\r\n\tThis book chapter’s main theme will be focused on transmission dynamics, pathogenesis, mechanisms of host interaction and response, epigenetics and markers, molecular diagnosis, RNA interacting proteins, RNA binding proteins, advanced development of tools for diagnosis, possible development of concepts for vaccines and anti drugs for RNA viruses, immunological mechanisms, treatment, prevention and control. \r\n\t
",isbn:"978-1-80355-667-3",printIsbn:"978-1-80355-666-6",pdfIsbn:"978-1-80355-668-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"52f8a3a1486912beae40b34ac557fed3",bookSignature:"Ph.D. Yogendra Shah",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11369.jpg",keywords:"HIV, Dengue, Zika, West Nile Virus, Chikungunya, Rabies, SARS-CoV2, MERS-CoV, Hanta Virus, Influenza, Whole Genome Sequencing, DNA Sequencing",numberOfDownloads:168,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 4th 2021",dateEndSecondStepPublish:"November 1st 2021",dateEndThirdStepPublish:"December 31st 2021",dateEndFourthStepPublish:"March 21st 2022",dateEndFifthStepPublish:"May 20th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"8 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Shah obtained his Ph.D. degree in Veterinary Medicine from Hokkaido University, Japan. He was awarded the Young Science and Technology Award from the Nepal Academy of Science and Technology (NAST) in 2019. His research interests include infectious diseases, zoonotic infectious diseases, and vector-borne diseases.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah",profilePictureURL:"https://mts.intechopen.com/storage/users/278914/images/system/278914.jpg",biography:"Dr. Yogendra Shah is a consultant microbiologist/virologist, senior research microbiologist, and lecturer at Seti Provincial Hospital, COVID-19 PCR laboratory, National Zoonoses and Food Hygiene Research Center, and Kathmandu College of Science and Technology, Nepal. He obtained a Ph.D. in Veterinary Medicine (Bacteriology) from the Graduate School of Veterinary Medicine, Hokkaido University, Japan, in 2017. His research focuses on better understanding the molecular epidemiological features/transmission dynamics of infectious diseases and zoonotic infectious diseases in Nepal by employing molecular techniques like ELISA, polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and DNA sequencing. He was awarded the Young Science and Technology Award from the Nepal Academy of Science and Technology (NAST) in 2019. His research interests include infectious diseases, zoonotic infectious diseases, and vector-borne diseases. 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1. Introduction
Giant cell tumor of bone (GCTB) is a primary tumor of bone usually arising in the meta-epiphysis of long bones, although potentially also occur in other parts of the skeleton, such as the spine or pelvis [1]. GCTB more often affects young patients in the second to forth decades of life [1, 2] and those living in urban (rather than rural) areas [3]. It is also associated with Paget’s disease [4]. The condition presents with localized pain, tenderness to touch, palpable mass, and decreased range of motion, as well as mechanical pain and joint swelling in patients with presentation near joints [5]. Rarely, it may present with pathological fracture [4].
GCTB is mostly a benign disease, but local recurrence rates are high and there is a small risk of metastatic spread, namely to the lungs [1, 6]. Risk factors for pulmonary metastases include young age, Enneking stage 3, local recurrence, and axial disease, but not treatment modality [6, 7]. Pulmonary metastases most often appear three to four years after initial diagnosis and rarely are the cause of death [8]. However, when GCTB metastasizes, mortality rate rises to 14–25% [8, 9].
Despite being a rare event, GCTB can also undergo malignant sarcomatoid transformation [10]. In these cases, malignant GCTB can present with three histologic subtypes: osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. This usually occurs following multiple recurrent lesions (e.g. Paget’s disease) and/or radiation therapy [5].
Multicentric GCTB in another rare form of tumor presentation, characterized by two or more distant lesions of histologically confirmed disease [11]. These lesions can present as synchronous (more common) or metachronous. Although multicentric GCTB appears to have demographic differences (patients are young and more commonly female), disease behavior − including local recurrence rates, pulmonary metastases pattern, and malignant transformation − seems to be similar to solitary GCTB [11].
Radiologically, GCTB presents as an osteolytic lesion with characteristic radiolucent and geographic (well-circumscribed) appearance and fading cortical bone, rarely showing periosteal reaction. GCTBs are usually eccentric masses in the epiphyseal region extending to subchondral bone (sclerotic metaphyseal margin) [5, 12].
Besides a high degree of suspicion in radiological exams (plain films, computed tomography [CT], and magnetic resonance imaging [MRI]), GCTB diagnosis must be histologically confirmed by core-needle or open biopsy [5]. Still, plain radiographs, CT scan, and MRI are useful for diagnosis and local staging. MRI is often performed to delineate neoplasm extent, namely soft tissue extension. Additionally, bone scintigraphy helps ruling out other asymptomatic bone lesions and chest CT scan should be performed to exclude lung involvement and guide treatment.
Based on radiological findings and according to Enneking and later Campanacci grading systems, GCTB can be classified in three grades [7, 13]:
Grade I (latent): well-defined margin (thin rim of mature bone) and intact cortex (not deformed).
Grade II (active): relatively well-defined margins but no radiopaque rim; cortex is thinned and moderately expanded. Grade II lesions with fracture are graded separately.
Grade II (aggressive): indistinct borders and cortex destruction, suggesting rapid and permeated growth.
This surgical staging system allows preoperative planning. Post-operatively, GCTB can also be graded based on histological features in grade 1 (typical), grade 2 (aggressive), or grade 3 (malignant) [14].
Due to lack of long-term follow-up data, GCTB prognosis is not well established to date [15]. However, the overall prognosis of benign GCTB is generally favorable. Recurrence rates are estimated at 25% [15] and can be as high as 50% after curettage alone [16]. Systemic treatment with bisphosphonates or denosumab seems to lower these figures [17]. Although secondary lung involvement is rare in benign GCTB and very uncommonly the cause of death, mortality rate is higher in these patients (14–25%) [8, 9, 18]. Regarding malignant GCTB (either primary or secondary), overall survival at 5 years is about 85% and poorest in older patients and those with distant disease at diagnosis, according to a Surveillance, Epidemiology and End Results (SEER) study involving 117 cases of malignant GCTB [19]. Smaller studies may indicate worse survival rates [20].
2. GCTB biology and pathogenesis
2.1 Histopathology
GCTB is histologically characterized by diffuse growth of receptor activator of nuclear factor kappa-B ligand (RANKL)-positive, round-to-oval polygonal or elongated mononuclear stromal cells, RANK-positive mononuclear cells of myeloid linage, and RANK-positive osteoclast-like giant cells, reflecting a physiopathology intimately linked to the RANKL/RANK pathway [17, 21, 22] (Figure 1). Small areas of osteoid matrix deposition, woven bone, and occasionally new bone are also observed in about 50% of GCTB samples, with different studies reporting an incidence between 22 and 52% [23].
Figure 1.
Representative images of RANKL (A) and RANK (B) immunohistochemistry in formalin-fixed and paraffin-embedded GCTB samples. (unpublished data).
The characteristic giant cells in GCTB are osteoclastic in nature [24, 25, 26, 27, 28] and represent the reactive component responsible for GCTB aggressive lytic behavior, leading to GCTB designation as osteoclastoma. These cells express RANK but not RANKL [26]. Profiling studies have shown that giant cells in GCTB are the result of CD33+ pre-osteoclast fusion that further fuse with CD14+ mononuclear cells [27] and express tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor, osteoclast markers, being capable of lacunar resorption [29].
However, in GCTB neoplastic cells are ovoid stromal cells, displaying markers of mesenchymal stem cells derived from the osteoblast lineage, but minimal expression of fully differentiated osteoblasts, like osteocalcin, alkaline phosphatase, osteoprotegerin (OPG), and TRAIL [29, 30, 31, 32, 33]. Twist-mediated downregulation of RUNX2, a major osteogenic regulator, has been shown to interrupt osteoblastic differentiation and depress osteoblast lineage markers in GCTB [34].
GCTB stromal cells express high levels of RANKL [27] and also produce other osteoclastogenic cytokines, like interleukin (IL)-1, −6, −11, and − 17, tumor necrosis factor-alpha (TNF-α), and macrophage colony-stimulating factor (M-CSF), through which osteoclast differentiation is stimulated from precursor cells [26]. Other characteristics supporting their neoplastic nature include dominance, increased proliferative potential, abundance of genetic alterations, and expression of more differentiation markers than multinucleated giant cells [22]. GCTBs are polyclonal in nature, with inconsistent chromosomal changes and telomere associations occurring in up to 72% of cases, although lacking prognostic value [35, 36, 37, 38]. Mononuclear stromal cell-exclusive mutation p.G34W (or p.G34L, p.G34M, p.G34R, or p.G34V in a small sub-set of cases) in the H3F3A gene, encoding histone 3.3 (H3.3) variant implicated in epigenetic reprogramming and memory, has been identified as GCTB-specific driver mutation [30].
Because G34W mutations occur more frequently than chromosomal abnormalities and can be causative risk factors for chromosomal structural remodeling in DNA synthesis, it has been hypothesized that this driver mutation causes chromosomal instability and defects, contributing to pleiotropic effects on cell cycle-related expression, immature osteoblastic differentiation, and chemokines, cytokines, and surface markers expression [22, 37]. Additionally, mutations in cyclin D1, p53, and MET have been linked to malignant transformation and GCTB recurrence [22].
