basic research or preclinical studies or discarded if they are not used for research. A cryopreservation period of 10 years for UC and UC-MSCs may be the first threshold to be checked. In addition, we disclose the information in website for the mothers who have not been explained about the new researches or new clinical trials at the first IC acquisition. Lastly, because unlike CB, the UC is a tissue considered as a part of the perinatal appendage, we must follow the tissue transport and medical disposal/waste regulations under the applicable laws or local rules and ethical standards.
\nRecently, there are an increasing number of private CB banks, which have initiated to serve the cryopreservation of UC, i.e., private CB and UC bank. Using private autologous CB, clinical trials for cerebral palsy caused by hypoxic ischemic encephalopathy (HIE) reported their efficacy [88], although the collection of CB is difficult for the baby in such a severe situation of delivery, resulting in the limited application entry. Recently, we obtained the proof of concept that the UC-MSCs attenuated the neurogenic and functional damage caused by intraventricular hemorrhage (IVH) in newborn model mice. Duke University implemented the clinical trial using allogeneic UC tissue-derived cells for the patients with HIE. Allogeneic off-the-shelf UC-MSCs are a promising source; however, we do not know the adverse events such as HLA antibody induction caused by long-term repeated injections of allogeneic cells. Therefore, autologous use of CB and UC is still challenged to be discussed continuously.
\nAlthough several problems still remain to be dissolved, operation of adequate CB and UC bank should be considered as the provider of cell source for regenerative and immune cell therapy, because of their prominent characteristics and convenient and noninvasive collection.
\nThis study was supported by Grants-in-Aids for Scientific Research from the Japan Agency for Medical Research and Development (AMED) (19be0504001h0002). We thank Kamisato A. PhD. for ethical support. We specially thank Takahashi A. MT, Ms. Hori A., Yamamoto Y. MT., Mr. Miharu Y. MT, Ms. Izawa, and MS. Nagaya N., for processing and quality management. We also thank the staff of NTT Medical Center Hospital and Yamaguchi Hospital, Tokyo, for their assistance with the collection of UC and CB.
\nMammalian cells face an estimate of 105 genomic injuries every day. These lesions are diverse and can include, among others, single (SSB) and double strand breaks (DSB), oxidative damage, DNA inter- and intra-strand crosslinking, base mismatches, bulky adducts, and photoproducts [1, 2]. This large variety of DNA lesions is directly related to the full range of mutation-causing agents that threaten the genome on a daily basis. Some of these agents are endogenously produced by the cell’s own metabolism and homeostasis, while others are generated exogenously. The frequency of appearance of these lesions is also diverse, and it may depend on the cell type or the developmental stage [1]. For instance, skin epithelial cells are much more susceptible to photoproducts caused by ultraviolet rays, an exogenous source of mutations that can only reach the outermost layers of our body. In contrast, reactive oxygen species (ROS) are endogenous metabolic byproducts that can induce oxidative base modifications and SSB, one of the most common genomic injuries. Cells with high energy and metabolic demands are, therefore, most susceptible to suffer SSB-related and other ROS-related injuries.
\nTo defend from the menacing threat that this wide range and number of lesions pose to the integrity of their genome, cells can invoke the DNA damage response (DDR), a vast network of overlapping pathways that is capable of tailoring a response depending on the type and extent of the lesion and the cell cycle stage at the moment of the injury [3, 4, 5, 6]. DDR requires the coordination of DNA repair pathways with cell cycle progression regulation, transcription activation, and apoptosis, among other pathways [5, 7, 8].
\nSomewhat surprisingly, mutations in genes belonging to DDR pathways correlate with neurodevelopmental defects and neurodegenerative pathologies [5, 9, 10, 11]. For instance, individuals with dysfunctional versions of SSB repair genes APTX, PNPK, or XRCC1 manifest different types of ataxias with ocular apraxia; whereas, defective TDP1, also involved in SSB repair, can cause spinocerebellar ataxia with axonal neuropathy [9, 12]. Similarly, mutations in DSB repair gene MRE11, or central DDR regulators ATM and ATR, can lead to cerebellar ataxia [5, 13]. Besides ataxias, microcephaly is commonly found linked to defects in several DDR associated genes [1, 5, 14]. Mutations in NBS1 and RAD50, two genes involved in end processing during DSB repair, can cause Nijmegen breakage syndrome (NBS) and NBS-like syndrome, respectively, both syndromes manifesting microcephaly among other conditions [5, 15, 16]. Microcephalia is also present in individuals with dysfunctional PNPK, LIG4—a gene involved in DSB repair—or Seckel Syndrome 1, a developmental disorder caused by some ATR mutations [9, 15]. Furthermore, around 25% of patients with defective nucleotide excision repair (NER)—a DDR pathway in charge of healing photoproducts created by UV light exposure—can also present microcephaly among other neurological problems [5]. Overall, this data suggest a strong and intriguing link between DDR, neurodevelopment, and neuropathology. This review focuses on ATM, its role during DDR, and the molecular basis of ataxia-telangiectasia (A-T), a neurodegenerative syndrome caused by defective or absent ATM.
\nATM and ATR are two kinases belonging to the protein phosphatidylinositol-3-kinase-like kinases (PIKK) family that function as the chief regulators of DDR [3, 11, 13]. Together, they coordinate all pathways implicated in DDR to offer an adequate and timely response proportionate to the type and extent of the genomic injury. Recently, DNA-PKcs, another member of the PIKK family, has also been found playing more substantial roles in regulating DDR than initially thought, albeit to a lesser extent that ATM and ATR [17].
\nATM is a very large kinase of 3056 amino acids and a molecular weight of 350.6 kD that resides in the nucleus as inactive homodimers. Upon DNA damage infliction, phosphorylation of a critical ATM residue disrupts dimerization, prompting monomers to undergo further phosphorylation to achieve full kinase activation [18, 19, 20]. Active ATM monomers phosphorylate substrates on serine or threonine residues followed by glutamine (S/TQ), and a significant amount of ATM substrates contain clusters of S/TQ sites in short stretches of the protein [21]. These so-called SCD domains can be used to mine the proteome for putative ATM targets [22, 23, 24]. Using mass spectrometry, a high-throughput screen for proteins phosphorylated following DNA damage found 686 putative DDR targets and the final number is estimated to surpass a thousand proteins [25]. These large numbers showcase the complexity of DDR, and the need for an orchestrated coordination of all pathways involved. Some of the most important direct ATM targets are CHK2 and p53, two downstream effectors that modulate pivotal DDR pathways like cell cycle progression regulation, DNA repair, or apoptosis [26, 27, 28].
\nATM is not only activated by different kinds of DNA damage but can also actively participate in several DNA repair mechanisms and coordinate their activities with other DDR-related pathways [7, 29]. During DSB repair, ATM plays crucial roles in the early end-processing events, signal amplification, and recruitment of other DNA repair proteins to the sites of damage [3, 13]. ATM functions in homologous recombination (HR) and nonhomologous end-joining (NHEJ), the two pathways entrusted by cells to repair DSBs. Whereas, NHEJ is active throughout the cell cycle, its function is mostly limited to G0/G1 as S/G2 phases prefer the more accurate HR, a mechanism that uses sister chromatids only present during those phases as repair templates. The first sensor of DSBs is PARP1, which in addition to binding breaks, also adds branches of poly-(ADP)-ribose to proteins post-translationally [30]. This so-called PARylation process activates and recruits several DNA repair proteins to the sites of damage [31]. One of them is the MRN complex—made up of MRE11, RAD50, and NBS1—that binds and activates ATM [32, 33]. Interaction with PARP1 and NBS1, thus, activates and recruits ATM to DSB sites, where it phosphorylates several downstream targets and effectors to amplify DDR signaling. For instance, ATM phosphorylates histone variant H2AX, which promotes MDC1 binding to the chromatin surrounding DSB [34, 35, 36]. Once there, ATM-mediated phosphorylation of MDC1 promotes its binding to MRN, and recruitment of more ATM to phosphorylate more H2AX, further spreading DDR signaling [13].
\nAlthough the complete process remains to be fully elucidated, it is clear that ATM is also involved in the decision-making process that selects either HR or NHEJ to repair a DSB [37, 38]. A crucial step in this process is the extent of end resection that takes place at DSB [39]. ATM directly phosphorylates CtIP and BRCA1, two HR proteins required for resection initiation and binding of RAD51 to ssDNA ends, respectively [40, 41, 42]. Once formed, RAD51 coated 3′ ssDNA ends steer repair toward HR by initiating strand invasion into the sister chromatid. Intriguingly, ATM phosphorylates p53BP1 and promotes its recruitment to sites of DNA damage [43]. Phosphorylated p53BP1 has opposing roles to CtIP and BRCA1, and favors the formation of p53BP1 containing complexes at DSB that counteract HR in favor of NHEJ repair [38, 44]. ATM also influences NHEJ by mediating DNA-PKcs phosphorylation and subsequent recruitment of Artemis, an end-processing nuclease, to DSB sites [45].
