Stability constant values obtained for Ni, Mg and Co complexes having different metal to ligand ratio.
\\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:"6339",leadTitle:null,fullTitle:"Towards Malaria Elimination - A Leap Forward",title:"Towards Malaria Elimination",subtitle:"A Leap Forward",reviewType:"peer-reviewed",abstract:'Towards Malaria Elimination - A Leap Forward was started to mark the occasion for renewed commitment to end malaria transmission for good (the WHO\'s call for "Malaria Free World" by 2030). This book is dedicated for the benefit of researchers, scientists, program and policy managers, students and anyone interested in malaria and other mosquito-borne diseases with the goal of sharing recent information on success stories, innovative control approaches and challenges in different regions of the world. Some main issues that emerged included multidrug-resistant malaria and pandemic risk, vaccines, cross-border malaria, asymptomatic parasite reservoir, the threat of Plasmodium vivax and Plasmodium knowlesi, insecticide resistance in Anopheles vectors and outdoor malaria transmission. This book is one little step forward to bring together in 17 chapters the experiences of malaria-expert researchers from five continents to present updated information on disease epidemiology and control at the national/regional level, highlighting the constraints, challenges, accomplishments and prospects of malaria elimination.',isbn:"978-1-78923-551-7",printIsbn:"978-1-78923-550-0",pdfIsbn:"978-1-83881-413-7",doi:"10.5772/intechopen.69750",price:139,priceEur:155,priceUsd:179,slug:"towards-malaria-elimination-a-leap-forward",numberOfPages:452,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"2ab88726cd9291b2b1c29889c948c902",bookSignature:"Sylvie Manguin and Vas Dev",publishedDate:"July 18th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6339.jpg",numberOfDownloads:28588,numberOfWosCitations:103,numberOfCrossrefCitations:82,numberOfCrossrefCitationsByBook:5,numberOfDimensionsCitations:200,numberOfDimensionsCitationsByBook:6,hasAltmetrics:1,numberOfTotalCitations:385,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 15th 2017",dateEndSecondStepPublish:"June 30th 2017",dateEndThirdStepPublish:"December 1st 2017",dateEndFourthStepPublish:"February 28th 2018",dateEndFifthStepPublish:"April 25th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"50017",title:"Prof.",name:"Sylvie",middleName:null,surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin",profilePictureURL:"https://mts.intechopen.com/storage/users/50017/images/3936_n.png",biography:"Sylvie Manguin is a Full Research Professor at the Institute of Research for Development (IRD), based at the University of Montpellier, France. She is a leading medical entomologist and academician researcher whose main interest concerns mosquitoes and vector-borne diseases such as malaria and dengue. She has developed studies on Anopheles mosquitoes from three continents (Asia, Africa, Americas) including molecular species identification, population genetics, phylogenetic, vectorial capacities, spatial surveillance, midgut microbiota biodiversity, salivary immunological markers and vector control approaches. She is the author of 90 indexed publications, six book chapters, three books including “Anopheles mosquitoes: New insights into malaria vectors” for which she is the Editor (InTech Open Access) and “Biodiversity of malaria in the World” (John Libbey Ed.), respectively published in 2013 and 2008. She is also the Secretary General of the International Federation of Tropical Medicine (IFTM) http://www.iftm-hp.org/board.html, member of the Editorial Boards of the Malaria Journal and Acta Tropica and she serves as reviewer in several international institutions and more than 20 scientific journals.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Institut de Recherche pour le Développement",institutionURL:null,country:{name:"France"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"151166",title:"Dr.",name:"Vas",middleName:null,surname:"Dev",slug:"vas-dev",fullName:"Vas Dev",profilePictureURL:"https://mts.intechopen.com/storage/users/151166/images/5604_n.jpg",biography:"Vas Dev has superannuated from services from the National Institute of Malaria Research, a premier research organization for malaria research, and served as Officer-in-Charge of one of its field stations based in Assam, north-eastern region of India for over 25 years. He was actively involved in operational research for evaluation of newer technologies for vector control, routine surveillance of antimalarial medicines for treatment of malaria, diagnostics and human resource development. His primary research interests are in vector biology with special reference to epidemiology and control of malaria. His research efforts have culminated in number of technologies, viz., long-lasting insecticidal nets, artemisinin-based combination therapy for treatment of drug-resistant malaria, rapid diagnostic test kits that all have been incorporated for benefit of State healthcare services of north-eastern states, major public and private sectors, and defense establishments alike resulting in substantial disease transmission reduction. He has over 150 research publications in index journals and serves as the member of editorial board of several scientific journals. He is the recipient of numerous coveted fellowships, awards and distinctions in his field of research, and is currently an active member of learned societies",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Malaria Research",institutionURL:null,country:{name:"India"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1131",title:"Global Health",slug:"global-health"}],chapters:[{id:"61376",title:"Malaria Elimination: Challenges and Opportunities",doi:"10.5772/intechopen.77092",slug:"malaria-elimination-challenges-and-opportunities",totalDownloads:1570,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"In 2016, 91 countries reported a total of 216 million cases of malaria, an increase of 5 million cases over the previous year, and the estimated malaria deaths worldwide were 445,000 like in 2015. This suggests that despite a substantial reduction in the malaria burden observed since 2010, largely attributed to the scale-up of effective control measures (vector control interventions, efficacious antimalarial treatment), the rate of decline of both clinical cases and malaria deaths has stalled since 2014 and in some regions even reversed. Achieving universal access to standard control interventions, such as case management, implementation of vector control methods, seasonal malaria chemoprevention, and intermittent preventive treatment for pregnant women, remains a priority. It is essential to contain emerging drug resistance in malarial parasite and insecticide resistance in mosquito vector species. Additional new interventions to accelerate interruption of transmission are in crucial need for their rapid integration within the standard control activities. These integrated control approaches must be implemented at community level with the active involvement of the local populations to reach high coverage. Finally, political and financial supports should be maintained and even doubled to reach the 2030 targets of the WHO global technical strategy for malaria.",signatures:"Umberto D’Alessandro",downloadPdfUrl:"/chapter/pdf-download/61376",previewPdfUrl:"/chapter/pdf-preview/61376",authors:[{id:"214368",title:"Prof.",name:"Umberto",surname:"D'Alessandro",slug:"umberto-d'alessandro",fullName:"Umberto D'Alessandro"}],corrections:null},{id:"60988",title:"The Artemisinin Resistance in Southeast Asia: An Imminent Global Threat to Malaria Elimination",doi:"10.5772/intechopen.76519",slug:"the-artemisinin-resistance-in-southeast-asia-an-imminent-global-threat-to-malaria-elimination",totalDownloads:1756,totalCrossrefCites:3,totalDimensionsCites:11,hasAltmetrics:0,abstract:"Malaria remains a leading cause of mortality and morbidity in many low- and middle-income countries. Artemisinin combination therapies (ACTs) have contributed to the substantial decline in the worldwide malaria burden, renewing the optimism that malaria elimination is achievable in some regions of the world. However, this prospect is threatened by the emergence of artemisinin resistance in Plasmodium falciparum leading to clinical failure of ACTs in Southeast Asia. Historically, drug resistance in P. falciparum has emerged in SEA and spread to Africa. Today, resistance to ACTs could reverse all the achievements of control and elimination efforts globally. With no new drug available, P. falciparum malaria must be eliminated from the Greater Mekong before it becomes untreatable.",signatures:"Aung Pyae Phyo and François Nosten",downloadPdfUrl:"/chapter/pdf-download/60988",previewPdfUrl:"/chapter/pdf-preview/60988",authors:[{id:"214099",title:"Dr.",name:"Aung",surname:"Pyae Phyo",slug:"aung-pyae-phyo",fullName:"Aung Pyae Phyo"},{id:"215774",title:"Prof.",name:"Francois",surname:"Nosten",slug:"francois-nosten",fullName:"Francois Nosten"}],corrections:null},{id:"62029",title:"Preparing for the Next Global Threat: A Call for Targeted, Immediate Decisive Action in Southeast Asia to Prevent the Next Pandemic in Africa",doi:"10.5772/intechopen.78261",slug:"preparing-for-the-next-global-threat-a-call-for-targeted-immediate-decisive-action-in-southeast-asia",totalDownloads:1441,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Global investments have had great impact on malaria—these are now at risk of being reversed. Cambodia is where drug resistance historically emerges and spreads globally to drive resulting pandemics—we are currently watching history repeat itself. Despite large investments and recent success in driving down overall rates of malaria, high levels of resistance to nearly all antimalarial drugs are now widespread in Cambodia. Malaria cases are again rising in both Cambodia and Vietnam. Nearly incurable malaria in this region is a real and present threat. Critical actions to prevent further spread of the emerging incurable parasites are: (1) Commitment and real sense of urgency through declaration of a “Public Health Emergency of International Concern” or a similar set of directives; (2) Establish leadership with sufficient authority, respect, expertise and operational funding; (3) Engage affected security forces to stop disease transmission and support elimination operations; (4) Utilize surveillance as a core intervention with result-based funding targeting malaria transmission foci with rapid and effective action. Immediate decisive action is needed in Southeast Asia to prevent the next malaria pandemic. This chapter highlights persistent gaps in the region with methods to address them. In 2015–2016, our collaboration with NIMPE pilot tested tools to intervene in actual forest transmission foci. Our study district saw a 96% decrease in malaria from 2014 to 2017, with the entire province seeing the largest decrease in Central Vietnam in this same timeframe. We describe methods to tackle transmission foci, with both an integrated prevention and treatment package. We call on all stakeholders to make changes to current investments to address this critical challenge.",signatures:"Colin Ohrt, Thang Duc Ngo and Thieu Quang Nguyen",downloadPdfUrl:"/chapter/pdf-download/62029",previewPdfUrl:"/chapter/pdf-preview/62029",authors:[{id:"217746",title:"Dr.",name:"Colin",surname:"Ohrt",slug:"colin-ohrt",fullName:"Colin Ohrt"},{id:"240534",title:"Dr.",name:"Thang Duc",surname:"Ngo",slug:"thang-duc-ngo",fullName:"Thang Duc Ngo"},{id:"240535",title:"Dr.",name:"Thieu Quang",surname:"Nguyen",slug:"thieu-quang-nguyen",fullName:"Thieu Quang Nguyen"}],corrections:null},{id:"61584",title:"Challenges in the Control and Elimination of Plasmodium vivax Malaria",doi:"10.5772/intechopen.77082",slug:"challenges-in-the-control-and-elimination-of-plasmodium-vivax-malaria",totalDownloads:1712,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The human malaria parasite Plasmodium vivax imposes unique challenges to its control and elimination. Primary among those is the hypnozoite reservoir of infection in endemic communities. It is the dominant source of incident malaria and exceedingly difficult to attack due to both inability to diagnose latent carriers and the potentially life-threatening toxicity of primaquine in patients with an inborn deficiency of G6PD, the only therapeutic option against hypnozoites. Large segments of endemic populations are not eligible for primaquine, and alternative strategies for managing the threat of relapse in any group have not been optimized or validated. Association of risk of primaquine failure against latent P. vivax with impaired alleles of P450 2D6 exacerbates the substantial pool of primaquine ineligibles. Resistance to chloroquine against acute P. vivax malaria commonly occurs; alternative therapies like ACTs are effective but seldom evaluated as a partner drug to primaquine in the essential radical cure. Many of the Anopheles mosquito vector of P. vivax in South and Southeast Asia, where >90% of infections occur, thrive in a diversity of habitats and exhibit wide ranges of feeding and breeding behavior. This chapter explores many of these challenges and possible approaches in controlling and eliminating endemic vivax malaria.",signatures:"Puji BS Asih, Din Syafruddin and John Kevin Baird",downloadPdfUrl:"/chapter/pdf-download/61584",previewPdfUrl:"/chapter/pdf-preview/61584",authors:[{id:"216332",title:"Dr.",name:"Puji",surname:"Budi Setia Asih",slug:"puji-budi-setia-asih",fullName:"Puji Budi Setia Asih"},{id:"216335",title:"Dr.",name:"Kevin",surname:"Baird",slug:"kevin-baird",fullName:"Kevin Baird"},{id:"239838",title:"Prof.",name:"Din",surname:"Syafruddin",slug:"din-syafruddin",fullName:"Din Syafruddin"}],corrections:null},{id:"61329",title:"Human and Simian Malaria in the Greater Mekong Subregion and Challenges for Elimination",doi:"10.5772/intechopen.76901",slug:"human-and-simian-malaria-in-the-greater-mekong-subregion-and-challenges-for-elimination",totalDownloads:1249,totalCrossrefCites:2,totalDimensionsCites:12,hasAltmetrics:0,abstract:"In recent years malaria initiatives have increasingly shifted from malaria control to a focus on achieving malaria elimination in the Southeast Asia region. However, this region experiences unique challenges in this transition due to its distinctive malaria ecosystem (mainly related to forests) and high volume of population movement (both within and between countries). These bioenvironmental factors increase the exposure of populations at higher risk due to their close association with forest, and contributes to outdoor and residual transmission. Given that this region has also historically been the source of resistance to anti-malarial drugs, the potential spread of artemisinin resistance via global transportation routes would pose a major threat to malaria control and elimination efforts worldwide. In addition, other factors also hinder the malaria elimination goal such as importation of parasite infection, uncontrolled monkey malaria (Plasmodium knowlesi), or the fact that many countries in this region experience mixed infections where P. vivax becomes a more predominant species as overall malaria transmission decreases. This chapter addresses these challenges in detail and provide recommendations and key priorities to overcome these obstacles to accelerate efforts for achieving malaria elimination.",signatures:"Jeffrey Hii, Indra Vythilingam and Arantxa Roca-Feltrer",downloadPdfUrl:"/chapter/pdf-download/61329",previewPdfUrl:"/chapter/pdf-preview/61329",authors:[{id:"151116",title:"Dr.",name:"Indra",surname:"Vythilingam",slug:"indra-vythilingam",fullName:"Indra Vythilingam"},{id:"214902",title:"Dr.",name:"Arantxa",surname:"Roca-Feltrer",slug:"arantxa-roca-feltrer",fullName:"Arantxa Roca-Feltrer"},{id:"215079",title:"Dr.",name:"Jeffrey",surname:"Hii",slug:"jeffrey-hii",fullName:"Jeffrey Hii"}],corrections:null},{id:"61559",title:"Understanding the Importance of Asymptomatic and Low- Density Infections for Malaria Elimination",doi:"10.5772/intechopen.77293",slug:"understanding-the-importance-of-asymptomatic-and-low-density-infections-for-malaria-elimination",totalDownloads:1761,totalCrossrefCites:2,totalDimensionsCites:7,hasAltmetrics:1,abstract:"In recent years, the use of more sensitive diagnostic techniques has demonstrated a significant number of malaria infections at densities beneath the limit of detection of conventional microscopy and rapid diagnostic tests (RDT). These low-density infections are almost always asymptomatic, found in all endemic settings, including those nearing elimination, and in all ages of the population. They typically account for a high proportion of all infections and since they have also been shown to be infectious to mosquitoes, low-density infections are thought to be important contributors to maintaining malaria transmission. However, there is currently no direct evidence that specifically targeting this low-density parasite reservoir will hasten progress towards elimination. In this chapter we review the data to date and identify knowledge gaps. We present potential scenarios for the causes of low-density infections, if and how these might drive transmission, and the likely impact of specifically targeting them.",signatures:"Chris Drakeley, Bronner Gonçalves, Lucy Okell and Hannah Slater",downloadPdfUrl:"/chapter/pdf-download/61559",previewPdfUrl:"/chapter/pdf-preview/61559",authors:[{id:"215238",title:"Prof.",name:"Chris",surname:"Drakeley",slug:"chris-drakeley",fullName:"Chris Drakeley"},{id:"215831",title:"Dr.",name:"Bronner",surname:"Goncalves",slug:"bronner-goncalves",fullName:"Bronner Goncalves"},{id:"215834",title:"Dr.",name:"Hannah",surname:"Slater",slug:"hannah-slater",fullName:"Hannah Slater"},{id:"215835",title:"Dr.",name:"Lucy",surname:"Okell",slug:"lucy-okell",fullName:"Lucy Okell"}],corrections:null},{id:"62169",title:"Insecticide Resistance in Malaria Vectors: An Update at a Global Scale",doi:"10.5772/intechopen.78375",slug:"insecticide-resistance-in-malaria-vectors-an-update-at-a-global-scale",totalDownloads:2358,totalCrossrefCites:16,totalDimensionsCites:39,hasAltmetrics:0,abstract:"Malaria remains the deadliest vector-borne disease in the world. With nearly half of the world’s population at risk, 216 million people suffered from malaria in 2016, with over 400,000 deaths, mainly in sub-Saharan Africa. Important global efforts have been made to eliminate malaria leading to significant reduction in malaria cases and mortality in Africa by 42% and 66%, respectively. Early diagnosis, improved drug therapies and better health infrastructure are key components, but this extraordinary success is mainly due the use of long-lasting insecticidal nets (LLINs) and indoor residual sprayings (IRS) of insecticide. Unfortunately, the emergence and spread of resistance in mosquito populations against insecticides is jeopardising the effectiveness of the most efficient malaria control interventions. To help establish suitable resistance management strategies, it is vital to better understand the distribution of resistance, its mechanisms and impact on effectiveness of control interventions and malaria transmission. In this chapter, we present the current status of insecticide resistance worldwide in main malaria vectors as well as its impact on malaria transmission, and discuss the molecular mechanisms and future perspectives.",signatures:"Jacob M. Riveron, Magellan Tchouakui, Leon Mugenzi, Benjamin D.