Biologically, Wnt/β-catenin and transforming growth factor beta (TGF-β) signaling pathways mediate the exacerbated proliferation of stromal cells in GCTB. β-catenin, cyclin D1, and p21 have been shown to be overexpressed in the nuclei of GCTB stromal cells [39]. Additionally, one study showed that protease activated receptor-1 (PAR-1) is also upregulated in GCTB downstream of TGF-β, via Smad3 and Smad4 [40]. In the study, PAR-1 knockout in GCTB stromal cells inhibited tumor growth, angiogenesis, and osteoclastogenesis in vitro and PAR-1 inhibition suppressed tumor growth and giant cell formation in vivo.
2.2 Physiopathology
GCTB physiopathology is not entirely understood, but there is compelling evidence that RANKL overexpression by mononuclear stromal cells plays a key role and elicits transformation of monocytic pre-osteoclast to osteoclast cells, ultimately resulting in osteolysis observed in these tumors [22, 41, 42, 43] (Figure 2). Accordingly, preclinical models have shown that OPG, a soluble decoy receptor for RANKL, inhibits monocyte activation and osteoclast differentiation [44].
In GCTB, stromal cell-derived monocyte chemoattractant protein-1 (MCP-1/CCL2) recruits bone marrow-derived CCR2/CXCR4-expressing monocytic osteoclast precursors from peripheral blood [45, 46]. Other soluble factors within GCTB microenvironment are chemotactic for myelomonocytic cells, including stromal cell-derived factor 1 (SDF-1/CXCL12), macrophage inflammatory protein 1-alpha (MIP-1α/CCL3), and M-CSF1 [26, 47]. Osteoclast precursors localized at GCTB microenvironment differentiate into active, bone resorbing, osteoclasts.
Different pre-clinical studies have shown that GCTB stromal cells with circulating mononuclear cells co-culture induces differentiation of osteolytic giant cells [41, 42, 43]. For differentiation to occur, RANKL expression in stromal cells is regulated by CCAAT/enhancer-binding protein beta (C/EBPβ), found to be overexpressed in GCTB [48], and also by parathyroid hormone-related peptide (PTHrP) in an autocrine manner [49]. Next, RANKL-induced cell fusion is co-stimulated by M-CSF and IL-34 [26] and enhanced by specific transmembrane proteins overexpressed in GCTB [50] and coupling components, like insulin-like growth factors (IGF) I and II [51].
RANK pathway activation in giant cells leads to up-regulation of nuclear factor of activated T cells c1 (NFATc1), an auto-regulated key transcription factor responsible for regulating expression of important genes involved in bone resorption, like cathepsin K or β3-integrin [52]. Cathepsin K is involved in initial steps of bone resorption, degrading collagen type I and remodeling the bone matrix, allowing migration. As bone resorption starts, TGF-β entrapped in bone matrix is activated by matrix metalloproteases (MMPs), stimulating giant cell migration [46], which is mediated by αvβ3 integrin attachment to the bone matrix [53].
MMPs have an important role in GCTB physiopathology. Apart from the above-mentioned role in giant cell migration via TGF-β activation, MMPs influence other major aspects within the tumor microenvironment, like angiogenesis, invasion, and metastatic development. MMP-2 and MMP-9 are key in all these processes [22]. In GCTB, the extracellular matrix metalloproteinase inducer (EMMPRIN) is responsible for inducing MMP expression. Higher EMMPRIN expression at multinuclear osteoclast-like giant cells has been observed in stage III GCTB, probably regulated by RANKL from stromal-like tumor cells [54].
As previously mentioned, metastases are extremely rare in GCTB and there are no clues on molecular or physiopathological events related with GCTB metastization to date.
2.3 Tumor markers
Pathophysiology of GCTB progression remains unclear and prognostic factors, treatment targets, and predictive biomarkers represent unmet needs.
Histologically, ambiguous giant cell-rich lesions − including benign GCTB, chondroblastoma, aneurysmal bone cyst, central giant cell granuloma of the jaw, and malignant giant cell–rich osteosarcoma − are often found, especially as small biopsy or curettage specimens [22]. In these cases, H3F3A gene p.G34W mutation can be used in the differential diagnosis, as it is almost GCTB-exclusive [30, 55]. Approximately 90% of GCTBs display the p.G34W mutation, with minor subsets (<2%) displaying p.G34L, p.G34M, p.G34R, or p.G34V variants. H3F3B p.K36M is the H3.3 mutation found in the vast majority (90–95%) of chondroblastomas [30].
H3.3 p.G34W mutant-specific immunohistochemistry (IHC; clone RM263, commercially available) is a highly sensitive and specific surrogate marker of H3F3A p.G34W mutation in GCTB [56, 57, 58], being useful for practical diagnosis in primary [58] or recurrent, metastatic, and secondary malignant GCTB [59]. Although denosumab therapy may decrease p.G34W expression [22], evidence shows that spindle cells and cells in and around immature bone in denosumab-treated GCTBs are H3.3 p.G34W-positive by IHC, with H3F3A mutations consistently detected in corresponding samples [56, 58, 60, 61], which may predict relapse risk [55].
Although rare, malignant GCTB may occur, and studies suggest that p.G34W mutation is preserved [55]. One report, however, showed loss of one H3F3A allele (probably the mutant allele) in GCTB malignant component, leading to negative p.G34W IHC [62].
p63, a member of the p53 family of transcription factors, has also been studied as biomarker in GCTB diagnosis. p63 immunostaining has been used in diagnosis of head and neck squamous cell carcinoma, prostate adenocarcinoma (negative for p63 in opposition to p63-positive benign prostatic tissue) [63], and poorly differentiated squamous cell carcinoma [64]. p63 has also been shown to be highly expressed in GCTB mononuclear neoplastic cells [65, 66, 67], but its usefulness is still to be determined. A meta-analysis of eight different studies including 335 GCTB patients showed that p63 is a helpful marker for GCTB diagnosis in critically ill patients, although it cannot be recommended as a single definitive diagnostic marker [68].
Finally, it has been suggested that high RANKL, IL-6, TNFα, SDF-1, and MCP-1 expression may help predict GCTB metastatic potential and prognosis, warranting further studies [69].
3. Treatment overview
Treatment options for localized GCTB include en bloc resection or curettage with or without local adjuvants, like phenol, liquid nitrogen, or polymethylmethacrylate [70]. Radiation therapy (RT) can also be used as an alternative to surgery for local control, with 5-year local control rates of 80% [71]. However, RT is associated with risk of malignant transformation into high-grade sarcoma, making surgery the preferred option when possible. Contrarily to palliative care in irresectable or distant disease, systemic neoadjuvant or adjuvant therapy with the RANKL-binding fully human monoclonal antibody denosumab is still not established [70, 72]. A treatment algorithm is depicted in Figure 3.
Figure 3.
Flowchart of GCTB treatment. Adapted from NCCN guidelines – Bone cancer [73]. CT, computorized tomography; MRI, magnetic resonance imaging; RT, radiation therapy; SC, subcutaneous.
4. Medical therapy
4.1 Denosumab
Denosumab is a fully human monoclonal antibody (IgG2) that binds with high affinity and specificity to RANKL [74], thereby inhibiting osteoclast-mediated osteolysis. Given GCTB pathophysiology and its association to RANKL/RANK pathway, denosumab has proven effective in this disease.
In patients with resectable GCTB, adjuvant denosumab at a 120 mg dosage administered subcutaneously every 28 days, with additional loading doses on days 8 and 15 on the first month, during 6 months after complete resection has been approved by both the Food and Drug Administration and European Medicines Agency [72, 75, 76]. However, this treatment is still debated. Studies supporting its use in the adjuvant setting are scarce and mostly rely in level IV evidence. Conversely, evidence from a systematic review by Luengo-Alonso [72] favored adjuvant denosumab, which showed a positive histological and clinical (pain relief) response. In patients with unresectable GCTB (either primary or recurrent) or when complete excision is possible but post-surgical severe morbidity and functional impairment is expected, neoadjuvant denosumab should be started (same dosing scheme as above) and response to treatment evaluated. Should the patient respond to denosumab and surgery be feasible with acceptable morbidity, then complete excision and possibly adjuvant denosumab for six months should be considered. On the other hand, the optimal denosumab duration is still debatable when treatment response is suboptimal or in cases of sacral or spinal GCTB, multiple lesions (including pulmonary metastases), or patient’s clinical ineligibility for surgery. Denosumab should be considered until progression or unacceptable toxicity (e.g., osteonecrosis of the jaw), provided at least partial response is achieved.
4.2 Bisphosphonates
Bisphosphonates inhibit osteoclast-mediated bone resorption and are used in cancer patients, especially in bone metastases setting. In GCTB patients, denosumab is the preferred systemic treatment option. However, evidence regarding the use of adjuvant denosumab is not consistent and some studies show lack of benefit in local recurrence rates [77, 78]. Bisphosphonates, like zoledronic acid (ZA), can be an option in the adjuvant setting. A recent meta-analysis of case–control studies showed that the use of adjuvant bisphosphonates in patients submitted to intralesional curettage may decrease local recurrence rates, independently of Campanacci staging [79]. In patients undergoing wide resection, bisphosphonates seem to have no benefit in local recurrence. A phase II non-randomized clinical trial of adjuvant ZA after extensive curettage in GCTB patients showed that ZA failed to prevent local recurrence [80]. Another phase II multicentric, randomized, open-label clinical trial showed no benefit with adjuvant ZA, although the study was terminated earlier due to poor accrual [81]. The use of adjuvant bisphosphonates should be evaluated on a case-by-case basis. In unresectable or metastatic GCTB, clinical studies addressing the use of bisphosphonates are also scarce. Overall, the role of bisphosphonates in the treatment of patients with GCTB remains to be clearly defined.
