\r\n\tThe purpose of the book is to bring together the latest knowledge about genetic diversity by presenting the studies of some of the scientists who are engaged in development of new tools and ideas used to reveal genetic diversity, often from very different perspectives. The book should prove useful to students, researchers and experts in the area of biology, medicine and agriculture.
",isbn:"978-1-80356-945-1",printIsbn:"978-1-80356-944-4",pdfIsbn:"978-1-80356-946-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"0b1e679fcacdec2448603a66df71ccc7",bookSignature:"Prof. Mahmut Çalışkan and Dr. Sevcan Aydin",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11643.jpg",keywords:"PCR Based Methods, Protein Based Methods, Sequencing, Conservation of Genetic Resources, Natural Variation, Molecular Markers, Genetic Manipulation in Animals, Resistance to Disease, Genetic Manipulation in Plants, Use of Microorganisms in Biotechnology, Genetic Differentiation, Gene Therapy and Gene Editing",numberOfDownloads:13,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 7th 2022",dateEndSecondStepPublish:"June 16th 2022",dateEndThirdStepPublish:"August 15th 2022",dateEndFourthStepPublish:"November 3rd 2022",dateEndFifthStepPublish:"January 2nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Professor of genetics and molecular biology and Head of Biotechnology division at İstanbul University in Turkey whose main research areas include plant molecular genetics, microbial biotechnology and characterization and biotechnological use of halophilic archaeal strains.",coeditorOneBiosketch:"Associate Professor of Biotechnology Division in Department of Biology at Istanbul University in Turkey whose main research areas include genetics, environmental biotechnology and bioengineering.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"51528",title:"Prof.",name:"Mahmut",middleName:null,surname:"Çalışkan",slug:"mahmut-caliskan",fullName:"Mahmut Çalışkan",profilePictureURL:"https://mts.intechopen.com/storage/users/51528/images/system/51528.png",biography:"Mahmut Çalışkan is a Professor of Genetics and Molecular Biology in the Department of Biology, Biotechnology Division, Istanbul University, Turkey. He obtained a BSc from Middle East Technical University, Ankara, and a Ph.D. from the University of Leeds, England. His main research areas include the role of germin gene products during early plant development, analysis of genetic variation, polymorphisms, and the characterization and biotechnological use of halophilic archaea.",institutionString:"Istanbul University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"8",institution:{name:"Istanbul University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:{id:"462767",title:"Dr.",name:"Sevcan",middleName:null,surname:"Aydin",slug:"sevcan-aydin",fullName:"Sevcan Aydin",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003QRfRpQAL/Profile_Picture_2022-03-24T08:49:06.jpg",biography:"Sevcan Aydın is an Associate Professor of Biotechnology Division in Department of Biology at Istanbul University in Türkiye. 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Immune privilege has been found to be responsible for the high rate of cornea graft survival. Cornea avascularity as well the absence of lymph nodes suppresses antigen transportation and presentation to naive T cells. The spectrum of neuropeptides and complement activation from the cornea combined with aqueous humor immune tolerance - also known as anterior chamber associated immune deviation (ACAID) - will make the cornea tissue become more adaptable and not easily responsive to any foreign antigen from the graft tissue [1, 2]. However, any form of inflammation, vascularization, infection, or previous graft failure will be considered high risk factors that cause rejection due to an adaptive immune response [3]. Loss of graft survival can be defined as a condition where the cornea loses its transparency after two weeks of clarity and is considered a failure if cornea edema persists at six months. Moreover, if in six months persistent graft edema remains unclear after treatment with a high dose immunosuppressive agent, it should be considered an irreversible rejection. On the other hand, it will be considered a reversible rejection if the graft reaches its clarity after successful treatment [4].
Cornea infection is considered a high-risk factor for corneal transplant rejection. No matter what causes the infection, any form of bacterial, fungal, and viral infection is recognized as factors that increase the risk for graft rejection. Several conditions like a poor ocular surface, coexisting allergies, trauma, or previous intraocular surgeries can disrupt and make conditions worse and accelerate the likely risk of developing graft failure [5, 6, 7].
Dry eye disease (DED) that affects tens of millions of people worldwide, is one of the most common types of ocular surface disorders which may initiate graft failure through an immunopathological response [8, 9]. Tear hyperosmolarity is also found to play a major role in the vicious cycle of dry eye disease that is associated with activation of inflammation [10]. Japanese researchers assessed that a DED cornea donor tissue acts as a significant risk factor for subsequent corneal allograft rejection. They found that donor corneas from patients with DED will activate inflammation by augmenting T-cells at the host, promoting dendritic cell maturation in the cornea and draining lymph nodes of the host, increased Th1 and Th17 frequencies and decreased Treg function in the recipient and this activates host T cells through a direct pathway of allosensitization. Therefore, the possibility of a cornea transplant recipient who received donor material from a patient with moderate to severe dry eye disease may predispose higher rejection rates in the grafted host [11].
Recipient characteristics such as the recipient’s indication for grafting, previous glaucoma drainage implant surgery and which type of keratoplasty technique performed may profoundly affect the number of endothelial cells lost and graft survival as well. Although there is depth of tissue differences in the amount of implanted cornea tissue between endothelial keratoplasty (EK) and posterior keratoplasty (PK), the endothelial cell loss was found to be similar [12] during 10 years of follow up (71% for EK vs. 78% for PK).
To estimate the possibility of corneal transplants being rejected, a good explanation about what is allograft rejection and when we can define a condition as a cornea graft failure are needed. The term cornea graft rejection refers to a specific immune response from the recipient after the donor tissue was transplanted and characterized by a successful clear cornea graft condition for two weeks following cornea transplantation. Graft failure is defined as primary graft failure if cornea edema was found to exist immediately after it was transplanted, and it never reached clarity. Any improper cornea tissue storage or surgical trauma can cause graft failure. The immune system is found to give a huge role in the graft tissue to develop rejection or failure. A previous study concluded that cornea transplant success not only depends on the donor and recipient tissue condition, but it also depends on what type of keratoplasty, and which immune pathway is involved (direct or indirect) [13].
The status of donor cornea conditions that are correlated with graft survival rates was studied in 2018. It was reported that donor tissue with a history of dry eye disease will cause a higher number in APCs from the recipient ocular surface draining lymph nodes (dLNs), induce the maturation of dendritic cells and show an increase in the number of CD4 effector T cells produced that will reduce the graft survival rate to 10% [11, 14].
In the same study, at two weeks after surgery, it was also found that an increase in interferon-γ (IFN-γ) and cytokine interleukin 17 (IL_17) secretion and a reduced number Foxp3 expression will interfere with the T regulatory cells ability to protect graft tissue from the recipient’s immune response and can lead to rejection [15, 16, 17, 18]. In conclusion, cornea graft survival rate is an estimated rate during a period of time that the graft tissue is able to maintain its clarity after transplantation. The successful and high cornea graft survival rate is related not only to its immune privilege but also the status of the recipient bed such as the amount of cornea tissue replaced (penetrating or lamellar keratoplasty), the underlying disease, the amount of vascularization, the presence of glaucoma, inflammation, the number of regrafts performed and larger graft size.