\nAlthough ATM is mostly activated by DSBs, recent data suggest that some lesions that are usually repaired by BER can also activate ATM and that ATM-dependent phosphorylation events can regulate BER [46]. Following base damage, BER requires the sequential action of DNA glycosylases—to remove damaged bases and create apyrimidinic or apurinic (AP) sites, PARP1—to PARylate the AP site, and endonucleases that will generate an SSB at the AP site [47]. These events can lead to ATM activation and the ATM-dependent phosphorylation of CHK2 [46]. Upon activation, CHK2 phosphorylates XRCC1, a BER protein required for sealing the nick and completing the repair.
\nDDR is capable of modulating DNA repair pathways through multiple effectors. For instance, both ATR and p53 regulate NER through quite distinct mechanisms. While ATR phosphorylates XPA, one of the earliest respondents to pyrimidine photodimers and other bulky lesions, DDR-dependent phosphorylation of p53 acts by upregulating expression of NER genes and recruiting XPC and TFIIH to sites of damage [7, 48, 49, 50, 51, 52]. ATR also regulates ICLR through the phosphorylation of several members of the Fanconi anemia group, a set of proteins that in combination with NER and HR, repair DNA cross-linkage damage [53, 54, 55]. Other examples of DDR-signaling-dependent regulation of DNA repair mechanisms include the upregulation of BER through the stimulatory binding of p53 to BER proteins, the promotion of HR that ensues after disruption of the p53-RPA complex by ATM, ATR and DNA-PKcs phosphorylation, and the PIKK-dependent phosphorylation of Werner syndrome and Bloom syndrome proteins involved in DSB repair [56, 57, 58, 59, 60].
\nOne of the most dangerous threats of DNA damage is the possibility of spreading to daughter cells during cell duplication. To prevent this, DDR is capable of halting cell cycle progression at any point during the cell cycle [61]. A series of overlapping mechanisms ensure that cells attempt DNA repair before progressing to the next cell cycle stage [7].
\nATM is in charge of preventing lesions produced during G1/G0 to enter S phase, which is particularly important for some of the most common DNA injuries like oxidative damage. Since G1/G0 duration is usually longer than other cell cycle phases, exposure to ROS and other mutating agents is also higher in these stages, and so is the appearance of related damage. ATM acts in conjunction with CHK2 and p53 to block G1/S transition by inhibiting CDK2, the cycle-dependent kinase that along with Cyclin E, triggers S-phase entry [62]. CDK2 inhibition is achieved by two overlapping mechanisms that have ATM at their apex. On one hand, ATM phosphorylation of CHK2 triggers phosphorylation of CDC25A, a phosphatase required for CDK2 activation and promoting entry into S-phase [63, 64]. On the other hand, ATM-dependent activation of p53 induces upregulation of p21, which acts as a CDK2 inhibitor [65].
\nReplicative stresses during S-phase trigger the activation of the Intra-S-phase checkpoint to ensure that replicative stress and other types of damages do not persist in the following cell cycle stages. ATR, not ATM, is the PIKK responsible for halting the cell cycle at this stage through the activation of the intra-S-phase [61]. During this checkpoint ATR, CHK1, and p53 act together and in overlapping ways to phosphorylate CDK2, which renders it unable to form an active CDK2/cyclin A complex [63, 66]. The final result is DNA synthesis termination, premature stalling, and subsequent halt of the cell cycle.
\nThe concerted action of ATR, CHK1, and p53 also controls the G2/M transition to ensure that no cell enters mitosis with lingering DNA damage from previous phases [67, 68, 69]. The importance of this checkpoint is highlighted by the presence of multiple overlapping and complementary mechanisms actively working together to inhibit CDK1/CyclinB1, the complex required to trigger entry into mitosis [66]. CDK1 phosphorylation has an inhibitory effect and thus, is the primary target of several of these mechanisms. After ATR-mediated activation, CHK1 phosphorylates CDC25C, a phosphatase required for CDK1 activation. Phosphorylated CDC25C binds to the 14-3-3 complex, which promotes its transport to the cytoplasm, effectively preventing CDK1 activation [70]. Active CHK1 also phosphorylates and activates WEE1, a kinase that promotes inhibitory phosphorylation of CDK1 [71]. Furthermore, ATR phosphorylates PLK1 and inhibits its role as WEE1 inhibitor, while p53 upregulates GADD45, which binds and further inhibits CDK1/CyclinB1 complex [72, 73]. Importantly, ATM also play roles in this combined effort to keep CDK1/CyclinB1 inhibited, as it can phosphorylate PLK1 and promote CHK1-mediated CDC25C phosphorylation [73, 74].
\nFinally, the Intra-M checkpoint is the last opportunity to prevent the transmission of damage to daughter cells. ATM and CHK1 govern this checkpoint through two distinct mechanisms that act sequentially during mitosis progression. First, inhibitory phosphorylation of PLK1 by CHK1 prevents it from acting during spindle formation and halts the cell cycle [74]. At a later point, ATR-mediated phosphorylation of Aurora B stimulates the inhibitory effect that this enzyme exerts over cytokinesis and delays exits of mitosis if the damage is detected [75].
\nActivation of DDR induces substantial changes to the transcriptome to equip cells with necessary tools and time to articulate a proper response. While the overall effect of DDR activation is an attenuation of global transcription and translation, many genes involved in DDR pathways must be upregulated instead [76]. For example, upregulation of XPC and other NER genes follows DDR activation, and as previously noted, DDR-mediated blocking of cell cycle progression is dependent on the induction of certain genes, namely p21 [77]. DDR exerts its influence on gene transcription through the action of several transcription factors that act as downstream effectors of DDR signaling. Some of the most important examples are p53 and BRAC1, AP-1, or E2F1. For instance, BRAC1 and p53 upregulate XPC during DDR-mediated NER upregulation; whereas, AP-1 induces the expression of XPF and XPG during the same process [76]. Other examples are p53 and AP-1 serving as transcription factors for MLH1 and MSH2—two mismatch repair genes—and E2F1 and AP-1 influencing the expression of BER components XRCC1 and APEX1, respectively.
\nParamount for DDR is its ability to trigger apoptosis when DNA damage is too extensive and incompatible with genome stability. Both ATM and ATR can promote apoptosis through the phosphorylation of p53, the chief regulator of apoptosis during DDR [78, 79, 80]. p53 can trigger apoptosis by playing dual roles as transcription factor activator and anti-apoptotic protein inhibitor. In the presence of unrepairable damage, p53 upregulates pro-apoptotic genes like PUMA or BAX, while binding and inhibiting anti-apoptotic proteins like BCL2 [81, 82]. In addition to apoptosis, extensive DNA damage can also induce senescence, a metabolic state that causes irreversible growth arrest [83]. Among other mechanisms, senescence can be induced during DDR by ATM and p53 upregulation of p21 [84].
\nATM and ATR also integrate into DDR several other pathways that are essential to provide an adequate and proportionate response to all kind of injuries. For instance, no proper DDR can occur without the upregulation of dNTP for DNA repair [85]. This upregulation requires tight control, as excessive dNTP production can lead to increased mutation frequency [86]. In the presence of DNA damage, DDR kinases regulate RNR—the kinase that catalyzes rate-limiting step during dNTP production—at multiple levels. For instance, p53 regulates the expression levels of RNR; whereas, ATM phosphorylation increases the stability of RNR [87]. In addition, ATR signaling inhibits degradation of some RNR subunits, further contributing to the regulation of dNTP levels by DDR kinases.
\nDysfunctional telomeres can also activate ATM and ATR and elicit a response that includes halting the cell cycle and induction of senescence [88]. Telomere dysfunction can arise when errors in the Shelterin complex render telomeres unprotected. Loss of protection at telomeres can also occur by the natural attrition of telomere length experienced during DNA replication in cells that do not express telomerase [89]. In both cases, DNA ends at telomeres can be mistakenly recognized as DNA damage events and activate DDR.
\nRecently, activation of autophagy has emerged as another tool that DDR can use to fight severe DNA damage. While autophagy was initially thought to be exclusively activated in response to cellular damage or starvation, there is clear evidence that DNA damage can also trigger autophagy [90]. For instance, the action of mTOR—the main autophagy inhibitor—can be repressed either in an ATM or PARP1 dependent manner following DNA damage, effectively promoting autophagy [7]. Consistent with this, in response to ROS mediated damage, ATM can induce selective degradation of mitochondria by autophagy (also known as mitophagy) and pexophagy—the autophagic degradation of peroxisomes [91, 92, 93]. Integration of autophagy pathways as part of DDR repertoire may allow cells in stress to attempt pro-survival pathways first before succumbing to apoptosis.