Chemotherapy agents and interferon-α have also been used to treat GCTB, as reported in case reports and small series, but results were poor and there are no clinical trials to guide their use. Anecdotal small retrospective case series and case reports have documented the use of doxorubicin [82, 83], cyclophosphamide [84], cisplatin plus doxorubicin [85], combination therapy with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, followed by high-dose methotrexate and vincristine [86], interferon alpha 2a [87] and interferon alpha 2b [88], with mixed results.
5. Conclusions and future directions
GCTB is a primary and mostly benign tumor of bone usually arising in the meta-epiphysis of long bones and more often affecting young patients. Despite its frequent benign nature, local recurrence rate is high and there is a non-negligible risk of distant metastization, namely to the lungs. Therefore, treatment should provide the best chance of curative outcome with minimal functional sequelae and quality of life impairment.
The main pillar of treatment is surgery, but systemic therapy has a role in adjuvant and palliative settings. Regarding GCTB pathophysiology, RANKL/RANK pathway is central to tumor development and denosumab, a monoclonal antibody against RANKL, is the most studied and most effective systemic therapy for the disease. Its use is particularly established in the palliative setting, i.e., in cases of unresectable disease, patient ineligibility for surgery, or lung involvement. Although less studied, bisphosphonates can also be an option. However, their role in GCTB medical management needs to be better clarified.
GCTB rare nature, particularly malignant GCTB, hampers the development of clinical trials to investigate new drugs for second-line treatment and establish the optimal treatment sequence (neo- vs. adjuvant denosumab or adjuvant denosumab vs. after recurrence, etc.). Currently, one clinical trial (NCT04255576) is studying the use of JMT103, a novel fully human IgG4 monoclonal antibody against RANKL, in GCTB [89]. Another clinical trial (NCT03449108) is using a different approach to address bone tumors, including GCTB [90], by studying the use of LN-145-S1, or autologous tumor infiltrating lymphocytes, in treatment-refractory or relapsed disease. As discussed above, mutations in cyclin D1, p53, and MET have been associated with GCTB malignant transformation and recurrence. This raises the hypothesis that cyclin-dependent kinase (CDK) inhibitors (e.g., ribociclib, palbociclib) and MET inhibitors (e.g., crizotinib) may be useful in this disease. Although these therapies have been approved in other tumors (CDK inhibitors in breast cancer and crizotinib in lung cancer), no studies are in place in GCTB yet. Another promising target is MMPs, specially MMP-2 and MMP-9, that play an important role in GCTB physiopathology, namely regarding tumor microenvironment, angiogenesis, invasion, and metastatic development. Preclinical studies in breast cancer used ML115, a bone-seeking MMP inhibitor, to prevent bone metastases [91], with promising results. Although still far from use in the clinical practice, this could be another potential therapy worth studying in GCTB. Several other clinical trials continue to investigate the use of denosumab, bisphosphonates, and local therapy (surgery/RT) [92, 93, 94, 95, 96, 97].
Acknowledgments
We thank Joana Cavaco Silva for her contribution as a medical writer. Authors acknowledge Joana Cavaco Silva for manuscript revision.
Conflict of interest
The authors declare no conflict of interest.
Nomenclature
BMP-2
Bone morphogenetic protein 2
CCR2
C-C chemokine receptor type 2
CXCR4
C-X-C chemokine receptor type 4
C/EBPβ
CCAAT/enhancer binding protein beta
CT
Computorized tomography
CDK
Cyclin-kinase inhibitors
DC-STAMP
Dendritic cell-specific transmembrane protein
EMMPRIN
Extracellular matrix metalloproteinase inducer
FFPE
Formalin-Fixed Paraffin-Embedded
GCTB
Giant cell tumor of the bone
H3.3
Histone 3.3
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IGF
Insulin-like growth factor
IL-1
Interleukin 1
M-CSF
Macrophage colony-stimulating factor
MIP-1α
Macrophage inflammatory protein 1-alpha;
MRI
Magnetic resonance imaging
MMP
Matrix metalloprotease
MCP-1
Monocyte chemoattractant protein-1
NFATc1
Nuclear factor of activated T cells c1
OC-STAMP
Osteoclast stimulatory transmembrane protein
PTHrP
Parathyroid hormone related peptide
RT
Radiation therapy
RANKL
Receptor activator of nuclear factor kappa-B ligand
RUNX2
Runt-related transcription factor 2
SC
Subcutaneous
SDF-1
Stromal cell-derived factor 1
TRAP
Tartrate-resistant acid phosphatase
TRAIL
TNF-related apoptosis inducing ligand
TGF-β
Transforming growth factor beta
TNF-α
Tumor necrosis factor-alpha
VEGF
Vascular endothelial growth factor
ZA
Zoledronic acid
\n',keywords:"denosumab, giant cell tumor of bone, RANKL, sarcoma, sarcomatoid transformation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76256.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76256.xml",downloadPdfUrl:"/chapter/pdf-download/76256",previewPdfUrl:"/chapter/pdf-preview/76256",totalDownloads:263,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:32,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"December 17th 2020",dateReviewed:"March 9th 2021",datePrePublished:"June 15th 2021",datePublished:"September 1st 2021",dateFinished:"April 13th 2021",readingETA:"0",abstract:"Giant cell tumor of bone (GCTB) is mostly a benign disease of the bone, although with high local recurrence rate and potential for metastatic spread, namely to the lungs. It is also a locally aggressive tumor, associated with severe morbidity and functional impairment due to bone destruction. Treatment is therefore required and should be offered at an early stage to allow complete resection, minimizing functional sequelae and local recurrence. Surgical resection is the mainstay of treatment, often followed by intralesional adjuvant therapy. GCTB has a particular biology, in which RANKL represents a key factor in tumor pathogenesis, thus making this molecule a valuable therapeutic target. Monthly administration of denosumab, a fully human monoclonal antibody directed against RANKL, has been studied in several clinical trials and shown a high rate of local control with favorable safety profile. In this chapter, current medical management, ongoing studies, and future directions in GCTB will be discussed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76256",risUrl:"/chapter/ris/76256",book:{id:"9500",slug:"recent-advances-in-bone-tumours-and-osteoarthritis"},signatures:"Raquel Lopes-Brás, Isabel Fernandes, Sandra Casimiro and Luís Costa",authors:[{id:"325844",title:"Dr.",name:"Luis",middleName:null,surname:"Costa",fullName:"Luis Costa",slug:"luis-costa",email:"luiscosta.oncology@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"344630",title:"Prof.",name:"Isabel",middleName:null,surname:"Fernandes",fullName:"Isabel Fernandes",slug:"isabel-fernandes",email:"fernandescristina@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"344631",title:"M.D.",name:"Raquel",middleName:null,surname:"Lopes-Brás",fullName:"Raquel Lopes-Brás",slug:"raquel-lopes-bras",email:"raquellopesbras@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Centro Hospitalar Lisboa Norte",institutionURL:null,country:{name:"Portugal"}}},{id:"349263",title:"Prof.",name:"Sandra",middleName:null,surname:"Casimiro",fullName:"Sandra Casimiro",slug:"sandra-casimiro",email:"scasimiro@medicina.ulisboa.pt",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. GCTB biology and pathogenesis",level:"1"},{id:"sec_2_2",title:"2.1 Histopathology",level:"2"},{id:"sec_3_2",title:"2.2 Physiopathology",level:"2"},{id:"sec_4_2",title:"2.3 Tumor markers",level:"2"},{id:"sec_6",title:"3. Treatment overview",level:"1"},{id:"sec_7",title:"4. Medical therapy",level:"1"},{id:"sec_7_2",title:"4.1 Denosumab",level:"2"},{id:"sec_8_2",title:"4.2 Bisphosphonates",level:"2"},{id:"sec_9_2",title:"4.3 Chemotherapy/systemic cytotoxic agents/interferon",level:"2"},{id:"sec_11",title:"5. Conclusions and future directions",level:"1"},{id:"sec_12",title:"Acknowledgments",level:"1"},{id:"sec_15",title:"Conflict of interest",level:"1"},{id:"sec_14",title:"Nomenclature",level:"1"}],chapterReferences:[{id:"B1",body:'Athanasou NA, Bansal M, Forsyth R, Reid RP, Sapi Z. Giant cell tumour of bone. In: Fletcher C, Bridge J, Hogendoorn P, Mertens F, editors. WHO classification of tumours of soft tissue and bone. 4th ed. 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The oncologist. 2019;24(7):889-e421.'},{id:"B82",body:'Dominkus M, Ruggieri P, Bertoni F, Briccoli A, Picci P, Rocca M, et al. Histologically verified lung metastases in benign giant cell tumours--14 cases from a single institution. Int Orthop. 2006;30(6):499-504.'},{id:"B83",body:'Yamamoto M, Fukushima T, Sakamoto S, Tomonaga M. Giant cell tumor of the sphenoid bone: long-term follow-up of two cases after chemotherapy. Surgical neurology. 1998;49(5):547-552.'},{id:"B84",body:'Osaka S, Toriyama M, Taira K, Sano S, Saotome K. Analysis of giant cell tumor of bone with pulmonary metastases. Clinical orthopaedics and related research. 1997(335):253-261.'},{id:"B85",body:'Stewart DJ, Belanger R, Benjamin RS. Prolonged disease-free survival following surgical debulking and high-dose cisplatin/doxorubicin in a patient with bulky metastases from giant cell tumor of bone refractory to “standard” chemotherapy. American journal of clinical oncology. 