The study done by Eghtedari reported that during a 5-year period, DALK gave better graft survival rates compared to DSAEK and PK in terms of corneal regrafting with a percentage of 1.2% compared to 5% and 8.25%. It is believed because the endothelial layer was not included for the DALK procedure. The primary disease of the cornea that led to transplantation is also proposed to be an important factor in future graft survival and important indicators such as infection (bacterial, herpetic, and fungal) being the major cause of graft rejection and need for repeat grafting (35%), with pseudo phakic bullous keratopathy as the second most common factor with 30.3% chances for corneal regraft. Other risk factors that determine graft survival are as follows: First, the quality of the donor cornea itself where a lower quality donor cornea that was used for tectonic purposes showed a lower survival rate compared to a higher quality donor cornea in keratoplasty for optical reasons. Secondly, glaucoma was found to be responsible for about 13% of regrafts cases. As for corneal vascularization, the existence of pannus was found in 25% of regrafts which is similar to the 10-year previous study that showed the graft survival rates of 35 to 40%. The immune privilege that normally is present in the cornea was interfered with by the lower impression of T regulatory cells caused by a small number of Foxp3 factors expressed [3, 18].
Tear hyperosmolarity is the core mechanism of dry eye disease (DED). The cause of DED can be divided into two forms, aqueous-deficient dry eye (ADDE) and evaporative dry eye (EDE). In ADDE, tear hyperosmolarity results when lacrimal secretion is reduced, with the normal process of evaporation from the eye. In EDE, tear hyperosmolarity is caused by excessive evaporation from the exposed tear film in the presence of a normally functioning lacrimal gland. Since tear osmolarity can only rise because of tear evaporation in both ADDE and EDE, tear hyperosmolarity is due to evaporation from the ocular surface and in that sense, all forms of DED are evaporative. EDE is a hyper-evaporative state. In DED, tear hyperosmolarity is considered to set up a cascade of signaling events within surface epithelial cells, that leads to the release of inflammatory mediators and proteases. Any etiology that induces an increase in tear hyperosmolarity will eventually create an ocular surface disorder. This in turn can activate each inflammatory mediator as a compensatory response.
As a disease caused by multiple factors, dry eye disease is characterized by the loss of homeostasis in the tear film along with ocular symptoms. Intercellular adhesion molecule (ICAM-1) is an over expressed and attracted lymphocyte function associated antigen-1 (LFA-1) receptor that is located at the surface of T cells can either be activated or inactivated. If ICAM-1 binds to LFA-1 receptor, it will release cytokine and cause the inactivated T cell to become activated. The higher amount of cytokine release, the higher number of activated T cells which leads to more severe tissue inflammation occurs [19, 20].
There are two kinds of immune systems, the first is also known as an innate immune system consisting of a component that is already in the location and responds immediately after it is exposed, with a general response. As for specific immune system response, it is formed by T cells and B cells that are located far from the exact location of the stimulus and launched with a specialized system after it is triggered after multiple stimuli.
As mentioned previously, the innate immune response is a fast and nonspecific immune response that is created by the ocular surface as a protection from any microbial invasion or toxin passage across its surface epithelium. Facilitated by the mucin layer of the tears, the glycocalyx changes at the conjunctiva, together with the cornea epithelium, along with production of a stream of antimicrobial defense proteins such as lysozyme, lipocalin, lactoferrin and trefoil peptides, makes the corneal and conjunctival epithelium considered as the “gatekeepers” of the ocular surface [21, 22, 23, 24, 25].
The hyperosmolar state of the tear film will also activate MAPK kinases and its master regulator NFkB. This regulator will produce interleukin-1 (IL-1) and TNF-ɑ that will up-regulate matrix metalloproteinase-9 (MMP-9) and associated with disruption of the epithelial cornea barrier [26]. The activation of pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) and the NOD-like receptors (NLR) will create an inflammatory response towards DED as part of innate immune response [27]. Induction in chemokines by the ocular surface will attract macrophages, dendritic cells, neutrophils and activated T cells [28, 29, 30, 31, 32, 33]. Moreover, blood vessel endothelial cells will produce an adhesion molecule called intracellular adhesion molecule-1 (ICAM-1) in DED [34]. This ICAM-1 will bind to inflammatory cells and express an integrin leukocyte function antigen-1 (LFA-1) causing migration and activation at the site of inflammation and lymphoid organs [35].
Accumulation of CD11c antigen presenting cells maturation and the activation of antigen specific CD4+ T cells in draining lymph nodes during desiccating stress, with the reduction of CD4+ T cell infiltration numbers in depleted macrophages was found as evidence that can explain why the ocular surface antigen presentation was considered as the first initiator of adaptive immune response [36]. The upregulation in major histocompatibility complex II (MHC II) and primed T cells that are recruited to a patient’s cornea and conjunctiva in DED found were also considered as another plausible pathway in local adaptive immune responses [37, 38]. Keep in mind that adaptive immune systems are evolving and becoming more specific through time by memorizing the first encounter antigen.
Because cornea is avascular and lymphatic free, the graft survival rate for corneal transplantation is the highest among all other organ transplants and this condition is often referred to as immune privilege of the cornea. Dendritic cells which are also known as the messenger cells of the immune system in cornea graft tissue, exist in an immature inactivated state which will result in immune quiescence in a healthy cornea. All cornea layers are found to have a very low expression of MHC class I and II antigens, limiting immunogenicity to foreign antigens. The transport of antigens and APCs to T cell-rich secondary lymphoid organs as a part of the immune system do not happen in the cornea because of its absence of lymph vessels. Cell membrane bound molecules are also expressed by the cornea - for instance Fas Ligand (FasL), MHC-Ib, tumor necrosis factor (TNF) and complement regulatory protein (CRP). These molecules guard from immune mediated inflammation and induce apoptosis of immune effector cells. FasL expressed by corneal epithelium and endothelium acts as a pro apoptotic molecule. It also will destroy polymorphonuclear neutrophils (PMNs) and effector T cells that express its receptor Fas/CD95, creating immune quiescence while protecting the cornea from immune mediated graft rejection [39, 40]. The corneal epithelium and stroma produce programmed death ligand-1 (PD-L1) which interacts with its receptor PD-1 on the T cells and leads to inhibition of T cells proliferating, induction of apoptosis and suppression of interferon (IFN-γ) secretion [41], promoting graft survival [42, 43].
Soluble immunosuppressive factors inside the anterior chamber will inhibit T cell and complement activation [44, 45]. This alloantigen specific peripheral immune tolerance from aqueous humor is also known as anterior chamber associated immune deviation (ACAID) which modulate the systemic cytotoxic immune response [46, 47] and suppresses delayed-type hypersensitivity. Therefore, ACAID also known as a factor that promote graft survival [48, 49].
All cells of each living individual express a surface polymorphic protein antigen also known as major histocompatibility complex (MHC) antigens that are located at chromosome 6. The variations in MHC genes are the reason why everyone has their own characteristic hence differentiate people one to another. Therefore, if the antigen between the donor and the recipient was mismatched, the recipient will directly reject the allograft tissue.
Human leukocyte antigen (HLA) is responsible for MHC expression [50]. There are two types of class for MHC expression. MHC type I (MHC-1) is found on all nucleated cells of the body and platelets. In the cornea, its antigens are expressed by corneal epithelial, stromal, and endothelial cells. These transmembrane glycoproteins are coded for HLA-A, -B and -C genes. As for MHC type II (MHC-II) is more specific compared to class I. It was limited only at the cell surface of immunocompetent antigen-presenting cells (APCs) like DCs, macrophages and Langerhans cells [51].
Foreign antigens carried by APCs and presented to naive T cells with the presence of MHC-II will stimulate molecules and recognize it as a non-self-antigen. Any inflammation, interferon gamma and surgery will induce the expression of MHC II antigens even more in the cornea [52].
Dendritic cells as the messenger of the immune system will bring the foreign antigen from their exact location of inflammation and transport them to the lymph node which will activate B cells at the spleen and T cells at the thymus glands. It is known that corneal DCs play a critical role in graft rejection through their ability to regulate T cell response to both self and foreign antigens of the cornea donor tissue.