\nMenze, Mu-Chun Chiang and Charles S. Wondji",downloadPdfUrl:"/chapter/pdf-download/62169",previewPdfUrl:"/chapter/pdf-preview/62169",authors:[{id:"212661",title:"Dr.",name:"Charles",surname:"Wondji",slug:"charles-wondji",fullName:"Charles Wondji"},{id:"215729",title:"Dr.",name:"Jacob",surname:"Riveron",slug:"jacob-riveron",fullName:"Jacob Riveron"},{id:"215730",title:"MSc.",name:"Magellan",surname:"Tchouakui",slug:"magellan-tchouakui",fullName:"Magellan Tchouakui"},{id:"215731",title:"MSc.",name:"Leon",surname:"Mugenzi",slug:"leon-mugenzi",fullName:"Leon Mugenzi"},{id:"215732",title:"MSc.",name:"Benjamin",surname:"Menze",slug:"benjamin-menze",fullName:"Benjamin Menze"},{id:"240599",title:"MSc.",name:"Mu-Chun",surname:"Chiang",slug:"mu-chun-chiang",fullName:"Mu-Chun Chiang"}],corrections:null},{id:"60966",title:"Malaria Elimination in the Greater Mekong Subregion: Challenges and Prospects",doi:"10.5772/intechopen.76337",slug:"malaria-elimination-in-the-greater-mekong-subregion-challenges-and-prospects",totalDownloads:1446,totalCrossrefCites:10,totalDimensionsCites:19,hasAltmetrics:1,abstract:"Malaria is a significant public health problem and impediment to socioeconomic development in countries of the Greater Mekong Subregion (GMS), which comprises Cambodia, China’s Yunnan Province, Lao People’s Democratic Republic, Myanmar, Thailand, and Vietnam. Over the past decade, intensified malaria control has greatly reduced the regional malaria burden. Driven by increasing political commitment, motivated by recent achievements in malaria control, and urged by the imminent threat of emerging artemisinin resistance, the GMS countries have endorsed a regional malaria elimination plan with a goal of eliminating malaria by 2030. However, this ambitious, but laudable, goal faces a daunting array of challenges and requires integrated strategies tailored to the region, which should be based on a mechanistic understanding of the human, parasite, and vector factors sustaining continued malaria transmission along international borders. Malaria epidemiology in the GMS is complex and rapidly evolving. Spatial heterogeneity requires targeted use of the limited resources. Border malaria accounts for continued malaria transmission and represents sources of parasite introduction through porous borders by highly mobile human populations. Asymptomatic infections constitute huge parasite reservoir requiring interventions in time and place to pave the way for malaria elimination. Of the two most predominant malaria parasites, Plasmodium falciparum and P. vivax, the prevalence of the latter is increasing in most member GMS countries. This parasite requires the use of 8-aminoquinoline drugs to prevent relapses from liver hypnozoites, but high prevalence of glucose-6-phosphate dehydrogenase deficiency in the endemic human populations makes it difficult to adopt this treatment regimen. The recent emergence of resistance to artemisinins and partner drugs in P. falciparum has raised both regional and global concerns, and elimination efforts are invariably prioritized against this parasite to avert spread. Moreover, the effectiveness of the two core vector control interventions—insecticide-treated nets and indoor residual spraying—has been declining due to insecticide resistance and increased outdoor biting activity of mosquito vectors. These technical challenges, though varying from country to country, require integrated approaches and better understanding of the malaria epidemiology enabling targeted control of the parasites and vectors. Understanding the mechanism and distribution of drug-resistant parasites will allow effective drug treatment and prevent, or slow down, the spread of drug resistance. Coordination among the GMS countries is essential to prevent parasite reintroduction across the international borders to achieve regional malaria elimination.",signatures:"Liwang Cui, Yaming Cao, Jaranit Kaewkungwal, Amnat\nKhamsiriwatchara, Saranath Lawpoolsri, Than Naing Soe, Myat\nPhone Kyaw and Jetsumon Sattabongkot",downloadPdfUrl:"/chapter/pdf-download/60966",previewPdfUrl:"/chapter/pdf-preview/60966",authors:[{id:"217491",title:"Dr.",name:"Liwang",surname:"Cui",slug:"liwang-cui",fullName:"Liwang Cui"},{id:"240119",title:"Prof.",name:"Yaming",surname:"Cao",slug:"yaming-cao",fullName:"Yaming Cao"},{id:"240120",title:"Prof.",name:"Jaranit",surname:"Kaewkungwal",slug:"jaranit-kaewkungwal",fullName:"Jaranit Kaewkungwal"},{id:"240121",title:"Mr.",name:"Amnat",surname:"Khamsiriwatchara",slug:"amnat-khamsiriwatchara",fullName:"Amnat Khamsiriwatchara"},{id:"240122",title:"Prof.",name:"Saranath",surname:"Lawpoolsri",slug:"saranath-lawpoolsri",fullName:"Saranath Lawpoolsri"},{id:"240123",title:"MSc.",name:"Than Naing",surname:"Soe",slug:"than-naing-soe",fullName:"Than Naing Soe"},{id:"240124",title:"Dr.",name:"Myat Phone",surname:"Kyaw",slug:"myat-phone-kyaw",fullName:"Myat Phone Kyaw"},{id:"240125",title:"Prof.",name:"Jetsumon",surname:"Sattabongkot",slug:"jetsumon-sattabongkot",fullName:"Jetsumon Sattabongkot"}],corrections:null},{id:"59967",title:"Ending Malaria Transmission in the Asia Pacific Malaria Elimination Network (APMEN) Countries: Challenges and the Way Forward",doi:"10.5772/intechopen.75405",slug:"ending-malaria-transmission-in-the-asia-pacific-malaria-elimination-network-apmen-countries-challeng",totalDownloads:1563,totalCrossrefCites:5,totalDimensionsCites:7,hasAltmetrics:0,abstract:"Member countries in the Asia Pacific Malaria Elimination Network (APMEN) are pursuing the global goal of malaria elimination by 2030. Different countries are in various phases of malaria elimination and this review aims to present a compilation of available evidence on the challenges and way forward for malaria elimination in APMEN countries. Malaria transmission in these States is complex. APMEN member countries include the largest populations living in areas of malaria transmission risk outside Africa. They are a global source for spread of artemisinin-based combination therapy (ACT) resistance, include the biggest burden of Plasmodium vivax and zoonotic malaria, and face many geopolitical and socio-economic factors that will challenge malaria elimination efforts. These challenges can be addressed in part through operational research to identify country-specific solutions, making better use of operational data such as through spatial decision support system (SDSS) approaches, strengthening surveillance, and cross-border initiative for coordinated action.",signatures:"Kinley Wangdi and Archie CA Clements",downloadPdfUrl:"/chapter/pdf-download/59967",previewPdfUrl:"/chapter/pdf-preview/59967",authors:[{id:"212325",title:"Dr.",name:"Kinley",surname:"Wangdi",slug:"kinley-wangdi",fullName:"Kinley Wangdi"},{id:"221224",title:"Prof.",name:"Archie",surname:"Clements",slug:"archie-clements",fullName:"Archie Clements"}],corrections:null},{id:"61600",title:"Malaria Elimination in the People’s Republic of China: Current Progress, Challenges, and Prospects",doi:"10.5772/intechopen.77282",slug:"malaria-elimination-in-the-people-s-republic-of-china-current-progress-challenges-and-prospects",totalDownloads:1618,totalCrossrefCites:3,totalDimensionsCites:14,hasAltmetrics:0,abstract:"In China, the malaria elimination program was launched in 2010 with the objective to eliminate this disease by 2020. Large-scale malaria control and elimination actions have been conducted with significant success since inception of the nationwide program. The incidence of locally acquired malaria has declined sharply along with the concomitant decrease of malaria-endemic areas from 762 counties reporting malaria in 2010 to just two counties adjacent to border areas (Yunnan, China-Myanmar and Tibet, China-India) in 2016. In total, 1723 counties (79%) and 134 prefectures (52%) had completed the malaria elimination internal assessment by the end of 2016. The year 2017 was the first year without report of indigenous malaria cases throughout the country. Hence, this chapter is meant to share the lessons learned from malaria elimination in China benefiting countries on the way to malaria elimination.",signatures:"Shaosen Zhang, Li Zhang, Jun Feng, Jianhai Yin, Xinyu Feng, Zhigui\nXia, Roger Frutos, Sylvie Manguin and Shuisen Zhou",downloadPdfUrl:"/chapter/pdf-download/61600",previewPdfUrl:"/chapter/pdf-preview/61600",authors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"},{id:"222596",title:"Prof.",name:"Roger",surname:"Frutos",slug:"roger-frutos",fullName:"Roger Frutos"},{id:"241436",title:"Dr.",name:"Shaosen",surname:"Zhang",slug:"shaosen-zhang",fullName:"Shaosen Zhang"},{id:"249302",title:"Prof.",name:"Shuisen",surname:"Zhou",slug:"shuisen-zhou",fullName:"Shuisen Zhou"},{id:"249874",title:"Ms.",name:"Li",surname:"Zhang",slug:"li-zhang",fullName:"Li Zhang"},{id:"249875",title:"Dr.",name:"Jun",surname:"Feng",slug:"jun-feng",fullName:"Jun Feng"},{id:"249876",title:"Dr.",name:"Jianhai",surname:"Yin",slug:"jianhai-yin",fullName:"Jianhai Yin"},{id:"249877",title:"Dr.",name:"Xinyu",surname:"Feng",slug:"xinyu-feng",fullName:"Xinyu Feng"},{id:"249880",title:"Dr.",name:"Zhigui",surname:"Xia",slug:"zhigui-xia",fullName:"Zhigui Xia"}],corrections:null},{id:"61663",title:"Declining Transmission of Malaria in India: Accelerating Towards Elimination",doi:"10.5772/intechopen.77046",slug:"declining-transmission-of-malaria-in-india-accelerating-towards-elimination",totalDownloads:1918,totalCrossrefCites:8,totalDimensionsCites:13,hasAltmetrics:1,abstract:"India is ecologically vast and has close to a billion-population living at risk of malaria. Given the evidence-based present-day intervention tools and large-scale implementation, India has recorded declining trends in disease transmission from 2 million cases in 2001 to close to a million cases in 2017 and embarked upon malaria elimination in keeping with the Global Technical Strategy by 2030. India is malaria endemic, but transmission intensities varied across its landscape with just few States of the east, central and northeast contributing bulk (80%) of total positive cases. Plasmodium falciparum and P. vivax are the predominant infections of which there has been steady increase in proportions of the former for constituting >60% of total cases what was 50:50 in 2001, a phenomenon attributed to emerging drug resistance. With the rolling out of the available intervention tools, malaria elimination is foreseeable yet there are multiple challenges which must be addressed to overcome the constraints. We strongly advocate continued disease surveillance and monitoring, universal coverage and intensification of core-interventions for prevention and treatment prioritizing high-risk States, strengthening cross-border collaborations for information sharing and coordinated activities, and above all sustained allocation of resources, creating the enabling environment to end malaria transmission.",signatures:"Sunil Dhiman, Vijay Veer and Vas Dev",downloadPdfUrl:"/chapter/pdf-download/61663",previewPdfUrl:"/chapter/pdf-preview/61663",authors:[{id:"244465",title:"Dr.",name:"Sunil",surname:"Dhiman",slug:"sunil-dhiman",fullName:"Sunil Dhiman"},{id:"244466",title:"Dr.",name:"Vijay",surname:"Veer",slug:"vijay-veer",fullName:"Vijay Veer"},{id:"249455",title:"Dr.",name:"Vas",surname:"Dev",slug:"vas-dev",fullName:"Vas Dev"}],corrections:null},{id:"62219",title:"Malaria Transmission in South America—Present Status and Prospects for Elimination",doi:"10.5772/intechopen.76964",slug:"malaria-transmission-in-south-america-present-status-and-prospects-for-elimination",totalDownloads:1595,totalCrossrefCites:5,totalDimensionsCites:15,hasAltmetrics:0,abstract:"Four countries (Brazil, Colombia, Peru, and Venezuela) together contributed ~80% of the 875,000 malaria cases reported in the Latin American region (2016). During the 10-year period (2005–2015) when global malaria incidence was dramatically reduced, Brazil and Colombia were an integral part of this trend, on track to meet the mid-term 2020 goal established by the World Health Organization. In Colombia, since 2015 at the cessation of a five-year globally funded malaria program, both incidence and proportion of Plasmodium falciparum infections have increased, mainly due to the budget constraints. Similarly, despite a strong record and major recognition for reducing malaria, in 2017, Brazil has seen a resurgence of malaria cases, but no increase in the proportion of Plasmodium falciparum to P. vivax. A globally funded malaria control program in Peru from 2005 to 2010 resulted in appreciable reduction in the annual parasitic incidence down to 1/1000 by 2011–2012, but soon after, the annual malaria incidence began to rise and by the end of 2017, there were 53,261 reported cases. To add to Venezuela’s political and financial woes, malaria continues to increase, such that, 300,189 cases were reported by the end of week 42, 2017. The only rational pathway to malaria elimination is sustained nation-level financial support that does not fall prey to political vicissitudes.",signatures:"Jan Evelyn Conn, Maria Eugenia Grillet, Margarita Correa and Maria\nAnice Mureb Sallum",downloadPdfUrl:"/chapter/pdf-download/62219",previewPdfUrl:"/chapter/pdf-preview/62219",authors:[{id:"154256",title:"Prof.",name:"Maria Anice",surname:"Sallum",slug:"maria-anice-sallum",fullName:"Maria Anice Sallum"},{id:"214033",title:"Prof.",name:"Jan",surname:"Conn",slug:"jan-conn",fullName:"Jan Conn"}],corrections:null},{id:"60602",title:"Malaria Eradication in the European World: Historical Perspective and Imminent Threats",doi:"10.5772/intechopen.76435",slug:"malaria-eradication-in-the-european-world-historical-perspective-and-imminent-threats",totalDownloads:1559,totalCrossrefCites:5,totalDimensionsCites:7,hasAltmetrics:1,abstract:"Malaria was introduced to Europe from the southeast during the Neolithic period and subsequently became established throughout the continent, due to the combination of favorable geomorphological and climatic conditions with the presence of adequately sized human and competent vector populations. Plasmodium vivax, P. malariae and P. falciparum all occurred in various areas of the continent, transmitted by numerous Anopheles species, mainly An. atroparvus in the northwest, An. labranchiae and An. sacharovi in the south. The height of malaria endemicity in the Early Modern Age was followed by decline in the twentieth century, particularly in the northwest, owing mainly to man-made contraction of vector breeding sites and improvement of living standards. Eradication was accomplished in 1974 through widespread drug treatment and residual insecticide spraying. Since then, despite the sustained presence of competent vectors and numerous malaria cases imported by travelers and immigrants, autochthonous transmission has been sporadic in Europe, probably due to prompt diagnosis and treatment afforded by robust healthcare services. Current and projected climatic conditions are conducive to malaria transmission, particularly vivax malaria, in several areas of Southern Europe. Moreover, the continuing immigration crisis may facilitate the buildup of an infectious parasite reservoir in the area. Although malaria resurgence is currently unlikely particularly in northwest Europe, it is of crucial importance to maintain disease awareness, diagnostic and clinical competence and robust public health infrastructure for surveillance and vector control to diminish the possibility of malaria transmission in Europe’s most vulnerable areas.",signatures:"Evangelia-Theophano Piperaki",downloadPdfUrl:"/chapter/pdf-download/60602",previewPdfUrl:"/chapter/pdf-preview/60602",authors:[{id:"213542",title:"Dr.",name:"Evangelia - Theophano",surname:"Piperaki",slug:"evangelia-theophano-piperaki",fullName:"Evangelia - Theophano Piperaki"}],corrections:null},{id:"61237",title:"Assessing Malaria Vaccine Efficacy",doi:"10.5772/intechopen.77044",slug:"assessing-malaria-vaccine-efficacy",totalDownloads:1360,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"After many years of silence, eradication of malaria is, once again, one of the top priorities on the agenda of many international health and development agencies. To meet this idealistic goal, a combination of control tools is needed. From this armentarium, a malaria vaccine is central to prevent infection and/or disease. However, numerous malaria vaccine candidates have shown limited efficacy in Phase II and III studies. One reason for these failures has been that the assessment of efficacy in the context of malaria has been difficult to standardize. In this article, we have reviewed and discussed the different ways to assess the outcome of a malaria vaccination.",signatures:"Laurent Rénia, Yun Shan Goh, Kaitian Peng, Marjorie Mauduit and\nGeorges Snounou",downloadPdfUrl:"/chapter/pdf-download/61237",previewPdfUrl:"/chapter/pdf-preview/61237",authors:[{id:"215401",title:"Prof.",name:"Laurent",surname:"Renia",slug:"laurent-renia",fullName:"Laurent Renia"},{id:"243625",title:"Dr.",name:"Yun Shan",surname:"Goh",slug:"yun-shan-goh",fullName:"Yun Shan Goh"},{id:"243626",title:"Dr.",name:"Katian",surname:"Peng",slug:"katian-peng",fullName:"Katian Peng"},{id:"243628",title:"Dr.",name:"Marjorie",surname:"Mauduit",slug:"marjorie-mauduit",fullName:"Marjorie Mauduit"},{id:"243629",title:"Dr.",name:"Georges",surname:"Snounou",slug:"georges-snounou",fullName:"Georges Snounou"}],corrections:null},{id:"61993",title:"Malaria Transmission-Blocking Vaccines: Present Status and Future Perspectives",doi:"10.5772/intechopen.77241",slug:"malaria-transmission-blocking-vaccines-present-status-and-future-perspectives",totalDownloads:1744,totalCrossrefCites:9,totalDimensionsCites:14,hasAltmetrics:1,abstract:"Transmission-blocking vaccines (TBVs) utilize Plasmodium sexual stage proteins to induce antibodies that prevent parasites from infecting blood-fed mosquitoes. This type of vaccine, which can be considered a “vaccine of solidarity,” reduces Plasmodium infections within communities without conferring direct protective immunity to the vaccine recipients. The leading TBV candidates have advanced to field clinical trials, where vaccine-induced antibody function has been demonstrated in mosquito-feeding assays. However, the duration of functional antibody responses has been short-lived; hence current development has focused on improved adjuvant and vaccine delivery systems to generate long-lasting immune responses. For the future implementation of TBVs, community perceptions and understandings should be considered, and education should be provided on the concept and its value. Implementation will need to be undertaken in harmony with current malaria control policies.",signatures:"Ogobara K. Doumbo, Karamoko Niaré, Sara A. Healy, Issaka Sagara\nand Patrick E. Duffy",downloadPdfUrl:"/chapter/pdf-download/61993",previewPdfUrl:"/chapter/pdf-preview/61993",authors:[{id:"220804",title:"Prof.",name:"Ogobara",surname:"Doumbo",slug:"ogobara-doumbo",fullName:"Ogobara Doumbo"}],corrections:null},{id:"60183",title:"Newer Approaches for Malaria Vector Control and Challenges of Outdoor Transmission",doi:"10.5772/intechopen.75513",slug:"newer-approaches-for-malaria-vector-control-and-challenges-of-outdoor-transmission",totalDownloads:2053,totalCrossrefCites:6,totalDimensionsCites:15,hasAltmetrics:0,abstract:"The effective and reliable management of malaria vectors is still a global challenge. Recently, it has been noted that the first vaccine against Plasmodium falciparum malaria, RTS,S/AS01 showed only transient protection, particularly in infants, and rapid resistance has been developing to artemisinin-based drugs. Therefore, the control of malaria mosquito vectors according to strategies of integrated vector management (IVM) is receiving emphasis. A rather wide number of novel mosquito control tools have been tested, including attractive toxic sugar baits, eave tubes, nano-synthesized pesticides loaded with microbial- and plant-borne compounds, biocontrol agents with little non-target effects, new adult repellents, oviposition deterrents, and even acoustic larvicides. However, their real-world applications remain limited. Most National Malaria Control Programs in Africa still rely on indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) to reduce malaria incidence but generally have insufficient impact on malaria prevalence. Here, we focus on facts, trends, and current challenges in the employment of the above-mentioned vector control tools in the fight against malaria. We emphasize the needs for better vector control tools used in IVM to overcome the challenges posed by outdoor transmission and growing levels of insecticide resistance, which are threatening the efficacy of LLINs and IRS.",signatures:"John C. Beier, André B.B. Wilke and Giovanni Benelli",downloadPdfUrl:"/chapter/pdf-download/60183",previewPdfUrl:"/chapter/pdf-preview/60183",authors:[{id:"212309",title:"Prof.",name:"John C.",surname:"Beier",slug:"john-c.