\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"327",leadTitle:null,fullTitle:"Ionic Liquids - Classes and Properties",title:"Ionic Liquids",subtitle:"Classes and Properties",reviewType:"peer-reviewed",abstract:"Room temperature ionic liquids (RTILs) are an interesting and valuable family of compounds. Although they are all salts, their components can vary considerably, including imidazolium, pyridinium, ammonium, phosphonium, thiazolium, and triazolium cations. In general, these cations have been combined with weakly coordinating anions. Common examples include tetrafluoroborate, hexafluorophosphate, triflate, triflimide, and dicyanimide. The list of possible anionic components continues to grow at a rapid rate. Besides exploring new anionic and cation components, another active and important area of research is the determinination and prediction of their physical properties, particularly since their unusual and tunable properties are so often mentioned as being one of the key advantages of RTILs over conventional solvents. 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Beckett",authors:[{id:"78238",title:"Prof.",name:"Kabwe",middleName:null,surname:"Nkongolo",fullName:"Kabwe Nkongolo",slug:"kabwe-nkongolo"},{id:"79019",title:"Dr.",name:"Melanie",middleName:null,surname:"Mehes-Smith",fullName:"Melanie Mehes-Smith",slug:"melanie-mehes-smith"},{id:"79022",title:"MSc",name:"Ramya",middleName:null,surname:"Narendrula",fullName:"Ramya Narendrula",slug:"ramya-narendrula"}]},{id:"30819",title:"Moving from Ecological Conservation to Restoration: An Example from Central Taiwan, Asia",slug:"moving-from-ecological-conservation-to-restoration-an-example-from-central-taiwan-asia",signatures:"Yueh-Hsin Lo, Yi-Ching Lin, Juan A. Blanco, Chih-Wei Yu and Biing T. Guan",authors:[{id:"51995",title:"Dr.",name:"Juan",middleName:"A.",surname:"Blanco",fullName:"Juan Blanco",slug:"juan-blanco"},{id:"61070",title:"Dr.",name:"Yueh-Hsin",middleName:null,surname:"Lo",fullName:"Yueh-Hsin Lo",slug:"yueh-hsin-lo"},{id:"121412",title:"Prof.",name:"Biing T.",middleName:null,surname:"Guan",fullName:"Biing T. Guan",slug:"biing-t.-guan"},{id:"121413",title:"Dr.",name:"Yi-Ching",middleName:null,surname:"Li",fullName:"Yi-Ching Li",slug:"yi-ching-li"},{id:"121903",title:"MSc.",name:"Chih-Wei",middleName:null,surname:"Yu",fullName:"Chih-Wei Yu",slug:"chih-wei-yu"}]},{id:"30820",title:"Restoration of Forest Ecosystems on Disturbed Lands on the Northern Forest Distribution Border (North-East of European Russia)",slug:"restoration-of-forest-ecosystems-on-disturbed-lands-on-the-northern-forest-distribution-border-north",signatures:"Irina Likhanova and Inna Archegova",authors:[{id:"89124",title:"Dr.",name:"Irina",middleName:null,surname:"Likhanova",fullName:"Irina Likhanova",slug:"irina-likhanova"},{id:"89138",title:"Dr.",name:"Inna",middleName:null,surname:"Archegova",fullName:"Inna Archegova",slug:"inna-archegova"}]},{id:"30821",title:"Close to Nature Management in High-Mountain Forests of Norway Spruce Vegetation Zone in Slovakia",slug:"close-to-nature-management-in-high-mountain-forests-of-norway-spruce-vegetation-zone-in-slovakia",signatures:"Martin Moravčík, Zuzana Sarvašová, Ján Merganič and Miroslav Kovalčík",authors:[{id:"88181",title:"Dr.",name:"Zuzana",middleName:null,surname:"Sarvasova",fullName:"Zuzana Sarvasova",slug:"zuzana-sarvasova"},{id:"88226",title:"Dr.",name:"Martin",middleName:null,surname:"Moravčík",fullName:"Martin Moravčík",slug:"martin-moravcik"},{id:"126678",title:"Dr.",name:"Miroslav",middleName:null,surname:"Kovalčík",fullName:"Miroslav Kovalčík",slug:"miroslav-kovalcik"},{id:"126681",title:"Dr.",name:"Ján",middleName:null,surname:"Merganič",fullName:"Ján Merganič",slug:"jan-merganic"}]},{id:"30822",title:"Interactions of Forest Road, Forest Harvesting and Forest Ecosystems",slug:"interactions-of-forest-road-forest-harvesting-and-forest-ecosystems",signatures:"Murat Demir",authors:[{id:"80947",title:"Dr.",name:"Murat",middleName:null,surname:"Demir",fullName:"Murat Demir",slug:"murat-demir"}]},{id:"30823",title:"Forest Transportation Systems as a Key Factor in Quality Management of Forest Ecosystems",slug:"forest-transportation-systems-as-a-key-factor-in-quality-management-of-forest-ecosystems",signatures:"Tibor Pentek and Tomislav Poršinsky",authors:[{id:"83078",title:"Prof.",name:"Tibor",middleName:null,surname:"Pentek",fullName:"Tibor Pentek",slug:"tibor-pentek"},{id:"88732",title:"Prof.",name:"Tomislav",middleName:null,surname:"Poršinsky",fullName:"Tomislav Poršinsky",slug:"tomislav-porsinsky"}]}]}],publishedBooks:[{type:"book",id:"616",title:"Forest Ecosystems",subtitle:"More than Just Trees",isOpenForSubmission:!1,hash:"00ecaa84de1aa2d7116ab5871b353b82",slug:"forest-ecosystems-more-than-just-trees",bookSignature:"Juan A. Blanco and Yueh-Hsin Lo",coverURL:"https://cdn.intechopen.com/books/images_new/616.jpg",editedByType:"Edited by",editors:[{id:"51995",title:"Dr.",name:"Juan",surname:"Blanco",slug:"juan-blanco",fullName:"Juan Blanco"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"617",title:"Sustainable Forest Management",subtitle:"Current Research",isOpenForSubmission:!1,hash:"a8d91cf4745e90f7510e056fd508dc46",slug:"sustainable-forest-management-current-research",bookSignature:"Jorge Martin Garcia and Julio Javier Diez Casero",coverURL:"https://cdn.intechopen.com/books/images_new/617.jpg",editedByType:"Edited by",editors:[{id:"88987",title:"Dr.",name:"Julio J.",surname:"Diez",slug:"julio-j.-diez",fullName:"Julio J. Diez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2073",title:"Sustainable Forest Management",subtitle:"Case Studies",isOpenForSubmission:!1,hash:"656069330afd66b7a27ca8963a544092",slug:"sustainable-forest-management-case-studies",bookSignature:"Jorge Martin-Garcia and Julio Javier Diez",coverURL:"https://cdn.intechopen.com/books/images_new/2073.jpg",editedByType:"Edited by",editors:[{id:"88987",title:"Dr.",name:"Julio J.",surname:"Diez",slug:"julio-j.