1995;18(2):144-148.'},{id:"B86",body:'Mella O, Dahl O, Bang G, Engedal H, Gøthlin J, Lunde OD. Chemotherapy of a malignant, metastasizing giant-cell tumor of bone: report of an unusual case and the response to combination chemotherapy. Cancer. 1982;50(2):207-211.'},{id:"B87",body:'Kaiser U, Neumann K, Havemann K. Generalised giant-cell tumour of bone: successful treatment of pulmonary metastases with interferon alpha, a case report. Journal of cancer research and clinical oncology. 1993;119(5):301-303.'},{id:"B88",body:'Wei F, Liu X, Liu Z, Jiang L, Dang G, Ma Q, et al. Interferon alfa-2b for recurrent and metastatic giant cell tumor of the spine: report of two cases. Spine. 2010;35(24):E1418-E1422.'},{id:"B89",body:'Efficacy and Safety of JMT103 in Patients With Giant Cell Tumor of Bone.'},{id:"B90",body:'LN-145 or LN-145-S1 in Treating Patients With Relapsed or Refractory Ovarian Cancer, Anaplastic Thyroid Cancer, Osteosarcoma, or Other Bone and Soft Tissue Sarcomas.'},{id:"B91",body:'Tauro M, Lynch CC. Bone seeking matrix metalloproteinase-2 (MMP-2) inhibitors can prevent bone metastatic breast cancer. Annals of Oncology. 2019;30:iii60-iii1.'},{id:"B92",body:'Long-term Safety Follow-up of Subjects With Giant Cell Tumor of Bone Treated With Denosumab in Study 20062004.'},{id:"B93",body:'Safety and Efficacy of Post-operative Denosumab Strategy for Giant Cell Tumor of Bone Treatment in China.'},{id:"B94",body:'Study of XGEVA® (Denosumab) in Chinese Adults and Skeletally Mature Adolescents With Giant Cell Tumor of the Bone.'},{id:"B95",body:'Safety and Efficacy Study of Denosumab in Patients With Recurrent or Unresectable Giant Cell Tumor of Bone.'},{id:"B96",body:'Local Bisphosphonate Effect on Recurrence Rate in Extremity Giant Cell Tumor of Bone.'},{id:"B97",body:'Giant Cell Tumor of the Extremities Treated With Surgery and/or Medical Treatment.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Raquel Lopes-Brás",address:"raquellopesbras@gmail.com",affiliation:'
Medical Oncology Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Portugal
Medical Oncology Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Portugal
LCosta Lab, Instituto de Medicina Molecular – João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Portugal
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1. Introduction
Parasitism is a complex relationship between two organisms and requires several adaptations at the molecular level to establish successful interactions throughout evolution. Intricate signaling systems are necessary to transduce each signal from host to pathogen and vice versa. These systems or networks are relevant because they capture various signals from the environment in which the parasite lives (host), release stimuli, and send signals between different organs and tissues to regulate complex biological processes.
Many host signals (molecules) modulate the development and growth of parasites and directly or indirectly interfere in the course of parasitic infection. It is as important to understand the mechanism of action of these molecules to improve the knowledge of the basic biology of parasitism as the description of the effects itself is necessary.
With the development of sequencing technologies, the difficulties and costs of sequencing a genome or transcriptome have been reduced significantly; consequently, the number of sequences available dramatically increased [1], including the sequences from platyhelminth genomes [2, 3, 4, 5, 6] and transcriptomes [7, 8, 9, 10, 11, 12]. This data collection allowed the scientific community to perform evolutive studies and investigate the signaling elements such as receptor, kinase and phosphatase proteins, and transcription factors [13, 14, 15, 16]. These advances reflect the understanding of the molecular crosstalk mechanism between host and parasites. Studying the signaling elements is essential to comprehend parasitism, parasite development and identify new targets for developing strategies against these diseases (Figure 1) [17, 18].
Figure 1.
Molecular cross-talk between parasite and host. Schematic representation of parasite and host cells, signaling pathways, and molecules secreted (potential ligands) by both organisms. The ellipses represent signaling elements as indicated in the figure and the different colors represent distinct signaling pathways; the hexagons represent second messengers, and the arrows indicate the sequential interaction between proteins of the signaling pathways that culminate in the activation of transcription of target genes that will trigger various cellular processes. Potential molecular targets for drugs and vaccines are highlighted in red circles.
This chapter reviews the host molecules (cytokines and hormones) and their effects and signals transduction pathways in platyhelminths. The most studied model of platyhelminth is Schistosoma mansoni (S. mansoni) and most of the information available in this chapter refers to this parasite.
2. Host cytokines’ effects on platyhelminths
Cytokines are small proteins (5–25 kDa) produced by many cells (especially from the immune system), which exert a signaling effect (at an autocrine, paracrine, or endocrine level) in a broad range of tissues [19]. Generally, cytokine studies focus on the immune system’s regulation when faced with an infection; however, we will describe how the host cytokines can modulate platyhelminths’ biological/physiological processes and their possible signaling pathways.
2.1 Interleukins (12, 2, 7, 4, and 1)
Interleukin-7 (IL-7) is a cytokine secreted by bone-marrow, endothelial, and epithelial-stromal cells essential in the hematopoietic system for the proliferation, differentiation, and development of B cells [20]. It is also involved in the thymic development of mature T lymphocytes, natural killer (NK), and lymphokine-activated killer (LAK) cells [21].
IL-7 interferes in the development of S. mansoni (in murine infection) [22]. Female knockout mice for the IL-7 gene (IL-7−/−) infected with S. mansoni showed significant differences in parasite development, egg-induced pathology, and worm recovery rate. It was also observed that fewer eggs were laid in vivo, and more dead eggs were detected without IL-7. The decreasing egg burden ameliorated the liver pathology, and morphological differences in the length of male and female worms in the IL-7−/− mice were observed [22].
Studies with radiolabeled IL-7 suggested that this cytokine did not bind directly on the parasite surface; hence, the observed effects of IL-7 deficient mice could be attributed to the cytokine’s interactions with the host’s immune and or endocrine responses [23, 24].
Interleukin-2 (IL-2) is a cytokine with autocrine and paracrine effects secreted by activated T-CD4 + cells [25]. Further investigations interrogated the modulation of S. mansoni development by IL-7 and IL-2 through the influence of these cytokines on CD4+ T (T helper) cells [26]. With the use of knockout mice for IL-7 receptor (IL-7Rα−/−) and IL-2 (IL-2−/−) for S. mansoni infection, the morphology of adult worms is affected. In both knockout mice, the infected mice produced smaller male worms than the control group. In the IL-7 receptor knockout mice, the parasite’s egg production was drastically reduced [26]. Studies with IL-2 receptor knockout mice (IL-2Rα−/−) infected with S. mansoni revealed a similar impact on the parasite’s development, using the knockout mice for the cytokine. Thus, it could be concluded that the modulation of IL-7 and IL-2 in S. mansoni development (adult growth and egg-laying and granuloma formation) is indirect; the cytokines act on the host’s CD4+ T cells [26].
Interleukin-12 (IL-12) and interleukin-4 (IL-4) reciprocally regulate differentiation of naïve CD4+ T lymphocytes and directly promote the development of CD4+ Th1 cells and the CD4+ T-cell differentiation in the Th2 phenotype (which also produces IL-4). In 2012, Cheng et al. [27] used an approach with hybridoma cells injected into different mice groups to evaluate the effect of monoclonal antibodies against IL-12 and IL-4 on parasite infection. The effect of IL-12 and IL-4 on worm development and granuloma formation in a murine infection by Schistosoma japonicum (S. japonicum) was evaluated. It was observed that, 24 days post-infection, the group of anti-IL-12 had a significant increase in the number of eggs per couple and eggs in the liver. The granuloma size and fibrosis in the liver in the anti-IL-12 mice were significantly more prominent on day 42. The decreasing of T helper 1 (Th1) cytokine expression through the blocking of IL-12 promotes the T helper 2 (Th2) cytokine expression and reduces Interferon-γ (IFN-γ) and Interferon-α (IFN-α) cytokine levels.
The length of worms in the anti-IL-12 group was increased; however, the degree of increase was different in males and females. The female size was higher in anti-IL-12 than in anti-IL-4 and control groups at 28 and 42 days post-infection, while the male size was higher just at 28 days in the anti-IL-12 [27]. The data in this study suggest that IL-12 deficiency benefits S. japonicum worm development in the early days of infection, indicating the action of cytokine against the schistosome. At the same time, its effect was reduced at 42 days post-infection, revealing a transitory effect. It is important to note that IL-12 promotes a Th1 response.