-beier",fullName:"John C. Beier"},{id:"238235",title:"Dr.",name:"Andre",surname:"Wilke",slug:"andre-wilke",fullName:"Andre Wilke"},{id:"238241",title:"Dr.",name:"Giovanni",surname:"Benelli",slug:"giovanni-benelli",fullName:"Giovanni Benelli"}],corrections:null},{id:"61802",title:"Entomological Surveillance as a Cornerstone of Malaria Elimination: A Critical Appraisal",doi:"10.5772/intechopen.78007",slug:"entomological-surveillance-as-a-cornerstone-of-malaria-elimination-a-critical-appraisal",totalDownloads:1895,totalCrossrefCites:6,totalDimensionsCites:22,hasAltmetrics:0,abstract:"Global capacity for developing new insecticides and vector control products, as well as mathematical models to evaluate their likely impact upon malaria transmission has greatly improved in recent years. Given that a range of new vector control products are now emerging that target a greater diversity of adult mosquito behaviours, it should soon be feasible to effectively tackle a broader range of mosquito species and settings. However, the primary obstacles to further progress towards more effective malaria vector control are now paucities of routine programmatic entomological surveillance, and capacity for data processing, analysis and interpretation in endemic countries. Well-established entomological methods need to be more widely utilized for routine programmatic surveillance of vector behaviours and insecticide susceptibility, the effectiveness of vector control products and processes, and their impacts on mosquito populations. Such programmatic data may also be useful for simulation analyses of mosquito life histories, to identify opportunities for pre-emptively intervening early in the life cycle of mosquitoes, rather than targeting transmission events occurring when they are older. Current obstacles to more effective utilization, archiving and sharing of entomological data largely centre around global inequities of analytical capacity. These prohibitive and unfair imbalances can be addressed by reorienting funding schemes to emphasize south-centred collaborations focused on malaria-endemic countries.",signatures:"Gerry F. Killeen, Prosper P. Chaki, Thomas E. Reed, Catherine L.\nMoyes and Nicodem J. Govella",downloadPdfUrl:"/chapter/pdf-download/61802",previewPdfUrl:"/chapter/pdf-preview/61802",authors:[{id:"217064",title:"Dr.",name:"Gerry",surname:"Killeen",slug:"gerry-killeen",fullName:"Gerry Killeen"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:[{id:"65",label:"highly cited contributor"}]},relatedBooks:[{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3432",title:"Current Topics in Public Health",subtitle:null,isOpenForSubmission:!1,hash:"bbfaa5b624db308171170cb70e9de196",slug:"current-topics-in-public-health",bookSignature:"Alfonso J. Rodriguez-Morales",coverURL:"https://cdn.intechopen.com/books/images_new/3432.jpg",editedByType:"Edited by",editors:[{id:"131400",title:"Prof.",name:"Alfonso J.",surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1809",title:"Insight and Control of Infectious Disease in Global Scenario",subtitle:null,isOpenForSubmission:!1,hash:"3ef57f4cdbc59a806312c24bff4e3097",slug:"insight-and-control-of-infectious-disease-in-global-scenario",bookSignature:"Priti Kumar Roy",coverURL:"https://cdn.intechopen.com/books/images_new/1809.jpg",editedByType:"Edited by",editors:[{id:"95723",title:"Dr.",name:"Roy",surname:"Priti",slug:"roy-priti",fullName:"Roy Priti"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"670",title:"Addictions",subtitle:"From Pathophysiology to Treatment",isOpenForSubmission:!1,hash:"9c807a142be4c589ba8d325568a2d9ae",slug:"addictions-from-pathophysiology-to-treatment",bookSignature:"David Belin",coverURL:"https://cdn.intechopen.com/books/images_new/670.jpg",editedByType:"Edited by",editors:[{id:"97877",title:"Dr.",name:"David",surname:"Belin",slug:"david-belin",fullName:"David Belin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"762",title:"Contemporary and Innovative Practice in Palliative Care",subtitle:null,isOpenForSubmission:!1,hash:"243832000765abc39fee7009494c2ab0",slug:"contemporary-and-innovative-practice-in-palliative-care",bookSignature:"Esther Chang and Amanda Johnson",coverURL:"https://cdn.intechopen.com/books/images_new/762.jpg",editedByType:"Edited by",editors:[{id:"86476",title:"Prof.",name:"Esther",surname:"Chang",slug:"esther-chang",fullName:"Esther Chang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5171",title:"Recent Advances in Drug Addiction Research and Clinical Applications",subtitle:null,isOpenForSubmission:!1,hash:"d4d43741fe591f3102735d26db3c51a0",slug:"recent-advances-in-drug-addiction-research-and-clinical-applications",bookSignature:"William M. Meil and Christina L. Ruby",coverURL:"https://cdn.intechopen.com/books/images_new/5171.jpg",editedByType:"Edited by",editors:[{id:"87876",title:"Dr.",name:"William M.",surname:"Meil",slug:"william-m.-meil",fullName:"William M. Meil"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1886",title:"Primary Care at a Glance",subtitle:"Hot Topics and New Insights",isOpenForSubmission:!1,hash:"aa9970e335b085064f8b2b9cc44fb81d",slug:"primary-care-at-a-glance-hot-topics-and-new-insights",bookSignature:"Oreste Capelli",coverURL:"https://cdn.intechopen.com/books/images_new/1886.jpg",editedByType:"Edited by",editors:[{id:"110047",title:"Dr.",name:"Oreste",surname:"Capelli",slug:"oreste-capelli",fullName:"Oreste Capelli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5796",title:"Dengue",subtitle:"Immunopathology and Control Strategies",isOpenForSubmission:!1,hash:"ea7594d938547fcd4fe8d358527695b0",slug:"dengue-immunopathology-and-control-strategies",bookSignature:"Márcia Aparecida Sperança",coverURL:"https://cdn.intechopen.com/books/images_new/5796.jpg",editedByType:"Edited by",editors:[{id:"176579",title:"Dr.",name:"Márcia Aparecida",surname:"Sperança",slug:"marcia-aparecida-speranca",fullName:"Márcia Aparecida Sperança"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7222",title:"Current Topics in Tropical Emerging Diseases and Travel Medicine",subtitle:null,isOpenForSubmission:!1,hash:"35b395a032b539cba98549da7d337bd1",slug:"current-topics-in-tropical-emerging-diseases-and-travel-medicine",bookSignature:"Alfonso J. Rodriguez-Morales",coverURL:"https://cdn.intechopen.com/books/images_new/7222.jpg",editedByType:"Edited by",editors:[{id:"131400",title:"Prof.",name:"Alfonso J.",surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5387",title:"Worldwide Wound Healing",subtitle:"Innovation in Natural and Conventional Methods",isOpenForSubmission:!1,hash:"7fce44f4147d70a5f22ce850dedc729a",slug:"worldwide-wound-healing-innovation-in-natural-and-conventional-methods",bookSignature:"Cesar Joao Vicente da Fonseca",coverURL:"https://cdn.intechopen.com/books/images_new/5387.jpg",editedByType:"Edited by",editors:[{id:"182006",title:"Prof.",name:"César",surname:"Fonseca",slug:"cesar-fonseca",fullName:"César Fonseca"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"66300",slug:"corrigendum-to-recovery-intervention-to-promote-social-connectedness-through-social-recreational-pro",title:"Corrigendum to: Recovery Intervention to Promote Social Connectedness through Social Recreational Programs for Persons with Dementia: A Critical Analysis",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/66300.pdf",downloadPdfUrl:"/chapter/pdf-download/66300",previewPdfUrl:"/chapter/pdf-preview/66300",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/66300",risUrl:"/chapter/ris/66300",chapter:{id:"65375",slug:"recovery-intervention-to-promote-social-connectedness-through-social-recreational-programs-for-perso",signatures:"Winnie Sun, Shelby-Lynne Clarke, Hanaan Madahey and Ping Zou",dateSubmitted:"November 12th 2018",dateReviewed:"December 22nd 2018",datePrePublished:"January 28th 2019",datePublished:"April 10th 2019",book:{id:"8268",title:"Advances in Dementia Research",subtitle:null,fullTitle:"Advances in Dementia Research",slug:"advances-in-dementia-research",publishedDate:"April 10th 2019",bookSignature:"Ghulam Md. 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Ashraf",coverURL:"https://cdn.intechopen.com/books/images_new/8268.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"199287",title:"Dr.",name:"Ghulam Md",middleName:null,surname:"Ashraf",slug:"ghulam-md-ashraf",fullName:"Ghulam Md Ashraf"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"219759",title:"Dr.",name:"Winnie",middleName:null,surname:"Sun",fullName:"Winnie Sun",slug:"winnie-sun",email:"winnie.sun@uoit.ca",position:null,institution:{name:"University of Ontario Institute of Technology",institutionURL:null,country:{name:"Canada"}}},{id:"284558",title:"Dr.",name:"Shelby-Lynne",middleName:null,surname:"Clarke",fullName:"Shelby-Lynne Clarke",slug:"shelby-lynne-clarke",email:"shelbylynne.clarke@gmail.com",position:null,institution:null},{id:"284561",title:"Dr.",name:"Hanaan",middleName:null,surname:"Madahey",fullName:"Hanaan Madahey",slug:"hanaan-madahey",email:"hanaan.madahey@uoit.net",position:null,institution:null},{id:"284562",title:"Dr.",name:"Ping",middleName:null,surname:"Zou",fullName:"Ping Zou",slug:"ping-zou",email:"pingz@nipissingu.ca",position:null,institution:null}]},book:{id:"8268",title:"Advances in Dementia Research",subtitle:null,fullTitle:"Advances in Dementia Research",slug:"advances-in-dementia-research",publishedDate:"April 10th 2019",bookSignature:"Ghulam Md. Ashraf",coverURL:"https://cdn.intechopen.com/books/images_new/8268.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"199287",title:"Dr.",name:"Ghulam Md",middleName:null,surname:"Ashraf",slug:"ghulam-md-ashraf",fullName:"Ghulam Md Ashraf"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11804",leadTitle:null,title:"CRISPR Technology",subtitle:null,reviewType:"peer-reviewed",abstract:"\r\n\tClustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated (Cas) protein is a system originated from bacteria that confer resistance to plasmids or phages and provides an adaptive immunity for the host. CRISPR RNAs (crRNAs) are transcribed from CRISPR locuses. Transactivating crRNA (tracrRNA) is partially complementary to and pairs with a pre-crRNA to form an RNA duplex cleaved by RNase III and a crRNA/tracrRNA hybrid acts as a guide for the endonuclease Cas, which cleaves the invading DNA. Currently, it has been successfully used in genome editing such as silencing, enhancing, or modification of specific genes. Plasmids are constructed to express crRNA and tracrRNA together as single-guide RNAs (sgRNA). By the Cas proteins and a specifically designed sgRNA, the organism’s genome can be cleaved at most locations with the only limitation being the availability of an NGG protospacer adjacent motif (PAM) sequence in the targeting site. Efficient genome engineering has been performed in human cells, bacteria, yeasts, zebrafish, nematodes, plants, animals, etc. These findings and their implications may be discussed in the broadest context possible. Future research directions may also be highlighted. In this book, we will explore the development of CRISPR-Cas encoding and its application in basic research.
",isbn:"978-1-80356-816-4",printIsbn:"978-1-80356-815-7",pdfIsbn:"978-1-80356-817-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"4051570f538bd3315e051267180abe37",bookSignature:"Dr. Yuan-Chuan Chen",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11804.jpg",keywords:"crRNA, tracr RNA, sgRNA, PAM sequence, Encoding, Silencing, Enhancing, Modification, Genetic Engineering, Animal Model, Delivery Tool, CRISPR",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 30th 2022",dateEndSecondStepPublish:"June 10th 2022",dateEndThirdStepPublish:"August 9th 2022",dateEndFourthStepPublish:"October 28th 2022",dateEndFifthStepPublish:"December 27th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"25 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Yuan-Chuan Chen completed his Ph.D. in Comparative Biochemistry at the University of California, Berkeley (UCB), USA. His studies are focusing on the discovery, production, application of biopharmaceuticals. Additionally, he is interested in basic research and human therapeutics using CRISPR/Cas9.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"185559",title:"Dr.",name:"Yuan-Chuan",middleName:null,surname:"Chen",slug:"yuan-chuan-chen",fullName:"Yuan-Chuan Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/185559/images/system/185559.jpg",biography:"Yuan-Chuan Chen completed his PhD in Comparative Biochemistry at the University of California, Berkeley (UCB), USA and had postdoctoral studies at the Taiwan Food and Drug Administration (TFDA). His research interests include Pharmacy/Pharmacology, Biochemistry, Microbiology/Virology, Cell/Molecule Biology, Biotechnology/Nanotechnology, Cell/Gene therapy and Policy/Regulation. He has participated in publishing many co-authored articles in peer-reviewed journals and book chapters in the fields of basic science, biomedicine, and related policy/regulation. He is now an assistant professor in Jenteh Junior College of Medicine, Nursing and Management, Taiwan. He is also an adjunct member in the biopharmaceutical division of Chinese Pharmacopoeia (Taiwan) Revising Committee (9th edition) and has reviewed many materials for Pharmacopoeia revising. His research is focusing on the discovery, production, application, perspectives and challenges of biopharmaceuticals. He is interested in basic research, the development of agricultural/industrial products and human therapeutics using the CRISPR/Cas9 system. Additionally, he is specialized in genomic studies including genomic analysis, gene function, and gene expression and control.",institutionString:"Jenteh Junior College of Medicine, Nursing and Management",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453623",firstName:"Silvia",lastName:"Sabo",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/453623/images/20396_n.jpg",email:"silvia@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"6694",title:"New Trends in Ion Exchange Studies",subtitle:null,isOpenForSubmission:!1,hash:"3de8c8b090fd8faa7c11ec5b387c486a",slug:"new-trends-in-ion-exchange-studies",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6694.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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The term stability of metal complex cannot be generalized since the complex may be stable to one reagent/condition and may decompose in presence of another reagent/condition. The stability of metal complexes can be explained with the help of two different aspects, namely, thermodynamic stability and kinetic stability [2]. Nevertheless, a metal complex is said to be stable if it does not react with water, which would lead to a decrease in the free energy of the system, i.e., thermodynamic stability. On the other hand, the complex is said to possess kinetic stability if it reacts with water to form a stable product and there is a known mechanism through which the reaction can proceed. For example, the system may not have sufficient energy available to break a strong bond, although once the existing bond is broken it could be replaced by new bond which is stronger than the older one [1]. Stability of complex compound is assigned to be its existence in aqueous solution with respect to its bond dissociation energy, Gibbs free energy, standard electrode potential, pH of the solution, and rate constant or activation energy for substitution reactions.
Thermodynamic stability of a complex refers to its tendency to exist under equilibrium conditions. It determines the extent to which the complex will be formed or be converted into another complex at the point of equilibrium. In other words, thermodynamic stability of complexes is the measure of tendency of a metal ion to selectively form a specific metal complex and is directly related to the metal-ligand bond energies. The thermodynamic stability of complexes is represented by formation constant. The formation constant is also known as stability constant, which is the equilibrium constant obtained for the formation metal complex [1, 2].