Antigen was recognized by the MHC class II at the surface of mature DCs. After it binds to its receptor at the surface of T cell/CD4, they will cause the replication of T cells into several types of T cells. The first type is T helper. Antigen that was present to it will be recognized by the CD8 and cause cytokine release. After cytokine release, T helper will differentiate into a cytotoxic T cell.
The second type of T cell is found actively in plasma cells differentiation into antibodies and create an immune memory at the first encounter antigen. It will recall a similar response every time the same pathogen exists. The third type is the T cell that will release cytokine to attract monocytes and macrophages at the inflammation site so the phagocytosis process can occur.
The role of dendritic cells in graft rejection was determined by regulating the T cells after the antigen was presented and recognized by the MHC class II antigen receptor at the surface of mature DC. Normally, these central corneal DCs will remain silent, dormant, and undifferentiated. However, any kind of stress like inflammation will activate DCs and after the DC reaches the cornea through bloodstream where the donor alloantigen was captured by lymphoid organs, it will be transported and presented back into T cell for further immune response [53].
Patients with dry eye disease will complain about foreign body sensation, blurred vision, and redness on their eyes due to the lack of tear production and rapid tear evaporation caused by poor tear stability as their characteristic. The lacrimal gland dysfunction creates an inflamed ocular surface, and it is considered as the pathognomonic sign of DED [54].
Post corneal graft patients often will develop ocular dryness as a side effect from consuming glaucoma medication that can lead to poorer healing process at the ocular surface. The mechanisms of the poorer healing process are as follows. Dryness at the ocular surface activates inflammatory mediators such as collagenase and will create a defect at the epithelium of the cornea if it was not treated which can lead to an infection or induce vascularization that can affect as a high-risk factor for corneal graft rejection [55]. Tear examination may show shorter tear break-up time (BUT) and an unstable tear film.
Glaucoma is the adverse effect because of long-term steroid topical medication usage. Contrarily, steroid eye drops are also very important to prevent graft rejection in post corneal transplant patients. Each glaucoma medication has their own mechanism in causing any cornea or ocular surface disorder. For example, beta blocker eye drops like timolol has been found to act on the beta receptors on lacrimal gland that will reduce basal tear turnover rate after one month of therapy [56]. Prostaglandin analog medication will obstruct the meibomian gland even more [57]. Brimonidine tartrate as the alpha-adrenergic agonist mostly used may predispose the patient into ocular allergy [58]. Although corneal thickness has been found to be related to carbonic anhydrase inhibitor brinzolamide eye drop, further investigation is still needed [59]. Ocular surface disease because of the long-term glaucoma medication use is related to the increment of macrophages found in the conjunctiva. The expression of inflammatory marker like antigen HLA-DR and Immunoglobulin E is higher in patient with prolonged glaucoma topical medication compared to untreated eyes [60, 61, 62].
LASIK as one of refractive surgery procedures will cause ocular dryness through the laser dissection at the corneal nerves that will interrupt the corneal reflex arc further and reduce the tear film production with substance P release which will increase the severity of inflammation [63, 64].
The mechanism in DED related post refractive surgery was thought to be similar to DED followed by perforating keratoplasty. The whole dissected corneal nerve using trephination in keratoplasty will release substance P because all corneal nerves are dissected during trephination. Substance P from keratocytes [65] will induce the secretion of interleukin 8 as a pro inflammatory chemokine. Kuchle et al. demonstrated that dry eye disease is a risk factor for graft rejection in PK through inflammatory mechanisms [66].
A smooth ocular surface can be achieved through intensive and frequent non-preserved tear supplements or hyaluronate eye drops [67]. Frequent drops using non-preserved tears is necessary for managing accumulated inflammatory cytokines. Hyaluronate eye drops have been reported to be effective in managing patients with ocular surface disorders through improving the corneal epithelial barrier function, promoting corneal wound healing, and reducing ocular surface tissue damage as well as minimizing the inflammation process in DED [68].
Epithelial rejection occurred at the first three months after surgery can be seen as a linear opacification at the cornea surface which stains with fluorescein. Although the dead epithelial cells are replaced rapidly by recipient epithelial cells, it is important to remember that these recipient epithelial cells have been sensitized by the donor which can progress to deeper rejection such as stromal or endothelial rejection in the future. It can be seen as a nummular infiltrate if the rejection reaches the stroma. However, endothelial rejection can be shown as keratic precipitates where the inflammatory cells adhere to the endothelial graft [69].
Topical steroid eye drops such as dexamethasone 0.1% or prednisolone acetate 1% are given every three hours per day for the first 2–3 months, then tapered gradually until it reaches zero in one year. These steroid drop regimens are different for each center. The purpose of steroid drops is to prevent and reverse any rejection episodes and avoid more endothelial cell loss. Lack of detecting signs of rejection will postpone graft treatment initiation. Delay in diagnosing or treating rejection will reduce graft sensitivity towards the treatment and may develop to an irreversible rejection [70, 71].
HLA matching is shown to be effective in predicting graft survival rates in a vascularized organ allotransplantation. However, the benefits from tissue matching in cornea transplantation are still debatable since the cornea has its own immune privilege as a non-vascularized tissue. Nevertheless, it was found that an active graft rejection is related to the donor HLA class I specific cytotoxic T cells.
The greater number of mismatches between HLA-A and HLA-B shows a higher risk of corneal tissue developing into graft rejection. These tissue mismatches are considered as a high-risk factor for rejection after corneal transplantation [72, 73, 74, 75, 76]. Whilst Collaborative Corneal Transplantation Studies (CCTS) suggest the necessity of HLA matching in corneal transplantation remains doubtful, it may be useful for high-risk patients although it is still not considered to do the tissue matching as part of routine preoperative assessment due to the donor cornea tissue available [77].
Minor histocompatibility antigens such as ABO blood antigens are a different class of cell surface proteins that are also expressed by the corneal epithelium. It is coded throughout the genome at various loci [78]. CCTS concluded with ABO blood matching, the possibility for someone having graft rejection is 41% if the ABO antigens are incompatible and 31% may experience rejection for the compatible ABO antigens. The study concluded ABO matching may still be considered useful in predicting corneal graft rejection. However, doing HLA matching is still debatable - not only because of the lack in the availability of cornea tissue globally but also its very expensive [79].
Cornea graft survival rates are influenced by many factors. Dry eye as part of ocular surface disorders is one important thing that we should care for. The aim for dry eye or OSD management is to treat the hyperosmolarity condition of the tear film to reduce the expression of a response from our immune system to any foreign antigens from desiccating stress or inflammation. Although the cornea has immune privilege due to being avascular and lymph node free, a successful prevention of immune rejection is better compared to immune suppression by immune modifying treatments such as gene therapy post transplantation. Minor histocompatibility complex tissue matching can be done due to its low cost. However, ABO antigens testing is not as specific as major histocompatibility tests.
Cornea as the only organ that has its own immune privilege is still in doubt for testing major histocompatibility complex tissue matching. Mainly, because most of major histocompatibility testing only work for class II but not shown effective for class I. Unfortunately, due to human major histocompatibility complex genes are highly polymorphic, any random allocation of HLA will achieve the required matching level in a very long time which are very unethical for our patients. If in the future, there will be a HLA matching that is highly specific, low cost and only needs a period of time to get the test result, probably the HLA testing can be applied as a routine evaluation to provide higher number of graft survival in the future.