-diez",fullName:"Julio J. Diez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4757",title:"Precious Forests",subtitle:"Precious Earth",isOpenForSubmission:!1,hash:"6bd8329fb8128da2fc08c1c6d8a22613",slug:"precious-forests-precious-earth",bookSignature:"Miodrag Zlatic",coverURL:"https://cdn.intechopen.com/books/images_new/4757.jpg",editedByType:"Edited by",editors:[{id:"174414",title:"Dr.",name:"Miodrag",surname:"Zlatic",slug:"miodrag-zlatic",fullName:"Miodrag Zlatic"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5455",title:"Global Exposition of Wildlife Management",subtitle:null,isOpenForSubmission:!1,hash:"0c60fd890b4af7771afc5211fdabe762",slug:"global-exposition-of-wildlife-management",bookSignature:"Gbolagade Stephen A. Lameed",coverURL:"https://cdn.intechopen.com/books/images_new/5455.jpg",editedByType:"Edited by",editors:[{id:"142349",title:"Dr.",name:"Lameed",surname:"Gbolagade Akeem",slug:"lameed-gbolagade-akeem",fullName:"Lameed Gbolagade Akeem"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],publishedBooksByAuthor:[]},onlineFirst:{chapter:{type:"chapter",id:"79573",title:"Immunotherapy against Gliomas",doi:"10.5772/intechopen.101386",slug:"immunotherapy-against-gliomas",body:'Primary malignant brain tumors remain one of the most lethal and clinically challenging of all cancers. Despite comprising only an estimated 1.3% of all new cancer cases, brain tumors represent one of the highest causes of cancer mortality with 18,600 (3.1%) deaths predicted in 2021 [1]. Glioblastoma (GBM) is one of the most common and aggressive of the primary malignant adult brain tumors with a median survival of less than 21 months despite standard of care which includes surgical resection, targeted radiation therapy, high-dose chemotherapy, and tumor-treating fields [2, 3, 4, 5, 6, 7, 8].
Cancer immunotherapies have emerged as new therapeutic mainstays in a variety of cancers [9, 10, 11, 12, 13, 14]. However, the unique characteristics of brain tumors pose extraordinary barriers that, thus far, have foiled efforts and the success of immunotherapeutic approaches. These characteristics include high tumor heterogeneity and relatively few coding mutations [15, 16], an immunosuppressive microenvironment [17, 18, 19, 20, 21, 22, 23], a relative lack of immune effector cell types [19, 24], and relative isolation from systemic circulation because of the blood-brain barrier [25, 26, 27, 28, 29]. This chapter will discuss some of the current immunotherapy types with emphasis on the prominent clinical trials for each and the limitations observed.
However, despite a lack of phase III trials demonstrating improved progression-free survival (PFS) and/or overall survival (OS) in many of these immunotherapies, incremental progress continues to be made in brain malignancies in both the clinical and preclinical settings. Novel immunotherapeutic strategies and combinations are currently being tested in the preclinical setting. This chapter will also discuss novel preclinical strategies to enhance immunotherapies, including modified chimeric antigen receptor (CAR) T cells, small molecular inhibitors that target immunologic pathways, and combinatorial checkpoint approaches.
Cancer vaccines involve exogenous administration of tumor antigens that can stimulate an adaptive immune system against tumor cells. The basic requirements for cancer vaccines include the delivery of tumor-specific antigens to antigen-presenting cells (APCs) such as dendritic cells (DCs), DC activation, activation of both T cell subsets and infiltration into the tumor microenvironment to exert durable responses [30]. Vaccine strategies have been employed against primary brain tumor targets using a variety of antigen substrates, including peptides, full-length proteins, RNA, and DNA in various formulations including antigens alone, antigens in combination with various local or systemic adjuvants, or dendritic cell vaccines. Though vaccination strategies have demonstrated a survival benefit in early phase clinical trials, there have yet to be any phase III clinical trials in patients with GBM demonstrating survival benefit. However, vaccination strategies continue to hold great promise with the rationale and hope that they would stimulate effective tumor-specific immunity, target tumor cells but not normal brain, and provide immunological memory against tumor recurrence [31].
Multiple single peptide vaccines have been generated to target a variety of tumor antigens including mutated isocitrate dehydrogenase 1 (IDH-R132H), survivin, Wilms Tumor 1 (WT1), and epidermal growth factor receptor variant III (EGFRvIII). Peptide vaccinations are highly specific and provide the benefit of reduced off-target effects, preventing autoimmune toxicities.
Mutated IDH1 defines a molecular subtype of diffuse glioma. A phase I trial of an IDH1(R132H)-specific peptide vaccine was conducted in 33 patients with newly diagnosed WHO grade 3 and 4 astrocytomas [32]. This study met its primary safety endpoint and demonstrated a three-year progression-free rate of 63% and a three-year death-free rate of 84% [33]. This study assessed intratumoral inflammatory reactions associated with the use of vaccines by the presence of pseudoprogression. Intriguingly, this study found high frequencies of pseudoprogression, 37.5% in the treatment group compared to 16.7% in a molecularly matched control cohort, indicating intratumoral inflammatory reactions. In one patient with pseudoprogression, the analysis found that a cluster of T cells was dominated by a single IDH1(R132H)-reactive T cell receptor.