\nWhile the complex relationships between DDR and inflammation are beginning to emerge, it is clear that ROS and other types of genomic injuries can elicit a pro-inflammatory response. As part of DDR, this pro-survival cell response is mediated mostly through ATM and PARP1 [94]. ATM directly binds and phosphorylates IKK-γ (NEMO), the regulatory subunit of the IKK complex that activates NF-kB [41]. Along with PARP1-mediated post-translational modifications, ATM phosphorylation of IKK-γ promotes activation of IKK and subsequent activation of NF-kB [41, 95, 96, 97]. Therefore, this critical pro-inflammatory enzyme is under DDR control, where it can function as a transcription factor promoting expression of pro-inflammatory cytokines and DNA repair genes [76, 94, 95, 98]. In addition, ATM is involved in a pro-inflammatory pathway known as senescence-associated secretory phenotype (SASP), a complex mechanism that secretes, among others, pro-inflammatory cytokines [94, 99].
\nA-T is an autosomal recessive genetic disease that affects 1 in every 40,000–100,00 births with an estimated 0.5–1% of the global population being carriers of the illness [100]. Patients confront a variety of clinical manifestations throughout their lives, with the inability to control body movements, or ataxia, being one the earliest to appear [101]. The underlying cause for the ataxia is progressive neurodegeneration, particularly of the cerebellum, which also induces dysarthria (speech difficulties), poor balance, and uncontrolled eye movements. Neurodegeneration involves the gradual disappearance of Purkinje, granular cells and the molecular layer of the cerebellar cortex, and expands to the brain stem and the spinal cord. A-T is also characterized by the presence of vascular abnormalities (telangiectasia) that manifest as red spider-like veins, present mostly in the eyes, but also found in cheeks, ears, neck, and other parts of patients’ bodies [102, 103].
\nIn addition to the ataxia and telangiectasia, A-T patients can suffer from a plethora of other clinical symptoms. They have a higher incidence of cancer, diabetes, and show premature aging. They manifest radiosensitivity, sterility, and immunodeficiencies with an elevated risk of developing autoimmune diseases such as arthritis, vitiligo, or immune thrombocytopenia [104]. Authors have also suggested that A-T patients may suffer from prolonged chronic inflammation [94]. Consistent with this, high levels of pro-inflammation cytokines are present in their serum even in the absence of infections [51, 52].
\nWhile mutations in other DDR gene can induce similar symptomatology, defective or absent, ATM is the sole genetic cause of A-T. Hundreds of pathogenic mutations have been identified in ATM from A-T patients, many of them altering splicing or causing frameshifts that result in premature termination codons. As a result, ATM is often either missing or containing truncations of different extents in A-T cells. Clinical manifestations correlate with the severity of the mutation, with milder forms of the syndrome appearing in individuals bearing mutations with mild effects on ATM function and vice versa [105].
\nThe most apparent clinical manifestation of the disease is probably also the most problematic to explain at the molecular level. The question of why mutations in a gene involved in DDR would have specific and discriminating effects in the neural system remains to be fully answered [5, 106]. One of the problems in answering this question is that mouse models lacking functional ATM reconstitute most of the pleiotropic effects of A-T, except for neurodegeneration [107, 108, 109].
\nIt is clear that during neurodevelopment, rapidly dividing cells—with high energetic demands and increased mitochondria respiration—face increasing levels of threats to the integrity of their genome [110, 111]. High metabolic rates increase ROS, and produce oxidative stress, which combined with the high demand for transcription, may render these cells more susceptible to faulty DNA repair mechanisms [110, 112]. This view is consistent with the high prevalence of neurological problems in patients bearing mutations in DNA repair genes [5, 9]. Authors have proposed a model where different stages during neurodevelopment are more susceptible to mutations in different DNA repair pathways, with HR having major roles during phases of rapid proliferation—when a sister chromatid is readily available—and NHEJ being required during late development when cells undergo differentiation in G1/G0 [9]. This would explain why mutations in HR often result in embryonic lethality; whereas, mutations in some NHEJ genes present neurodevelopment problems such as microcephalia. In this model, single strand lesion repair would be required for post-developmental maintenance of neural tissue.
\nCerebellum neurodegeneration in A-T patients also establishes ATM as a requirement to maintain neural tissue. The accumulation of unrepaired lesions during development—and beyond—results in degeneration problems later [113]. This is likely to happen at any tissue, but it would affect the neural system in particular, and with greater virulence, due to the longevity of its cells and the subsequent longer exposure to mutagenic agents. This injury build-up would occur progressively, mimicking the progressive nature of neurodegeneration in A-T patients.
\nSupporting this view, there are clear indications that neural A-T cells are under genotoxic stress. Mice cells lacking ATM gradually accumulate DSBs and show depleted levels of oxidized and reduced forms of NAD in cerebellar tissue, a hallmark of cells undergoing high levels of oxidative stress [114]. Interestingly, depletion of NAD levels only occurs in cerebellar tissues, but not in other parts of the brain, indicating that oxidative stress may be particularly acute in the cerebellum. These data are consistent with other studies that found high levels of oxidative stress in the cerebellum and Purkinje cells in particular, which likely explains the higher prevalence of neurodegeneration in the cerebellum than in other parts of the neural system [115]. The reason for the localized high levels of oxidative stress in cerebellar tissue compared to other regions of the neural system is not known, nor is the reason for the lack of a cerebellar degeneration phenotype in mice lacking ATM despite increased levels of oxidative damage.
\nThese studies strongly suggest that the inability to repair damage caused by oxidative stress is the more plausible cause of cerebellar neurodegeneration in A-T and thus, the roles of ATM during the repair of single strand lesions may provide the molecular basis for the disease. The correlation between impaired single strand lesions repair and failure of neural tissue maintenance was further corroborated in mice that showed extensive neuron loss in the cerebellum when XRCC1 expression was selectively prevented in their brain [116]. While ATM mostly acts in DSB repair, it can also play roles during single strand lesion repair. As mentioned before, SSBs can activate ATM and promote BER by the ATM-mediated phosphorylation of XRCC1 (see Section 2.1) [46]. Whether or not, impairment of this DDR branch is related to the neurodegeneration observed in A-T remains to be elucidated.
\nAuthors have also proposed that neurological problems arising in A-T patients may be related to the faulty resolution of R-loops in locations where active transcription is halted due to the presence of DNA lesions [9, 13]. R-loops are hybrids formed by two strands of DNA and one of RNA that are generated in a variety of circumstances and locations and are known to pose a risk to genome stability [117]. Paused RNA polymerase sites activate ATM, which then elicit a response that includes interactions with spliceosome components that may mediate R-loop resolution [118]. In the cerebellum, the combination of high levels of oxidative stress with high demands of transcription may produce an abnormally high amount of paused transcription sites due to DNA damage. In the absence of ATM, R-loops may not be adequately resolved, eventually creating a scenario incompatible with cell life.
\nThe localized abnormal vascular formations that A-T patients show in several parts of their bodies—particularly in the eyes—is one of the most obvious and yet least investigated phenotypes of the disease [119]. Telangiectasia is highly prevalent in A-T, only missing in patients bearing mild ATM mutations that maintain some residual protein function [120]. Very little is known about the molecular mechanism that prompts telangiectasia when ATM is absent or dysfunctional. The current model proposes that oxidative stress caused by a lack of functional ATM may upregulate HIF1A levels, a hypoxia-activated transcription factor that can induce vascularization by increasing the levels of angiogenesis factor VEGF [120]. Intriguingly, SAPS also induces secretion of VEGF, suggesting a link between this DDR controlled pathway and vascularization [121, 122].
\nA-T patients can show low levels of at least one type of immunoglobulin, inadequate antibody responses to infections and abnormal T and B lymphocyte counts [123, 124]. These phenotypes can be attributed to the roles that ATM has in regulating NHEJ during V(D)J recombination and class-switch recombination (CSR), two recombination processes required to produce antibody diversity during adaptive immunity. Both V(D)J and CSR involve induction of programmed DSBs followed by ATM-aided NHEJ repair [125]. For instance, during V(D)J ATM localizes to break sites and regulate NHEJ components, while p53BP1 phosphorylation by ATM is a crucial event during CSR. The regulatory roles that ATM exerts on these two processes are likely to be extensive and involve other DDR pathways. In A-T patients with immunodeficiencies, programmed DSBs remain unrepaired, and their persistence can cause severe T and B-cell developmental problems [126, 127, 128].