As mentioned in the literature, a high-risk condition such as corneal vascularization, DED and prolonged use of antiglaucoma medication can reduce the corneal graft survival rate. Therefore, the application of anti VEGF through injection on the subconjunctival, an adjunct non-preservative topical lubricant in glaucoma medication and the use of lifitegrast as the antagonist of LFA-1 and inhibits T cell formation in dry eye management will probably useful and create a promising result related to a higher graft survival rate in the future.
To conclude, a prospective clinical trial to investigate the role of preexisting DED in the context of corneal transplantation and its influence on graft survival is needed. Understanding the role of HLA in corneal graft rejection from an immunological point of view as well as the necessity of conducting a comprehensive knowledge of the HLA tissue matching will create other options to prevent graft rejection. Future pharmacotherapies for DED with novel targets are the focus of ongoing research, and several promising treatment options are expected.
The author would like to thank Professor John S. Jarstad, MD, FAAO, FRSM UK(oph), Professor of Clinical Ophthalmology Comprehensive, Cataract & Refractive Surgery, Department of Ophthalmology, Tampa for his contribution in English language editing.
The author declares no conflict of interest.
Chagas disease (CD), the parasitic infection caused by the kinetoplastid protozoan
It is alarming that 6–7 million people are estimated to have CD worldwide, with
CD represents economic losses in excess of $1.2 billion/year to endemic countries in South America, in addition to more than $7 billion a year at global levels [21], including treatment and loss of productivity. Since no proven effective and approved vaccines are available for this disease, chemotherapy represents the only therapeutic intervention, as well as an important way to control them.
CD etiological treatment is directed according to the phase and clinical presentation of the disease, which is mandatory in the acute phase, congenital cases, or reactivation due to immunosuppression. In the chronic phase, the trypanocidal treatment is indicated in children and adolescents, recent infection, and women of childbearing age [22].
Although CD was discovered and is studied for over a century [14], the etiologic treatment is still based on solely two drugs (Figure 1): the nitrofuran derivative nifurtimox (NFX; Lampit®, Bayer; 5-nitrofuran(3-methyl-4-(5′-nitrofurfurylideneamine)tetrahydro-4H-1,4-tiazine-1,1-dioxide), and the 2-nitromidazole benznidazole (BZ; LAFEPE; N-benzyl-2-nitroimidazole-acetamide) [23]. Both NFX and BZ were shown to produce remarkable ultrastructural alterations in mammal cells and tissues [24, 25], which were apparently more pronounced in NFX-treated animals [26]. Therefore, experimental chemotherapy studies approaching parasites as
Molecular structures of the nitroheterocyclic drugs employed in the treatment of Chagas disease: the 2-nitroimidazole benznidazole (A) and the 5-nitrofuran nifurtimox (B).
The CD therapeutics remain unsatisfactory, as they are associated with adverse effects [30, 31, 32], affecting 84.8 and 95.2% of patients treated with BZ and NFX, respectively [33], which may be severe, leading to the irreversible suspension of therapy in CD, in ≈20% [34, 35], ≈30% [36, 37], 41.5% [38], and up to 50% of the cases [39, 40]. Treatment suspension using NFX was reported in 43.8% of patients [33]. In an early study based on small samples, NFX was reported to be associated to definitive treatment interruption in 75% of patients [38]. Nevertheless, treatment intolerance was reported at similar levels with the use of the two drugs, approached by the same team [34, 35], but adverse effects, including neuropsychiatric events, may be more frequently associated to NFX [33]. In addition, it was reported that among patients who had discontinued BZ treatment and were treated with NFX, 12.3% also developed adverse effects that required definitive discontinuation of therapy [39]. Nevertheless, NFX was reported to be safe as a second-line therapy in patients who discontinued BZ [41].
Most CD patients are not treated because of the insufficient diagnosis and low cure rates observed in chronically infected patients [42], although treatment may diminish the disease progression and cardiovascular events [43, 44]. In addition, the CD treatment accomplishes only a parasitological cure, and a clinical cure is hardly proved [43, 45]. Whereas the
As the dormancy state of
An important study [63] approached the persistent parasite elimination, but the use of higher BZ doses might pose higher risks for patients. In this regard, the polyamine and thiol synthesis
Besides considerable severe adverse effects, one of the greatest problems of CD therapeutics is the selection of resistant parasites, impairing its effectivity, therefore causing refractory cases. BZ and NFX resistance is readily developed
Despite significant time and resources investments by innumerous research institutions over the world, only a few therapeutic candidates advanced the pipeline to treat neglected diseases such as CD [67]. It is alarming that it usually takes over 10 years to develop new drugs, whereas resistant parasites are rapidly selected. Also, there are naturally resistant
Oxidative stress is a central phenomenon involved in aging, cancer, transmissible or infectious diseases, including COVID-19 [72], nontransmissible chronic conditions, such as metabolic diseases, autoimmune and degenerative disorders, inflammation, metal poisoning, etc. [73, 74, 75], produced by the imbalance on the production/uptake of oxidant/antioxidant species [76].
A plethora of antioxidant defenses evolved in order to balance the redox homeostasis [76, 77]. Oxidant species such as superoxide (O2•−) and hydrogen peroxide (H2O2) are detoxified by SOD and catalase, respectively. Most cells rely also on the peptide glutathione (GSH), able to chelate reactive oxidant species (ROS) via cysteine sulfhydryl (SH) group and function as substrate for enzymes including GSH reductase and GSH peroxidase [78].
Although most of these processes are evolutionary conserved, some of the antioxidant defenses pathways differ between mammals and pathogens, therefore comprise potential chemotherapy targets. Contrary to mammals, GSH in trypanosomatid parasites mostly takes part in the adduct with the polyamine spermidine, forming
Metabolomics and gene expression studies [81] reveal the participation of both GSH and the spermidine synthesis pathway, indicating the participation of trypanothione, in the regulation of redox metabolism in trypanosomatids. GSH is very relevant not only in oxi-reductive homeostasis, as this molecule is also related to detoxification and resistance to different drugs/xenobiotics in tumor cells [82, 83] binding to drugs that are extruded via multidrug resistance transporters [84]. TSH binding to NFX and BZ is involved in the detoxication of these trypanocides [85, 86]. Therefore, glutathione/trypanothione can promote the action/reverse resistance to different drugs.
Interestingly, polyamine play pivotal roles in parasite cells [91, 92], including
Parasitic diseases such as CD are correlated to oxidative stress [97, 98], associated to triggered chronic inflammatory reactions [99, 100]. Endogenous oxidative stress may be produced by cell organelles, mainly mitochondria [101, 102]. The CD myocarditis is characterized by intense oxidative stress due both to inflammatory response associated to neutrophils and macrophages NADPH oxidase (Nox) activity and the macrophage superoxide produced by Nox2 is required for parasite control in early infection [103]. The mitochondrial ROS produced by cardiomyocytes plays a relevant role in intracellular oxidative stress and inflammation, causing myocardium tissue damage [104, 105, 106]. These events are not independent since mitochondrial ROS may trigger proinflammatory cytokines via NFkB and PARP/PAR pathways [107], and the mitochondrial MnSOD activity may revert much of the inflammatory foci and necrosis [105], and ineffective antioxidant defense is associated to oxidative stress [108]. Exosome or extracellular vesicles liberation may also contribute to inflammation and oxidative stress [107, 109]. The oxidative stress is also involved in neurodegeneration in both cardiac and gastrointestinal tissues [110]. The chronic oxidative stress in the nervous tissue is associated to cognitive deficit, which can be reversed by BZ treatment [111].