Survivin is an anti-apoptotic protein expressed in malignant gliomas. One early phase study assessed the survivin peptide vaccine in nine patients with survivin-positive malignant gliomas and found it to be safe and tolerable [34]. The treatment group had a median PFS of 17.6 weeks and a median OS of 86.6 weeks compared to an analysis of phase II chemotherapy trials of patients with recurrent glioma with a PFS of 10 weeks and OS of 30 weeks [35]. A phase II trial was initiated with the survivin peptide vaccine in 63 participants with newly diagnosed glioblastoma [36]. In 2020, a trial update found 96.8% of patients did not experience disease progression within 6 months with a 93.5% survival rate a year after diagnosis [37]. This is an ongoing study.
Wilms Tumor 1 (WT1) is a pleiotropic transcription factor with functional roles in GBM that range from driving cellular proliferation [38] to inhibiting apoptosis [38, 39]. An uncontrolled nonrandomized phase II trial of WT1 peptide vaccination for patients with recurrent WT1-positive GBM was conducted with 21 patients. This study demonstrated that the vaccination was safe and produced a clinical response with a median PFS period of 20.0 weeks, median overall survival after initial vaccination of 36.7 weeks, and a 6 month PFS of 33.3% [40]. The median PFS and median OS found in this study were said to be comparable to various combination regimens of chemotherapy and/or radiotherapy.
Epidermal growth factor receptor (EGFR) amplification is enriched in the classical subset of GBM and is seen in 57.4% of primary GBM patients [41, 42]. Epidermal growth factor receptor variant III (EGFRvIII) regulates EGFR activity by inducing the expression of EGFR ligands [43]. A phase II trial assessed the immunogenicity of an EGFRvIII-targeted peptide vaccine [44]. The 6-month PFS after vaccination was 67% (versus 59% in the historical cohort) with a median overall survival of 26.0 months (versus 15.0 months in the matched control group) [45]. However, no benefit was observed in a randomized phase III trial [46]. Further analysis found significant loss of EGFRvIII expression in a subset of patients with tumor tissue available at recurrence in both those that received the vaccine and in those receiving standard-of-care chemoradiation [47].
To date, single peptide vaccines have yet to lead to clinical benefit in phase III trials in brain cancers. The EGFRvIII work hints that the selection of a single molecular target as a peptide vaccine might be inadequate to overcome the considerable challenges of tumor antigen down-regulation and tumor heterogeneity. Thus, targeting multiple targets could lead to robust durable responses. Thus, studies investigating multi-peptide vaccines, with several tumor antigen targets, have now been initiated.
To identify multiple tumor-associated peptides for immunotherapy, a study set out to assess the potential of using HLA-associated tumor peptidomes as a source of tumor-associated antigens to be used in immunotherapy [48]. The components found gave rise to the multipeptide vaccine IMA950. A phase I/II set out to assess IMA950 and its 11 tumor-associated peptides which include brevican (BCAN); chondroitin sulfate proteoglycan 4 (CSPG4); fatty acid-binding protein 7, brain (FABP7); insulin-like growth factor 2 messenger mRNA-binding protein 3 (IGF2BP3), neuroligin 4, X-linked (NLGN4X); neuronal cell adhesion molecule (NRCAM), protein tyrosine phosphatase, receptor-type, z polypeptide 1 (PTPRZ1); tenascin C (TNC); Met proto-oncogene (MET); baculoviral IAP repeat-containing 5 (BIRC5); and hepatitis B virus core antigen [48]. In this study, IMA950 was adjuvanted with poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose) [49]. The multi-peptide vaccine was used in 19 patients, 16 with GBM and 3 with grade III astrocytoma. Results showed a median overall survival of 19 and 17 months for the whole cohort and GBM patients-only, respectively, with a PFS of 68% at 6 months for the whole cohort and 69% for GBM patients only when calculated from the study entry [50]. There was no mention of a historical control group used as a comparator in this study. Due to the findings in this study, a follow-up trial is actively recruiting patients with recurrent GBM to test IMA950/poly-ICLC alone or in combination with pembrolizumab, a checkpoint inhibitor that will be discussed later [51].
Another multi-peptide vaccine was generated based on observations of three tumor-associated antigens that were observed to be highly expressed in pediatric gliomas. This vaccine targets the peptide epitopes of EPH receptor A2 (EphA2; a tyrosine kinase), interleukin-13 receptor alpha 2 (IL-13Rα2), and survivin. This study was conducted in 26 pediatric patients with diffuse brainstem gliomas (BSG) or high-grade gliomas (HGG) [52]. Results showed a median survival of 13.3 months from diagnosis in the overall cohort with a median survival of 12.7 months in the BSG group and a median survival of 25.1 months in the HGG group. Though no historical control group was discussed in this phase I study, the authors mentioned that for children with BSGs, current therapies at the time failed to increase median overall survival beyond 9–12 months [53].
Though these studies are showing promising results, the lack of clear indication of efficacy and eventual tumor progression in these phase I-III trials may be attributed to the multiple obstacles in place by brain cancers including the high degree of heterogeneity of antigenic expression, an outgrowth of subclones not expressing the antigens, lack of major histocompatibility complex molecules and/or an immunosuppressive tumor microenvironment.