In general, the metal complexes are not prepared from their corresponding starting materials in gaseous phase but are prepared in aqueous solution. In aqueous solution, a metal cation gets hydrated to give aqua complex of the type [M(H2O)x]n+. When a ligand replaces water molecule from aqua complex ion, a new metal complex is formed and equilibrium is established as shown:
where x is the number of water molecules, n is the oxidation number of the metal cation, and L is the neutral and monodentate ligand. For simplicity, the above reaction can be written in generalized form as given:
The equilibrium constant K
In the above equation, the concentration of water is not included. Since the solution is dilute, the water molecules which enter the bulk solution do not have much influence on the equilibrium constant. It is observed from Eq. (3) that the higher the value of K
The steady decrease in the value of stepwise formation constants from K1 to Kn is due to:
Increase in the number of ligands in coordination sphere that causes to decrease the number of H2O molecules to be replaced and thus the probability of replacement of water molecules decreased
Electrostatic factor
Steric hindrance with increase in number of ligands
Statistical factors (number of replaceable positions)
However, in some cases, it is found that Kn+1 > Kn because of unusual structural changes and changes in electronic configuration of the metal ion. The change in electronic structure of the metal ion causes the variation in the crystal field stabilization energy (CFSE). The complex with higher CFSE value will be stable, and the equilibrium constant for that complex formation will be high. One such example is the formation of [CdBr4]2− complex in aqueous solution. The reaction of aqua complex [Cd(H2O)6]2+ with Br− ligand exhibits four stepwise equilibrium or stepwise formation constants K1, K2, K3, and K4. The order of stepwise formation constants is observed as follows, K1 > K2 > K3 < K4, which is not in agreement with the common trend of K1 > K2 > K3 > K4. Aqua complex of most of the M2+ ions including Cd2+ are octahedral, whereas the halo complexes of Cd2+ ion are tetrahedral. The reaction sequence for the formation of [CdBr4]2− is given as follows:
In the final step, there is an unusual structural change from six coordinated octahedral [Cd(H2O)3Br3]− complex to four coordinated tetrahedral [CdBr4]2− complex in addition to change in the electronic configuration which lead to K4 > K3.
The formation constant (K
Since ∆G° is a thermodynamic property, the formation constant is the measure of thermodynamic stability. From Eqs. (4) to (6), it can be interpreted that the thermodynamic stability of a complex can be measured in terms of formation constant, Gibbs free energy change, and standard electrode potential. A high negative value of ∆G° indicates that the position of equilibrium favors the product (complex); hence the complex formed will be more stable.
The formation constant describes the formation of a complex from metal cation and ligands. Bjerrum (1941) defined that the formation of a metal complex in aqueous solution takes place by replacing the water molecule by another ligand (L) [5, 6]. It is assumed that this reaction does not occur in a single step but occurs in several steps, and each step is characterized by its individual equilibrium constant called as stepwise formation constant (K). For example, consider the formation of a complex [MLn] formed by the following reactions:
By assuming the value of activity coefficients as unity, the equilibrium constant K1 for the complex (ML) having one ligand (L) will be given as
When the metal complex ML reacts with one more ligand L,
and the equilibrium constant K2 will be
Similarly, for the formation of the complex MLn from MLn−1 and L, the equilibrium constant is represented as follows,
The equilibrium constants K1, K2, …, Kn are known as stepwise formation constants. On the other hand, the equilibrium constant for the overall reaction may be considered as
where β1, β2, β3, …, βn are the equilibrium constants called as overall formation constants and K1, K2, K3, …, Kn are stepwise stability or formation constants. The products of stepwise constants are Ks and βs are related one another. For example, consider the product of stepwise formation constants K1, K2, K3, …, Kn.
Above equation indicates that the overall formation constant (β) is equal to the product of the stepwise formation constant K1, K2, K3, …, Kn.
Kinetic stability is related to the reactivity of the metal complexes in solution and deals with the rate of the reaction, its activation energy, etc. Kinetic stability is also related to how fast a compound reacts rather than how stable it is. It aids in determining the rate at which the reaction occurs to establish the equilibrium [7].
The term kinetic stability of complexes is classified into labile and inert by Taube on the basis of rate of the reactions. When the rate of substitution of ligands is high, the complex is said to be labile. For example, the copper complex of the formula [Cu(NH3)4(H2O)2]2+ is labile. In aqueous solution the complex is blue in color, and when concentrated hydrochloric acid is added to this solution, the solution turns green giving rise to complex [CuCl4]2+. On the other hand, in inert complexes the rate of ligand exchange is very slow, and the ligands are very exchanged with difficulty. For example, the cobalt complex [Co(NH3)6]3+ reacts slowly, and no reaction takes place at room temperature when conc. HCl was added to the aqueous solution. However, only one NH3 ligand was found to be substituted by Cl ligand, when the aqueous solution of the complex was heated with 6M hydrochloric acid.
For metal complexes, the stability and reactivity are described in thermodynamic and kinetic terms, respectively. In particular, the terms stable and unstable are related to thermodynamic aspects, whereas labile and inert terms are related to kinetic aspects. As a rule of thumb, a metal complex is said to be labile if it reacts within 1 min at 25°C, and if it takes longer time, it is considered to be inert.
Thermodynamic stability refers to the energy change that occurs while starting materials are converted to products, that is, ∆G, for the reaction. The change in free energy is given by the equation ∆G = ∆H−T∆S = −RTlnK, where ∆S is the entropy, ∆H is the enthalpy, and K is the equilibrium constant for the reaction. Kinetic stability refers to reactivity or the ability of the metal complex to undergo ligand substitution reactions. Complexes which undergo extremely rapid ligand substitution reaction are referred to as labile complexes, and complexes that undergo extremely slow ligand substitution reaction are referred to as inert complexes. Sometimes the thermodynamic and kinetic stabilities of complexes are parallel to one another, but often they do not. One of the suitable examples for thermodynamically stable and kinetically inert complex is [Ni(CN)4]2− as it undergoes ligand substitution reaction very rapidly. On the other hand, the cobalt complex [Co(NH3)6]3+ is thermodynamically unstable but kinetically inert. The complex [Co(NH3)6]3+ is thermodynamically unstable since the complex was observed to decompose very rapidly with rate in the order of 1025 in acidic solution. However, no ligand substitution reaction is found when the complex is kept in acidic solution for several days; hence the complex is kinetically inert. From the above two examples, it can be interpreted that the stability of a complex mainly depends upon the conditions, and it is always recommended to specify the conditions such as pH, temperature, etc. while mentioning the stability of the complex. In brief, it is not necessary for a stable complex to be inert and an unstable complex to be labile.
Consider the three complexes [Ni(CN)4]2−, [Mn(CN)6]3−, and [Cr(CN)6]3−. All the complexes are thermodynamically stable, but kinetically they behave in a different manner. The rate of exchange can be measured when carbon-14-labelled cyanide ions are reacted with metal complexes in solution. It indicates that [Ni(CN)4]2− is labile, [Mn(CN)6]3− is less labile, and [Cr(CN)6]3− is inert and proves that not all stable complexes are inert and vice versa.
There are several factors that can affect the stability of the metal complexes [2, 5, 8, 9], which include:
Nature of the central metal ion
Nature of the ligand
Chelating effect
Macrocyclic effect
Resonance effect
Steric effect or steric hindrance
In metal cations, higher oxidation state forms more stable complex than lower oxidation states with ligands such as NH3, H2O, etc. Even few exceptions are there like CO, PMe3, o-phenanthroline, bipyridyl, CN−, which form more stable complex with lower oxidation state metals.
The stability of metal complex increases with decrease in size of the metal cations. For M2+ ions, the general trend in stability for complexes is
This trend in stability is known as Irving-Williams series.
This order of stability is also in good agreement with the charge to radius ratio concept because the radii decrease from Ba2+ to Cu2+ and then increased to Zn2+. The order of size of dipositive ions is
Basic character of ligands: The greater is the basic character of ligand, the more easily it can donate its lone pair of electrons to the central metal ion and hence greater is the complex stability. In 3D-series metal ion, order of stability of complex with NH3, H2O, and F− is:
The nature of metal-ligand bond also affects the stability of metal complexes. The higher the covalent character, the greater will be the complex stability. For example, the stabilities of silver complexes have different halide ligands which are in the following order:
Ligands having vacant p- or d-orbital tend to form π bond and hence form stable complexes with metals. Ligands that are capable of forming such π bond are CO, CN−, alkene, phenanthroline, etc.
The chelate effect is that the complexes resulting from coordination of metal ions with the chelating ligand are thermodynamically much more stable than the complexes with non-chelating ligands [10, 11]. Chelating ligands are molecules which can bind to single metal ion through several bonds and are also called as multidentate ligands. Simple (and common) examples include ethylenediamine and oxalate. Non-chelating ligands are ligands that bond to just one site, such as chloride, cyanide, and water.
The chelate effect can be understood by comparing the reaction of a metal ion, respectively, with a chelating ligand and with a monodentate ligand having similar/comparable donating groups. During the comparison study, the number of coordination should be maintained equal in both the cases, for example, the value obtained while adding a bidentate ligand is compared with the value obtained for two monodentate ligands. For example, coordination of metal ion with chelating ligand 2,2′-bipyridine can be compared with that of monodentate pyridine ligand. Another such comparison can be made between coordination behavior of chelating 1,2-diaminoethane (ethylenediamine = en) and monodentate ammonia. Such comparison studies revealed that the metal complex formed from chelating ligands are thermodynamically more stable than the complex formed from monodentate ligand. For example, formation of complexes from hydrated cadmium ion, [Cd(H2O)4]2+ with methylamine (CH3NH2), ethylenediamine (en) and triethylenetetramine (trien), and their stability is in the following order:
A macrocyclic ligand is a cyclic molecule that contains nine or more atoms in the cyclic structure and has three or more potential donor atoms which can coordinate to the metal ion. It has been observed that the stability of metal complexes in the presence of macrocyclic ligand of appropriate size is higher than the stability of complexes coordinated to open-ended multidentate chelating ligands. Some notable examples of macrocyclic ligands include cyclic crown polyether, heme, etc. [12].
Resonance increases the stability of the complexes. For example, acetylacetonate anion ligand shows resonance, and as a result it forms stable complexes upon reacting with metal ion (Figure 1). The ligand-metal π bonding increases the delocalization of electrons compared to free enolate as shown below and leads to increased stability (Figure 2).
Resonance structure of acetonylacetonate ligand.
Acetonylacetonate-metal complex.
The presence of bulky substituents in the ligands can affect the stability of the metal complex, and this type of destabilization of metal complex due to bulkiness of the substituent is called as steric effect [13]. For example, consider the ligand 8-hydroxy quinoline and its methyl substituted derivative 2-methyl-8-hydroxy quinolone. Both are bidentate ligands and form chelated complexes with Ni2+ ion as shown in Figure 3.
Chelating complexes of Ni(II) ion showing steric effect.
The complex (II) is less stable than complex (I) because of bulky group attached to an atom adjacent to donor atom which cause a steric hindrance and lower the stability of the complex.
The crystal field stabilization energy (CFSE) is one of the most important factors that decides the stability of the metal complexes. CFSE is the stability that arises when a metal ion coordinates to a set of ligands, which is due to the generation of a crystal field by the ligands. Thus, a higher value of CFSE means that the complex is thermodynamically stable and kinetically inert. Some of the notable examples of complexes that have high CFSE are low spin 5d6 complexes of Pt4+ and Ir3+ and square planar 5d8 complexes of Pt2+. All these complexes are thermodynamically stable and kinetically inert, which undergo ligand substitution reactions extremely slowly [3, 4].
The determination of metal complexes involves several methods including spectroscopic and potentiometric methods. The determination of stability constant is very significant to understand the role and behavior of ligand(s) in stabilizing the metal complexes and found applications in the fields of biology, environmental study, metallurgy, food chemistry, and many other industrial processes. Some of the methods that are used for the determination of stability constants are given as follows.
UV-Vis spectroscopic technique has been used to determine the stability constant and composition of a complex [14]. The formation of metal complex is indicated by the change in absorbance in the UV-Vis spectroscopy. The relationship between absorbance (A) and concentration is given by Beer’s law as shown.
where ԑ = molar extinction coefficient, l = path length of the absorption cell, c = concentration of the complex.
From the above equation, the concentration (c) of the metal complex can be calculated by measuring absorbance (A) using spectrophotometer and knowing the molar extinction coefficient (ԑ) at that wavelength (λ) and path length (l). For example, consider the formation constant (K
By knowing the values of [MLn+], [M], and [L], Kf can be calculated. [MLn+], [M], and [L] can be calculated as follows:
where CL and CM are the total concentrations of the ligand and metal ion, respectively.
From Beer’s law
On rearranging
On substituting Eq. (11) in (8), we get
Similarly, from Eqs. (9) and (11), we get
By introducing the values of [MLn+], [Mn+], and [L] from Eqs. (11) to (13) in the formation constant Eq. (7), we can determine the value of K
Job’s method of continuous variations (MCV) is used to determine the complex formation as well as stability constants [14, 15]. Job’s method is basically used to determine the composition of metal complexes, and this is the modified version of spectroscopic method. This method is applicable in the case of solutions, where the formation of one metal complex takes place.
This method includes the following steps:
Make a volume of 10 mL solutions of metal complex containing different proportions of metal ion as well as ligand. The number of solutions should be 10.
Sr. no. of solution: | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
Volume of metal ion (mL) | 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 |
Volume of ligand (mL) | 9 | 8 | 7 | 6 | 5 | 4 | 3 | 2 | 1 | 0 |
Here the total concentration of the solution is constant, i.e., sum of concentration of the metal, CM, and the ligand, CL, is fixed. Therefore:
In the next step, optical densities of the solutions prepared in the previous step are to be determined spectrophotometrically at the wavelength of light which is strongly absorbed by metal complex but does not get absorbed by metal ion and ligand.
A plot between mole fraction (
On the extrapolation of the curve, the legs of the curve intersect each other at a point which is the point of maximum absorbance.
Suppose MLn is the formula of the complex, then
Determination of the composition of metal complex Job’s method of continuous variation.
Eq. (14) can be rewritten as:
From this equation, namely,
On reducing Eq. (16), we get.
By dividing (17) by (18), we get.
The composition of the complex, MLn, can be determined by the value of n as obtained from Eq. (19). There are some drawbacks of this method. One of the drawbacks is that this method is applicable where, under experimental conditions, only one complex is formed. Also, the total volume of the solutions which contain metal ion and ligand should not be changed. The method of continuous variations has also found tremendous application in the field of organometallic chemistry [16].
The type and extent of interaction existing between the metal ion and ligand can be investigated by various experimental methods [17, 18, 19, 20, 21], and each method requires different experimental conditions and resulted in differences in the interpretation of reaction mechanism and stability constants. Bjerrum’s method to determine the stability constant is also known as potentiometric method. This method is based on the competition between hydrogen ion and metal ion for ligand which is a weak base. Consider a metal ion and an acid such as nitric acid are added to a ligand in aqueous solution; the following equations are obtained:
When acid reacts with ligand
where Ka is acid association constant of the ligand
When metal ion reacts with ligand
where K
Let us consider CH, CM, and CL are the total concentrations of acid, metal ion, and ligand, respectively. Then
By solving above three equations and using the acid association constant Ka, we get
The concentration terms of [ML+], [M+], and [L] can be calculated potentiometrically by using a pH meter and by substituting the values of [ML+], [M+], and [L] in the formation constant (K
In the potentiometric or pH-metric determination of stability constant, a ligand and an acid such as nitric acid are titrated against standard NaOH during which period the pH of the solution has to be measured after each addition. Throughout the experimental studies, several conditions must be maintained such as
For electrical neutrality
The total concentration of the ligand is given as follows:
The protonation of the ligand can be represented as
The equilibrium constant Ka is given as
By combining Eqs. (21)–(23), we get
[OH−] and [H+] are negligible as compared to [Na+] at near neutral solution. Hence Eq. (24) becomes
The above equation is used to calculate the value of pKa of ligand.
When a ligand is titrated with a solution containing Mn+ ion and an equivalent amount of H+, the resulting solution will have an equilibrium mixture of H+, OH−, HL, L−, Mn+, M(n−1)+L, M(n−2)+L2, etc. By measuring the pH values with the help of pH meter and knowing the concentrations of Mn+, H+, HL, etc., one can calculate the stepwise stability constants K1, K2, K3, etc. During the evaluation of equilibrium constants, the concentrations of Mn+ and L− are varied, and such variations in the concentration will lead to changes in the ionic strength of the solutions. In order to maintain the constant ionic strength, a large excess of an ionic salt is added to the reaction mixture. The presence of large excess of ionic salt will compensate any changes in the ionic strength of the solution. The ionic salts that are added for such purpose should not react with M2+ or L−, and commonly used salts include KNO3 and NaClO4, due the low affinity of NO3− and ClO4− ions for most of the M2+ ions. For example, KNO3 was added in excess during the binding study of the ligand p-aminobenzoic acid with Ni, Mg, and Co metal ions. The p-aminobenzoic acid has two coordination sites such as amino and carboxylate groups and has a pKa value of 5.9153. The stability constant values obtained for Ni, Mg, and Co complexes are depicted in Table 1.
Metal | M:L ratio | |||
---|---|---|---|---|
1:1 | 1:2 | 1:5 | 2:3 | |
Ni | 8.492 | 14.8593 | 8.3598 | 3.4649 |
Mg | 8.4664 | 8.3392 | 7.0794 | 11.1943 |
Co | 8.590 | 5.3186 | 8.6337 | 6.2330 |
Stability constant values obtained for Ni, Mg and Co complexes having different metal to ligand ratio.