Finally, interleukin-1 (IL-1) from Biomphalaria glabrata (B. glabrata), the intermediate host of S. mansoni, also affects the parasite. In the vertebrate’s immune system, the cytokine IL-1 mediates cytotoxic, humoral, and inflammatory responses, induces leukocyte recruitment to the inflammation site, and is involved in the cytotoxic reactive oxygen intermediate (ROI) production mechanism in the effector cells [28]. In the immune defense system of the invertebrate B. glabrata, molecules with functional homology to the vertebrate IL-1 (SnaIL-1) have been detected and isolated. It was observed that, in response to schistosome infection’s primary sporocysts, susceptible snail strains exhibit a decrease in plasmatic SnaIL-1 levels, while the SnaIL-1 cytokine levels rise in resistant strains. Also, when the susceptible snails are treated with a recombinant human Interleukin-1β (rhIL-1β), there is a rapid phagocytosis activation and ROI production at the same levels found in the resistant snail strains [29].
In 1998, Connors et al. [30] investigated if the treatment of two strands of susceptible B. glabrata with rhIL-1β had effect on the infection of the invertebrate host (directly or mediating by hemocyte’s activity). After 15 days of exposure, the authors observed a significant decrease of 50% in the number of counted miracidia on snails from both treated groups. Histological analysis of snail tentacles performed 3 days after exposure revealed a significantly higher percentage of dead or disrupted parasites compared to the control. In-vitro assays using hemocytes-free cultured parasites in contact with the plasma from rhIL-1β -injected snails showed an immediate killing effect on the parasites.
These results imply that the cytokine may stimulate in-vivo induction of a cell-free killing mechanism in the B. glabrata. Parasites’ killing seems to have no connection with the hemocyte’s encapsulation of the parasites, suggesting the presence of both a humoral cytotoxic molecule and a cellular signaling mechanism. Injection of the recombinant human IL-1β on the susceptible snails has activated the otherwise reduced cytotoxic capabilities of the snail’s immune system; however, other factors such as reduced number of hemocytes compared to resistant strains may limit the killing of the parasites. Further, invertebrates’ cytokine-like activity may occur in molecules with substantially different structures from their mammalian counterparts, obviating the need for more analysis of the elements involved in the host-parasite signaling mechanisms.
2.2 Transforming growth factor-β (TGF-β)
TGF-β plays an essential role in wound healing, angiogenesis, immunoregulation, and cancer development. These cytokine’s effects are dual-sided, contributing to the differentiation of regulatory (suppressive) T cells (Tr cells) and inflammatory Th17 cells. In mammals, all leukocytes produce at least one isoform of TGF-β [31]. TGF-β is locally produced by the host’s immune system cells in response to the presence of helminth parasites.
In the genome of Taenia solium (T. solium) and Taenia crassiceps (T. crassiceps, a canine tapeworm), protein-coding genes for the pivotal signaling elements were identified [32]. TsTGFβR1, TsTGFβR2, TGF-β Type I, Bone Morphogenetic Protein (BMP) Type-I receptor Tr-3, and activin (TGF-ligand) were identified and had a high identity with Echinococcus sp. The expression of TsTGFβR1, TsTGFβR2 at mRNA, and protein level was detected in T. solium and T. crassiceps cysticerci. It showed that both TGF receptors are expressed in the parasite’s teguments more prominently in the tegument of T. crassiceps and the periphery of T. solium cysticerci from the brain than in the cysticerci from skeletal muscle of infected pigs. It is interesting because the TGF-β levels in the cerebrospinal fluid are higher than in serum, suggesting that the exposure to the host’s molecule could be involved in cysticerci growth and differentiation [32].
It is interesting to note that T. solium and T. crassiceps cysticerci were in vitro exposed to three concentrations of recombinant human TGFβ-1 (0.001, 0.01, and 0.1 ng/mL). The human cytokine caused a significant increment in the size of cysticerci in T. crassiceps. In the T. solium cysticerci, a considerable improvement in the survival rate was observed with no effect on its size. The parasite could internalize the host’s TGF-β via endocytosis as a regulatory event. However, these effects may be mediated by the direct interaction of the host’s cytokine with the parasite receptors. The results observed on the parasites in an in vitro treatment and the antibody recognition of receptors are lower when TGF- β incubation occurs. The lower antibody recognition of both Type-I and Type-II parasite receptors when cysticerci were cultured with increasing levels of TGF-β suggests that TGF-βcould bind the Type-II receptor (avoiding the recognition of antibody), then the complex TGF-β-TsTGFβR2 receptor would recruit the Type-I receptor, forming a complex which would prevent the bounding of Type-I receptor antibody. These results point to hTGF-β as a factor in cysticerci growth and survival, which could also play a role in the lack of effectiveness of cysticidal treatment of patients.
In S. mansoni, several TGF-β signaling pathway elements have been identified and described, including two TGF-β receptors (SmTβR1 and SmTβR2), one homolog gene to Inhinbin/Activin (SmInAct), a homolog to the BMP (SmBMP), Smp300/CBP, Smad2, and Smad4. In female worms, these elements could play a role in vitelline cell development and egg embryogenesis, as these molecules’ expression is detected in these organs (reviewed in [33].
Oliveira et al. [34] studied the effects of the human TGF-β (hTGF-β) on the gene expression profile of S. mansoni adult worms. Microarray experiments were performed with RNA extracted from adult worms that were in vitro treated with the human cytokine. This experiment revealed that changes in the expression influence the pattern of treated worms. With this approach, 381 genes were detected as differentially expressed, with 316 down-regulated and 65 up-regulated. These genes are related to biological functions such as muscular system development and function, tissue morphology, cellular assembly and organization, organ development, tissue development and cellular growth, and proliferation. Some functions, such as contractile fiber and myosin complex, hydrolase activity, and adenyl ribonucleotide binding, are related to the down-regulated genes. It correlates with the already described TGF-β induction of cytoskeleton remodeling through the myosin chain and Rho GTPase [35, 36].
Figure 2 summarizes host cytokines’ direct or indirect effect on the parasites.
Figure 2.
Influences of mammals and invertebrate host’s cytokines on platyhelminths. (A) Cytokines. (B) Vertebrate immune system cells. (C) Platyhelminthes. (D) Cytokine. (E) Invertebrate effector cells. (F) S. mansoni primary sporocysts. Some cytokines (TNF-α and TGF-β) exert direct effects on the parasite; on the other hand, other cytokines (such as interleukins) exert effects on immune system cells and these cells regulate parasites´ biological processes.
2.3 The example of human Tumor Necrosis Factor-α (TNF- α) on S. mansoni
Human TNF-α and its effect on S. mansoni are excellent examples of how the comprehension of the molecular crosstalk between host and pathogen has increased in the last decades. Some studies have described the influence of the pro-inflammatory cytokine TNF-α on the fecundity and metabolism of the parasite S. mansoni. Amiri et al. [37] described that human TNF-α induces the formation of granulomas and causes a positive effect on the parasite’s egg-laying. Controversially, it was shown that egg-laying decreases and induces changes in the uptake of tyrosine [38] and methionine [39] on S. mansoni in the presence of the human cytokine. It was also documented that parasites’ egg-laying and fecundity occurred later when immunodeficient mice (SCID) were used for infection with the parasite [40]. Finally, Davies et al. [41] reported that host TNF-α promotes the parasite survival and the development of adult worms.
In this context, the molecular mechanism started to be elucidated by searching for S. mansoni homologous gene to the human TNF-α receptor. A homolog gene was identified and characterized (SmTNFR) [42] and generated a transcript of 1967 nucleotides that encodes a receptor composed of 599 amino acids. The predicted protein has an extracellular portion that contains four TNF-α conserved domains (cysteine-rich domains), the main characteristic of the TNF receptor family. Extracellular domains’ modular architecture is similar to the neural growth factor receptor (NGFR). The first analysis of the intracellular portion revealed no conserved domains, which is not expected in a homologous gene to NGFR characterized by Death Domain (DD), which makes it similar to TNF-R2, a non-death domain. The transcript expression level (mRNA) is detected in all developmental stages, but the highest expression level is detected in cercaria [42].
Parallel to the description of SmTNFR, other homolog genes for a possible signaling pathway were also identified. It is interesting to highlight that all elements required and activated by the human TNF-R2 signaling pathway (which does not have DD and, therefore, is not related to the activation of apoptosis) were found [42].
Recently, through in-silico analysis, 29 genes of homologous receptors to SmTNFR in other species of parasitic flatworms were identified. The homologs may evidence conservation of the TNF-α signaling pathway in a part of helminths. Additionally, highly conserved homologs of endogenous TNF-α ligands only in free-living flatworms were also identified. This suggests that the loss of the endogenous ligand (observed in parasitic flatworms) and the consequent use of the host’s ligand was an event that occurred throughout the evolutionary process, as a cause or consequence of the parasitism [43].
Further, TNFR homologs identified in platyhelminths had conserved DD, which was concluded after the analysis of the secondary structure of intracellular regions. The intracellular portion of all receptors was reanalyzed, and evidence of the presence of DD was found in most SmTNFR homologs in platyhelminths but with different levels of conservation. Generally, cestodes have a more conserved DD than trematodes. This urges us to rethink the possible signaling pathway triggered by SmTNFR, since this receiver was initially classified as without DD [42].