The aforementioned peptide cancer vaccines require uptake and activation of endogenous antigen-presenting cells (APCs) such as DCs. These DCs then present antigens to tumor-specific T cells leading to T cell activation. To circumvent the reliance of endogenous DC antigen loading and activation, some studies utilize DC vaccines and load DCs
A phase I trial of the DC vaccine DCVax-L was completed which loads autologous DCs with tumor lysate from newly diagnosed or recurrent GBM participants [54]. In this trial that enrolled 23 patients, the 1-year survival rate was 91% with a median OS of 31.4 months from the time of initial surgical diagnosis. The authors compared this median OS to the median OS of 18.6 months found in a large study of GBM patients who underwent tumor resection and chemoradiotherapy [55]. However, the study noted that it was unclear whether the extended survival of participants is a direct result of the vaccine effects or good responses to follow-up therapies after failing the vaccine [56]. DCVax-L has since gone on to a large phase III clinical trial with 331 participants with the primary endpoint of PFS and the secondary endpoint of OS [57]. Preliminary results of the study reveal a median OS of 23.1 months from surgery in the overall intention-to-treat population (ITT) and 34.7 months from surgery in patients with a methylated O6-methylguanine-DNA-methyltransferase (MGMT) gene promoter. The authors compared the median OS in the ITT population to a median OS of 15–17 months from surgical intervention typically achieved with a standard of care in past studies. The PFS was not evaluated in this interim analysis. In this blinded interim survival analysis, the authors found that patients were living longer than expected and that this warrants further follow-up and analyses [58].
ICT-107 is another DC vaccine loaded with synthetic tumor-associated peptides of antigens commonly overexpressed in CD133-positive cancer stem cells that includes Erbb2 (HER2), second tyrosinase-related protein (TRP-2), glycoprotein 100 (gp100), melanoma-associated antigen 1 (MAGE-1), IL-13Rα2, and absent in melanoma 2 (AIM-2). In a phase I trial of 21 participants who were HLA-A1 or HLA-A2-positive and with newly diagnosed GBM (n = 17), recurrent GBM (n = 3), or with a brain stem glioma (n = 1), the median PFS was 16.9 months with a median OS of 38.4 months. These results suggest a correlation with prolonged OS and PFS though no comparator group or historic controls were mentioned [59]. The same group then conducted a phase II randomized, double-blind, placebo-controlled study using ICT-107 in 124 participants with newly diagnosed GBM following resection and radiotherapy with concomitant temozolomide [60]. The primary endpoint of median OS was not increased but a significant increase in the PFS by 2.2 months was observed in the intent-to-treat population treated with ICT-07 (11.2 months versus 9 months) [61]. A phase III trial was halted due to insufficient financial resources [62].
Another pair of studies made use of the immunodominant cytomegalovirus (CMV) antigen phosphoprotein 65 (pp65) in their DC vaccines. This antigen is expressed in GBM but not in normal brains [63]. The first was a randomized blinded phase I clinical trial in 12 patients with newly diagnosed GBM who received pre-conditioning in the form of tetanus/diptheria toxoid (a potent recall antigen) or unpulsed mature DCs before bilateral vaccinations with DCs pulsed with CMV pp65 RNA [64]. Td pre-conditioning led to a significant increase in both median PFS and median OS compared to the DC alone cohort which had a median PFS and OS of 10.8 and 18.5 months (consistent with patients treated with standard of care) [65]. A later study from the same group evaluated DCs pulsed with CMV pp65 RNA along with dose-intensified temozolomide (TMZ) and adjuvant GM-CSF [64]. Here they observed a median PFS of 25.3 months and a median OS of 41.1 months in the treatment group compared to 8.0 months and 19.2 months in historical controls, respectively [66]. A phase II randomized, blinded, placebo-controlled trial of DCs pulsed with CMV pp65 and Td is underway with a target of 120 patients [67]. Another phase II trial utilizing DCs pulsed with CMV pp65 was recently completed with results pending which is assessing whether basiliximab, a monoclonal anti-CD25 antibody, may inhibit the functional and quantitative recovery of T-regulatory cells after TMZ-induced lymphopenia in newly diagnosed GBM [68].
The potential for DC vaccines is vast in their ability to generate antitumor immunity however, to date, they have provided suboptimal and overall unsatisfactory clinical benefits in large trials. Work now includes methods to improve
The principal breakthrough in cancer treatment over the last 15 years is the introduction of immune checkpoint inhibitors (ICIs) blocking the immune checkpoints programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic lymphocyte antigen 4 (CTLA-4). Immune checkpoints are negative regulators of T-cell immune function and are central for the modulation of physiological immune responses and the maintenance of self-tolerance. T cells are created in the thymus where they undergo positive and negative selection and undergo apoptosis if they fail to recognize self-MHC or bind too strongly to MHC with self-peptides. This process is called central tolerance [72]. T cells that appropriately respond to MHC molecules are then sent into the circulation where they eventually interact with APCs displaying mutated self-proteins (in cancers) or foreign antigens (in infection) [73]. However, central tolerance is sometimes incomplete and some T cells escape and become autoreactive. To prevent autoreactivity, there are multiple inhibitory checkpoint pathways that regulate the activation of T cells at multiple levels during an immune process called peripheral tolerance [74].
Central to cancer immunotherapy is that tumor cells can take advantage of peripheral tolerance and hijack these checkpoint mechanisms, inhibiting T cells from attacking. The arrival of checkpoint inhibitors in 2011 introduced a new mechanism to treat cancer and revolutionized cancer management in a variety of solid tumors [75, 76, 77, 78]. There are now several FDA-approved monoclonal antibodies against solid tumors including ipilimumab targeting CTLA-4, pembrolizumab, and nivolumab targeting PD-1, and atezolizumab and durvalumab targeting PD-L1. However, despite numerous articles describing preclinical efficacy of checkpoints in central nervous system (CNS) tumors, activity against brain metastases from melanoma and non-small-cell lung cancer [79, 80], and multiple studies describing increased PD-L1 expression in GBM [81, 82], no FDA approval has occurred for immune checkpoints in GBM. Here, we will discuss some of the phase III trials that have occurred with immune checkpoint inhibitors, what has been learned, and where the research is going.
One randomized phase III study assessed the effect of nivolumab versus bevacizumab (anti-vascular endothelial growth factor A) in 439 patients with recurrent glioblastoma [83]. The study found no statistical difference between the median OS of nivolumab monotherapy (9.8 months) and bevacizumab (10.0 months) [84]. Interestingly, this study observed that corticosteroid use at baseline seemed to be associated with worse outcomes in the nivolumab group. This may be due to the direct effects of corticosteroids on T cell function which may abrogate activation or priming of the immune system.