\nThere is growing evidence that the innate immune response may be tightly linked to several clinical manifestations observed in A-T patients. Lack of ATM creates high levels of ROS and oxidative damage, which is known to induce pro-inflammatory cytokines [111, 129, 130]. ATM-deficient cells cannot trigger pexophagy and other forms of autophagy to counteract the negatives effect of oxidative damage, further compounding the problem [91]. Persistent genotoxic stress can, therefore, create chronic inflammation in A-T patients, a condition linked to several A-T symptoms: increased levels of cardiovascular and autoimmune diseases, insulin resistance, and aging. Tellingly, the immune response contributes to neurodegeneration during Alzheimer’s disease, possibly suggesting that in A-T patients, chronic inflammation may also contribute to neurodegeneration in cerebellar tissues suffering high levels of genotoxic stress [131].
\nSeveral DDR pathways contribute to the increased cancer risk seen in A-T patients. The inability of A-T cells to coordinate DNA repair with other DDR pathways can leave unrepaired genomic injuries and elevate the number of mutations in cells—including perilous DSBs—rendering cells highly sensitive to ionizing radiation. Lack of ATM permits these mutations to escape cell cycle checkpoints control and be transmitted to daughter cells, further contributing to tumorigenesis. This process can continue unchecked, as the genomic instability that it produces does not trigger apoptosis when ATM is absent or dysfunctional.
\nOne of the most common malignancies in A-T patients is breast cancer [132]. Even heterozygous individuals bearing debilitating mutations in just one of the ATM genes also have increased breast cancer incidence. While many DDR components are likely to participate in breast cancer tumorigenesis, the loss of the direct control that ATM exerts over BRAC1 is likely one of the major contributing factors. Lymphomas of B-cell origin and leukemia of T-cell origin are also very common in A-T patients, as unrepaired programmed DSBs persisting in developing T and B cells can often be the substrate of translocations [133].
\nBoth male and female A-T patients show infertility due to abnormal meiosis progression. During meiosis, ATM controls the number of DSBs created by SPO11 and ensures their even distribution in the genome [134]. This is achieved by recruiting ATM to SPO11-generated DSBs, which inhibits the formation of further cuts in the vicinity of break sites. Mice models have shown a meiotic arrest in prophase I, faulty synapsis, and chromosome fragmentation leading to massive germ cell loss [107, 135], suggesting that the loss of ATM’s roles during meiosis is the underlying cause of infertility in A-T patients.
\nA-T patients can suffer from insulin resistance and thus, have a higher risk of developing diabetes, a clinical feature that they share with carriers of the disease. The cause for this phenotype is likely to be multifactorial, but it is well-defined that ATM phosphorylates several targets—e.g., translation regulation 4E-BP1—in response to insulin [25]. Furthermore, a lack of fully functional ATM correlates with an inhibition of IRS1 (insulin receptor substrate 1) and low levels of IGF1-R (insulin-like growth factor1 receptor), suggesting possible mechanisms causing this clinical feature [94, 136, 137].
\nWhile much progress has been made to understand A-T at the molecular level, there are still important questions that remain unanswered. This is especially true for the cerebellar neurodegeneration observed in A-T patients, where unknown tissue-specific factors may be at play. The genesis and the extent of some of the A-T clinical features are likely to be the result of interwoven relationships between many pathways and pathologies described in here and hence, elucidating their connections will be crucial to fully understand the disease and develop effective tools for its treatment.
\nThis manuscript was funded and supported by the Smith Chair in Biology at the University of St. Thomas.
\nI have no conflict of interest to declare.
\nIntechOpen is the first native scientific publisher of Open Access books, with more than 116,000 authors worldwide, ranging from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery. Established in Europe with the new headquarters based in London, and with plans for international growth, IntechOpen is the leading publisher of Open Access scientific books. The values of our business are based on the same ones that any scientist applies to their research -- we have created a culture of respect, collegiality and collaboration within an atmosphere that’s relaxed, friendly and progressive.
",metaTitle:"Social Media Community Manager and Marketing Assistant",metaDescription:"We are looking to add further talent to our team in The Shard office in London with a full-time Marketing and Communications Specialist position. The candidate will bring with them a creative and enthusiastic mindset, high level problem-solving skills, the latest marketing and social media platforms skills and strong involvement in community-best practices to engage with researchers and scholars online. The ideal candidate will be a dynamic, forward thinking, approachable team player, able to communicate with all in the global, growing company, with an ability to understand and build a rapport within the research community.",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"We are looking to add further talent to our team in The Shard office in London with a full-time Social Media Community Manager and Marketing Assistant position. The candidate will bring with them a creative and enthusiastic mindset, high level problem-solving skills, the latest marketing and social media platforms skills and strong involvement in community-best practices to engage with researchers and scholars online. The ideal candidate wll be a dynamic, forward thinking, approachable team player, able to communicate with all in the global, growing company, with an ability to understand and build a rapport within the research community.
\\n\\nThe Social Media Community Manager and Marketing Assistant will report to the Senior Marketing Manager. They will work alongside the Marketing and Corporate Communications team, supporting the preparation of all marketing programs, assisting in the development of scientific marketing and communication deliverables, and creating content for social media outlets, as well as managing international social communities.
\\n\\nResponsibilities:
\\n\\nEssential Skills:
\\n\\nDesired Skills:
\\n\\nWhat makes IntechOpen a great place to work?
\\n\\nIntechOpen is a global, dynamic and fast-growing company offering excellent opportunities to develop. We are a young and vibrant company where great people do great work. We offer a creative, dedicated, committed, passionate, and above all, fun environment where you can work, travel, meet world-renowned researchers and grow your career and experience.
\\n\\nTo apply, please email a copy of your CV and covering letter to hogan@intechopen.com stating your salary expectations.
\\n\\nNote: This full-time position will have an immediate start. In your cover letter, please indicate when you might be available for a block of two hours. As part of the interview process, all candidates that make it to the second phase will participate in a writing exercise.
\\n\\n*IntechOpen is an Equal Opportunities Employer consistent with its obligations under the law and does not discriminate against any employee or applicant on the basis of disability, gender, age, colour, national origin, race, religion, sexual orientation, war veteran status, or any classification protected by state, or local law.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'We are looking to add further talent to our team in The Shard office in London with a full-time Social Media Community Manager and Marketing Assistant position. The candidate will bring with them a creative and enthusiastic mindset, high level problem-solving skills, the latest marketing and social media platforms skills and strong involvement in community-best practices to engage with researchers and scholars online. The ideal candidate wll be a dynamic, forward thinking, approachable team player, able to communicate with all in the global, growing company, with an ability to understand and build a rapport within the research community.
\n\nThe Social Media Community Manager and Marketing Assistant will report to the Senior Marketing Manager. They will work alongside the Marketing and Corporate Communications team, supporting the preparation of all marketing programs, assisting in the development of scientific marketing and communication deliverables, and creating content for social media outlets, as well as managing international social communities.
\n\nResponsibilities:
\n\nEssential Skills:
\n\nDesired Skills:
\n\nWhat makes IntechOpen a great place to work?
\n\nIntechOpen is a global, dynamic and fast-growing company offering excellent opportunities to develop. We are a young and vibrant company where great people do great work. We offer a creative, dedicated, committed, passionate, and above all, fun environment where you can work, travel, meet world-renowned researchers and grow your career and experience.
\n\nTo apply, please email a copy of your CV and covering letter to hogan@intechopen.com stating your salary expectations.
\n\nNote: This full-time position will have an immediate start. In your cover letter, please indicate when you might be available for a block of two hours. As part of the interview process, all candidates that make it to the second phase will participate in a writing exercise.
\n\n*IntechOpen is an Equal Opportunities Employer consistent with its obligations under the law and does not discriminate against any employee or applicant on the basis of disability, gender, age, colour, national origin, race, religion, sexual orientation, war veteran status, or any classification protected by state, or local law.