The stability constant values for Ni shows the trend 2:3 < 1:5 < 1:1 < 1:2, while the trend for Co is 1:2 < 2:3 < 1:1 < 1:5 and for Mg it is 1:5 < 1:2 < 1:1 < 2:3. The values obtained from the above study indicates that 1:2 complex of Ni complex is more stable, whereas Co complex is stable in 1:5 ratio and that of Mg is more stable in the ratio of 2:3.
The Irving and Rossotti method for the determination of stability constant is also based on the principle of potentiometric method [21]. Using this method, the formation curve of metal complex can directly be calculated with the help of pH meter. Another major advantage of this method over the Bjerrum’s method is that the calculation is simple and does not require hydrogen ion concentration. Moreover, this method can be used for types of ligands that are conjugate to weak acids. The calculation of stability constant using this method involves the following steps.
Step 1: The following solutions were titrated separately against base solution
Titration with free acid (A)
Titration with free acid + ligand (A + L)
Titration with free acid + ligand + metal (A + L + M)
Step 2: Calculation of formation functions n, nA, and PL using the values used/obtained from above three titrations
The term formation function “n,” also called as ligand number, is defined as the average number of ligands attached per metal center and is calculated using the following equation
The term nA is similar to n and is defined as the average number of protons bound to the ligand which are not coordinated to the metal center. PL gives the free ligand exponent. All the three terms n, nA, and PL can be calculated with the help of following equations
where N is the normality of base used; V0 is the initial volume of the solution; V1, V2, and V3 are the volume of base consumed during the (A), (A + L), and (A + L + M) titrations, respectively, at same pH value; T0L is the initial concentration of ligand; ℇ0 is the initial concentration of acid; γ is the number of titrable or replaceable protons.
Step 3: Determination of formation curves: by plotting formation function (n) against PL and nA against pH for a HL (protonated ligand) system.
The value formation constants corresponding to formation of protonated ligand are obtained by plotting nA against pH. Similarly, the stepwise stability constants for the formation of metal complexes are obtained from the formation curve resulted by plotting n against PL.
The thermodynamic and kinetic stability of coordination compounds along with the various factors affecting the stability of metal complexes have been discussed in this chapter. Stability constant and its determination have also been listed.
Authors acknowledge National Institute of Technology Kurukshetra, Haryana, India, for its support.
There is no conflict of interest.
Meningiomas (MN) are a type of central nervous system (CNS) tumors that arise from the leptomeningeal arachnoid covering the encephalon and the spinal cord, more specifically, from the arachnoid cap cells [1]. In adults, MN accounts for approximately 37.6% of all primary brain tumors, and corresponds to the most common intracranial tumor in adults over 35 years [1, 2]. According to Ostrom et al., incidence of MN in the United States (US) is 8.83 per 100,000 per year [3]. Around 90% of all MN cases are diagnosed intracranially, with the rest arising from the spinal arachnoid [4]. The median age at diagnosis for MN is 65 years [4] with the majority of patients being in the range of 55–74 [4]. Cases in the pediatric population are extremely rare, corresponding only to 0.4–4.6% of all pediatric tumors [2]. There is a female predominance in case proportion, with a female:male ratio of 3:1 for all MN, and 9:1 for spinal cord MNs [2, 5]. MNs are characterized for being slow in growth and often not infiltrative, with an insidious development of symptoms. Clinical presentation of MN might vary from patient to patient, with tumor localization being the main determining factor of clinical features. Signs and symptoms might include headaches because of increased intracranial pressure, focal neurological deficits (mainly cranial nerve focalization), and seizures. In the case of MN developing in the frontal lobe, personality changes, altered mental status and mood disturbances might appear [6].
According to the World Health Organization (WHO), MN is classified in three subtypes: common type or WHO grade I, atypical/intermediate type or WHO grade II and the anaplastic/malignant type or WHO grade III. These high-grade tumors might develop
As high-grade MN continue to be a difficult to treat condition, with high recurrence and low response rates, molecular insights into precision medicine have been investigated in the last two decades. With a better understanding of the cellular and molecular pathways underlying MN pathophysiology, recurrence and malignancy, newer therapies have been considered as possible candidates for the treatment of these conditions. Some agents include newer systemic chemotherapeutic agents like trabectedin, inhibitors of the Epidermal Growth Factor Receptor (EGFR) like erlotinib and gefitinib, inhibitors of the Platelet-Derived Growth Factor Receptor (PDGFR), inhibitors of mTOR, especially from the complex 1 (mTORC1) as well as its upstream and downstream elements (AKT/PI3K and MEK). The biological process of angiogenesis is also under research, with ongoing trials with anti-angiogenic agents from the Tyrosine Kinase Inhibitors (TKIs) targeting the Vascular Endothelial Growth Factor (VEGF) pathway, as well as antibody agents like bevacizumab. As it is expected, immunotherapy with checkpoint inhibitors is also under current investigation, with anti-PD1 and anti-PD-L1 monoclonal antibodies being tested in clinical trials. In this chapter we are going to cover the molecular biology of MNs, especially in the cases of grade II and grade III MN. We will also discuss the current knowledge in systemic treatments as well as therapies in clinical trials and possible candidates that are being tested
Advancements in understanding the pathophysiology and molecular biology of MNs are critical for improving risk evaluation and prognosis. Similarly, to design novel treatments aimed at blocking canonical pathways involved in carcinogenesis and disease evolution. As molecular analyzes of meningiomas continue to evolve, several cytogenetic, genomic, epigenetic, and expression alterations associated with tumor aggressiveness and proclivity for recurrence have been identified as potential biomarkers to enhance risk stratification [12]. Recently, several seminal studies evaluating the genomics of intracranial meningiomas have rapidly changed the understanding of the disease. The importance of NF2 (neurofibromin 2), TRAF7 (tumor necrosis factor [TNF] receptor-associated factor 7), KLF4 (Kruppel-like factor-4), AKT1, SMO (smoothened), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), and POLR2 (RNA polymerase II subunit A) demonstrates that there are at least six distinct mutational classes of meningiomas. In addition, six methylation classes of meningioma have been appreciated, enabling improved prognosis prediction compared with traditional WHO grades. Genomic studies have shed light on the nature of recurrent meningioma, distinct intracranial locations and mutational patterns, and a potential embryonic cancer stem cell-like origin [13, 14, 15, 16] (Figure 1).
Main cytogenetic and recurrent genetic alterations in recurrent and high-grade meningiomas according to the WHO classification and anatomical location.
A large number of meningiomas possess a normal karyotype, with an overall low incidence of genomic alterations (including somatic copy number alterations—SCNA, rearrangements, and low mutational burden) [17, 18, 19]. However, these disruptions increase following tumor grade, the number of recurrences, and biological aggressiveness. More than half of all identified genomic alterations involve the NF2, which underlies inherited Neurofibromatosis syndrome. Indeed, the most significant SCNA in meningioma is chromosome 22 monosomy, which is present in ~56% of cases and leads to losing the genomic locus containing NF2 (22q12.2) [20, 21]. Among grade I meningiomas, those carrying NF2 alterations are more likely to progress than those with a normal karyotype. In addition, the frequency of NF2 aberrations increases with tumor grade.
Loss of heterozygosity on chromosome 1p is present in 16% of MNs [22]. Characterization of the smallest region of overlapping deletion on this chromosome spans ~3.7 megabases and identified 59 genes, 17 of which have putative tumor-suppressive functions based on gene ontology. The protein methyltransferase and tumor suppressor RIZ1, is located on chromosome 1p, and studies implicate its loss of expression in meningioma progression [23]. Loss of the CDKN2A/CDNK2B locus on chromosome 9q is common in grade II meningiomas that transition to anaplastic lesions [24]. Additionally, a study showed that the levels of p16 and p15, the proteins encoded by CDKN2A and CDKN2B, may hold prognostic significance and/or represent a promising therapeutic target [25]. Recently, Nassiri et al. described four consensus molecular groups of MN by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation, and messenger RNA abundance in a unified analysis [26]. These molecular groups predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of defined molecular groups and uncovered highly abundant and group-specific protein targets [26].
Globally, meningiomas have a low mutation rate (~3.5 mutations per megabase) compared to other cancers [25]. Various efforts to genotype the disease using NGS have identified NF2 mutations as the predominant alteration in spontaneous and Neurofibromatosis syndrome-associated tumors [24], at a frequency of ~40% in low grade and nearly 80% in high-grade tumors [27]. MNs related to alterations in NF2 were more common in the cerebral convexities and posterior skull base than those found in other anatomic locations, and up to 13% were associated with other co-mutations, including single mutations in CREBBP, PIK3CA (R108H), PIK3R1, BRCA1, and SMARCB1 [27]. Unfortunately, within NF2 mutated meningiomas, none of these identified mutations can predict the chance of recurrence, which can vary widely.
TERT promoter mutations have recently been reported in ~6% of all MNs, with ~80% of these also harboring alterations (mutations or deletions) at the NF2 locus [28]. Similar to overall mutational burden, TERT mutations increase with tumor grade. In grade I MN, TERT C228T and C250T mutations are linked with transformation to higher grades [28], prompting many neuro-oncologists to consider standardized testing for TERT promoter mutations. Further studies demonstrate that the presence of C228T and C250T correlates with increased TERT mRNA and functional increases in telomerase activity [29]. In grade II or III tumors, univariate analysis revealed a significant association with decreased PFS (progression-free survival; median 12.5 vs. 26 months,
Non-NF2 mutated meningiomas, which generally have a benign behavior, are usually chromosomally stable, and often located in the anterior, medial, or skull base regions, possess a distinct mutational landscape [27]. Recent high throughput sequencing studies suggest an average of only 1.56 (SD ± 1.07) genomic alterations (GAs) per non-NF2 mutated tumor [31]. The pro-apoptotic E3 ubiquitin ligase, tumor necrosis factor receptor-associated factor 7 (TRAF7) is mutated ~25% of all meningiomas [31]. Such alterations occur in the C-terminal WD40 protein interaction domain, suggesting they may alter protein-protein interactions with MAPK and NF-kB family members [32]. While TRAF7 mutation is mutually exclusive with NF2 mutations, it is almost always correlated with PI3K and activating E17K mutation in AKT1, with the K409Q alteration of KLF4 [33].
AKT1, also referred to as protein kinase B, is a well-known oncogene. AKT activation relies on the PI3K pathway and is recognized as a critical node in the mTOR pathway. The E17 hotspot is the most characterized of AKT1 mutations and leads to constitutive activation of the protein. Mutations in AKT1 have also been shown to confer resistance to allosteric kinase inhibitors in vitro and are oncogenic in many solid tumors. Specifically, the E17K mutation is found in 7–12% of grade I meningiomas [34], is enriched in the meningothelial subtype [17], and is predictive of decreased PFS in olfactory groove tumors [35]. Altering the same signaling pathway PIK3CA mutations are also found in ~7% of non-NF2 tumors and are mutually exclusive with AKT1 mutation [36]. Targeted sequencing of this gene revealed novel non-synonymous mutations, A3140T and A3140G, which are reported as pathogenic, and C112T, which is also predicted to be pathogenic [31]. Indeed, increased PI3K signaling is related to aggressive behavior, especially within high-grade meningiomas [37], suggesting that therapeutics targeted toward this pathway may be a potential option.
Sequencing of 71 meningiomas genes recently identified two novel missense mutations in FGFR3, T932C, and G1376C, both of which were predicted to be pathogenic [31]. Identifying these mutations in patients with skull base low-grade tumors was associated with a good prognosis, given the absence of recurrence and the requirement of IMRT. KLF4 gene encodes a protein that belongs to the Kruppel family of transcription factors. The encoded zinc finger protein is required to control the G1-to-S transition of the cell cycle following DNA damage by mediating the tumor suppressor gene p53. In addition, KLF4 is involved in the differentiation of epithelial cells and may also function in skin, skeletal, and kidney development [38]. In meningiomas, KLF4 is thought to act as a tumor suppressor gene, expressed in low-grade tumors and downregulated in anaplastic tumors. At the genomic level, KLF4 is mutated in ~12% of grade I meningiomas, virtually all of which are of the secretory sub-type and harbor TRAF7 mutations [39]. All identified KLF4 mutations result in a K409Q substitution within the DNA binding domain, which likely alters several protein functions [40].
SMO (Smoothened, Frizzled Class Receptor) gene encoded a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. Mutations in SMO, which result in L412F or W535L substitutions, lead to functional activation of Hedgehog signaling in meningioma [17, 41]. These mutations are present in ~5.5% of grade I meningiomas and are mutually exclusive with TRAF7, KLF4, and AKT1 mutations [27]. Meningiomas with the L412F mutation are more likely to recur (XX) and are enriched at the midline, perhaps due to the role that Hedgehog signaling plays in hemisphere separation during development [36]. Mutations in the Hedgehog family member SUFU are also found at low frequencies in sporadic meningiomas, and their germinal counterpart is also present in familial meningiomatosis [42]. Additional hedgehog family germline mutations occur in SMARCE1 and SMARCB1, though these carry less risk of recurrence than familial NF2 mutations [43, 44].
POLR2A (RNA Polymerase II Subunit A) catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. In addition, POLR2A is the largest and catalytic component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. POLR2A encodes RPB1 (DNA-directed RNA polymerase II subunit), a gene found altered in about 6% of meningiomas [42]. From another perspective, inactivating somatic and germline mutations or gene deletions in the BAP1 tumor suppressor gene are explicitly found within high-grade rhabdoid meningioma [45]. Also, the loss of BAP1 is correlated with tumor aggressiveness and decreased time to progression. Alterations in the SWI/SNF pathway, specifically mutations in ARID1A, were recently found in 12% of high-grade meningiomas. Other components of this canonical pathway, including SMARCB1, SMARCA4, and PBRM1, are altered in up to 15% of patients with non-NF2-dependent meningiomas [46].
Through whole-genome analysis, global DNA methylation profiling has demonstrated that higher methylation levels are associated with increased tumor aggressiveness and risk of recurrence. DNA methylation is an epigenetic change hypothesized to contribute to genomic instability by silencing genes involved with DNA repair and control of cell cycling. Evidence suggests that methylation status may predict tumor behavior more accurately than the current WHO classification, thus, DNA methylation status has been proposed as an alternative classification system for MNs [47]. The most important genes involved in the DNA methylation of MNs are tissue inhibitors of metalloproteinase 3 (TIMP3), cyclin-dependent kinase inhibitor 2A (CDKN2A), and tumor protein 73 (TP73), which are hypermethylated in at least 10% of cases [48]. TIMP3 hypermethylation results in transcriptional downregulation and inhibits its tumor suppressor properties [49]. In addition, TIMP3 is frequently hypermethylated in higher-grade MNs (40–60%) and is related to a decrease in relapse-free time and increased biological aggressiveness [50]. Notably, TIMP3 is found on chromosome 22q12, and almost all cases with gene hypermethylation had a concurrent allelic loss of 22q. About 60–80% of high-grade meningiomas carry TP73 promoter methylation, a queue event not common in grade I tumors, suggesting its potential use as a marker for high-grade lesions [51].
Recently, several studies highlighted the importance of global methylation profiles in the molecular subclassification of meningiomas [52], Olar et al. demonstrated that unsupervised clustering of DNA methylation data classified meningiomas into two distinct subgroups associated with recurrence-free survival. A statistically significant association between DNA methylation subclasses and tumor recurrence was maintained after adjusting for clinical factors, such as WHO grade and Simpson grade [41]. Similarly, Sahm et al. identified two major groups and six subgroups of meningiomas based on unsupervised clustering of DNA methylation data, with significantly different genomic makeup and clinical behaviors. Interestingly, most non-NF2 meningiomas clustered together into a single benign subgroup [53]. These initial efforts suggest that epigenetic signatures may have solid clinical associations with tumor recurrence, to a more significant extent than can be correlated with mutational genetic analysis and could be used clinically to stratify patients. An additional manifestation of the importance of epigenetic changes in meningioma clinical behavior was recently shown, describing an increased risk of recurrence in tumors that show a loss of histone H3K27 trimethylation [54].
Classically, the identification of meningiomas using immunohistochemistry has been done using the expression of the progesterone receptor (PR) and the epithelial membrane antigen (EMA). However, over the last few years, it has been found that the specificity of RP for the diagnosis of high-grade meningiomas is low, especially when trying to differentiate between clear cell, fibrous, and microcystic subtypes. Likewise, EMA expression correctly identifies ~90% of grade I meningiomas, but only 75% of grade III, with even lower specificity rates for secretory and microcystic subtypes [55]. Due to these markers’ poor performance, the expression of somatostatin receptor 2A (SSTR2A) in combination with EMA was included, a profile that provides a sensitivity of 100% and specificity of 95%, regardless of tumor grade. Likewise, recent work suggests that the absence of Sox10 and STAT6 [56, 57] are superior approaches to distinguishing meningioma from schwannoma, solitary fibrous tumor, and synovial sarcoma.
In addition, marking for lymphocyte infiltration can contribute to the grading of meningiomas and the prediction of response to some interventions. Most low-grade meningiomas possess a high percentage of CD-3+ T-lymphocytes but relatively few CD20+ B cells; however, across tumor grades, these populations are greatly enriched compared to those seen in peripheral blood mononuclear cells (PBMC) [58]. Flow cytometry analysis reveals evidence of class switching in B cells, an increased percentage of CD8+ cells compared to CD4+ T cells, and a prevalence of CD45RO+/CD45RA− effector cells compared to naive T cells [59]. This information allows predicting that tumor-infiltrating immune cells have had exposure to various tumor antigens despite low BMR. Among high-grade meningiomas and particularly anaplastic tumors, there is a reduction in the count of CD4+, CD8+, and PD-1+ T cells, and an increase in the number of FoxP3+ T-regulatory cells (Tregs) [60]. This immune cell phenotype, also observed in other tumor types, is associated with tumor-mediated evasion of the immune system.