Additionally, a phase III study compared nivolumab versus temozolomide in newly diagnosed patients with unmethylated MGMT GBM [85]. In 2019, Bristol-Myers Squibb announced that the study did not meet its primary endpoint, which assessed overall survival [86].
Another randomized phase III single-blind study set out to compare TMZ plus radiation therapy combined with nivolumab or placebo in newly diagnosed patients with MGMT-methylated glioblastoma [87]. In 2019, Bristol-Myers Squibb provided an update that the nivolumab group did not meet one of its primary endpoints, progression-free survival, but that the data monitoring committee recommended continuing the trial to allow the other primary endpoint, overall survival, to mature [88]. The final results are pending.
It remains to be seen whether the lack of demonstrated efficacy of checkpoint therapeutic efficacy is due to difficulty getting to the tumor site or the tumor itself. Though it has been shown that T cells can traffick to the CNS, the relatively immune-privileged CNS may prove to be a limitation if checkpoint inhibition must enter into these tumors to be effective [20]. However, at least one study demonstrated clinically meaningful intracranial efficacy with ipilimumab combined with nivolumab in patients with melanoma with untreated brain metastasis, suggesting that immune checkpoint strategies can target tumors located intracranially [80]. Lack of effective checkpoint strategies in primary CNS tumors could be due to a variety of challenges that interplay with one another. First, glioblastomas generally are considered cold tumors, lacking intratumoral inflammatory cells though this is also considered to be heterogenous. Lack of efficacy could also be due to the relatively low mutational burden since it has been consistently shown that malignancies with a high burden of clonal neoantigens have a higher response rate to checkpoint inhibition [89]. Also, the high degree of heterogeneity found within gliomas, makes specific immunological targeting difficult. Lastly, the observed systemic T cell dysfunction and sequestration imposed by an intracranial tumor remain another domineering challenge as this singly does away with the requirement of a viable T cell compartment for immune checkpoints to act on [90].
Though multiple challenges must be overcome for immune checkpoint inhibitors to overcome glioblastoma specifically, a better understanding of treatment resistance in addition to many promising synergistic combinatorial approaches will provide important incremental advances to efficacy. Finally, as seen in other solid tumors, resistance to immune checkpoint blockade leads to upregulation of a host of alternative inhibitory immune checkpoint molecules that are currently also being targeted in ongoing clinical trials. These new inhibitory immune checkpoint targets potentially offer increased therapeutic targets to be used as single agents or in combination with other immunotherapies [91].
Immunotherapy can be considered active or passive. The difference between each centers on how they modulate the immune system. Active immunotherapy, such as the aforementioned vaccines, relies on the process of endogenous immune cells activation, producing a durable response and generation of immunological memory. Passive immunotherapy, however, produces an immediate response due to the administration of cytokines, antibodies, or immune cells. A form of passive immunotherapy is adoptive cellular therapy (ACT) which specifically allows for the
LAK cells were thought to be a promising candidate for adoptive cellular therapies due to their ease of generation (culturing peripheral blood lymphocytes in the presence of IL-2), rapid expansion, the long shelf life
Another phase I/II trial was initiated in 40 patients with GBM who had autologous LAK cells placed in the tumor cavity. Findings from this study showed a median survival from the original diagnosis of 17.5 months compared to 13.6 months in a contemporary age-matched group [94]. The same group conducted a phase II trial with LAK cell treatment in 33 GBM patients who had not experienced clinical or radiographic evidence of progressive disease during or shortly after completion of initial therapy which showed a median survival from diagnosis of 20.5 months with a 1-year survival of 75%. The authors stated that 20.5 months median survival is 88% longer than the 12-month survival associated with GBM and 33% longer than the 15-month median survival observed in the clinical trials that established the benefit of temozolomide therapy [95].
Overall, the use of LAK has since fallen out of favor [20, 96]. In phase III randomized trial of IL-2 with or without LAK in the treatment of patients with advanced renal cell carcinoma (RCC), the addition of LAK did not improve the response rate against RCC [97]. It is thought the efficacy of LAK cell ACT is due to the amplification of a subset of therapeutic cells found in the peripheral blood that are reactive against tumors [96]. Thus, the use of tumor-infiltrating lymphocytes (TILs; discussed later), which are more specific to the target tumor, might have better potential.
The NK cell ACT field is rapidly expanding in both biological understanding of NK cells, including their distinct immune checkpoints [98, 99] in addition to clinical development of NK cell ACT. These cytotoxic cells are part of the innate immune system and have many advantageous characteristics which include rapid
An early preliminary trial was conducted in nine patients with recurrent malignant gliomas using autologous NK cells injected into the tumor cavity, using a reservoir system, and intravenously. This study found that NK cell therapy was safe with some clinical benefit demonstrating three patients with partial response (50% decrease in tumor volume), two with a minor response (25% decrease in tumor volume), seven with progressive disease (increase of 25% in tumor volume), and four with no change [100].
Currently, there is at least three phase I trials in the process utilizing NK cells in high-grade gliomas [105, 106, 107].
As mentioned before, ACT allows for
As the name implies, tumor-infiltrating lymphocytes are thought to have undergone
A major recent advancement in adoptive cellular therapies has been the development of chimeric antigen receptors as a means for T cells to bypass MHC restriction, and dependence and have specificity for a cell surface antigen. CAR T cell therapy recently received approval targeting CD19 in B cell leukemia and lymphoma [114]. CAR T cells are genetically modified to express an extracellular single-chain variable fragment that specifically recognizes a tumor cell’s surface antigen. The extracellular binding fragment is bound to intracellular signaling domains and/or co-stimulatory domains that allow for T cell activation when the fragment is bound to its cognate antigen. CAR T cells have the advantage of recognizing target antigens independent of HLA and also disregarding tumor cell immunoevasion by MHC expression reduction.