Parallelly, Oliveira et al. [42] investigated the effect of human TNF-α on the gene expression profile in newly transformed schistosomula (NTS) and adult worms. NTSs (3 h after transformation) were treated with human TNF-α for 1 h (at the concentration of 20 ng/mL), and adult worms treated with human TNF-α for 1 h and 24 h. Microarray experiments revealed 548 genes with altered expression in NTSs after treatment with the human cytokine (309 up-regulated and 239 down-regulated). These genes are involved in biological functions related to the regulation of gene expression, cell proliferation and growth, and cell development. Two groups of differentially expressed genes were identified in adult worms treated for 1 h and 24 h. One group had transient changes in expression, that is, an inverse change pattern within 24 h compared to the pattern obtained within 1h. This group comprises 1365 genes, 821 of which have their expression level increased in 1 h of treatment and decreased in 24 h, and 544 have the opposite expression pattern. The second group has sustained changes in its expression level in 1 h and 24 h; this group comprises 492 genes, 337 being with the expression level increased by treatment with human TNF-α and 155 with the expression level decreased. These differentially expressed genes were organized in gene expression networks, and the most significantly enriched network interacts with TNF-α in other organisms. The network suggests that the parasite response to the human cytokine is conserved and similar to the reaction in humans [42]. Interestingly, the enzyme lactate dehydrogenase (responsible for producing lactate) was differentially expressed in schistosomula and adult worms treated with human TNF-α.
Thus, it was described that human TNF-α induces the phosphorylation of different proteins in adult male worms after in vitro treatment for 15 min. Differentially phosphorylated proteins were related to muscle contraction, cytoskeletal remodeling, cell signaling, and metabolism. Lactate dehydrogenase and a subunit of ATP synthase are differentially phosphorylated proteins. These results indicate that this enzyme, in the glycolytic pathway of the parasite, is being potentially regulated by the host’s TNF-α in its expression level (mRNA) and activity [44].
Since the literature description of egg-laying is contradictory, and lactate dehydrogenase is differentially expressed and phosphorylated, the effect of TNF-α on egg-laying and metabolism was investigated in the adult parasites, in an in vitro treatment with doses of the human cytokine (5, 20, and 40 ng/mL) during 5 days [45].
The average number of eggs/couple increased on the second day in the treatment with 40 ng/mL. On the third day, there was a significant decrease in the average of eggs/couple for the treatments with 20 and 40 ng/mL; besides, there was a decrease for the doses of 5 and 40 ng/mL on the fourth day of incubation with the cytokine. The most important observation is that the total number of eggs was not different between treatments and control over the 5 days of treatment. The conclusion is that although egg-laying dynamics were affected, the fecundity was not. The host’s TNF-α causes a decrease in the half-life of the egg-laying; therefore, when faced with the stimulus, couples lay eggs more quickly, but not in greater or lesser amounts than the respective negative control [45].
The TNF-α treatment induced significant changes in lactate concentration or possibly the glucose uptake when there was also a change in egg-laying. On the third day of treatment, for example, when lactate production decreased, the number of eggs laid was also reduced, indicating that energy metabolism is a relevant actor regulated by human TNF-α and interferes in the production dynamics and egg-laying [45].
In addition, the increase in the accumulation of adenosine triphosphate (ATP) in adult worms on the fifth day was observed. The compromised egg-laying can explain it at this time: the high demand for ATP is destined for oogenesis and, when not necessary, this molecule can accumulate, especially against the modulation induced by the human cytokine [45]. It is also interesting to note that one subunit of ATP synthase is regulated by human TNF-α [44].
Figure 3 summarizes the history of the characterization of the effects of TNF-α on Schistosoma mansoni. It is an exciting example of how a cytokine effect can be elucidated like a puzzle, piece by piece.
Figure 3.
Timeline of main discoveries described in the literature about host TNF-α and its effects on S. mansoni.
3. Host hormones influences in metabolism, development, and viability of platyhelminths
The interaction between host and parasite depends on the ability of the parasite to successfully adapt to the host’s microenvironment, allowing for a complete life cycle and parasite development [46]. That relationship suffers interference from age, sex, and reproductive status of the host and influences the hormonal profile [47]. Hormones, especially sex steroids, are fundamental for many biological processes such as reproduction, growth, development, and immunity. Parasites can evade the immune system. They can also exploit the host’s hormones to improve their growth and reproduction, demonstrating that these organisms have mechanisms to interact with the host’s molecules [48, 49].
Female supremacy is an older concept that assumes that female mammals suffer less parasitism than males. The statement that supports this paradigm implies that sexual dimorphism to parasite infections is based, principally, on the host immune system and has less interference of direct effects of hormones on parasites. Analysis of literature contests this paradigm, showing that publications represent few host-parasite systems, most of which have a medical bias, exploring, in general, human infections. Furthermore, there is no definition of infection and the immune parameters that contribute to host resistance or susceptibility to parasitism, casting doubt on the protective effect of those immune indicators. There are several exceptions to female supremacy: in malaria, toxoplasmosis, and cysticercosis, females are more affected by parasite infections than males [50].
Another line of discussion focuses on the influence of host sex in the genetic diversity of parasites. In this study of 2006, the researchers showed that independent of sex, schistosomes have more genetic diversity in male hosts. The authors postulated three hypotheses that explain the genetic variability of schistosomes: the relationship between rat-sex and duration of infection by cercaria; a combination of rat sex and specific habitat on host males that can contribute to more genetic diversity in parasites; a host sex bias in immunocompetence that select more diverse clones in male rats [51].
Together, these pieces of evidence raise new questions about the participation of host hormones in the host-parasite relationship. Do differences in concentrations of sex hormones between males and females have a significant role in the susceptibility to parasite infections? Can host hormones directly affect parasite biology? Do the parasites exploit the host hormones for their growth? Here in this topic, we aim to review the interaction between host hormones and platyhelminths, especially in S. mansoni, T. crassiceps, and T. solium.
As previously mentioned, hormones are important for the modulation of immune responses. The influence of host sex on resistance and susceptibility to parasitism in CBAJ/mice infected with S. mansoni showed the following results: females and castrated males had the worst survival rates, with 80% dead after 16 weeks of infection, compared to under 40% of infected males that died. In another experiment, investigators revealed that schistosomula grow better in the low testosterone level group, as noticed by the higher recovery rates of adult worms per cercaria. A possible explanation is the differences promoted by testosterone in the decline of infection effects, represented by a more pronounced organomegaly in the liver and spleen in females and castrated males, which are early pre-mortality indicators. These results start a discussion about the relationship between the host sex and differences in the parasite infection [52, 53].
When it comes to cestodes, we also see the effects of hormones on immunity. To test the influence of androgens in the parasite loads, the researchers investigated the effect of testosterone, dihydrotestosterone (DHT), and 17β-estradiol in castrated female and male mice infected with T. crassiceps. The castration triplicated the parasite burden in males and had the opposite effect in females, decreasing the number of parasites by 45%. The treatment with testosterone and DHT reduces de parasite loads in both genders, respectively, 60% and 70%. However, estradiol treatment increases the parasite number in female and male mice three times. Another experiment shows that parasite infection in male mice results in a high level of estradiol, a lower 90% testosterone, and a 95% decrease in DHT [54].
The antibodies’ and cytokines’ production is also affected by the sex steroids levels. In general, testosterone and DHT have no effect on the production of IgG, IL-6, and IL-10 in both sexes. On the other hand, the production of IL-2 and IFN-γ increases significantly in both sexes, and DHT promotes 70% recovery of the cytokines in males. Estradiol increases levels of anti-parasite IgG by 60% and duplicates IL-6 and IL-10 production in males and females. Those results demonstrated that androgens increase the cellular response in T. crassiceps infection with a specifically TH1 pattern. Oppositely, estrogens produce a TH2 immune response, which has no value in stopping the parasite’s growth [54].
The effect of progesterone is also investigated in T. crassiceps and T. solium cysticercosis. In T. crassiceps treatment with progesterone, the number of parasites increases by three folds in male and two folds in female mice. Estradiol is increased two times in both genders, suggesting that progesterone is metabolized in the gonad. The cytokines, IL-4, IL-6, and IL-10 levels increase under the infection, with no change after progesterone treatment. In addition, IL-2, TNF-α, and IFN-γ concentration in the spleen is not modified with infection and treatment, but IL-2 is undetected in both sexes infected, and IFN-γ and TNF-α are increasing in progesterone-treated mice. Moving to T. solium, progesterone treatment decreases tapeworm length and increases IL-4, IL-6, and TNF-α in the duodenum, combined with a polymorphonuclear leukocytes infiltration. Once again, these results show that progesterone modulates TH1 immune response in T. crassiceps and improves intestinal mucosal immunity [55, 56].
Host hormones also directly affect the biology of parasites. Previous experiments showed that dehydroepiandrosterone (DHEA) and DHEA-S have a protected effect on mice infected with S. mansoni [57]. Another study demonstrated a negative correlation between DHEAS and intensity of parasitism, and this decline of S. mansoni infection also correlated to age [58]. Researchers investigated the effects of hypothalamic-pituitary-adrenal axis (HPA) hormones on S. mansoni, including DHEA. Cercariae are more affected than schistosomula and adults, with 100% dead after 48 h of culture, showing a concentration- and time-dependence.
Interestingly, males and paired worms are more resistant to the harmful effects of DHEA than females and separated worms. This fact suggests a beneficial effect of the relationship between female and male worms [59]. T. crassiceps is negatively affected by DHEA treatment with lower reproduction, motility, and viability [60].