Du et al. report high levels of PD-L1 mRNA, which correlated to protein expression levels, in ~40% of grade I, 60% of grade II, and 77–88% of grade III meningiomas [59]. Nevertheless, Everson et al. only identified PD-L1 expression in 25% of grade III cases, with no expression detected in grade I or II cases [25]. The controversy has been amplified since PD-L1 does not predict outcomes. However, in the future, the expression of TIM-3 and LAG-3 could be helpful to consider the use of agonist monoclonal antibodies [58]. Another potential biomarkers that could predict the response to targeted therapies are EGFR expression, which is present in up to 90% of meningiomas [25]. Furthermore, the expression of TOP2A (35% of the samples) is associated with a higher tumor grade and could be useful to assess the usefulness of anthracyclines or trabectedin. Likewise, TOP1 over-expression is observed in 29% of meningiomas and correlates with sensitivity to irinotecan and topotecan, while elevated levels of PDGFR and c-MET are observed in more than 20% of cases [25] (Figure 2).
Signaling pathways and potential targets implicated in high-grade meningiomas.
The classical first-line treatment for all MNs is surgery. However, high grade meningiomas have a high recurrence rate; up to 60% of tumors may recur after 15 years of complete resection [12, 61]. Unfortunately, at the moment there are no standard effective treatments determined because of lack of existent evidence [12]. The use of systemic treatments as standard care remains experimental and is reserved for cases of recurrent/progressive disease not suitable for surgery or radiotherapy [62]. Hereafter we are going to present some of the systemic strategies currently in used and under study. A summary of the main therapies that have shown some benefit in MN treatment can be seen in Table 1, and a summary of current active clinical trials is shown in Table 2.
Type of agent | Medication | Mechanism of action |
---|---|---|
Chemotherapy | Temozolomide | Alkylating agent |
Irinotecan | Topoisomerase 1 inhibitor | |
Hydroxyurea | Ribonucleotide reductase inhibitor | |
Trabectedin | Mechanism unclear | |
Plant-derived agents | AKBA | Induction of apoptosis and antiinflammatory |
Curcumin | Interaction with multiple cell signaling proteins | |
EGFR antagonists | Gefitinib | EGFR antagonist |
Erlotinib | EGFR antagonist | |
Monoclonal antibodies | Humanized antibodies to EGFR | |
PDGFR antagonists | Imatinib | PDGFR antagonist |
Satinib | PDGFR inhibitors | |
Nilotinib | PDGFR inhibitors | |
mTOR inhibitors | Temsirolimus | mTOR inhibitor |
Vistusertib | mTOR inhibitor | |
Everolimus | mTOR inhibitor | |
VEGFR antagonists | Bevacizumab | Humanized monoclonal antibody to VEGFR |
Cediranib | VEGFR antagonist | |
Combination antagonists | Sorafenib | VEGFR and PDGFR antagonist |
Sunitinib | VEGFR and PDGFR antagonist | |
Vatalanib | VEGFR and PDGFR antagonist | |
Hormonal agents | Megestrol Mifepristone | Progesterone receptor partial agonist Progesterone receptor competitive antagonist |
Tamoxifen | Estrogen receptor antagonist | |
Octreotide Pasireotide | Somatostatin mimetic Somatostatin mimetic | |
Pegvisomant | Growth hormone receptor antagonist | |
Lutathera | Somatostatin receptor afinity and radiation β- emission | |
Fenretinide | Synthetic retinoid induces apoptosis | |
Immunomodulators | IFNα 2B | Antiproliferative and antiangiogenic |
Nivolumab Pembrolizumab Aveoumab Sintilimab | PD-1 receptor and ligand inhibitors | |
Trametinib | Inhibits MEK1 and MEK2 | |
Alpelisib | PI3K inhibitor | |
Ipililumab | CTLA-4 blockade | |
Oncolytic virus | Adenovirus | Antineoplastic effect against the malignant meningioma and significant tumor regression |
Herpes virus | Replication of adenovirus and oncolysis at high dose and at a lower dose meningioma cells killing | |
Farnesyl transferase inhibitors | Tipifarnib | Farnesyl transferase inhibitor |
Possible adjunctive agents | Calcium channel blockers | Reduction of intracellular calcium concentrations |
Statins | MAPK pathway inhibition | |
Antiretrovirals | Protein downregulation | |
RNAi | Antisense abrogation of mRNA strands |
A summary of different agents with promising evidence in the treatment of high-grade meningioma.
ClinicalTrials.gov Identifier | Status | Intervention | Arms | Outcomes |
---|---|---|---|---|
NCT03071874 | Active, not recruiting | AZD2014 a dual mTORC1/mTORC2 inhibitor | Experimental: AZD2014 | PFS OS Radiographic response rate Duration of radiographic response Frequency of adverse events |
NCT02648997 | Recruiting | Nivolumab 240 mg every 2 weeks Nivolumab 480 mg once every 4 weeks | Experimental: Cohort 1 (original cohort): Nivolumab Monotherapy | PFS Median PFS Median OS Objective radiologic response rate Adverse events |
Ipilimumab 1 mg/kg every 3 weeks Nivolumab 480 mg once every 4 weeks Nivolumab 3 mg/kg every 3 weeks External Beam RT | Experimental: Cohort 2: Nivolumab in Combination with Ipilimumab | PFS Median PFS Median OS Objective radiologic response rate Adverse events | ||
NCT03279692 | Active, not recruiting | Pembrolizumab | Experimental: Pembrolizumab | PFS OS Toxicity Intracraneal response |
NCT04997317 | Recruiting | 177Lu-DOTA-JR11 (Phase 0); Cycle 1 and Cycle 2 (cross-over) 177Lu-DOTATOC (Phase 0); Cycle 1 and Cycle 2 (cross-over), Cycle 3 and 4 | Active Comparator: Phase 0: Group A | Change in Tumor-to-dose limiting organ dose ratio T-to-bone marrow Change in Tumor-to-dose limiting organ dose ratio T-to-kidney Assessment of treatment safety (phase I/II) by number of AEs graded according to CTCAE v5.0 |
177Lu-DOTA-JR11 (Phase 0); Cycle 1 and Cycle 2 (cross-over) 177Lu-DOTATOC (Phase 0); Cycle 1 and Cycle 2 (cross-over), Cycle 3 and 4 | Active Comparator: Phase 0: Group B | |||
177Lu-DOTA-JR11 (Phase I/II) | Active Comparator: Phase I/II | |||
NCT03971461 | Recruiting | Lutathera | Experimental: Lutathera | PFS at 6 months Objective response rate OS at 12 months PFS OS |
NCT04082520 | Recruiting | Gallium Ga 68-DOTATATE Lutetium Lu 177 Dotatate Magnetic Resonance Imaging Positron Emission Tomography Quality-of-Life Assessment Questionnaire Administration | Treatment (gallium Ga 68-DOTATATE PET/MRI, Lutathera) | PFS at 6 months OS PFS Adverse events incidence Change in quality of life Local control Duration of local control Objective response to treatment Response rate by volumetric analysis |
NCT03016091 | Recruiting | Pembrolizumab | Experimental: Arm 1 IV Pembrolizumab | PFS at 6 months PFS at 12 months OS |
NCT03604978 | Recruiting | Ipilimumab Nivolumab Stereotactic Radiosurgery | Patients receive nivolumab | Maximum tolerated combination of radiosurgery and nivolumab plus or minus ipilimumab Incidence of adverse event profile Objective response rate Objective radiological response PFS OS Changes of peripheral T-cells |
NCT02333565 | Unknown | Everolimus Octreotide | Experimental: Combinaison everolimus and octreotide | PFS rate |
NCT04501705 | Recruiting | Apatinib mesylate | Experimental: test group | PFS-6% ORR OS |
NCT03267836 | Recruiting | Avelumab Proton surgery | Experimental: Avelumab + proton therapy | Immunogenicity Safety of therapy Pathologic response PFS OS |
NCT04728568 | Recruiting | Sintilimab | Experimental: Sintilimab | PFS at 6 months OS |
NCT03631953 | Recruiting | Trametinib Alpelisib | Experimental: Alpelisib in combination with Trametinib administered | Dose Limiting Toxicity (DLT) rate of combination Alpelisib and Trametinib |
NCT00904735 | Unknown | Hydroxyurea Imatinib mesylate | Experimental: Arm I Patients receive hydroxyurea and imatinib | PFS Survival Response rate according to MacDonald criteria Toxicity as assessed by NCI CTCAE v. 3.0 |
Hydroxyurea | Experimental: Arm II Patients receive hydroxyurea |
A summary of currently ongoing clinical trials that assess the effectiveness and safety of different systemic therapies in high-grade meningiomas.
It is known that chemotherapy is poorly effective as adjuvant treatment after surgery and radiotherapy. Some clinical trials and case series have shown a minimal or no impact in patients’ outcomes. However, some agents are being tested in several clinical trials [63].
Hydroxyurea is a ribonucleotide reductase inhibitor that was initially developed to treat myeloproliferative disorders and chronic myelogenous leukemia [64]. It induces apoptosis in meningioma cells, arresting meningioma cells in the S-phase of the cell cycle [63]. In pre-clinical trials from Schrell et al., they demonstrated that hydroxyurea prevent recurrence for 24 months in patients who had complete resection [65, 66]. However, clinical trials, failed to provide similar results showing that 50% of the patients achieve stable disease, a median PFS of 44–176 weeks and acceptable toxicity [63, 65, 66, 67, 68, 69, 70, 71]. Other retrospective studies with small sample sizes, have shown a median PFS of 10–80 weeks [64]. Weston et al. also found that hydroxyurea may prevent progression, but does not reduce tumor size and causes significant side effects [72]. It is important to emphasize that in these trials many patients did not received radiotherapy or that radiotherapy was administered concurrently, making data interpretation difficult [73]. In addition, a retrospective study of 60 patients from Chamberlain et al. reported a disease progression in 65% of the patients and a median PFS of 4 months in patients treated with hydroxyurea after recurrence (Chamberlain and Johnston, 2011). Finally, some studies suggest hydroxyurea may have outcomes equivalent to those when radiation therapy was used [74].
Additionally, some studies reported reduction of hydroxyurea efficacy when other concomitant therapies are administrated [64]. In a study by Reardon et al., hydroxyurea and imatinib were used to treat patients with recurrent refractory meningiomas, a good tolerance was reported; however, the combination did not affect survival [75]. Other authors suggest that chemotherapy should be based on expression of drug resistance genes, in patients whose mRNA analysis predicted sensitivity to chemotherapy. In these cases, a concomitant treatment with mitoxantrone and hydroxyurea reported long-term efficacy [61]. Currently, some investigators are looking for the role of hydroxyurea as an adjunct to other therapies, such as calcium channel blockers, as calcium channel antagonists have an inhibitory effect on meningioma growth in culture [76]. For this matter, Ragel et al. reported that calcium channel antagonists can block stimulatory effects of growth factors on meningioma cell cultures and increase hydroxyurea effectiveness [77]. Evidence of hydroxyurea treatment in patients with high grade meningioma varies widely across patients. Demonstrating that this treatment is generally well-tolerated but evidence in tumor control is not conclusive to establish a standard treatment in high-grade MNs.
Trabectedin it is an alkylating agent used in soft tissue sarcomas. It inhibits transcription, its mechanism is not completely understood but some studies reported decreased cell proliferation, induction of apoptosis and inhibition of transcription factor binding by binding to the minor groove of the DNA helix [78]. In the randomized phase II clinical trial NCT02234050 by EORTC Brain Tumor Group (EORTC-1320-BTG), treatment with trabectidin in grade II/III meningiomas did not improve PFS or OS and it was associated with significantly higher toxicity as compared to local standard care. A median PFS of 4.17 months was reported in the local standard care arm and of 2.43 months in the trabectedin arm (hazard ratio [HR] for progression, 1.42; 80% CI, 1.00–2.03;
Temozolomide another alkylating agent, used as standard care in management of glioma. It does not prolong PFS in clinical trials of recurrent meningioma [80]. It is believed that the no effect on meningioma could be due to intact activity of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) [63, 81, 82].
Chamberlain et al. reported a median time tumor progression of 4.6 years and median OS of 5.3 years in patients treated with cyclophosphamide, doxorubicin, and vincristine. They also reported high toxicity and very low response. However, without a control group the results are difficult to interpret [83]. Some small case series also reported results by administrating cyclophosphamide, adriamycin, vincristine, isofosfamide/mesna or adriamycin/dacarbazine, but the evidence is limited [84]. In some in vitro an in vivo animal studies, was reported that irinotecan has an anti-meningioma effect. However, it did not show benefits in phase II clinical trials [81, 82, 85].
Finally, some preclinical studies evaluated the response of Plant-Derived Chemotherapeutic Agents. Curic et al. described an antitumorigenic properties from curcumin (from the spice plant
Unlike other solid tumors, MN presents with a low mutation rate of approximately 3.5 mutations per megabase [25]. However, the case of high-grade MNs has been evaluated recently. Bi et al. analyzed 39 samples of high-grade MN and found an average of 23 (range 1–223) nonsynonymous coding alterations. This number of alterations is similar to that of craniopharyngioma and thyroid cancer, but considerably lower than other aggressive tumors like head and neck carcinoma, colorectal carcinoma and melanoma [34]. Because of its relatively low mutational burden, very few potential molecular targets have been identified. Interestingly, Bi et al. found that non-NF2 driver mutations in high-grade MN was considerably lower than in low grade MN, which reduces the number of possible targets than can be addressed. In the other hand, NF2 is usually altered in high-grade MN (80% of cases) more frequently than in low grade MN (40%). Most of genetic and regulatory alterations that have been described in high grade MN occur downstream to a disrupted NF2 protein. Some of the pathways altered might involve Rac1/Cdc42, Ras/JNK and the master regulator AP-1 [89]. Furthermore, one of the main pathways associated with NF2 is the mTOR signaling cascade. NF2 naturally acts as a repressor of the mTORC1 and mTORC2, and when it is mutated, unregulated activation of this pathway occurs. Based on this, mTOR and some of its upstream/downstream effectors (Akt/PI3K) have been identified as potential targets. Other pathways regulated by receptor tyrosine kinases (RTKs) like EGFR, PDGFR and VEGFR (angiogenesis) are also being studied.
The EGFR pathway has been demonstrated to play a role in the tumorigenesis of a great proportion of meningioma cases. Torp et al. demonstrated that EGFR expression is not detectable in healthy and injured adult human meninges, but is expressed in cases of meningioma [90]. Arnli et al. also showed that EGFR was absent in healthy meninges but present in MN [91]. Narla et al. analyzed 79 samples of MN using immunohistochemistry, to detect EGFR expression. They found that EGFR was expressed in all different grades of MN, but its expression was considerably higher in grade I MN (82.93%), than grade II MN (35.71%) and grade III MN (20%) (
Similar results were published by Wernicke et al. who found in a cohort of 89 MN samples that EGFR expression was more common in grade I MN than in other grades. They also showed that the staining percentage (SP) of immunoreactive cells was associated with histopathologic subtypes (
In 2010, results from a phase II trial of erlotinib and gefitinib for the treatment of MN were published. Erlotinib is an orally available, reversible TKI directed against EGFR. Its use has been approved in different neoplastic disorders including non-small cell lung cancer (NSCLC) and pancreatic cancer [98]. Gefitinib is a first-generation EGFR-TKI also approved for the treatment of locally advanced and advanced NSCLC [99]. In 2010, a clinical trial enrolled patients with recurrent histologically confirmed MN that were treated with no more than 2 chemotherapy regimens.
The study evaluated 25 patients with a median age of 57 years. From this cohort, 16 patients received gefitinib and 9 received erlotinib. Nine patients had atypical MN and 8 had anaplastic MN. PFS and OS were assessed at 6 and 12 months. For patients with low-grade histology, PFS-6 was 25%, PFS12 was 13%, OS-6 was 63% and OS12 50%. In the other hand, high-grade meningiomas seemed to respond a little better with a PFS6 of 29%, PFS-12 18%, OS6 71% and OS-12 65%. When statistical analysis was done no significant difference between low-grade and high-grade MN was seen [100]. Survival outcomes were not significantly better than that of standard treatment.
In 2020 Ferluga et al. found that STAT1 is overexpressed and present a constitutive phosphorylation in MN. They also found that this overactivation was not associated with the JAK-STAT pathway but instead it was induced by the constitutive phosphorylation of EGFR. They even demonstrated that STAT1 knockdown models presented a significant reduction of cellular proliferation as well as a deactivation of AKT and ERK1/2. The most interesting finding of this study was that the researchers used BM-1 cells and exposed them to three different EGFR inhibitors, two from second generation (canertinib and afatinib) and one first generation (erlotinib). After exposure to canertinib and afatinib, a decrease in about 60% of STAT1 expression was seen as well as an almost complete elimination of phosphorylated forms of STAT1, this effect was not seen after exposure to erlotinib.
Lapatinib is a dual EGFR/ErbB2 inhibitor currently approved for the treatment of advanced breast cancer with ErbB2 (HER2) expression [101]. There is preclinical evidence of lapatinib efficacy in decreasing tumoral growth in NF2-related Schwannomas. Ammoun et al. demonstrated that when NF2 is mutated or lost, there is an upregulation of different RTKs in Schwannoma, with EGFR and HER2 being two of the highest expressed [102]. Similar results have been seen in NF2-related MN. When the researchers added lapatinib at 5 and 10 μM concentrations to cultures of Schwannoma cells derived from patients’ samples, they found that lapatinib successfully induced inhibition of the intracellular pathways downstream HER2, including ERK 1/2 and Akt. They also showed that after 24 h of exposure to lapatinib, cell viability decreased in a dose-dependent manner, with statistically significant differences between both concentrations of lapatinib to baseline, and from lapatinib 5 μM to lapatinib 10 μM [102].