A phase I safety study was conducted using autologous CAR T cells targeting EGFRvIII in 10 recurrent EGFRvIII+ GBM patients [115]. The median OS was 251 days (~8 months; PFS could not be calculated due to the confounding factor of neurosurgical intervention in most of the patients). No specific historical controls were mentioned though the authors stated that GBM patients with significant residual disease after surgery have an average survival that is around ~6 months. The group demonstrated that EGFRvIII specific CAR T cells were found in the brain tumor and exerted antigen-directed activity. They also found that most of the patients had decreased expression of EGFRvIII in tumors resected after CAR T therapy [116].
Another member of the family of EGFR-related receptor tyrosine kinase is HER2. HER2 is commonly overexpressed in high-grade gliomas [117, 118, 119, 120]. A phase I dose-escalation study was initiated to assess the safety and antitumor efficacy of autologous HER2-specific CAR T cells in 17 patients with progressive recurrent GBM [121]. This study found that though HER2-specific CAR T cells did not expand, they were detected in peripheral blood for up to 12 months. They found that eight patients had clinical benefit from either partial response or stable disease. The median OS was 11.1 months from the first CAR T cell infusion and 24.5 months from diagnosis with an 18-month OS of 29.4% [122]. As a comparator, this study mentions achieving similar outcomes as another study that used bevacizumab and lomustine where the median OS was 12 months with an 18-month OS of 20% [123].
Similar to the aforementioned peptide and DC vaccines, there are CAR T approaches targeting IL-13Rα2 due to its expression in a majority of adult and pediatric GBM tumors but not in normal brains [124, 125]. One group demonstrated that administration of IL-13Rα2-specific CAR T cells was feasible and showed evidence for transient anti-glioma responses in two out of three patients with recurrent GBM [126, 127]. The same group has initiated an ongoing phase I study utilizing IL-13Rα2-specific CAR T cell administration into the resected tumor cavity and the ventricular system in patients with recurrent or refractory malignant glioma [128]. A case report derived from this phase I study observed regression of all CNS tumors along with concomitant increases in cytokines and immune cells in the cerebrospinal fluid. Subsequent relapse was later found to be due to IL-13Rα2-negative tumors [129].
These studies demonstrate the barriers found in targeting single antigens in a highly heterogenous tumor. Newer approaches for enhanced CAR T therapy efficacy will require targeting multiple antigens, a combinatorial approach with other immunotherapies, or the development of CAR T cell designs that induce significant epitope spreading [20]. Aside from antigen target constructs, current work in CAR T therapy looks toward maximizing and maintaining the activity of the administered CAR T cells to overcome barriers in the solid tumor microenvironment [130]. As mentioned with cancer vaccines, the benefit will likely occur with the combination of CAR T therapy and immune checkpoint blockade. Another strategy is to express chemokine receptors in CAR T cells to improve their tumor-directed trafficking (discussed below) or, conversely, express blocking chemokines and receptors expressed by tumor cells to inhibit recruitment of inhibitory immune cells. Another strategy is disrupting the tumor vasculature with anti-VEGFR CAR T therapy. Strategies are also looking into the combination of depleting immune-inhibitory cells to then allow for CAR T therapies to maintain durable responses. Though CAR T therapy remains a promising therapy for GBM, further work is needed to lead to clinical benefit.
Glioma stem cells (GSCs) are a subpopulation of glioma cells with stem-like properties. These cells are thought to promote tumor initiation, chemo- and radio-resistance, and tumor invasiveness. GSCs were first defined by their expression of prominin 1 or CD133, however, it was later discovered that CD133-negative cells were also capable of causing tumor initiation. In addition, several different models of GSC initiation have been proposed.
Vora
An additional novel method of targeting GSCs is through the use of NK cells. These cells are cytotoxic lymphocytes capable of killing target tumor cells. GSCs have been shown to express activating ligands of NK cells, such as CD155 and B7-H6. In addition, NK cells were shown to be able to lyse GSCs
CAR T cells combine the single-chain variable fragment (scFV) of monoclonal antibodies with the internal component of the T cell receptor. There are three main generations of CAR T cells—first-generation CAR T cells include an scFV as well as CD3ζ endodomain. The second generation built upon this by adding a costimulatory molecule such as CD28 or 4-1-BB to promote expansion. Finally, third-generation CAR T cells consist of an scFV, CD3ζ, as well as two or more costimulatory molecules. CAR T cells, especially third-generation CAR T cells, have had great success in patients with B cell malignancies [133].
However, single-agent CAR T cells have had limited success in patients with CNS malignancies. This is likely due to several factors, including a high degree of heterogeneity in the tumor microenvironment (TME), loss of antigen during tumor progression, exhaustion of the CARs within the TME, and finally upregulation of immunosuppressive molecules that inhibit CAR T cell killing [134].