17β-estradiol (E2), progesterone (P4), testosterone (T4), and dihydrotestosterone (DHT) also modulate the parasite physiology. Estrogens stimulated the reproduction and viability of T. crassiceps, with E2 being more effective than P4. These hormones are also involved in a high expression of genes c-fos and c-jun of the parasite, correlated to differentiation, reproduction, and apoptosis, showing a relative impact on viability changes. Since this parasite expressed estrogen and androgen receptors (excluding P4), sex steroids can bind these specific receptors and directly affect reproduction [61]. E2 and P4 also increase the expression of actin, tubulin, and myosin, major components of flame cells of the excretory system, benefiting the growth of T. crassiceps [62]. Progesterone also affects the development of T. solium by promoting evagination, maintaining motility, and inducing growth of the worms by two times [63].
In contrast to the positive effects of estrogens, T4 and DHT have deleterious actions, inhibiting the reproduction and reducing the viability of parasites. Additionally, they reduce the expression of c-fos and c-jun, explaining the changes in reproduction and growth of T. crassiceps. This data also agrees that cysticerci grow better in female and castrated males, proposing that the differences in sex steroids’ concentrations in males and females are involved [61]. Moreover, T4 and DHT reduce the viability of the parasite by almost 90%, disrupting tegument and changing the structure of flame cells, with direct interaction with actin, tubulin, and myosin, without changes in their expression. This interaction results in the intoxication of the parasite, which explains the significant reduction in viability [64].
These findings improve the critical role of host sex hormones on the host-parasite relationship. Those sex hormones can determine the course of infection by direct effects like modulation in growth, reproduction, and viability or indirect effects such as changes in gene expression and immune system of the host, which sometimes benefit the host and other, permitting the parasite to exploit the microenvironment (Figure 4). The knowledge that estrogens and progesterone are related to positive effects on parasites and androgens protecting the host can urge the investigation of the beneficial use of sex steroids as new therapeutic targets to the parasitic infections. It is currently known that taximofen, an antiestrogen, and RU486, a progesterone antagonist, can negatively affect the reproduction and growth of T. crassiceps and T. solium, respectively [50, 63]. In this way, more discovery of the crosstalk between parasites and sex hormones can change the scenario about antiparasitic drugs, permitting a faster development process with high efficacy and low toxicity [65].
Figure 4.
Effects of sex steroids in parasites S. mansoni, T. crassiceps, and T. solium. Estrogens like E2 and P4 have positive effects on parasites and also modulate the immune response to the Th2 pattern. In contrast, testosterone, dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA) decrease parasite growth and reproduction and increase Th1 cytokines, which protect the host.
Figure 4 summarizes the effect of host hormones in the platyhelminths.
4. Conclusions and perspectives
We have reviewed some host molecules and their effects on the parasite. It is interesting to note how many distinct molecules produced along with the immune response (cytokines, pro or anti-inflammatory) or regularly produced by the endocrine system (such as sexual hormones) may interfere with parasites’ development and fecundity. The study of molecular targets of this signaling is relevant to understanding how the evolution prepares the parasite’s genome to respond and adapt to different signals from the environment and the hosts.
These biological models are exciting for system biology sciences and drug and vaccines discoveries; however, for a better understanding, functional genomic approaches must be improved to be applied in platyhelminths models to clarify the contribution of the signaling elements in the transduction and regulation of parasites’ biological process.
As technologies have been developed and adapted, much information will be obtained from these particularly complex and challenging biological models. As information increases, new solutions for combating parasitic diseases will be elaborated and applied.
\n',keywords:"platyhelminths, signaling pathways, molecular crosstalk, cytokines, hormones",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81384.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81384.xml",downloadPdfUrl:"/chapter/pdf-download/81384",previewPdfUrl:"/chapter/pdf-preview/81384",totalDownloads:23,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 19th 2021",dateReviewed:"February 17th 2022",datePrePublished:"April 21st 2022",datePublished:null,dateFinished:"April 19th 2022",readingETA:"0",abstract:"Parasitic infection is an intimate relationship between host and parasite with exchange of signal and complex signaling systems involved in these organisms’ molecular crosstalk. With the advances of knowledge due to the genomic and transcriptomic projects in the last two decades, several genes and the molecular mechanism involved in the biological function of platyhelminths have been described. Cytokines, hormones, and other molecules from the host have influenced the growth, development, and reproduction of platyhelminths. We are going to review the effects of host cytokines (IL-1, IL-4, IL-12, IL-7, TGF-β, TNF-α) and hormones (T4, estrogen, progesterone, and androgens) that directly or indirectly affect parasites’ development and reproduction, and the possible associated signaling pathway. These are excellent models for system biology studies, and the generated knowledge may be helpful in the development of new strategies to combat these helminthiases.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81384",risUrl:"/chapter/ris/81384",signatures:"Ednilson Hilário Lopes-Junior, Rafaella Pontes Marques, Claudio Romero Bertevello and Katia Cristina Oliveira",book:{id:"11380",type:"book",title:"Parasitic Helminths and Zoonoses - From Basic to Applied Research",subtitle:null,fullTitle:"Parasitic Helminths and Zoonoses - From Basic to Applied Research",slug:null,publishedDate:null,bookSignature:"Prof. Jorge Morales-Montor, Dr. Víctor Hugo Del Río-Araiza and Dr. Romel Hernández Bello",coverURL:"https://cdn.intechopen.com/books/images_new/11380.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-568-3",printIsbn:"978-1-80355-567-6",pdfIsbn:"978-1-80355-569-0",isAvailableForWebshopOrdering:!0,editors:[{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Host cytokines’ effects on platyhelminths",level:"1"},{id:"sec_2_2",title:"2.1 Interleukins (12, 2, 7, 4, and 1)",level:"2"},{id:"sec_3_2",title:"2.2 Transforming growth factor-β (TGF-β)",level:"2"},{id:"sec_4_2",title:"2.3 The example of human Tumor Necrosis Factor-α (TNF- α) on S. mansoni",level:"2"},{id:"sec_6",title:"3. Host hormones influences in metabolism, development, and viability of platyhelminths",level:"1"},{id:"sec_7",title:"4. Conclusions and perspectives",level:"1"}],chapterReferences:[{id:"B1",body:'Human genome at ten: The sequence explosion. Nature. 2010;464:670-671. DOI: 10.1038/464670a'},{id:"B2",body:'Howe KL, Bolt BJ, Shafie M, Kersey P, Berriman M. WormBase ParaSite—A comprehensive resource for helminth genomics. Molecular and Biochemical Parasitology. 2017;215:2-10'},{id:"B3",body:'Tsai IJ, Zarowiecki M, Holroyd N, Garciarrubio A, Sanchez-Flores A, Brooks KL, et al. 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Transcriptome profiling of lung schistosomula, in vitro cultured schistosomula and adult Schistosoma japonicum. Cellular and Molecular Life Sciences. 2006;63:919-929'},{id:"B9",body:'Anderson L, Amaral MS, Beckedorff F, Silva LF, Dazzani B, Oliveira KC, et al. Schistosoma mansoni egg, adult male and female comparative gene expression analysis and identification of novel genes by RNA-Seq. PLoS Neglected Tropical Diseases. 2015;9:e0004334'},{id:"B10",body:'Lu Z, Sessler F, Holroyd N, Hahnel S, et al. Schistosome sex matters: A deep view into gonad-specific and pairing-dependent transcriptomes reveals a complex gender interplay. Scientific Reports. 2016;6:31150. DOI: 10.1038/srep31150'},{id:"B11",body:'Li WH, Yang Y, Zhang NZ, Wang JK, Liu YJ, Li L, et al. Comparative transcriptome analyses of the developmental stages of Taenia multiceps. Frontiers in Veterinary Science Frontiers Media SA. 2021;8:707'},{id:"B12",body:'Wu X, Fu Y, Yang D, Zhang R, Zheng W, Nie H, et al. Detailed transcriptome description of the neglected Cestode Taenia multiceps. PLoS One. 2012;7:e45830'},{id:"B13",body:'Osman A, Niles EG, Verjovski-Almeida S, LoVerde PT. Schistosoma mansoni TGF-β receptor II: Role in host ligand-induced regulation of a schistosome target gene. PLoS Pathogens. 2006;2:0536-0550'},{id:"B14",body:'Avelar LGA, Nahum LA, Andrade LF, Oliveira G. Functional diversity of the Schistosoma mansoni tyrosine kinases. Journal of Signal Transduction. 2011;2011:1-11'},{id:"B15",body:'Zhang C, Li J, Aji T, Li L, Bi X, Yang N, et al. Identification of functional MKK3/6 and MEK1/2 homologs from Echinococcus granulosus and investigation of Protoscolecidal activity of mitogen-activated protein kinase signaling pathway inhibitors In vitro and In vivo. Antimicrobial Agents and Chemotherapy. 2019;63:e01043-e01018'},{id:"B16",body:'Yang M, Li J, Wu J, Wang H, Guo B, Wu C, et al. 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Parasites and Vectors. 2020;13:491'},{id:"B44",body:'Oliveira KC, Carvalho MLP, Bonatto JMC, Schechtman D, Verjovski-Almeida S. Human TNF-α induces differential protein phosphorylation in Schistosoma mansoni adult male worms. Parasitology Research. 2016;115:817-828'},{id:"B45",body:'Lopes-Junior EH, Amaral MS, Kanamura CT, Pinto PLS, Krüger RF, Verjovski-Almeida S, et al. Human TNF-α affects the egg-laying dynamics and glucose metabolism of Schistosoma Mansoni adult worms in vitro. Parasites and Vectors. 2022;15:176'},{id:"B46",body:'Beckage NE. Host-parasite hormonal relationships: A common theme? Experimental Parasitology. 1991;72:332-338'},{id:"B47",body:'vom Steeg LG, Klein SL. Sex steroids mediate bidirectional interactions between hosts and microbes. Hormones and Behavior. 2017;88:45-51'},{id:"B48",body:'Escobedo G, Roberts CW, Carrero JC, Morales-Montor J. Parasite regulation by host hormones: An old mechanism of host exploitation? 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International Journal of Biological Sciences. 2011;7:1443-1456'},{id:"B57",body:'Fallon PG, Richardson EJ, Jones FM, Dunne DW. Dehydroepiandrosterone sulfate treatment of mice modulates infection with Schistosoma mansoni. Clinical and Diagnostic Laboratory Immunology. 1998;5:251-253'},{id:"B58",body:'Abebe F, Birkeland KI, Gaarder PI, Petros B, Gundersen SG. The relationships between dehydroepiandrosterone sulphate (DHEAS), the intensity of Schistosoma mansoni infection and parasite-specific antibody responses. APMIS. 2003;111:319-328'},{id:"B59",body:'Morales-Montor J, Mohamed F, Ghaleb AM, Baig S, Hallal-Callerost C, Damian RT. In vitro effects of hypothalamic-pituitary-adrenal axis (HPA) hormones on Schistosoma mansoni. The Journal of Parasitology. 2001;87:1132-1139'},{id:"B60",body:'Vargas-Villavicencio JA, Larralde C, Morales-Montor J. Treatment with dehydroepiandrosterone in vivo and in vitro inhibits reproduction, growth and viability of Taenia crassiceps metacestodes. 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Article ID 591079'},{id:"B64",body:'Ambrosio JR, Valverde-Islas L, Nava-Castro KE, Palacios-Arreola MI, Ostoa-Saloma P, Reynoso-Ducoing O, et al. Androgens exert a cysticidal effect upon Taenia crassiceps by disrupting flame cell morphology and function. PLoS One. 2015;10:e0127928'},{id:"B65",body:'Hernández-Bello R, Escobedo G, Guzmán C, Ibarra-Coronado EG, López-Griego L, Morales-Montor J. Immunoendocrine host–parasite interactions during helminth infections: From the basic knowledge to its possible therapeutic applications. Parasite Immunology. 2010;32:633-643'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Ednilson Hilário Lopes-Junior",address:null,affiliation:'
Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
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As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
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The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
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1,400 GBP Chapter - Edited Volume
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During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
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What isn't covered by the Open Access Publishing Fee?