Thus, the use of adjuvant antioxidant agents may ameliorate the cardiac pathogenesis [107, 112, 113]. Interestingly, vitamin C, widely considered antioxidant, can at high concentrations also function as a prooxidant, undergoing pH-dependent autoxidation, leading to H2O2 formation [114, 115]. In CD models, ascorbic acid can also reduce parasitemia, promote BZ action, and enhance animal survival in murine infection [116, 117].
ROS production comprises a well-known microbicidal immune effector mechanism [118]; therefore parasite borne antioxidant systems are not only virulence factors [119]. Besides the parasiticidal activity, ROS may function as signaling molecules promoting parasite proliferation. As in the Paracelsus adage, “The dose makes the poison” (Latin:
Numerous therapeutic strategies exploit redox systems [124], including protozoal diseases [125], such as CD [126]. Therefore, antioxidant systems including SOD, trypanothione, and enzymes action on this glutathione-spermidine adduct (
Up to 2% of the O2 reaching the mitochondrial matrix is converted to O2•− (superoxide anions) forming H2O2 via SOD [149]. Like mammalian cells,
Because of the prooxidant effects of antiparasitic drugs [126, 153, 154, 155], ROS detoxifying systems may comprise valuable scape mechanisms from pharmaceutical intervention [156] and programmed cell death triggered by mitochondrial O2•− [157].
The prooxidant capacity of both NFX and BZ, particularly in the former, is due to redox cycling with the production of O2•− [126, 158, 159, 160]. Superoxide may be not produced by BZ in the parasite, but in the host cell [161]. Therefore, FeSOD is linked to BZ resistance in
Sirtuins are a highly conserved family of enzymes that deacetylate lysine residues on histone and non-histone proteins, using NAD+ as a cosubstrate, regulating cellular antioxidant/Redox mechanisms [172, 173]. It is noteworthy that SIRT3, 4, and 5 are found in the mitochondrial matrix [174]. As cardiomyocyte mitochondrial dysfunction plays a central role in chagasic myocarditis (
Selenium and selenium-containing compounds show beneficial effects both in murine [178, 179, 180] and human
This activity maybe largely dependent on redox regulation as this inflammatory infection is associated with intense oxidative stress, and selenium may be antioxidant [187] and anti-inflammatory [188], as well as catalyze hydrogen peroxide (H2O2) reduction [189], therefore possibly diminishing the oxidative stress in infected cardiomyocytes, by impairing the Fenton reaction in the presence of iron.
The combination of different drugs may pose the advantage of supra-additive effects, which may be synergistic, in parasite models such as
The identification of drug combinations with multiple targets can lead to the use of novel multitarget mechanisms able to cope with the challenge of multigenic diseases [194] and/or chronic infections with complex pathophysiology. It is noteworthy that the pharmaceutical properties of the combination may be absent in the components alone [195], generating the innovative concept or science field termed polypharmacology with numerous applications on drug repurposing [196] and CD [197]. As the philosopher Aristotle (384–322 B.C.) stated: “The whole is greater than the sum of its parts.”1
Furthermore, drug combinations are largely employed for preventing drug resistance [198, 199, 200, 201, 202, 203, 204]. However, this strategy is not constantly successful as the reports of resistance to the sulfadoxine-pyrimethamine combination began in the same year this antimalarial regimen entered the clinic [205]. Similarly, the discovery of artemisinin (ART) costed Youyou Tu over 30 years of hard work [206] and was worthy a Nobel Prize, but
Approaching repositioned drugs with available pharmacokinetic and toxicological properties can shorten the long and expensive path between
Drug repositioning maybe a promising approach in CD [214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227]. Similarly, drug combinations may be instrumental in CD [197, 228, 229, 230, 231, 232, 233], and both strategies may be employed and associated [214, 234, 235, 236]. Furthermore, drug combinations can increase success of drug repositioning [237]. In addition, it was accurately hypothesized that the combined use of repurposed drugs with BZ could be more efficacious than BZ alone [238].
Disulfiram (DS, 1,1′-disulfanediylbis(N,N-diethylmethanethioamide) also termed tetraethylthiuram disulfide; CAS no. 97-77-8; Molecular Formula: C10H20N2S4), a repositioned drug used in alcoholism and marketed as Antabuse® (Figure 2), was approved for medical use over 70 years ago and is widely used since then [239, 240].
Molecular structures of disulfiram (A) and sodium diethyldithiocarbamate (B).
At the very beginning, the discovery of thiocarbamates and its derivatives was serendipitous and showed clear signs of versatile perspectives that unequivocally culminated in the present promising repurposing strategies for both pharmaceutical and industrial applications [241, 242].
In the 1930s and 1940s, dithiocarbamates such as dimethyldithiocarbamates and diethyldithiocarbamates were used as pesticides against fungal pathogens on different crops [243], besides biocides in household products [244].
The industry plant physician E. E. Williams in 1937 observed that workers using tetramethylthiuram monosulfide and disulfide to facilitate the rubber vulcanization became alcohol-intolerant and quit consuming alcoholic beverages. The DSF-induced alcohol aversion was described in 1948 [245]. At that time, DSF was approached as a vermicide and employed as an ointment to treat scabies.
Afterward, besides alcoholism, DSF started to be studied for heavy metal poisoning, cancer [246, 247, 248, 249], HIV [243, 250], as well as cocaine dependence, pathological gambling, and other psychiatric disorders [239] and other form of addiction, for example, the d-methamphetamine abuse [251]. Further tests are being performed focusing applications such as Alzheimer’s disease [252], Lyme disease and babesiosis [253], tuberculosis [254], non-tuberculous mycobacteria infections [255], giardiasis [256], amoebiasis [257], obesity [258] and to revert drug resistance in different types of cancer [259, 260, 261], tuberculosis [262] bacterial infections [263], mycosis [264], giardiasis [265], etc. The repositioning of low-cost drugs such as DS is considered a “salvation” for global healthcare system [266].
Sodium diethylcarbamodithioate (Figure 2) (DETC also known as sodium (diethylcarbamothioyl)sulfanide; CAS no. 148-18-5; Molecular Formula: C5H11NS2.Na) is the first derivative of DSF, involved in many of the biological activities of the latter.
Seemingly DETC is less toxic than aspirin [243], widely used, and well tolerated in humans [267] for decades being used up to 800 mg/twice/week, with no adverse effects [268]. DETC also known as Imuthiol or Dithiocarb was used as immunomodulator with good results on AIDS patients [269, 270] and was clinically employed in chronic bronchitis, rheumatoid arthritis, tuberculosis, and chronic infection [271].
In a seminal report on its antiparasitic activity, DETC was demonstrated to be leishmanicidal [272]. Afterward, novel delivery systems were developed to optimize the leishmanicidal activity of DETC [273, 274, 275]. In this regard, novel drug delivery systems are also developed for DSF [276]. The data obtained on Leishmania amazonensis motivated us to move to CD, employing the repositioned drug DSF combined to the drug of first choice BZ. Tests on NFX are in progress.
It is worth remembering that CD pathophysiology is associated with oxidative stress (
Both DSF and DETC have antiparasitic activity on
In our study, the DSF-BZ combination is promising since the antagonism of SOD activity can enhance oxidative stress in cancer cells [249] and
Putative mechanisms of action of disulfiram (DSF) or diethyldithiocarbamate (DETC) in combination with trypanocides in
CD etiological therapy is often associated to severe adverse effects caused by the highly toxic drugs (
DSF/DETC have neuroprotective [285], hepatoprotective [277], and nephroprotective [286] and even radioprotective [287, 288] activity. These protective effects may be beneficial in the treatment of parasitic diseases, because in the treatment of experimental infection by
Thus, the development of low-toxicity therapies may be expected, as DSF may have a protective action against the toxic effects of drugs such as cyclophosphamide [290], ifosfamide [291], N-nitrosodimethylamine [292], isoniazid [293] and the toxicity of α-naphthylisothiocyanate [294], acetaminophen [295], pyrrolizidines [296], the lethal effects of hypoxia [297], ischemia [298], as well as lead [299], cadmium [300], mercury, and other heavy metals [301]. Thus, DSF combinations can enable the development of safe medicines. Regarding CD, the cardioprotective and antioxidant activities of DSF/DETC as well as atrial neuroprotection [302] are particularly desirable [303, 304, 305, 306]. In addition, DSF is effective as prophylactics in experimental colitis [307].