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5822},{group:"region",caption:"Middle and South America",value:2,count:5289},{group:"region",caption:"Africa",value:3,count:1761},{group:"region",caption:"Asia",value:4,count:10546},{group:"region",caption:"Australia and Oceania",value:5,count:909},{group:"region",caption:"Europe",value:6,count:15938}],offset:12,limit:12,total:119319},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{topicId:"300"},books:[],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:28},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:8},{group:"topic",caption:"Business, Management and Economics",value:7,count:3},{group:"topic",caption:"Chemistry",value:8,count:10},{group:"topic",caption:"Computer and Information Science",value:9,count:10},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:10},{group:"topic",caption:"Engineering",value:11,count:26},{group:"topic",caption:"Environmental Sciences",value:12,count:3},{group:"topic",caption:"Immunology and Microbiology",value:13,count:4},{group:"topic",caption:"Materials Science",value:14,count:7},{group:"topic",caption:"Mathematics",value:15,count:3},{group:"topic",caption:"Medicine",value:16,count:49},{group:"topic",caption:"Neuroscience",value:18,count:3},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:4},{group:"topic",caption:"Psychology",value:21,count:5},{group:"topic",caption:"Robotics",value:22,count:2},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:2}],offset:12,limit:12,total:0},popularBooks:{featuredBooks:[{type:"book",id:"9154",title:"Spinal Deformities in Adolescents, Adults and Older Adults",subtitle:null,isOpenForSubmission:!1,hash:"313f1dffa803b60a14ff1e6966e93d91",slug:"spinal-deformities-in-adolescents-adults-and-older-adults",bookSignature:"Josette Bettany-Saltikov and Gokulakannan Kandasamy",coverURL:"https://cdn.intechopen.com/books/images_new/9154.jpg",editors:[{id:"94802",title:"Dr.",name:"Josette",middleName:null,surname:"Bettany-Saltikov",slug:"josette-bettany-saltikov",fullName:"Josette Bettany-Saltikov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",isOpenForSubmission:!1,hash:"b9db6d2645ef248ceb1b33ea75f38e88",slug:"satellite-systems-design-modeling-simulation-and-analysis",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10201",title:"Post-Transition Metals",subtitle:null,isOpenForSubmission:!1,hash:"cc7f53ff5269916e3ce29f65a51a87ae",slug:"post-transition-metals",bookSignature:"Mohammed Muzibur Rahman, Abdullah Mohammed Asiri, Anish Khan, Inamuddin and Thamer Tabbakh",coverURL:"https://cdn.intechopen.com/books/images_new/10201.jpg",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",middleName:null,surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10413",title:"A Collection of Papers on Chaos Theory and Its Applications",subtitle:null,isOpenForSubmission:!1,hash:"900b71b164948830fec3d6254b7881f7",slug:"a-collection-of-papers-on-chaos-theory-and-its-applications",bookSignature:"Paul Bracken and Dimo I. Uzunov",coverURL:"https://cdn.intechopen.com/books/images_new/10413.jpg",editors:[{id:"92883",title:"Prof.",name:"Paul",middleName:null,surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9515",title:"Update in Geriatrics",subtitle:null,isOpenForSubmission:!1,hash:"913e16c0ae977474b283bbd4269564c8",slug:"update-in-geriatrics",bookSignature:"Somchai Amornyotin",coverURL:"https://cdn.intechopen.com/books/images_new/9515.jpg",editors:[{id:"185484",title:"Prof.",name:"Somchai",middleName:null,surname:"Amornyotin",slug:"somchai-amornyotin",fullName:"Somchai Amornyotin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8148",title:"Investment Strategies in Emerging New Trends in Finance",subtitle:null,isOpenForSubmission:!1,hash:"3b714d96a68d2acdfbd7b50aba6504ca",slug:"investment-strategies-in-emerging-new-trends-in-finance",bookSignature:"Reza Gharoie Ahangar and Asma Salman",coverURL:"https://cdn.intechopen.com/books/images_new/8148.jpg",editors:[{id:"91081",title:"Dr.",name:"Reza",middleName:null,surname:"Gharoie Ahangar",slug:"reza-gharoie-ahangar",fullName:"Reza Gharoie Ahangar"}],equalEditorOne:{id:"206443",title:"Prof.",name:"Asma",middleName:null,surname:"Salman",slug:"asma-salman",fullName:"Asma Salman",profilePictureURL:"https://mts.intechopen.com/storage/users/206443/images/system/206443.png",biography:"Professor Asma Salman is a blockchain developer and Professor of Finance at the American University in the Emirates, UAE. An Honorary Global Advisor at the Global Academy of Finance and Management, USA, she completed her MBA in Finance and Accounting and earned a Ph.D. in Finance from an AACSB member, AMBA accredited, School of Management at Harbin Institute of Technology, China. Her research credentials include a one-year residency at the Brunel Business School, Brunel University, UK. Prof. Salman also served as the Dubai Cohort supervisor for DBA students under the Nottingham Business School, UK, for seven years and is currently a Ph.D. supervisor at the University of Northampton, UK, where she is a visiting fellow. She also served on the Board of Etihad Airlines during 2019–2020. One of her recent articles on “Bitcoin and Blockchain” gained wide visibility and she is an active speaker on Fintech, blockchain, and crypto events around the GCC. She holds various professional certifications including Chartered Fintech Professional (USA), Certified Financial Manager (USA), Women in Leadership and Management in Higher Education, (UK), and Taxation GCC VAT Compliance, (UK). She recently won an award for “Blockchain Trainer of the Year” from Berkeley Middle East. Other recognitions include the Women Leadership Impact Award by H.E First Lady of Armenia, Research Excellence Award, and the Global Inspirational Women Leadership Award by H.H Sheikh Juma Bin Maktoum Juma Al Maktoum.",institutionString:"American University in the Emirates",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"American University in the Emirates",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9959",title:"Biomedical Signal and Image Processing",subtitle:null,isOpenForSubmission:!1,hash:"22b87a09bd6df065d78c175235d367c8",slug:"biomedical-signal-and-image-processing",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/9959.jpg",editors:[{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9685",title:"Agroecosystems",subtitle:"Very Complex Environmental Systems",isOpenForSubmission:!1,hash:"c44f7b43a9f9610c243dc32300d37df6",slug:"agroecosystems-very-complex-environmental-systems",bookSignature:"Marcelo L. Larramendy and Sonia Soloneski",coverURL:"https://cdn.intechopen.com/books/images_new/9685.jpg",editors:[{id:"14764",title:"Dr.",name:"Marcelo L.",middleName:null,surname:"Larramendy",slug:"marcelo-l.-larramendy",fullName:"Marcelo L. Larramendy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"2160",title:"MATLAB",subtitle:"A Fundamental Tool for Scientific Computing and Engineering Applications - Volume 1",isOpenForSubmission:!1,hash:"dd9c658341fbd264ed4f8d9e6aa8ca29",slug:"matlab-a-fundamental-tool-for-scientific-computing-and-engineering-applications-volume-1",bookSignature:"Vasilios N. Katsikis",coverURL:"https://cdn.intechopen.com/books/images_new/2160.jpg",editors:[{id:"12289",title:"Prof.",name:"Vasilios",middleName:"N.",surname:"Katsikis",slug:"vasilios-katsikis",fullName:"Vasilios Katsikis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9161",title:"Frailty in the Elderly",subtitle:"Understanding and Managing Complexity",isOpenForSubmission:!1,hash:"a4f0f2fade8fb8ba35c405f5ad31a823",slug:"frailty-in-the-elderly-understanding-and-managing-complexity",bookSignature:"Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/9161.jpg",editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5330},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9154",title:"Spinal Deformities in Adolescents, Adults and Older Adults",subtitle:null,isOpenForSubmission:!1,hash:"313f1dffa803b60a14ff1e6966e93d91",slug:"spinal-deformities-in-adolescents-adults-and-older-adults",bookSignature:"Josette Bettany-Saltikov and Gokulakannan Kandasamy",coverURL:"https://cdn.intechopen.com/books/images_new/9154.jpg",editors:[{id:"94802",title:"Dr.",name:"Josette",middleName:null,surname:"Bettany-Saltikov",slug:"josette-bettany-saltikov",fullName:"Josette