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Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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The purpose of this chapter is to show the current panorama of the immunological mechanisms involved in the pathogenesis of periodontal disease.",book:{id:"8202",slug:"periodontal-disease-diagnostic-and-adjunctive-non-surgical-considerations",title:"Periodontal Disease",fullTitle:"Periodontal Disease - Diagnostic and Adjunctive Non-surgical Considerations"},signatures:"José Luis Muñoz-Carrillo, Viridiana Elizabeth Hernández-Reyes, Oscar Eduardo García-Huerta, Francisca Chávez-Ruvalcaba, María Isabel Chávez-Ruvalcaba, Karla Mariana Chávez-Ruvalcaba and Lizbeth Díaz-Alfaro",authors:null},{id:"65145",title:"Treatment of Gingival Enlargement",slug:"treatment-of-gingival-enlargement",totalDownloads:2034,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Gingival enlargement or overgrowth is a common disease of gingiva. The causative factors may range from inflammation due to local factors to conditioned enlargement and neoplastic enlargements. They commonly present as bulbous interdental gingival, diffuse swelling of gingival. Due to the unaesthetic appearance of the overgrown gingiva, treatment becomes inevitable. This results in excision of overgrowth known as gingivectomy. The first gingivectomy procedure was explained by Robicsek in 1884 and later by Zentler (1918). Grant (1979) defined gingivectomy as excision of soft tissue wall of pathologic periodontal pocket. Gingivectomy procedures can be done by means of scalpel, laser, electrosurgery and chemosurgery. The ultimate result remains the same indifferent of the method used. However the amount of remaining keratinized gingival and esthetic appearance is of supreme importance.",book:{id:"7060",slug:"gingival-disease-a-professional-approach-for-treatment-and-prevention",title:"Gingival Disease",fullTitle:"Gingival Disease - A Professional Approach for Treatment and Prevention"},signatures:"Shruti Bhatnagar",authors:[{id:"270317",title:"Dr.",name:"Shruti",middleName:null,surname:"Bhatnagar",slug:"shruti-bhatnagar",fullName:"Shruti Bhatnagar"}]},{id:"61980",title:"Periodontal Diseases in Patients with Special Health Care Needs",slug:"periodontal-diseases-in-patients-with-special-health-care-needs",totalDownloads:1293,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"A wide variation of people with an impairment or disability requires a “special care dentistry” once their general manifestations directly act in the oral cavity. This target public is inserted into the following categories: neuromotor disability, sensory disability, mental disorder, infecto-contagious diseases, chronic systemic diseases, and systemic conditions. Among the several oral illnesses found in these groups, periodontal diseases have been the most frequent, becoming a major challenge for the dental practitioners. Thus, we described the microbiological, histopathological, and clinical features of periodontal diseases in each “special health care needs” group. Advances in “Omic” technologies have suggested the application of molecular biology methods to assess the genomics (genes), proteomics (proteins), transcriptomics (mRNA), and metabolomics (metabolites) aspects of periodontal diseases. These researches aim to promote a better understanding of the mechanisms involved in the pathogenesis and in the identification of new biomarkers of periodontal diseases that help in diagnosis of periodontal diseases and in tissue responses after treatments of gingivitis and periodontitis. As an alternative therapy, some bioactive materials and photobiomodulation may be indicated once they strongly stimulate the periodontal tissue regeneration, attenuate the inflammatory processes, and/or promote the reconstruction of the microstructure of the periodontium.",book:{id:"7244",slug:"periodontology-and-dental-implantology",title:"Periodontology and Dental Implantology",fullTitle:"Periodontology and Dental Implantology"},signatures:"Mônica Fernandes Gomes, Andrea Carvalho De Marco, Lilian Chrystiane Giannasi and Miguel Angel Castillo Salgado",authors:[{id:"205710",title:"Associate Prof.",name:"Mônica",middleName:"Fernandes",surname:"Gomes",slug:"monica-gomes",fullName:"Mônica Gomes"},{id:"243846",title:"Dr.",name:"Andrea",middleName:null,surname:"Carvalho De Marco",slug:"andrea-carvalho-de-marco",fullName:"Andrea Carvalho De Marco"},{id:"243847",title:"Dr.",name:"Miguel Angel",middleName:null,surname:"Castillo Salgado",slug:"miguel-angel-castillo-salgado",fullName:"Miguel Angel Castillo Salgado"},{id:"243848",title:"Dr.",name:"Lilian Chrystiane",middleName:null,surname:"Giannasi",slug:"lilian-chrystiane-giannasi",fullName:"Lilian Chrystiane Giannasi"}]},{id:"20291",title:"Gingival Indices: State of Art",slug:"gingival-indices-state-of-art",totalDownloads:41984,totalCrossrefCites:9,totalDimensionsCites:23,abstract:null,book:{id:"352",slug:"gingival-diseases-their-aetiology-prevention-and-treatment",title:"Gingival Diseases",fullTitle:"Gingival Diseases - 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Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",slug:"current-topics-in-neglected-tropical-diseases",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Alfonso J. 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He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. 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Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. 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She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334239",title:"Prof.",name:"Leung",middleName:null,surname:"Wai Keung",slug:"leung-wai-keung",fullName:"Leung Wai Keung",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Hong Kong",country:{name:"China"}}}]}},subseries:{item:{id:"20",type:"subseries",title:"Animal Nutrition",keywords:"Sustainable Animal Diets, Carbon Footprint, Meta Analyses",scope:"An essential part of animal production is nutrition. Animals need to receive a properly balanced diet. One of the new challenges we are now faced with is sustainable animal diets (STAND) that involve the 3 P’s (People, Planet, and Profitability). We must develop animal feed that does not compete with human food, use antibiotics, and explore new growth promoters options, such as plant extracts or compounds that promote feed efficiency (e.g., monensin, oils, enzymes, probiotics). These new feed options must also be environmentally friendly, reducing the Carbon footprint, CH4, N, and P emissions to the environment, with an adequate formulation of nutrients.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11416,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. He teaches various degree courses in zootechnics, sheep production, and agricultural sciences and natural resources.\n\nDr. Ronquillo’s research focuses on the evaluation of sustainable animal diets (StAnD), using native resources of the region, decreasing carbon footprint, and applying meta-analysis and mathematical models for a better understanding of animal production.",institutionString:null,institution:{name:"Universidad Autónoma del Estado de México",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"175762",title:"Dr.",name:"Alfredo J.",middleName:null,surname:"Escribano",slug:"alfredo-j.-escribano",fullName:"Alfredo J. 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In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/121901",hash:"",query:{},params:{id:"121901"},fullPath:"/profiles/121901",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()