As drug resistance limits the successful CD therapy, the
DSF [313] affects the redox balance of the cell, to GSH oxidation [314], reducing GSH levels [54] at least in part through the formation of complexes with its different derivatives [312, 315]. DETC can also reduce the GSH/non-protein thiol levels, also leading to the reduction of glutathione peroxidase activities [53, 316].
The combinations tested here may also contribute to resistance reversal, also through DETC-mediated inhibition of Fe-dependent SOD, which is linked to resistance to BZ in
Furthermore, DSF can be used against cancer cells targeting the ubiquitin-proteasome system [317], and the ubiquitin-proteasome pathway is a therapeutic target in
In this way, the strategy based of combinations of the repositioned drugs proposed here can achieve effectiveness, with selectivity and, therefore, safety in the CD treatment and sheds new light on perspectives for new therapeutic strategies.
Translational research in biomedical sciences translates basic research and experimental discoveries into health taking the route from benchtop to bedside. This important field has gained substantial attention and investments in the last two decades [319].
In order to reach a proof of concept on the effectivity of the DSF-BZ combination in human infection, a partnership was established gathering different units of Fiocruz. The present study comprises a translational approach that began with experiments in vitro, on the bench and now reaches the clinical stage at the Evandro Chagas National Institute of Infectious Diseases-Fiocruz, coordinated by the team of the Clinical Research Laboratory of Chagas Disease, with assistance of the Clinical Research platform. Therefore, the phase I/II clinical trial was elaborated (Figure 4) and published recently [320].
Design of the clinical trial for testing the BZ-DSF combination. Reproduced from Ref. [
The use of DSF/DETC combined to BZ in CD treatment comprises a potential innovative therapeutical tool, possibly overcoming adverse reactions and refractory cases. Since these repositioned drugs exert cytoprotective effects, reducing the adverse reactions of many drugs, safe combinations can be potentially identified, leading to the development of well-tolerated medication. Therefore, therapy interruption can be precluded, consequently increasing patient adherence. In addition, as DSF/DETC can inhibit p-glycoprotein activity as well as reduce GSH levels, two molecules involved in drug extrusion from MDR+ parasites, it is reasonable to suppose the combination could eventually revert/downmodulate natural/acquired resistance phenotypes. Thus, treatment may be effective even in refractory cases. We are now approaching the clinical response of chronic phase CD patients. A possible proof of concept may lead to the development of a safe and effective medication, with profound implications in treatment prognosis, presumably improving the quality of life of the patients.
This research was sponsored by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq grant no. 443886/2018-0 to RMS and CNPq grant no. 314717/2020 to MAVS), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Rio de Janeiro (FAPERJ grant no. 211.167/2019 to RMS; FAPERJ grant no. 260475/2021 and 259286/2021 to MAVS and FAPERJ grant no. 204.388/2021 to AMSF) and Fundação Oswaldo Cruz (Fiocruz grant no. 6221125199 to MAVS).
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Wrzal and Diana A. Averill-Bates",authors:[{id:"61148",title:"Prof.",name:"Diana",middleName:null,surname:"Averill-Bates",slug:"diana-averill-bates",fullName:"Diana Averill-Bates"},{id:"62367",title:"Dr.",name:"Ahmed",middleName:null,surname:"Bettaieb",slug:"ahmed-bettaieb",fullName:"Ahmed Bettaieb"},{id:"62368",title:"Dr.",name:"Paulina",middleName:null,surname:"K. Wrzal",slug:"paulina-k.-wrzal",fullName:"Paulina K. Wrzal"}]},{id:"43632",doi:"10.5772/53110",title:"The Importance of Cancer Cell Lines as in vitro Models in Cancer Methylome Analysis and Anticancer Drugs Testing",slug:"the-importance-of-cancer-cell-lines-as-in-vitro-models-in-cancer-methylome-analysis-and-anticancer-d",totalDownloads:5063,totalCrossrefCites:22,totalDimensionsCites:52,abstract:null,book:{id:"3002",slug:"oncogenomics-and-cancer-proteomics-novel-approaches-in-biomarkers-discovery-and-therapeutic-targets-in-cancer",title:"Oncogenomics and Cancer Proteomics",fullTitle:"Oncogenomics and Cancer Proteomics - Novel Approaches in Biomarkers Discovery and Therapeutic Targets in Cancer"},signatures:"Daniela Ferreira, Filomena Adega and Raquel Chaves",authors:[{id:"155129",title:"Prof.",name:"Raquel",middleName:null,surname:"Chaves",slug:"raquel-chaves",fullName:"Raquel Chaves"},{id:"157394",title:"M.Sc.",name:"Daniela",middleName:"Perneta",surname:"Ferreira",slug:"daniela-ferreira",fullName:"Daniela Ferreira"},{id:"157395",title:"Dr.",name:"Filomena",middleName:null,surname:"Adega",slug:"filomena-adega",fullName:"Filomena Adega"}]},{id:"24601",doi:"10.5772/22656",title:"Combination Chemotherapy in Cancer: Principles, Evaluation and Drug Delivery Strategies",slug:"combination-chemotherapy-in-cancer-principles-evaluation-and-drug-delivery-strategies",totalDownloads:4908,totalCrossrefCites:3,totalDimensionsCites:38,abstract:null,book:{id:"374",slug:"current-cancer-treatment-novel-beyond-conventional-approaches",title:"Current Cancer Treatment",fullTitle:"Current Cancer Treatment - Novel Beyond Conventional Approaches"},signatures:"Ana Catarina Pinto, João Nuno Moreira and Sérgio Simões",authors:[{id:"48598",title:"Prof.",name:"Sergio",middleName:null,surname:"Simoes",slug:"sergio-simoes",fullName:"Sergio Simoes"},{id:"54753",title:"Dr.",name:"Ana",middleName:null,surname:"Pinto",slug:"ana-pinto",fullName:"Ana Pinto"},{id:"54754",title:"Prof.",name:"Joăo",middleName:null,surname:"Moreira",slug:"joao-moreira",fullName:"Joăo Moreira"}]},{id:"22475",doi:"10.5772/24666",title:"Extracellular Matrix Microenvironment in Glioma Progression",slug:"extracellular-matrix-microenvironment-in-glioma-progression",totalDownloads:2511,totalCrossrefCites:14,totalDimensionsCites:27,abstract:null,book:{id:"355",slug:"glioma-exploring-its-biology-and-practical-relevance",title:"Glioma",fullTitle:"Glioma - Exploring Its Biology and Practical Relevance"},signatures:"Marzenna Wiranowska and Mumtaz V. Rojiani",authors:[{id:"58793",title:"Dr.",name:"Marzenna",middleName:null,surname:"Wiranowska",slug:"marzenna-wiranowska",fullName:"Marzenna Wiranowska"},{id:"137692",title:"PhD.",name:"Mumtaz",middleName:null,surname:"Rojiani",slug:"mumtaz-rojiani",fullName:"Mumtaz Rojiani"}]},{id:"28097",doi:"10.5772/29559",title:"Characterization of the Cell Membrane During Cancer Transformation",slug:"characterization-of-the-cell-membrane-during-cancer-transformation",totalDownloads:2833,totalCrossrefCites:8,totalDimensionsCites:25,abstract:null,book:{id:"655",slug:"colorectal-cancer-biology-from-genes-to-tumor",title:"Colorectal Cancer Biology",fullTitle:"Colorectal Cancer Biology - From Genes to Tumor"},signatures:"Barbara Szachowicz-Petelska, Izabela Dobrzyńska, Stanisław Sulkowski and Zbigniew A. Figaszewski",authors:[{id:"78361",title:"Prof.",name:"Zbigniew",middleName:null,surname:"Figaszewski",slug:"zbigniew-figaszewski",fullName:"Zbigniew Figaszewski"},{id:"78379",title:"Prof.",name:"Barbara",middleName:null,surname:"Szachowicz-Petelska",slug:"barbara-szachowicz-petelska",fullName:"Barbara Szachowicz-Petelska"},{id:"78745",title:"Dr.",name:"Izabela",middleName:null,surname:"Dobrzynska",slug:"izabela-dobrzynska",fullName:"Izabela