Bettany-Saltikov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",isOpenForSubmission:!1,hash:"b9db6d2645ef248ceb1b33ea75f38e88",slug:"satellite-systems-design-modeling-simulation-and-analysis",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10201",title:"Post-Transition Metals",subtitle:null,isOpenForSubmission:!1,hash:"cc7f53ff5269916e3ce29f65a51a87ae",slug:"post-transition-metals",bookSignature:"Mohammed Muzibur Rahman, Abdullah Mohammed Asiri, Anish Khan, Inamuddin and Thamer Tabbakh",coverURL:"https://cdn.intechopen.com/books/images_new/10201.jpg",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",middleName:null,surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10413",title:"A Collection of Papers on Chaos Theory and Its Applications",subtitle:null,isOpenForSubmission:!1,hash:"900b71b164948830fec3d6254b7881f7",slug:"a-collection-of-papers-on-chaos-theory-and-its-applications",bookSignature:"Paul Bracken and Dimo I. Uzunov",coverURL:"https://cdn.intechopen.com/books/images_new/10413.jpg",editors:[{id:"92883",title:"Prof.",name:"Paul",middleName:null,surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9515",title:"Update in Geriatrics",subtitle:null,isOpenForSubmission:!1,hash:"913e16c0ae977474b283bbd4269564c8",slug:"update-in-geriatrics",bookSignature:"Somchai Amornyotin",coverURL:"https://cdn.intechopen.com/books/images_new/9515.jpg",editors:[{id:"185484",title:"Prof.",name:"Somchai",middleName:null,surname:"Amornyotin",slug:"somchai-amornyotin",fullName:"Somchai Amornyotin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8148",title:"Investment Strategies in Emerging New Trends in Finance",subtitle:null,isOpenForSubmission:!1,hash:"3b714d96a68d2acdfbd7b50aba6504ca",slug:"investment-strategies-in-emerging-new-trends-in-finance",bookSignature:"Reza Gharoie Ahangar and Asma Salman",coverURL:"https://cdn.intechopen.com/books/images_new/8148.jpg",editors:[{id:"91081",title:"Dr.",name:"Reza",middleName:null,surname:"Gharoie Ahangar",slug:"reza-gharoie-ahangar",fullName:"Reza Gharoie Ahangar"}],equalEditorOne:{id:"206443",title:"Prof.",name:"Asma",middleName:null,surname:"Salman",slug:"asma-salman",fullName:"Asma Salman",profilePictureURL:"https://mts.intechopen.com/storage/users/206443/images/system/206443.png",biography:"Professor Asma Salman is a blockchain developer and Professor of Finance at the American University in the Emirates, UAE. An Honorary Global Advisor at the Global Academy of Finance and Management, USA, she completed her MBA in Finance and Accounting and earned a Ph.D. in Finance from an AACSB member, AMBA accredited, School of Management at Harbin Institute of Technology, China. Her research credentials include a one-year residency at the Brunel Business School, Brunel University, UK. Prof. Salman also served as the Dubai Cohort supervisor for DBA students under the Nottingham Business School, UK, for seven years and is currently a Ph.D. supervisor at the University of Northampton, UK, where she is a visiting fellow. She also served on the Board of Etihad Airlines during 2019–2020. One of her recent articles on “Bitcoin and Blockchain” gained wide visibility and she is an active speaker on Fintech, blockchain, and crypto events around the GCC. She holds various professional certifications including Chartered Fintech Professional (USA), Certified Financial Manager (USA), Women in Leadership and Management in Higher Education, (UK), and Taxation GCC VAT Compliance, (UK). She recently won an award for “Blockchain Trainer of the Year” from Berkeley Middle East. Other recognitions include the Women Leadership Impact Award by H.E First Lady of Armenia, Research Excellence Award, and the Global Inspirational Women Leadership Award by H.H Sheikh Juma Bin Maktoum Juma Al Maktoum.",institutionString:"American University in the Emirates",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"American University in the Emirates",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9959",title:"Biomedical Signal and Image Processing",subtitle:null,isOpenForSubmission:!1,hash:"22b87a09bd6df065d78c175235d367c8",slug:"biomedical-signal-and-image-processing",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/9959.jpg",editors:[{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9685",title:"Agroecosystems",subtitle:"Very Complex Environmental Systems",isOpenForSubmission:!1,hash:"c44f7b43a9f9610c243dc32300d37df6",slug:"agroecosystems-very-complex-environmental-systems",bookSignature:"Marcelo L. Larramendy and Sonia Soloneski",coverURL:"https://cdn.intechopen.com/books/images_new/9685.jpg",editors:[{id:"14764",title:"Dr.",name:"Marcelo L.",middleName:null,surname:"Larramendy",slug:"marcelo-l.-larramendy",fullName:"Marcelo L. Larramendy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8564",title:"Cell Interaction",subtitle:"Molecular and Immunological Basis for Disease Management",isOpenForSubmission:!1,hash:"98d7f080d80524285f091e72a8e92a6d",slug:"cell-interaction-molecular-and-immunological-basis-for-disease-management",bookSignature:"Bhawana Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8564.jpg",editors:[{id:"315192",title:"Dr.",name:"Bhawana",middleName:null,surname:"Singh",slug:"bhawana-singh",fullName:"Bhawana Singh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9515",title:"Update in Geriatrics",subtitle:null,isOpenForSubmission:!1,hash:"913e16c0ae977474b283bbd4269564c8",slug:"update-in-geriatrics",bookSignature:"Somchai Amornyotin",coverURL:"https://cdn.intechopen.com/books/images_new/9515.jpg",editedByType:"Edited by",editors:[{id:"185484",title:"Prof.",name:"Somchai",middleName:null,surname:"Amornyotin",slug:"somchai-amornyotin",fullName:"Somchai Amornyotin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9021",title:"Novel Perspectives of Stem Cell Manufacturing and Therapies",subtitle:null,isOpenForSubmission:!1,hash:"522c6db871783d2a11c17b83f1fd4e18",slug:"novel-perspectives-of-stem-cell-manufacturing-and-therapies",bookSignature:"Diana Kitala and Ana Colette Maurício",coverURL:"https://cdn.intechopen.com/books/images_new/9021.jpg",editedByType:"Edited by",editors:[{id:"203598",title:"Ph.D.",name:"Diana",middleName:null,surname:"Kitala",slug:"diana-kitala",fullName:"Diana Kitala"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",isOpenForSubmission:!1,hash:"b9db6d2645ef248ceb1b33ea75f38e88",slug:"satellite-systems-design-modeling-simulation-and-analysis",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",editedByType:"Edited by",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10413",title:"A Collection of Papers on Chaos Theory and Its Applications",subtitle:null,isOpenForSubmission:!1,hash:"900b71b164948830fec3d6254b7881f7",slug:"a-collection-of-papers-on-chaos-theory-and-its-applications",bookSignature:"Paul Bracken and Dimo I. Uzunov",coverURL:"https://cdn.intechopen.com/books/images_new/10413.jpg",editedByType:"Edited by",editors:[{id:"92883",title:"Prof.",name:"Paul",middleName:null,surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9154",title:"Spinal Deformities in Adolescents, Adults and Older Adults",subtitle:null,isOpenForSubmission:!1,hash:"313f1dffa803b60a14ff1e6966e93d91",slug:"spinal-deformities-in-adolescents-adults-and-older-adults",bookSignature:"Josette Bettany-Saltikov and Gokulakannan Kandasamy",coverURL:"https://cdn.intechopen.com/books/images_new/9154.jpg",editedByType:"Edited by",editors:[{id:"94802",title:"Dr.",name:"Josette",middleName:null,surname:"Bettany-Saltikov",slug:"josette-bettany-saltikov",fullName:"Josette Bettany-Saltikov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8148",title:"Investment Strategies in Emerging New Trends in Finance",subtitle:null,isOpenForSubmission:!1,hash:"3b714d96a68d2acdfbd7b50aba6504ca",slug:"investment-strategies-in-emerging-new-trends-in-finance",bookSignature:"Reza Gharoie Ahangar and Asma Salman",coverURL:"https://cdn.intechopen.com/books/images_new/8148.jpg",editedByType:"Edited by",editors:[{id:"91081",title:"Dr.",name:"Reza",middleName:null,surname:"Gharoie Ahangar",slug:"reza-gharoie-ahangar",fullName:"Reza Gharoie Ahangar"}],equalEditorOne:{id:"206443",title:"Prof.",name:"Asma",middleName:null,surname:"Salman",slug:"asma-salman",fullName:"Asma Salman",profilePictureURL:"https://mts.intechopen.com/storage/users/206443/images/system/206443.png",biography:"Professor Asma Salman is a blockchain developer