Bielamowicz
Several other modified CARs have shown increased efficacy relative to their first-generation counterparts. Krenciute
In the context of neuroblastoma, disialoganglioside (GD2) represents a promising tumor-associated target for CAR T cell therapy. GD2 has been shown to promote malignant phenotypes such as proliferation, migration, and invasion [137]. In a phase I clinical trial, GD2-specific CAR T cells were evaluated in neuroblastoma patients in combination with cyclophosphamide and fludarabine as well as the checkpoint inhibitor, anti-PD-1 [138]. Although the therapy was found to be safe, only modest anti-tumor responses were observed [139]. To improve upon the efficacy of these CAR T cells, Moghimi
Another promising CAR T cell target for brain tumors is CD70. In terms of normal immunology, CD70 is a co-stimulatory molecule expressed in activated immune cells. However, Jin
A huge limitation of CAR T cells is the eventual expression of exhaustion molecules, leading to a lack of anti-tumor efficacy. Weber
Myeloid-derived suppressor cells (MDSCs) have been shown to be expanded in the periphery of GBM patients [144]. MDSCs within the TME have been shown to contribute to tumor immunosuppression via the secretion of immunosuppressive molecules such as arginase 1 and inducible nitric oxide synthase (iNOS). Alban
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor shown to be upregulated in GBM and is correlated with decreased survival. Wightman
Alghamri
Tumor-treating fields (TTFs) work as a non-invasive anti-cancer therapy via alternating electric fields. As stated earlier, TTFs are already FDA-approved for GBM in combination with temozolomide. Voloshin
As stated earlier, ICI as monotherapies has had limited success in patients with CNS-derived malignancies. Therefore, several groups are evaluating combinatorial ICI approaches to enhance anti-tumor effects. Flores
Alternatively, Flores-Toro
Finally, Sabbagh
Malignant brain tumors pose a unique and difficult set of challenges including high tumor heterogeneity and tumor antigen loss, low mutation burden, an immunosuppressive microenvironment, systemic T cell dysfunction, and relative isolation from systemic circulation due to the blood-brain barrier. These overwhelming obstacles have, thus far, limited immunotherapy efficacy. Despite these hurdles, immunotherapies are making incremental advances to overcome these challenges simultaneously [152, 153]. New developments are occurring in the peptide vaccine platforms by the conjugation with toll-like receptor agonists which can enhance activation of DCs to elicit tuned immune responses [154, 155, 156]. Studies are also moving forward to focus on targeting multiple antigens simultaneously to combat tumor antigen loss in CAR T therapy [157]. Other groups are working on addressing the immunosuppressive tumor microenvironment and T cell exhaustion with several studies underway in a variety of cancers that combine vaccines and immune checkpoint inhibitors [158]. In the CAR T therapy arena, groups are overcoming T cell exhaustion by knocking out the checkpoint molecules [159, 160], endowing CAR T cells with the capabilities of secreting anti-PD-L1 antibodies [161], and linking the PD-1 extracellular domain to the CD28 intracellular domain to lead to an activation signal instead of inhibition [162, 163]. Other groups are working on overcoming the blood-brain barrier challenge by using laser interstitial thermal therapy or the aforementioned low-intensity pulsed ultrasound to cause local disruption and permeability which may increase trafficking of therapies to the tumor site [151, 164, 165]. These approaches utilizing various combinations and novel technologies may provide solutions to the aforementioned obstacles.
In summary, the next advances in immunotherapies for CNS malignancies will come from enhanced foundational understanding of immune cells and the tumor microenvironment, better mechanistic understandings of current immunotherapy resistance, increased rational combinations of current immunotherapies with complementary mechanisms of action, and novel immunotherapeutic approaches. Together, the above-mentioned clinical studies and novel preclinical work provide an optimistic future in cancer with much-needed improvement in patient survival.
This work was supported by the University of Florida Clinical and Translational Science Institute, which is supported in part by the NIH National Center for Advancing Translational Sciences under the award TL1TR001428. NIH funding was also received through the National Cancer Institute (F30CA232641 to MS) (T32CA257923 to BDD) and the National Institute of Neurological Disorders and Stroke (R01NS112315 and R01NS111033 to CF). Additionally, this work was supported by Alex’s Lemonade Stand Foundation and the University of Florida MD-PhD Training Program.
CF holds interest in iOncologi, Inc., a biotechnology company focused on immuno-oncology. Other authors declare no conflicts of interest.
We thank all of the patients and their families who participated in the referenced studies that made this work possible and allows us to move the needle forward on patient outcomes.
IntechOpen publishes different types of publications
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Metallurgical properties of sinter and pellets (reducibility, strength, softening and melting temperatures) with different contents of red mud in iron ore raw materials are also presented, including the technology of red mud usage in ferrous metallurgy carried out through industrial and laboratorial tests. Additionally, the main technical and economic indicators of blast furnace smelting (productivity, coke consumption, chemical composition of pig iron and slag, etc.) are presented. The possibility and expediency of utilisation of red mud in a blast furnace are shown.",book:{id:"7557",slug:"recovery-and-utilization-of-metallurgical-solid-waste",title:"Recovery and Utilization of Metallurgical Solid Waste",fullTitle:"Recovery and Utilization of Metallurgical Solid Waste"},signatures:"Andrey Dmitriev",authors:null},{id:"37118",doi:"10.5772/33969",title:"Size Reduction by Grinding as an Important Stage in Recycling",slug:"comminution-as-an-important-stage-in-recycling",totalDownloads:5409,totalCrossrefCites:3,totalDimensionsCites:6,abstract:null,book:{id:"2254",slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Marek Macko",authors:[{id:"98075",title:"Dr.",name:"Marek",middleName:null,surname:"Macko",slug:"marek-macko",fullName:"Marek Macko"}]}],mostDownloadedChaptersLast30Days:[{id:"77881",title:"Chemical Recycling of Polyolefins (PE, PP): Modern Technologies and Products",slug:"chemical-recycling-of-polyolefins-pe-pp-modern-technologies-and-products",totalDownloads:391,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Chemical recycling is one of the most intensively developed potential solutions for the global plastic waste issue. This broadly defined term covers several different technologies that lead to many diverse products. Polyolefins (polyethylene and polypropylene) can be chemically recycled by pyrolysis (cracking) or gasification. These polymers’ chemical composition and structure make them a great potential source of valuable hydrocarbons or carbon atoms for syngas production. Thermal and catalytic cracking of polyethylene and polypropylene can be optimised to maximise specific types of hydrocarbons that, after optional additional processing, such as hydrotreatment, steam cracking or distillation, can be used as intermediates in petrochemical plants, fuels or fuel components, monomers for polymerisation of new, virgin polymers or as specialty chemicals (final market