Dobrzynska"},{id:"78746",title:"Dr.",name:"Stanislaw",middleName:null,surname:"Sulkowski",slug:"stanislaw-sulkowski",fullName:"Stanislaw Sulkowski"}]}],mostDownloadedChaptersLast30Days:[{id:"54281",title:"Towards Metabolic Engineering of Podophyllotoxin Production",slug:"towards-metabolic-engineering-of-podophyllotoxin-production",totalDownloads:1710,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"The pharmaceutically important anticancer drugs etoposide and teniposide are derived from podophyllotoxin, a natural product isolated from roots of Podophyllum hexandrum growing in the wild. The overexploitation of this endangered plant has led to the search for alternative sources. Metabolic engineering aimed at constructing the pathway in another host cell is very appealing, but for that approach, an in-depth knowledge of the pathway toward podophyllotoxin is necessary. In this chapter, we give an overview of the lignan pathway leading to podophyllotoxin. Subsequently, we will discuss the engineering possibilities to produce podophyllotoxin in a heterologous host. This will require detailed knowledge on the cellular localization of the enzymes of the lignan biosynthesis pathway. Due to the high number of enzymes involved and the scarce information on compartmentalization, the heterologous production of podophyllotoxin still remains a tremendous challenge. At the moment, research is focusing on the last step(s) in the conversion of deoxypodophyllotoxin to (epi)podophyllotoxin and 4′-demethyldesoxypodophyllotoxin by plant cytochromes.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Christel L. C. Seegers, Rita Setroikromo and Wim J. Quax",authors:[{id:"196901",title:"Prof.",name:"Wim",middleName:null,surname:"Quax",slug:"wim-quax",fullName:"Wim Quax"},{id:"197867",title:"MSc.",name:"Christel L.C.",middleName:null,surname:"Seegers",slug:"christel-l.c.-seegers",fullName:"Christel L.C. 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A number of new agents are currently in clinical development with promising selective activity against cancer cell lines and cancer-related molecular targets. This book chapter discusses 14 of such compounds isolated from African plants from 15 plant families. Also contained in this book chapter are compounds from African plants that hold prospect as potential anticancer agents as informed by their in vitro and in vivo preclinical studies. It is, therefore, worthwhile that researchers in the African continent and the world over should keep on working on identifying biomolecules with potential in cancer management.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Newman Osafo, Yaw Duah Boakye, Christian Agyare, Samuel\nObeng, Judith Edem Foli and Prince Amankwaah Baffour Minkah",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"186987",title:"Dr.",name:"Yaw Duah",middleName:null,surname:"Boakye",slug:"yaw-duah-boakye",fullName:"Yaw Duah Boakye"},{id:"196452",title:"Dr.",name:"Newman",middleName:null,surname:"Osafo",slug:"newman-osafo",fullName:"Newman Osafo"},{id:"201381",title:"Ms.",name:"Judith",middleName:null,surname:"Edem Foli",slug:"judith-edem-foli",fullName:"Judith Edem Foli"},{id:"201382",title:"Mr.",name:"Prince",middleName:"Amankwah Baffour",surname:"Minkah",slug:"prince-minkah",fullName:"Prince Minkah"},{id:"204731",title:"Mr.",name:"Samuel",middleName:null,surname:"Obeng",slug:"samuel-obeng",fullName:"Samuel Obeng"}]},{id:"53856",title:"Early-Stage Progression of Breast Cancer",slug:"early-stage-progression-of-breast-cancer",totalDownloads:1711,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"Breast cancer can be defined as a group of diseases with heterogeneous origins, molecular profiles and behaviors characterized by uncontrolled proliferation of cells within the mammary tissue. Around one in eight women in the US will develop breast cancer in their lifetime, making it the second most frequently diagnosed cancer behind skin cancer [1]. In 2015, an estimated 231,840 cases of invasive carcinoma were diagnosed, and over 40,000 deaths were caused by breast cancer which accounts for almost 7% of all cancer mortality each year. In 2015, 60,290 cases of in situ breast cancer were diagnosed, representing over 14% of all new cancer cases among women and men. The steep increase in diagnosis of early‐stage breast cancer over the past 10 years is believed to be a result of more frequent mammography. However, since over half of these in situ lesions will not progress to invasive breast cancer, controversies have arisen about approaches to treatment and prevention of progression of early‐stage in situ breast cancer. Understanding the mechanisms of transition of normal breast to in situ pre‐neoplastic lesions and invasive breast cancer is currently a major focus of breast cancer research with implications for preventive and clinical management of breast cancer. In this review, we give an overview of current knowledge on the molecular and pathological changes that occur during early‐stage progression of breast cancer and describe some of the current models that are used to study this process.",book:{id:"5431",slug:"breast-cancer-from-biology-to-medicine",title:"Breast Cancer",fullTitle:"Breast Cancer - From Biology to Medicine"},signatures:"William Kietzman, Anna T. Riegel and Virginie Ory",authors:[{id:"190578",title:"Prof.",name:"Anna",middleName:null,surname:"Riegel",slug:"anna-riegel",fullName:"Anna Riegel"},{id:"190580",title:"Dr.",name:"Virginie",middleName:null,surname:"Ory",slug:"virginie-ory",fullName:"Virginie Ory"},{id:"190583",title:"MSc.",name:"William",middleName:null,surname:"Kietzman",slug:"william-kietzman",fullName:"William Kietzman"}]}],onlineFirstChaptersFilter:{topicId:"190",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81836",title:"Perspective Chapter: Cervical Cancer Elimination by 2030—The W.H.O Goal: Neo Challenges and Next Gen Solutions “TIT for TAT”—The Community Competency Model of Raj ©",slug:"perspective-chapter-cervical-cancer-elimination-by-2030-the-w-h-o-goal-neo-challenges-and-next-gen-s",totalDownloads:12,totalDimensionsCites:0,doi:"10.5772/intechopen.104660",abstract:"Cervical Cancer is the fourth most common cancer among women, worldwide. It accounts for 600,000 new cases per year, and 340,000 deaths globally (WHO 2020 data). It causes a lot of maladies and suffering for women, in the age group of 30–60 years, especially in the poor community of developing countries. Cervical cancer is a great public health problem and is a cause of grave concern for the health system in Low-Middle-Income Countries—LMIC. But cervical cancer is amenable for early detection and successful treatment of precancer stages. Human Papilloma Virus—HPV vaccines offer a high level of primordial prevention, against cervical cancer. Therefore, the World Health Organization, in 2018, has called for “Elimination of Cervical Cancer by 2030.” The objective is to reduce the incidence rate of cervical cancer to below 4/100,000, by the year 2030. This leads to many “Neo Challenges” and also opens the door for “Next Gen Solutions”. The author, with vast experiences in his Cervical Cancer Screening Projects of IARC/ WHO, at Tamil Nadu, India, during 2000–2007, advocates a strategy called “TIT for TAT—The Community Competency model of Raj©.”",book:{id:"10793",title:"Molecular Mechanisms in Cancer",coverURL:"https://cdn.intechopen.com/books/images_new/10793.jpg"},signatures:"Rajamanickam Rajkumar"},{id:"81872",title:"Benign