and Professor of Finance at the American University in the Emirates, UAE. An Honorary Global Advisor at the Global Academy of Finance and Management, USA, she completed her MBA in Finance and Accounting and earned a Ph.D. in Finance from an AACSB member, AMBA accredited, School of Management at Harbin Institute of Technology, China. Her research credentials include a one-year residency at the Brunel Business School, Brunel University, UK. Prof. Salman also served as the Dubai Cohort supervisor for DBA students under the Nottingham Business School, UK, for seven years and is currently a Ph.D. supervisor at the University of Northampton, UK, where she is a visiting fellow. She also served on the Board of Etihad Airlines during 2019–2020. One of her recent articles on “Bitcoin and Blockchain” gained wide visibility and she is an active speaker on Fintech, blockchain, and crypto events around the GCC. She holds various professional certifications including Chartered Fintech Professional (USA), Certified Financial Manager (USA), Women in Leadership and Management in Higher Education, (UK), and Taxation GCC VAT Compliance, (UK). She recently won an award for “Blockchain Trainer of the Year” from Berkeley Middle East. Other recognitions include the Women Leadership Impact Award by H.E First Lady of Armenia, Research Excellence Award, and the Global Inspirational Women Leadership Award by H.H Sheikh Juma Bin Maktoum Juma Al Maktoum.",institutionString:"American University in the Emirates",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"American University in the Emirates",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10201",title:"Post-Transition Metals",subtitle:null,isOpenForSubmission:!1,hash:"cc7f53ff5269916e3ce29f65a51a87ae",slug:"post-transition-metals",bookSignature:"Mohammed Muzibur Rahman, Abdullah Mohammed Asiri, Anish Khan, Inamuddin and Thamer Tabbakh",coverURL:"https://cdn.intechopen.com/books/images_new/10201.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",middleName:null,surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9959",title:"Biomedical Signal and Image Processing",subtitle:null,isOpenForSubmission:!1,hash:"22b87a09bd6df065d78c175235d367c8",slug:"biomedical-signal-and-image-processing",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/9959.jpg",editedByType:"Edited by",editors:[{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editedByType:"Edited by",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8760",title:"Structure Topology and Symplectic Geometry",subtitle:null,isOpenForSubmission:!1,hash:"8974840985ec3652492c83e20233bf02",slug:"structure-topology-and-symplectic-geometry",bookSignature:"Kamal Shah and Min Lei",coverURL:"https://cdn.intechopen.com/books/images_new/8760.jpg",editedByType:"Edited by",editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1180",title:"Cognitive Neuropsychology",slug:"cognitive-neuropsychology",parent:{title:"Neuropsychology",slug:"life-sciences-neuroscience-neuropsychology"},numberOfBooks:8,numberOfAuthorsAndEditors:231,numberOfWosCitations:110,numberOfCrossrefCitations:47,numberOfDimensionsCitations:138,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"cognitive-neuropsychology",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"8938",title:"Inhibitory Control Training",subtitle:"A Multidisciplinary Approach",isOpenForSubmission:!1,hash:"bd82354f3bba4af5421337cd42052f86",slug:"inhibitory-control-training-a-multidisciplinary-approach",bookSignature:"Sara Palermo and Massimo Bartoli",coverURL:"https://cdn.intechopen.com/books/images_new/8938.jpg",editedByType:"Edited by",editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6816",title:"Eat, Learn, Remember",subtitle:null,isOpenForSubmission:!1,hash:"19bd9ad093da278ec19278cade15ed1a",slug:"eat-learn-remember",bookSignature:"Aise Seda Artis",coverURL:"https://cdn.intechopen.com/books/images_new/6816.jpg",editedByType:"Edited by",editors:[{id:"99453",title:"Dr.",name:"Aise Seda",middleName:null,surname:"Artis",slug:"aise-seda-artis",fullName:"Aise Seda Artis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3079",title:"Therapeutic Hypothermia in Brain Injury",subtitle:null,isOpenForSubmission:!1,hash:"f585bf9f728f35c841d3afb05ec11c48",slug:"therapeutic-hypothermia-in-brain-injury",bookSignature:"Farid Sadaka",coverURL:"https://cdn.intechopen.com/books/images_new/3079.jpg",editedByType:"Edited by",editors:[{id:"101031",title:"Dr.",name:"Farid",middleName:null,surname:"Sadaka",slug:"farid-sadaka",fullName:"Farid Sadaka"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2119",title:"Miscellanea on Encephalopathies",subtitle:"A Second Look",isOpenForSubmission:!1,hash:"2881c23482aaaccf648a51319e3f8af9",slug:"miscellanea-on-encephalopathies-a-second-look",bookSignature:"Radu Tanasescu",coverURL:"https://cdn.intechopen.com/books/images_new/2119.jpg",editedByType:"Edited by",editors:[{id:"72305",title:"Dr.",name:"Radu",middleName:null,surname:"Tanasescu",slug:"radu-tanasescu",fullName:"Radu Tanasescu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"682",title:"Miscellanea on Encephalopathies",subtitle:null,isOpenForSubmission:!1,hash:"ab4c06a22583d820ecffbd3de1ee4b22",slug:"miscellanea-on-encephalopathies",bookSignature:"Radu Tanasescu",coverURL:"https://cdn.intechopen.com/books/images_new/682.jpg",editedByType:"Edited by",editors:[{id:"72305",title:"Dr.",name:"Radu",middleName:null,surname:"Tanasescu",slug:"radu-tanasescu",fullName:"Radu Tanasescu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"748",title:"Topics in Neuromodulation Treatment",subtitle:null,isOpenForSubmission:!1,hash:"032222862a490b0d0d5ef9650e600e9f",slug:"topics-in-neuromodulation-treatment",bookSignature:"Jose D. Carrillo-Ruiz",coverURL:"https://cdn.intechopen.com/books/images_new/748.jpg",editedByType:"Edited by",editors:[{id:"74752",title:"Dr.",name:"José Damián",middleName:null,surname:"Carrillo-Ruiz",slug:"jose-damian-carrillo-ruiz",fullName:"José Damián Carrillo-Ruiz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"563",title:"Brain Injury",subtitle:"Pathogenesis, Monitoring, Recovery and Management",isOpenForSubmission:!1,hash:"6e40d2cf6eebee2041b76a70987f4258",slug:"brain-injury-pathogenesis-monitoring-recovery-and-management",bookSignature:"Amit Agrawal",coverURL:"https://cdn.intechopen.com/books/images_new/563.jpg",editedByType:"Edited by",editors:[{id:"100142",title:"Prof.",name:"Amit",middleName:null,surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2034",title:"Brain Injury",subtitle:"Functional Aspects, Rehabilitation and Prevention",isOpenForSubmission:!1,hash:"97fb870ccfe237f3270c3ae1b7a7dacd",slug:"brain-injury-functional-aspects-rehabilitation-and-prevention",bookSignature:"Amit Agrawal",coverURL:"https://cdn.intechopen.com/books/images_new/2034.jpg",editedByType:"Edited by",editors:[{id:"100142",title:"Prof.",name:"Amit",middleName:null,surname:"Agrawal",slug:"amit-agrawal",fullName:"Amit Agrawal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:8,mostCitedChapters:[{id:"33530",doi:"10.5772/27840",title:"Traumatic Brain Injury and Inflammation: Emerging Role of Innate and Adaptive Immunity",slug:"traumatic-brain-injury-and-inflammation-emerging-role-of-innate-and-adaptive-immunity",totalDownloads:6330,totalCrossrefCites:10,totalDimensionsCites:18,book:{slug:"brain-injury-pathogenesis-monitoring-recovery-and-management",title:"Brain Injury",fullTitle:"Brain Injury - Pathogenesis, Monitoring, Recovery and Management"},signatures:"Efthimios Dardiotis, Vaios Karanikas, Konstantinos Paterakis, Kostas Fountas and Georgios M. Hadjigeorgiou",authors:[{id:"31282",title:"Dr.",name:"Georgios",middleName:null,surname:"Hadjigeorgiou",slug:"georgios-hadjigeorgiou",fullName:"Georgios Hadjigeorgiou"},{id:"51986",title:"Prof.",name:"Kostas",middleName:"N.",surname:"Fountas",slug:"kostas-fountas",fullName:"Kostas Fountas"},{id:"71779",title:"Dr.",name:"Efthimios",middleName:null,surname:"Dardiotis",slug:"efthimios-dardiotis",fullName:"Efthimios Dardiotis"},{id:"79705",title:"Dr.",name:"Vaios",middleName:null,surname:"Karanikas",slug:"vaios-karanikas",fullName:"Vaios Karanikas"},{id:"79706",title:"Prof.",name:"Konstantinos",middleName:"N",surname:"Paterakis",slug:"konstantinos-paterakis",fullName:"Konstantinos Paterakis"}]},{id:"30498",doi:"10.5772/27042",title:"Mental