products). Gasification of plastic waste transforms polymers into a mixture of hydrogen, carbon monoxide and carbon dioxide, which can be further used as a source of these gasses, transformed into chemicals and fuels, or used directly to produce energy. This chapter presents all of these process paths with examples of existing technologies and their level of technology readiness and perspectives for scale-up.",book:{id:"10855",slug:"waste-material-recycling-in-the-circular-economy-challenges-and-developments",title:"Waste Material Recycling in the Circular Economy",fullTitle:"Waste Material Recycling in the Circular Economy - Challenges and Developments"},signatures:"Daria Frączak",authors:[{id:"353408",title:"Dr.Ing.",name:"Daria",middleName:null,surname:"Frączak",slug:"daria-fraczak",fullName:"Daria Frączak"}]},{id:"77840",title:"Recent Advances in Pre-Treatment of Plastic Packaging Waste",slug:"recent-advances-in-pre-treatment-of-plastic-packaging-waste",totalDownloads:321,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"There is an urgent need to close the loop of plastic waste. One of the main challenges towards plastic packaging waste recycling is the presence of a variety of contaminants. These contaminants include organic residues, additives, labels, inks and also other plastic types that can be present in the waste stream due to missorting or in multimaterial structures (e.g. multilayer films in packaging). In this context, pre-treatment processes are a promising route to tackle the difficulties that are encountered in mechanical and chemical recycling due to these contaminants. This chapter gives better insight on the already existing pre-treatment techniques and on the advances that are being developed and/or optimized in order to achieve closed-loop recycling. Some of these advanced pre-treatments include chemical washing to remove inks (deinking), extraction methods to remove undesired plastic additives and dissolution-based pre-treatments, such as delamination and dissolution-precipitation techniques.",book:{id:"10855",slug:"waste-material-recycling-in-the-circular-economy-challenges-and-developments",title:"Waste Material Recycling in the Circular Economy",fullTitle:"Waste Material Recycling in the Circular Economy - Challenges and Developments"},signatures:"Rita Kol, Martijn Roosen, Sibel Ügdüler, Kevin M. Van Geem, Kim Ragaert, Dimitris S. Achilias and Steven De Meester",authors:[{id:"95620",title:"Dr.",name:"Dimitris S.",middleName:null,surname:"Achilias",slug:"dimitris-s.-achilias",fullName:"Dimitris S. 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The proven metalized pellet-producing process would be highlighted that green pellets made from iron-bearing sludge are dried and preheated in a traveling grate firstly, and then reduced at high temperature in a rotary kiln or a rotary hearth furnace (RHF) to get direct reduced iron (DRI), served as a good iron source for blast furnace.",book:{id:"7557",slug:"recovery-and-utilization-of-metallurgical-solid-waste",title:"Recovery and Utilization of Metallurgical Solid Waste",fullTitle:"Recovery and Utilization of Metallurgical Solid Waste"},signatures:"Hu Long, Dong Liu, Lie-Jun Li, Ming-Hua Bai, Yanzhong Jia and Wensheng Qiu",authors:null},{id:"77937",title:"An Evaluation of Recycled Polymeric Materials Usage in Denim with Lifecycle Assesment Methodology",slug:"an-evaluation-of-recycled-polymeric-materials-usage-in-denim-with-lifecycle-assesment-methodology",totalDownloads:259,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Today, World economy is only 8.6% circular, which creates a huge potential in materials reuse. To close the Emission Gap by 2032, this percentage needs to be doubled. The circular economy ensures that with less virgin material input and fewer emissions. With the help of effective recycling technologies, virgin material use can be decreased and especially petroleum based materials impact can fall within planetary boundaries. This book chapter analyzes different chemical and biological recycling technologies, their advantages and challenges in denim production. Moreover, Life Cycle Assessment (LCA) analysis will be used to evaluate the environmental impact of recycled polymeric materials usage in denim fabrics. 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She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. 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She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. 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He is also Member of the Laboratory of genetic, animal and feed resource and member of Animal science Department of INAT. He graduated from Higher School of Agriculture of Mateur, University of Carthage, in 2002 and completed his masters in 2006. Dr. M’HAMDI completed his PhD thesis in Genetic welfare indicators of dairy cattle at Higher Institute of Agronomy of Chott-Meriem, University of Sousse, in 2011. 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Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. The interest of Javier's lab is the study of cell signaling with a special focus on Ca2+ signaling, and how Ca2+ transport modulates the cytoskeleton, migration, differentiation, cell death, etc. He is especially interested in the study of Ca2+ channels, and the role of STIM1 in the initiation of pathological events.",institutionString:null,institution:{name:"University of Extremadura",country:{name:"Spain"}}},{id:"217323",title:"Prof.",name:"Guang-Jer",middleName:null,surname:"Wu",slug:"guang-jer-wu",fullName:"Guang-Jer Wu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217323/images/8027_n.jpg",biography:null,institutionString:null,institution:null},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/148546/images/4640_n.jpg",biography:null,institutionString:null,institution:null},{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272889/images/10758_n.jpg",biography:null,institutionString:null,institution:null},{id:"242491",title:"Prof.",name:"Angelica",middleName:null,surname:"Rueda",slug:"angelica-rueda",fullName:"Angelica Rueda",position:"Investigador Cinvestav 3B",profilePictureURL:"https://mts.intechopen.com/storage/users/242491/images/6765_n.jpg",biography:null,institutionString:null,institution:null},{id:"88631",title:"Dr.",name:"Ivan",middleName:null,surname:"Petyaev",slug:"ivan-petyaev",fullName:"Ivan Petyaev",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lycotec (United Kingdom)",country:{name:"United Kingdom"}}},{id:"423869",title:"Ms.",name:"Smita",middleName:null,surname:"Rai",slug:"smita-rai",fullName:"Smita Rai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424024",title:"Prof.",name:"Swati",middleName:null,surname:"Sharma",slug:"swati-sharma",fullName:"Swati Sharma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"439112",title:"MSc.",name:"Touseef",middleName:null,surname:"Fatima",slug:"touseef-fatima",fullName:"Touseef Fatima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424836",title:"Dr.",name:"Orsolya",middleName:null,surname:"Borsai",slug:"orsolya-borsai",fullName:"Orsolya Borsai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",country:{name:"Romania"}}},{id:"422262",title:"Ph.D.",name:"Paola Andrea",middleName:null,surname:"Palmeros-Suárez",slug:"paola-andrea-palmeros-suarez",fullName:"Paola Andrea Palmeros-Suárez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Guadalajara",country:{name:"Mexico"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular economy, Contingency planning and response to disasters, Ecosystem services, Integrated urban water management, Nature-based solutions, Sustainable urban development, Urban green spaces",scope:"