Prostatic Hyperplasia: Epidemiology, Pathophysiology, and Clinical Manifestations",slug:"benign-prostatic-hyperplasia-epidemiology-pathophysiology-and-clinical-manifestations",totalDownloads:11,totalDimensionsCites:0,doi:"10.5772/intechopen.104823",abstract:"The prostate secretes 20% of the seminal fluid. One of its main pathologies is benign prostatic hyperplasia (BPH), the most common benign disease in older men. It has an 8–10% prevalence in men 40 years of age and older, increasing to more than 90% in men over 90 years, with lower urinary tract symptoms being one of its main complications. Although the etiology of BPH is not still fully known, testosterone and estradiol have shown a permissive role. Likewise, other factors have emerged, such as inflammation, growth factors, and prolactin, which influence the development of BPH. These factors act through binding to specific receptors, intervening in BPH and prostate cancer development. Existing treatments significantly reduce clinical symptoms, including lower urinary tract symptoms. However, it is a nonpreventable disease; some factors can reduce its incidence: diet, physical activity, and moderate consumption of alcohol and tobacco, some of which have been proposed to have a protective role. Therefore, this chapter aims to update the preclinical and clinical evidence on the etiology of this disease, briefly describing the epidemiology, clinical manifestations, and therapeutic and preventive modalities in managing BPH.",book:{id:"10793",title:"Molecular Mechanisms in Cancer",coverURL:"https://cdn.intechopen.com/books/images_new/10793.jpg"},signatures:"Luz Irene Pascual Mathey"},{id:"81779",title:"Cancer Genes and Breast Cancers",slug:"cancer-genes-and-breast-cancers",totalDownloads:21,totalDimensionsCites:0,doi:"10.5772/intechopen.104801",abstract:"Cancer is the name given to all malignant tumors, the main reason for which is uncontrolled growth, and the tumor, which has become a mass as a result of uncontrolled cell proliferation, also attacks the surrounding cells and envelops the whole body (metastasis) in the later stages of the disease. Although cancer is an important health problem, it is not a common disease in childhood. On the other hand, statistics show that cancer affects one in three adults, causes up to 20% of all deaths, and covers about 10% of treatment costs in developed countries. Although it is known that cancer develops under the influence of genetic and environmental factors, environmental factors are more prominent in the formation of some types of cancer. Breast cancer is one of the cancer types known to have tumor suppressor genes in its etiology. These tumor suppressor genes are BRCA1 and BRCA2 genes. Studies have shown that these two genes are particularly effective in the development of familial breast cancers. These types of cancers occur much earlier than non-familial cancers. The research, two genes; It has shown that it is especially effective in the development of familial breast cancers.",book:{id:"10793",title:"Molecular Mechanisms in Cancer",coverURL:"https://cdn.intechopen.com/books/images_new/10793.jpg"},signatures:"Metin Budak and Hatice Segmen"},{id:"81028",title:"Molecular Genetic Mechanisms in Cancers of Keratinocytic Origin",slug:"molecular-genetic-mechanisms-in-cancers-of-keratinocytic-origin",totalDownloads:21,totalDimensionsCites:0,doi:"10.5772/intechopen.103134",abstract:"Keratinocytic cancers (KC) comprise a group of diseases that have a broad spectrum clinically and pathologically. At one end of the spectrum are benign proliferations (acanthomas), and at the other end are malignant tumors with aggressive growth and metastatic potential. Traditionally, about 80% of KC cases have basal cell carcinoma (BCC) and 20% have cutaneous squamous cell carcinoma (cSCC). Both tumors have different phenotypic features due to different oncogenic pathways. cSCC is biologically different and requires a different approach due to the higher risk of local recurrence, metastasis and death. Genetic factors play an important role in the development of KC. Family and family history studies, the presence of KC as a feature of rare hereditary syndromes, and genetic association studies give us clues in this regard. More than 20 genetic syndromes associated with KC have been described. Some syndromes are associated with multiple BCC, some with multiple cSCC, and some with both BCC and cSCC. Environmental risk factors include exposure to ultraviolet light radiation and immunosuppression in both tumors. Exposure to ionizing radiation is most common in BCC, while smoking and photosensitive drug use are among the environmental risk factors for cSCC. Molecular, epidemiological, and clinical studies will help better understand the cellular processes involved in tumorigenesis, and develop new strategies for treating and preventing KCs.",book:{id:"10793",title:"Molecular Mechanisms in Cancer",coverURL:"https://cdn.intechopen.com/books/images_new/10793.jpg"},signatures:"Yildiz Gürsel Ürün"},{id:"80850",title:"Splicing in Cancer",slug:"splicing-in-cancer",totalDownloads:35,totalDimensionsCites:0,doi:"10.5772/intechopen.102707",abstract:"Defects in splicing, especially alternative splicing have been frequently found in cancers. Mutations in the splicing regulatory elements of important genes involved in cancers or the genes encoding regulatory splicing machinery could play a key role in carcinogenesis. Alterations in regulator factors in splicing have emerged as a new class of oncoproteins and tumor suppressor genes. Understanding the molecular mechanism of how defects in splicing and in particular alternative splicing are involved in carcinogenesis, could lead to new strategies to cancer therapy. Here, we review the molecular mechanism of splicing and regulatory factors involved in alternative splicing, as well as the aberrant splicing that affects cancer hallmarks. Finally, we summarize new approaches in cancer therapy based on splicing.",book:{id:"10793",title:"Molecular Mechanisms in Cancer",coverURL:"https://cdn.intechopen.com/books/images_new/10793.jpg"},signatures:"Mehdi Moghanibashi and Parisa Mohamadynejad"},{id:"80759",title:"Molecular Epidemiology of High-Risk Human Papillomavirus Infection in Burkina Faso",slug:"molecular-epidemiology-of-high-risk-human-papillomavirus-infection-in-burkina-faso",totalDownloads:55,totalDimensionsCites:0,doi:"10.5772/intechopen.102327",abstract:"The aim of the present study was to determine the distribution of high-risk human papillomavirus (HR-HPV) genotypes in childbearing age women, teenage girls, HIV-infected women, women with high-grade precancerous lesions and cervical cancer, sex workers, men, and otolaryngology tumor cases in Burkina Faso. This descriptive cross-sectional study with several target groups, consisted of 2386 samples from Burkina Faso. HR-HPV genotypes were characterized using real-time multiplex PCR. The prevalence of HR-HPV ranged from 15.63 to 72.31% depending on the target population and the nature of the samples. The most predominant genotypes in descending order were HPV-56, HPV-52, HPV-39, HPV-59, HPV-51, HPV-35, HPV-31, HPV-18, HPV-68, HPV-16, HPV-66, HPV-58, HPV-45, and HPV-33. The results of the present study show a wide variation in the distribution of HR-HPV genotypes in Burkina Faso. 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"243698",title:"Dr.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. 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