The same group of researchers also tested lapatinib during a phase II clinical trial, with good results in terms of volumetric response, progression-free survival and safety profile [103]. Six years after this trial, the authors did a retrospective analysis of patients presenting with NF2-related meningiomas from the same cohort of patients with Schwannoma. Eight patients fulfilled criteria for analysis. After two months under treatment with lapatinib, the best volumetric response achieved was 26.1%. It is important to mention that in the group that was receiving lapatinib, two tumors increased in volume by more than 20%. Results from this analysis were confusing, with no clear benefit of lapatinib, however, the sample was extremely small, and the analysis was retrospective. This study might influence the development of future, prospective, larger clinical trials specifically for patients with MN [104].
In 2001, Crombet et al. published their results on the efficacy of a mouse anti-human neutralizing monoclonal antibody against EGFR (ior egf/r3). They performed a phase I clinical trial using this antibody in 9 patients with high-grade brain tumors that persisted or relapased after surgery. Only one of the patients had MN (hemangiopericytic). The patient had 48 years old and a Karnofsky Performance Score of 90. She received four doses of 160 mg of antibody. At the end of the study, no objective response was seen in any of the patients, however the remained with stable disease until 6 months after the last antibody dose [105]. Even though EGFR inhibition has revolutionized cancer care in neoplasms with high incidence like NSCLC and colorectal cancer, these effects have not been seen in brain tumors, even when EGFR upregulation has been proved. Further studies must be performed with newer and more effective EGFR inhibitors, including monoclonal antibodies.
PDGFR is another RTK whose expression is critical during development, as well as in the growth and differentiation of certain cell lineages. Its role in multiple chronic diseases have been studied, and it is considered a possible target in conditions like cancer, fibrosis, neurological disorders and atherosclerosis. The PDGF/PDGFR axis promotes cell proliferation, survival and migration primarily in cells of mesenchymal origin [106]. The ligands for PDGFR are four different polypeptide chains (PDGF-A, PDGF-B, PDGF-C and PDGF-D) which can be organized in an array of dimers that behave as functional growth factors (PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC and PDGF-DD [107]. These ligands have two different receptors, PDGFRα and PDGFRβ. The different ligands bind to the receptors with a differential specificity. PDGF-A, -B and -C will bind strongly to PDGFRα while the others will bind to PDGFRβ [106].
It has been demonstrated that MN expresses different forms of PDGF ligands, namely PDGF-AA and PDGF-BB, and expresses considerable levels of PDGFRβ. It has been shown that the PDGF/PDGFR axis might play a key role in the tumorigenesis of MN. Black et al. proved that PDGFRβ in MN cells derived from patients are susceptible to the stimulation with PDGF-BB ligands, with a shown increased in the activation of MAPK [21] and c-fos, a critical part of the master regulator AP-1, and a recognized proto-oncogene [108, 109]. Unlike EGFR expression, PDGFR levels appear to be higher in atypical and anaplastic MN than in grade I MN. In those MN that express PDGFR and the aforementioned PDGF ligands, there is an autocrine loop that supports maintenance and cell growth [109]. Todo et al. demonstrated that there is a considerable decrease in meningioma cells proliferation when these cells are given a neutralizing antibody against PDGF-BB. They saw a similar but less potent behavior when an anti-PDGF-AA antibody, also suggesting that the PDGF-BB pathway is the most important for meningioma maintenance [110].
Imatinib, a potent PDGF inhibitor currently used in different conditions (mainly chronic myeloid leukemia), has also been proven in MN patients. Imatinib possess a very low IC50 of 0.1 μM, this is especially important in MN as the blood-brain-barrier might decrease the flux of imatinib and other drug particles into the brain. In the NABTC 01–08 study, 23 patients with MN were enrolled, with 13 patients bearing low grade tumors, five with atypical MN and five with anaplastic MN. Response was only evaluated in 19 patients from whom 10 patients experienced disease progression. The rest of the patients remained disease stable. Median PFS was only 2 months, with a PFS6 of 29.4%. When analyzed separately, PFS for grade I MN was 3 months and PFS6 was as high as 45%. In the case of high-grade MN, PFS was 2 months but PFS6 was 0%.
The current landscape of PDGF inhibition is somewhat promising. Other agents like sunitnib, MLN518, dasatinib, AMN 107, pazopanib, sorafenib, CP673451 and CHIR 265 have been studied [111]. Furthermore, combination therapies using imatinib and other different agents like hydroxyurea [112], which has showed some benefit in the treatment of glioblastoma in a Phase I/II trial [113].
The mTORC1 (mammalian target of rapamycin complex 1) pathway has been reported to interact with merlin as a negative regulator of cell growth control [114]. mTOR is a serine/threonine kinase involved in cell signaling controlling transcription, actin cytoskeleton organization, translational activation, and metabolism in response to environmental cues [9]. The protein exists in two distinct multiprotein complexes. The rapamycin-sensitive complex mTORC1 regulates cell growth and proliferation in response to growth factors and metabolic conditions, whereas the rapamycin-insensitive mTORC2 regulates locally restricted growth processes within a cell and is involved in cell migration. Merlin was shown to enhance the kinase activity of mTORC2 [115].
Previously, Pachou et al. [116] found that mTORC1 is activated in the majority of MNs (7–10%) and that systemic mTORC1 inhibition can impair meningioma tumor formation in vivo. In addition, Akt is well known to be an upstream element of mTORC1 and to be activated in meningioma cells by platelet-derived growth factor [117]. PDGF also induces phosphorylation of p70S6K, the expression of which was reported to be increased in malignant MNs [118].
Several groups analyzed the biological effects of everolimus and temsirolimus on meningioma cell viability. They could clearly show that both inhibitors were effective in reducing meningioma cell viability and proliferation [114]. Moreover, evidence was found that the NF2 gene status may affect the response to both inhibitors but differentially activated mTOR pathways could not explain this result in isogenic meningioma cell lines with and without merlin expression [119]. Further, octreotide was shown to augment the inhibitory effect on the mTOR pathway in meningioma cell lines because mTOR inhibition increases the hyperphosphorylation of AKT which thereby increases cell proliferation [120].
In 2020, Graillon et al. reported the results of the CEVOREM trial, a phase II open label study that evaluated the combination of everolimus and octreotide in 20 high-grade MNs patients. Furthermore, four patients harbored NF2 germline mutation [121]. The overall PFS6 was 55% (95% CI 31.3–73.5%), and 6- and 12-month OS rates were 90% (95% CI 65.6–97.4%) and 75% (95% CI 50.0–88.7%), respectively. A decrease >50% was observed in the growth rate at 3 months in 78% of tumors. In addition, the median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (
In a small trial, everolimus has also been studied in conjunction with bevacizumab without finding any objective tumor response but showing a slight increase in PFS for those with high-grade MNs (NCT00972335) [122]. In this study, 88% of the 18 patients showed SD for a median duration of 10 months (2–29 months). Nevertheless, overall median PFS was 22 months (95% CI 4.5–26.8), higher for patients with WHO grade II and III than grade I tumors (22.0 months vs. 17.5 months). Four patients discontinued treatment due to toxicity (proteinuria, 2; colitis, 1, thrombocytopenia, 1), but another grade 3 toxicity was uncommon, and no patient had grade 4 toxicity. The interesting improvement in higher histological grade MNs could be due to their increased vasculature and the increased dependence on the mTOR pathway of these lesions [122].
There is currently a phase 0, single group assignment, trial for everolimus in NF2 mutant MNs and vestibular schwannomas (NCT01880749). There are two single group assignment phase II trials of another mTOR inhibitor, AZD2014; NCT03071874 for recurrent grade II/III MNs and NCT02831257 for NF2 patients with MNs. These trials will help determine the efficacy of mTOR inhibition in patients with these challenging lesions. Besides, a case report of a female patient with metastatic meningotheliomatous meningioma involving the brain and the lung was treated with the pan-AKT inhibitor, AZD5363 for AKT1E17K mutation, showed a favorable and durable response [123]. Ex vivo cultured meningioma cells revealed sensitivity to the drug as shown by pan-AKT accumulation on immunoblots. The patient has been treated for more than a year with a response which warrants further research [123].
Angiogenesis depends on the balance between angiogenic and anti-angiogenic regulators [124]. Among the former, VEGF has been demonstrated to play an essential role in stimulating angiogenesis by promoting the migration, proliferation, and tube formation of endothelial cells. VEGF upregulation has been shown in MNs, suggesting its role as a pro-angiogenic factor responsible for edema formation in these tumors [125, 126, 127].
Neoangiogenesis in MNs is regulated by the balance between concentrations of both VEGF and semaphorin 3A (SEMA3A) in the tumor’s microenvironment rather than by VEGF alone [125]. Accordingly, neo-angiogenesis would be blocked or stimulated depending on the prevalence of VEGF or SEMA3A with a high ratio between VEGF and SEMA3A as a negative predictor of recurrences [125]. Additionally, VEGF expression in MNs seems to be enhanced by hypoxia-inducible factor 1-alpha [128] and EGF [129], and reduced by dexamethasone.
Caveolin-1 (cav-1), which is a 20-KDa protein mainly expressed by fibroblasts, endothelial cells, myocytes, and adipocytes, seems to be involved in the oncogenesis and progression of several neoplasms, including MNs [130]. Similar to what has been reported in several solid tumors, a significant correlation has been shown between tumor-cell-derived cav-1 and microvascular density (MVD) in MNs [131], suggesting that this protein behaves as a pro-angiogenic factor. Consistent with this hypothesis, cav-1 has been shown to regulate endothelial cell growth and differentiation and to stimulate capillary tubule formation in vitro [132]. Moreover, VEGF-mediated pathological angiogenesis is strikingly reduced in cav-1 knock-out mice [133]. On the other hand, the association between cav-1 expression and MVD may also be related to factors regulating both the MNs neo-angiogenesis and cav-1 expression. Indeed, cav-1 may function as a pro-tumorigenic factor that can stimulate cell proliferation, following its tyrosine-14 phosphorylation by Src kinase [134].
Endothelin-1 (ET-1) has been demonstrated to play a role in the mechanism of meningioma tumorigenesis via the ETA receptor [135]. ET-1 expression/upregulation may contribute to meningioma growth by inducing the formation of new blood vessels. Indeed, a significant correlation has been shown between the expression of ET-1 and that of VEGF or MVD in MNs, in agreement with its proangiogenic action in these tumors.
Following these biological considerations, several angiogenesis inhibitors, such as bevacizumab, sunitinib, and vatalanib, have been evaluated in phase II trials with promising results [136]. The efficacy and safety of bevacizumab were evaluated in grades II and III MNs, finding a PFS6 of 43.8%. In addition, a review of 22 additional case reports for a total of 92 patients revealed a PFS of 16.8 months with 6 months PFS of 73% in those exposed to bevacizumab [137]. A phase II trial designed for all grades recurrent MNs that included 15 patients (15, 22, and 13 grade I, II, and III, respectively) showed stability of the disease in 100% of benign tumors and 82–85% among those with high-grade injuries. In addition, the PFS6, the median PFS, and OS, were 87%, 22.5 months, and 35.6 months for patients with grade I tumors, while this distribution was 77%, 15.3 months, and not reached for grade II, and 46%, 3.7 months, and 12.4 months for grade III, respectively [138]. There is an ongoing phase II trial evaluating bevacizumab in recurrent and progressive MNs (NCT01125046).
Kaley et al. reported a prospective, multicenter single-arm phase 2 trial that investigated the efficacy of sunitinib, a tyrosine kinase inhibitor that inhibits VEGF and PDGF receptors, which are over-expressed in MNs [139]. Thirty-six patients with grade II and III recurrent or progressive MNs were enrolled. They were heavily pre-treated (median five recurrences) and received sunitinib at 50 mg per day for days 1–28 of a 42-day cycle. The PFS6 was 42%, the median PFS was 5.2 months (95% CI 2.8–8.3), and the median overall survival was 24.6 months (16.5–38.4). Adverse events included four (8%) intratumoral hemorrhages, of which one was fatal, one (2%) grade 4 thrombotic microangiopathy, and one (2%) grade 3 gastrointestinal perforation. MRI perfusion in the exploratory group indicated that sunitinib is an active agent, and expression of VEGFR2 predicted PFS with a median of 1.4 months in VEGFR2-negative patients versus 6.4 months in VEGFR2- positive patients (
Evidence suggests that meningioma growth could be hormone dependent because of the female predominance specially after puberty and reproductive years. Additionally, that 30% of the meningiomas are estrogen receptor positive and 70% are progesterone receptor positive [76]. It is also known, that high grade meningiomas express more estrogen receptors whereas benign meningiomas express more progesterone receptors [141]. It is also important to add, that approximately 90% of meningiomas express somatostatin receptors [142]. Therefore, hormonal therapies have been utilized in high grade meningioma treatment.
Due to estrogen receptors low expression, treatment with tamoxifen (estrogen receptor antagonist) has not shown effective results. Additionally, there is not any reports of androgen receptor antagonists in meningiomas [143]. In 1993 Goodwin et al. in a retrospective case series of 21 patients with meningioma treated with tamoxifen, they reported response in only 1 patient and disease progression in 10 patients [144]. Additionally, in a case study from Markwalder et al. a small group of patients with inoperable meningiomas that received tamoxifen were studied and only two patients show radiographical partial response [145].
Currently, due to the lack of evidence of anti-estrogenic agents’ effect on meningioma no recommendation is available. Mifepristone is a progesterone receptor inhibitor. In a study published in 1991 by Wolfsberger et al., they used mifepristone as treatment of unresectable meningioma patients, they reported that five patients showed reduction of tumor size on neuroimaging and visual field improvement; in addition, three patients experienced headache relief and improvement in extraocular muscle function. No toxicities were reported [141]. Other study by Lamberts et al. reported stable disease in three patients, tumor size reduction in other three patients and no toxicities were reported [146]. These studies were limited because of the small sample size and tumor stage wasn’t described in any of them. Therefore, more studies are needed to conclude the effect of mifeprisotne in high grade meningiomas. Other trial by Ji et al. reported a median PFS of 10 months and a median OS of 31 months in the mifepristone arm of patients with recurrent meningioma [147]. Additionally, in 2006 Grunberg et al. reported a reduction of less than 10% of the tumor area without clinical improvement in eight patients with unresectable meningioma who received mifepristone [148].
Megestrol acetate is an oral progesterone agonist that was used in a small trial. However no response was observed in high grade meningiomas [76]. So far there is no evidence that supports the use of progesterone receptor inhibitors in high grade meningiomas.
Somatostatin is important in regulation and proliferation of normal cells and tumor cells. It is known that meningiomas report the highest frequency of somatostatin receptor expression in brain tumors, especially the sst2A subtype. It is also reported that somatostatin inhibits meningioma growth in vitro in most studies, but increases meningioma proliferation in some [76].
Chamberlan et al. reported that 31% of patients demonstrated a partial radiographic response and 44% achieved PFS at 6 months with minimal toxicity in patients treated with octreotide (a somatostatin agonist). Furthermore, one-third of patients showed stable disease after treatment [149]. Therefore, somatostatin analogs are recommended for systemic treatment of unresectable or radiorefractory relapsed meningiomas [150]. The phase II CEVOREM trial explored the efficacy of the combination of everolimus (an mTOR inhibitor) and octreotide in high grade meningiomas treatment. The trial reported that the 6-month progression-free survival rate was 55% and the 6-month overall survival was 90% and 12-month survival rate was 90%. Additionally, a decrease of more than 50% was observed in the growth rate at 3 months in 78% of the tumors. That happens because, octreotide suppressed AKT activation during everolimus treatment and synergistically reduced expression of downstream proteins [121]. The previous results suggest that the combination of everolimus and octreotide could be a very good option to treat high grade meningiomas, however more studies are needed. In other phase II trial by Johnson et al. only 2 of 12 high grade cases experience long progression-free intervals, but at the end all patients experienced disease progression with median time of 17 weeks; a median survival 2.7 years was reported and octreotide was well-tolerated [151]. Additionally, an in- vitro study by Graillon et al. reported a significant anti-proliferative effects octreotide, but no apoptotic response [152].
Parasoreotide (SOM230C) is an intramuscularly long-acting somatostatin analogue. In the phase II trial by Norden et al., they reported that pasireotide has limited activity in recurrent meningiomas, a PFS-6 of 17% and median PFS of 15 weeks were reported. Furthermore, expression of somatostatin receptor was predictive of favorable response. However the findings in this trial require further investigation [153]. These findings are promising, nevertheless, larger randomized studies should be conducted to make a solid conclusion.
Growth hormone is secreted by the pituitary gland, and it induces production of insulin-like growth factor-I (IGF-I-), these hormones influence normal growth and metabolism [73]. There is existent evidence that reports abuntant growth hormone receptors expression in meningioma cells. There is also reported that inhibition of these receptors represents a decreased meningioma cell proliferation [154]. McCutcheon et al. reported that administration of pegvisomant reduces meningioma growth and in some cases causes tumor regression. Pegvisomant blocks growth hormone receptors and induces downregulation of the GH/IGF-I axis [155]. In other study, Puduvalli et al. reported that fenretinide, a synthetic retinoid, induced apoptosis in meningioma primary cells tested, it also increases levels of the death receptor DR5 and causes mitochondrial membrane depolarization. They also reported eradication of IGF-I proliferation in the meningioma cells [156].
Finally, insulin-like growth factor-II acts like IGF-I. In multiple studies have reported that the invasiveness of meningiomas is correlated to levels of IGF-II expression [157]. However, several studies are needed to establish IGF-II blockade could be an option to treat patients with meningiomas. These results provide preliminary evidence, but further studies are needed to explore these options as treatment against meningioma.