Fatigue; A Common Long Term Consequence After a Brain Injury",slug:"mental-fatigue-a-common-long-term-consequence-after-a-brain-injury",totalDownloads:12672,totalCrossrefCites:2,totalDimensionsCites:15,book:{slug:"brain-injury-functional-aspects-rehabilitation-and-prevention",title:"Brain Injury",fullTitle:"Brain Injury - Functional Aspects, Rehabilitation and Prevention"},signatures:"Birgitta Johansson and Lars Rönnbäck",authors:[{id:"68660",title:"Dr.",name:"Birgitta",middleName:null,surname:"Johansson",slug:"birgitta-johansson",fullName:"Birgitta Johansson"}]},{id:"33534",doi:"10.5772/27205",title:"Alzheimer's Factors in Ischemic Brain Injury",slug:"alzheimer-s-factors-in-ischemic-brain-injury",totalDownloads:2139,totalCrossrefCites:1,totalDimensionsCites:7,book:{slug:"brain-injury-pathogenesis-monitoring-recovery-and-management",title:"Brain Injury",fullTitle:"Brain Injury - Pathogenesis, Monitoring, Recovery and Management"},signatures:"Ryszard Pluta and Mirosław Jabłoński",authors:[{id:"69204",title:"Prof.",name:"Ryszard",middleName:null,surname:"Pluta",slug:"ryszard-pluta",fullName:"Ryszard Pluta"}]}],mostDownloadedChaptersLast30Days:[{id:"30498",title:"Mental Fatigue; A Common Long Term Consequence After a Brain Injury",slug:"mental-fatigue-a-common-long-term-consequence-after-a-brain-injury",totalDownloads:12676,totalCrossrefCites:2,totalDimensionsCites:15,book:{slug:"brain-injury-functional-aspects-rehabilitation-and-prevention",title:"Brain Injury",fullTitle:"Brain Injury - Functional Aspects, Rehabilitation and Prevention"},signatures:"Birgitta Johansson and Lars Rönnbäck",authors:[{id:"68660",title:"Dr.",name:"Birgitta",middleName:null,surname:"Johansson",slug:"birgitta-johansson",fullName:"Birgitta Johansson"}]},{id:"42416",title:"Therapeutic Hypothermia: Implications on Drug Therapy",slug:"therapeutic-hypothermia-implications-on-drug-therapy",totalDownloads:3776,totalCrossrefCites:1,totalDimensionsCites:5,book:{slug:"therapeutic-hypothermia-in-brain-injury",title:"Therapeutic Hypothermia in Brain Injury",fullTitle:"Therapeutic Hypothermia in Brain Injury"},signatures:"Kacey B. Anderson and Samuel M. Poloyac",authors:[{id:"153465",title:"Dr.",name:"Samuel",middleName:"L.",surname:"Poloyac",slug:"samuel-poloyac",fullName:"Samuel Poloyac"}]},{id:"35733",title:"Drug-Induced Encephalopathy",slug:"drug-induced-encephalopathy",totalDownloads:19381,totalCrossrefCites:5,totalDimensionsCites:6,book:{slug:"miscellanea-on-encephalopathies-a-second-look",title:"Miscellanea on Encephalopathies",fullTitle:"Miscellanea on Encephalopathies - A Second Look"},signatures:"Niels Hansen",authors:[{id:"85908",title:"Dr.",name:"Niels",middleName:null,surname:"Hansen",slug:"niels-hansen",fullName:"Niels Hansen"}]},{id:"64666",title:"Introductory Chapter: Eat, Learn, Remember",slug:"introductory-chapter-eat-learn-remember",totalDownloads:493,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"eat-learn-remember",title:"Eat, Learn, Remember",fullTitle:"Eat, Learn, Remember"},signatures:"Aise Seda Artis",authors:[{id:"99453",title:"Dr.",name:"Aise Seda",middleName:null,surname:"Artis",slug:"aise-seda-artis",fullName:"Aise Seda Artis"}]},{id:"33470",title:"Prelemniscal Radiations Neuromodulation in Parkinson Disease´s Treatment",slug:"prelemniscal-radiations-neuromodulation-in-the-treatment-of-parkinson-s-disease",totalDownloads:2653,totalCrossrefCites:0,totalDimensionsCites:2,book:{slug:"topics-in-neuromodulation-treatment",title:"Topics in Neuromodulation Treatment",fullTitle:"Topics in Neuromodulation Treatment"},signatures:"José D. Carrillo-Ruiz, Francisco Velasco, Fiacro Jiménez, Ana Luisa Velasco, Guillermo Castro, Julián Soto, Victor Salcido",authors:[{id:"74752",title:"Dr.",name:"José Damián",middleName:null,surname:"Carrillo-Ruiz",slug:"jose-damian-carrillo-ruiz",fullName:"José Damián Carrillo-Ruiz"},{id:"74787",title:"Dr.",name:"Francisco",middleName:null,surname:"Velasco",slug:"francisco-velasco",fullName:"Francisco Velasco"},{id:"74788",title:"Dr.",name:"Fiacro",middleName:null,surname:"Jiménez",slug:"fiacro-jimenez",fullName:"Fiacro Jiménez"},{id:"74799",title:"Dr.",name:"Ana Luisa",middleName:null,surname:"Velasco",slug:"ana-luisa-velasco",fullName:"Ana Luisa Velasco"},{id:"74806",title:"Dr.",name:"Julian",middleName:null,surname:"Soto",slug:"julian-soto",fullName:"Julian Soto"},{id:"74808",title:"Prof.",name:"Victor",middleName:"Manuel",surname:"Salcido",slug:"victor-salcido",fullName:"Victor Salcido"}]},{id:"42406",title:"Therapeutic Hypothermia in Traumatic Brain Injury",slug:"therapeutic-hypothermia-in-traumatic-brain-injury",totalDownloads:4860,totalCrossrefCites:1,totalDimensionsCites:2,book:{slug:"therapeutic-hypothermia-in-brain-injury",title:"Therapeutic Hypothermia in Brain Injury",fullTitle:"Therapeutic Hypothermia in Brain Injury"},signatures:"Farid Sadaka, Christopher Veremakis, Rekha Lakshmanan and Ashok Palagiri",authors:[{id:"101031",title:"Dr.",name:"Farid",middleName:null,surname:"Sadaka",slug:"farid-sadaka",fullName:"Farid Sadaka"},{id:"102527",title:"Dr.",name:"Christopher",middleName:null,surname:"Veremakis",slug:"christopher-veremakis",fullName:"Christopher Veremakis"},{id:"152995",title:"Dr.",name:"Ashok",middleName:null,surname:"Palagiri",slug:"ashok-palagiri",fullName:"Ashok Palagiri"},{id:"153044",title:"Dr.",name:"Rekha",middleName:null,surname:"Lakshmanan",slug:"rekha-lakshmanan",fullName:"Rekha Lakshmanan"}]},{id:"69748",title:"When Aggression Is Out of Control: From One-Person to Two-Person Neuropsychology",slug:"when-aggression-is-out-of-control-from-one-person-to-two-person-neuropsychology",totalDownloads:376,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"inhibitory-control-training-a-multidisciplinary-approach",title:"Inhibitory Control Training",fullTitle:"Inhibitory Control Training - A Multidisciplinary Approach"},signatures:"J. Gagnon, J.E. Quansah and W.S. Kim",authors:null},{id:"33542",title:"Mechanisms of Neuroprotection Underlying Physical Exercise in Ischemia - Reperfusion Injury",slug:"mechanisms-of-neuroprotection-underlying-physical-exercise-in-ischemia-reperfusion-injury",totalDownloads:2259,totalCrossrefCites:3,totalDimensionsCites:5,book:{slug:"brain-injury-pathogenesis-monitoring-recovery-and-management",title:"Brain Injury",fullTitle:"Brain Injury - Pathogenesis, Monitoring, Recovery and Management"},signatures:"David Dornbos III and Yuchuan Ding",authors:[{id:"90244",title:"Dr.",name:"Yuchuan",middleName:null,surname:"Ding",slug:"yuchuan-ding",fullName:"Yuchuan Ding"},{id:"119759",title:"Dr.",name:"David III",middleName:null,surname:"Dornbos",slug:"david-iii-dornbos",fullName:"David III Dornbos"}]},{id:"35738",title:"Encephalopathy Associated with Psychotropic Drug Therapy",slug:"encephalopathy-associated-with-psychotropic-drug-therapy",totalDownloads:4165,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"miscellanea-on-encephalopathies-a-second-look",title:"Miscellanea on Encephalopathies",fullTitle:"Miscellanea on Encephalopathies - A Second Look"},signatures:"Yuji Odagaki",authors:[{id:"76341",title:"Dr.",name:"Yuji",middleName:null,surname:"Odagaki",slug:"yuji-odagaki",fullName:"Yuji Odagaki"}]},{id:"69720",title:"A View from the Start: A Review of Inhibitory Control Training in Early Childhood",slug:"a-view-from-the-start-a-review-of-inhibitory-control-training-in-early-childhood",totalDownloads:364,totalCrossrefCites:1,totalDimensionsCites:2,book:{slug:"inhibitory-control-training-a-multidisciplinary-approach",title:"Inhibitory Control Training",fullTitle:"Inhibitory Control Training - A Multidisciplinary Approach"},signatures:"Erin Ruth Baker, Qingyang Liu and Rong Huang",authors:null}],onlineFirstChaptersFilter:{topicSlug:"cognitive-neuropsychology",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"chapter.detail",path:"/books/novel-perspectives-of-stem-cell-manufacturing-and-therapies/umbilical-cord-blood-and-cord-tissue-bank-as-a-source-for-allogeneic-use",hash:"",query:{},params:{book:"novel-perspectives-of-stem-cell-manufacturing-and-therapies",chapter:"umbilical-cord-blood-and-cord-tissue-bank-as-a-source-for-allogeneic-use"},fullPath:"/books/novel-perspectives-of-stem-cell-manufacturing-and-therapies/umbilical-cord-blood-and-cord-tissue-bank-as-a-source-for-allogeneic-use",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()