Existent evidence, shows that recombinant interferon-α (INF-α) is a biologic agent able to inhibit DNA synthesis, it binds to the interferon-a/b receptor and is involved in cell resistance to viral infection [64]. In 1991 in vitro studies also reported that interferon-alpha inhibits tumor cells growth [158].
In 1997 Kaba et al., reported a minor reduction of tumor size in one patient and a stable disease that lasted up to 14 months in four of six patients with recurrent unresectable meningioma who received INF-α 2b [159]. Other study in 2001, reported a stable disease that lasted up to eight years in nine of twelve patients treated with INF-α [160]. In 2008 Chamberlain and Glantz, reported in a phase II study that 26 of 35 patients that received treatment with INF-α demonstrated stable disease after the first 3 cycles and that 9 patients developed progressive disease. Additionally, a PFS rate was 54% at 6 months and 31% at 12 months were reported, median time to tumor progression was 7 months and median survival was 8 months. Furthermore, no patient demonstrated neuroradiographic complete or partial response, fatigue, anemia and leukopenia were the most common toxicities but overall, the drug was safe. A limitation form this study is that it was conducted only in patients with refractory grade I meningiomas [161]. Currently, these options are used as therapy for recurrent meningiomas or progression following surgery and radiation. It is also used for meningiomas that no respond to standard treatment options. Nevertheless, evidence that supports the use of interferons for meningiomas is poor.
Oncolytic viruses are biologic anti-tumor agents that selectively kill tumor cells leaving non tumoral cells intact [63]. A lot of oncolytic viruses have been investigated in different clinical trials, however no clinical trials have been conducted in meningiomas [162].
There are a few preclinical trials conducted in meningioma models. In 2005 Grill et al. evaluated the efficacy of conditionally replicating adenovirus (Ad) for oncolysis of meningiomas of 12 patients. Four different Ads were constructed and tested on meningioma cells and spheroids: Ad with an E1ACR2 deletion (Ad.d24), Ad with complete E1 region (Ad.E1+), Ad encoding the luciferase marker gene (Ad.Luc) and Ad encoding the luciferase gene in the E3 region (Ad.E1Luc). They demonstrated replication of adenovirus and oncolysis in primary cell cultures of meningioma cells at high dose (greater than 50 plaque-forming units per cell). Additionally, they also reported that at a lower dose (5 plaque-forming units per cell), Ad.d24 kills meningioma cells more efficiently than Ad.E1+ in benign, atypical, and malignant meningiomas [163].
Herpes virus it has a large dsDNA with more than 30 kb making the virus encoding for nonessential genes, this feature allows for genetic manipulation. Additionally, herpesviruses have a good safety profile, because they replicate in the nucleus without causing insertional mutagenesis [164].
In 1992, Market et al. added thymidine kinase-negative herpes simplex-I mutant virus, d/sptk, to meningioma cell cultures. They reported an antineoplastic effect against the malignant meningioma and significant tumor regressions [165]. In the study from Yazaki et al., reported that mutant herpes simplex virus (termed G207) can replicate and kill cells from human malignant meningiomas in cell culture. They also reported tumor growth reduction in nude mice harboring human malignant meningioma [166]. Additionally, it is reported that efficacy of oncolytic herpes simplex viruses (HSV) as single agent is unsatisfactory; so in 2006 Liu et al. demonstrated that oncolytic HSV encoding dnFGFR enhances antitumor efficacy [167]. In 2016 Nigim et al., reported that G47∆, an oncolytic HSV derived from G207, was able to replicate and kill several human primary meningioma cultures in vitro. They also reported that this treatment prolonged survival, with 20% of mice surviving more than160 days. Furthermore, a lack of signs of encephalitic associated with G47∆ treatment was reported [168]. In 2018, they also reported that the mechanism of action of oHSV enables killing NF2 intact and mutant meningiomas and meningiomas that harbor other mutations [63].
Several studies have demonstrated the ability of oncolytic viruses to recruit T cells and induce immune responses against virus and tumor. Furthermore, some studies have demonstrated that oncolytic viruses combined with other cancer therapies, create synergistic effects in brain cancer treatment. Although many questions remain to be answered to fully exploit the therapeutic potential of oncolytic viruses against meningiomas [169].
Several studies have aimed to characterize the interactions between MNs and the immune system. Specifically, studies of the immune microenvironment in MNs have revealed that NY-ESO-1, PD-L1, PD-L2, B7-H3, and CTLA-4 are expressed in MNs and may be at least partly responsible for the suppression of the anti-tumor immune response [170, 171]. PD-L1 is expressed in MNs, and expression levels are higher for higher-grade tumors [172]. The expression of these proteins has been associated with tumor progression, recurrence, and poor survival outcomes. Fang et al. extensively characterized the immune infiltrate in MNs and found that the immune cells infiltrating MNs are mainly antigen-experienced T cells and B cells [58]. In their study, B cells were activated and underwent immunoglobulin class switching, somatic hypermutation, and clonal expansion. T-cells demonstrated evidence of antigen exposure and increased expression of PD-1 and TIM-3, which can be a sign of an exhausted phenotype. Tumor-infiltrating lymphocytes in MNs are mainly T-cells. Interestingly in anaplastic MNs, the number of CD4 and CD8 T-cells is low. At the same time, the proportion of Tregs is increased [59]. These data support the notion that an immunosuppressive microenvironment in MNs may contribute to tumor progression.
In a mouse model of meningioma, infusion of anti-PD1 antibody avelumab plus highly-active NK cells (HaNK) led to increased survival, showing the importance of innate NK cell activity [173]. Currently there are two case reports on PD-L1 checkpoint inhibition for recurrent MNs [174, 175]. The cases report disease-free recurrence for >2 years in one patient and > 6 months in another patient, with both having reductions in tumor volume, cerebral edema, and patient-reported symptoms following nivolumab treatment. Based on the existing evidence on PD-L1 expression in recurrent MNs, five clinical trials are enrolling patients with to receive anti-PD1 antibodies nivolumab, avelumab, or pembrolizumab. An ongoing phase II trial is designed to compare nivolumab alone to combination therapy with the anti-CTLA-4 antibody ipilimumab (NCT02648997). A phase Ib trial will investigate the preoperative use of avelumab in combination with hypo-fractionated proton radiotherapy for 3 months to evaluate its effect on the size of unresected MNs (NCT03267836). The other trials are recruiting patients with recurrent MNs to receive adjuvant immunotherapy as PD1 blockade.
Chimeric Antigen Receptor (CAR) T cell therapies are a novel therapeutic approach to cancer. The standard treatment consists in the leukapheresis of autologous peripheral blood mononuclear cells from the patient bearing the tumor. After successful leukapheresis, T cell isolation is performed. T cells are then grown in culture and are further transduced with a lentiviral vector carrying an integrative plasmid that encodes the CAR, which is essentially a fusion protein containing a single-chain variable fragment derived from a full antibody, plus a transmembrane domain and different array of intracellular co-receptor and co-stimulatory domains that will trigger the intracellular signaling necessary for T cell activation [176].
CAR-T cell therapies were initially approved in 2017 (axi-cel and tisa-cel) for the treatment of relapsed/refractory diffuse large B cell lymphoma and relapsed/refractory B-cell acute lymphoblastic leukemia [177]. Unfortunately, the landscape of CAR-T cell therapies in solid tumors has not been promising, mainly due to different resistance from typical features of the tumor microenvironment like high acidity, immune effector exhaustion induction and the extracellular matrix. Different workaround strategies have been explored to address these problems and currently, highly engineered cells and very complex therapies (CAR-Ts in combination with checkpoint inhibition, or small molecules, or chemotherapy, or immunomodulators) are under study in different clinical trials [178].
Brain tumors have not been an exception in CAR-T development, with glioblastoma being the most attacked condition. Tang et al. reported a case of a patient with an anaplastic MN that underwent three surgical resections and had an Ommaya device implanted. IHC from her tumor sample showed a high expression of B7-H3, also known as CD276 ([179], p. 3). The researchers prepared CAR-Ts from autologous PBMCs, and during CAR-T development patient recur and CAR-Ts were administered in three doses via the Ommaya device. A fourth surgical treatment was performed as patient was progressing quickly, and unfortunately the patient died one day after surgery. Post-mortem analysis of the tumor sample showed that CAR-T indeed penetrated the tumor and successfully targeted some cells expressing B7-H3, however, as not all the tumor was expressing this molecule, antigen loss and selection of other cells with a different transcriptome occurred [180]. Even though results were not as expected, this case marks an important step toward the development of cell therapies of different natures, to treat brain tumors, especially those of high recurrency and aggressiveness.
Treatment in MN has remained similar since some decades ago. Major improvements in survival are achieved mainly by surgery and radiation therapy. Most cases of MN will respond to these conventional therapies, however, transformation of low-grade MN to high-grade MN, or de novo high-grade MN are highly recurrent and impose a very low survivability. For these tumors, surgery and radiation therapy are less than enough. With the era of genomic analysis and a better understanding of the genetic basis of cancer, different molecular targets and new therapeutic approaches have been studied for high-grade MN treatment. In this review we went through the main critical advancements in evidence that suggests that molecular targeting might be the future of high-grade MN treatment. To the date, all these molecular approaches are still under study, a conventional management is still the mainstay, but we hope in the following years, new evidence of the clinical relevance of these therapies is available and introduction of them into the therapeutic arsenal could be a true.
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Successful treatment of oral cancer patients is a complex issue that requires a multidisciplinary approach, including oral and maxillofacial surgeons, oral and maxillofacial radiologists, ENT specialists, medical and radiological oncologists, prosthodontists, dentists, speech therapists, supportive care experts, and also pathologists or, if possible, oral and maxillofacial pathologists.",book:{id:"8631",slug:"prevention-detection-and-management-of-oral-cancer",title:"Prevention, Detection and Management of Oral Cancer",fullTitle:"Prevention, Detection and Management of Oral Cancer"},signatures:"Nihat Akbulut and Ahmet Altan",authors:[{id:"262769",title:"Dr.",name:"Nihat",middleName:null,surname:"Akbulut",slug:"nihat-akbulut",fullName:"Nihat Akbulut"},{id:"268500",title:"Dr.",name:"Ahmet",middleName:null,surname:"Altan",slug:"ahmet-altan",fullName:"Ahmet Altan"}]},{id:"63395",title:"The Impact of Sequencing Human Genome on Drug Design to Treat Oral Cancer",slug:"the-impact-of-sequencing-human-genome-on-drug-design-to-treat-oral-cancer",totalDownloads:892,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Of all the known cancers, oral cancer is the most preventable and it is the second most deadly cancer after the breast cancer. Out of 609,640 deaths of overall cancers, 13,500 died of oral cancer. In spite of this enormous increase in loss of life, there are no useful drugs to treat oral cancer. Sequencing human genome identifies with precision and accuracy the specific mutations responsible for causing oral cancer. In this chapter, a novel approach to design drugs to attack mutated genes in squamous cell carcinoma responsible for causing oral cancer is proposed. Alkylating aziridines attack single-stranded DNA shutting off genes. Using dinitrobenzamide dye as a carrier for aziridine, we successfully made a novel class of drugs (CB 1954) which shuts off gene of a solid tumor, Walker Carcinoma 256, in rats. We translated the animal work in humans by using quinone as a carrier for aziridines making AZQ (US Patent 4,146,622) for attacking glioblastoma for treating brain cancer in humans. We propose to search for a carrier for aziridines to attack squamous cell carcinomas to treat oral cancer. Ethical issues are discussed. Since tobacco smoking causes oral cancer, it is the most preventable disease.",book:{id:"8631",slug:"prevention-detection-and-management-of-oral-cancer",title:"Prevention, Detection and Management of Oral Cancer",fullTitle:"Prevention, Detection and Management of Oral Cancer"},signatures:"Abdul Hameed Khan",authors:[{id:"262416",title:"Dr.",name:"Abdul Hameed",middleName:null,surname:"Khan",slug:"abdul-hameed-khan",fullName:"Abdul Hameed Khan"}]},{id:"67124",title:"Introductory Chapter: Head and Neck Cancer",slug:"introductory-chapter-head-and-neck-cancer",totalDownloads:884,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"8631",slug:"prevention-detection-and-management-of-oral-cancer",title:"Prevention, Detection and Management of Oral Cancer",fullTitle:"Prevention, Detection and Management of Oral Cancer"},signatures:"Sivapatham Sundaresan and Paliarasu Rajapriya",authors:[{id:"187272",title:"Dr.",name:"Sivapatham",middleName:null,surname:"Sundaresan",slug:"sivapatham-sundaresan",fullName:"Sivapatham Sundaresan"}]},{id:"66850",title:"Thyroid Anatomy",slug:"thyroid-anatomy",totalDownloads:964,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"In ancient times, the Celsius first identified the masses in the neck and reported that their surgical removal was fatal. The sources related to thyroid surgery show that the success of the neck masses with the surgical intervention was limited until the second half of the nineteenth century. Among the names leading the development of thyroid surgery in contemporary times are Emil Theodor Kocher, Theodor Billroth, William James Mayo, and William Stewart Halsted. In this chapter, we will be investigating thyroid gland embryology, histology, and anatomy that is essential to the practicing thyroid surgeon.",book:{id:"7883",slug:"knowledges-on-thyroid-cancer",title:"Knowledges on Thyroid Cancer",fullTitle:"Knowledges on Thyroid Cancer"},signatures:"Sinan Binboga, Eyup Gemici and Elif Binboga",authors:[{id:"291528",title:"Dr.",name:"Sinan",middleName:null,surname:"Binboga",slug:"sinan-binboga",fullName:"Sinan Binboga"},{id:"295739",title:"Dr.",name:"Eyup",middleName:null,surname:"Gemici",slug:"eyup-gemici",fullName:"Eyup Gemici"},{id:"295740",title:"Dr.",name:"Elif",middleName:null,surname:"Binboga",slug:"elif-binboga",fullName:"Elif Binboga"}]}],onlineFirstChaptersFilter:{topicId:"1081",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:133,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"June 25th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. 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. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!1,annualVolume:null,editor:null,editorTwo:null,editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,annualVolume:11400,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,annualVolume:11401,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,annualVolume:11402,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. 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"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:58,paginationItems:[{id:"81961",title:"Antioxidants as an Adjuncts to Periodontal Therapy",doi:"10.5772/intechopen.105016",signatures:"Sura Dakhil Jassim and Ali Abbas Abdulkareem",slug:"antioxidants-as-an-adjuncts-to-periodontal-therapy",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Trauma",coverURL:"https://cdn.intechopen.com/books/images_new/11567.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"82357",title:"Caries Management Aided by Fluorescence-Based Devices",doi:"10.5772/intechopen.105567",signatures:"Atena Galuscan, Daniela Jumanca and Aurora Doris Fratila",slug:"caries-management-aided-by-fluorescence-based-devices",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"81894",title:"Diet and Nutrition and Their Relationship with Early Childhood Dental Caries",doi:"10.5772/intechopen.105123",signatures:"Luanna Gonçalves Ferreira, Giuliana de Campos Chaves Lamarque and Francisco Wanderley Garcia Paula-Silva",slug:"diet-and-nutrition-and-their-relationship-with-early-childhood-dental-caries",totalDownloads:11,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Dental Caries - The Selection of Restoration Methods and Restorative Materials",coverURL:"https://cdn.intechopen.com/books/images_new/11565.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"81595",title:"Prosthetic Concepts in Dental Implantology",doi:"10.5772/intechopen.104725",signatures:"Ivica Pelivan",slug:"prosthetic-concepts-in-dental-implantology",totalDownloads:27,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Current Concepts in Dental Implantology - From Science to Clinical Research",coverURL:"https://cdn.intechopen.com/books/images_new/10808.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}}]},overviewPagePublishedBooks:{paginationCount:8,paginationItems:[{type:"book",id:"6668",title:"Dental Caries",subtitle:"Diagnosis, Prevention and Management",coverURL:"https://cdn.intechopen.com/books/images_new/6668.jpg",slug:"dental-caries-diagnosis-prevention-and-management",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Zühre Akarslan",hash:"b0f7667770a391f772726c3013c1b9ba",volumeInSeries:1,fullTitle:"Dental Caries - Diagnosis, Prevention and Management",editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",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",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7139",title:"Current Approaches in Orthodontics",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7139.jpg",slug:"current-approaches-in-orthodontics",publishedDate:"April 10th 2019",editedByType:"Edited by",bookSignature:"Belma Işık Aslan and Fatma Deniz Uzuner",hash:"2c77384eeb748cf05a898d65b9dcb48a",volumeInSeries:2,fullTitle:"Current Approaches in Orthodontics",editors:[{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",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}]},{type:"book",id:"7572",title:"Trauma in Dentistry",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7572.jpg",slug:"trauma-in-dentistry",publishedDate:"July 3rd 2019",editedByType:"Edited by",bookSignature:"Serdar Gözler",hash:"7cb94732cfb315f8d1e70ebf500eb8a9",volumeInSeries:3,fullTitle:"Trauma in Dentistry",editors:[{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",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",institutionURL:null,country:{name:"Turkey"}}}]},{type:"book",id:"7060",title:"Gingival Disease",subtitle:"A Professional Approach for Treatment and Prevention",coverURL:"https://cdn.intechopen.com/books/images_new/7060.jpg",slug:"gingival-disease-a-professional-approach-for-treatment-and-prevention",publishedDate:"October 23rd 2019",editedByType:"Edited by",bookSignature:"Alaa Eddin Omar Al Ostwani",hash:"b81d39988cba3a3cf746c1616912cf41",volumeInSeries:4,fullTitle:"Gingival Disease - A Professional Approach for Treatment and Prevention",editors:[{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",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. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. 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. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. 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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. 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Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},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:"