Blood serum metabolites (Means ± SEM) in dairy heifers fed on control and foreign probiotic yeast.
\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 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:"11066",leadTitle:null,fullTitle:"The Monte Carlo Methods - Recent Advances, New Perspectives and Applications",title:"The Monte Carlo Methods",subtitle:"Recent Advances, New Perspectives and Applications",reviewType:"peer-reviewed",abstract:"In applied mathematics, the name Monte Carlo is given to the method of solving problems by means of experiments with random numbers. This name, after the casino at Monaco, was first applied around 1944 to the method of solving deterministic problems by reformulating them in terms of a problem with random elements, which could then be solved by large-scale sampling. But, by extension, the term has come to mean any simulation that uses random numbers. Monte Carlo methods have become among the most fundamental techniques of simulation in modern science. This book is an illustration of the use of Monte Carlo methods applied to solve specific problems in mathematics, engineering, physics, statistics, and science in general.",isbn:"978-1-83968-760-0",printIsbn:"978-1-83968-759-4",pdfIsbn:"978-1-83968-761-7",doi:null,price:119,priceEur:129,priceUsd:155,slug:"the-monte-carlo-methods-recent-advances-new-perspectives-and-applications",numberOfPages:232,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"d1488c96b5b4d4909e963b9a91b1632f",bookSignature:"Abdo Abou Jaoudé",publishedDate:"March 9th 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11066.jpg",numberOfDownloads:3492,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:null,numberOfDimensionsCitations:1,numberOfDimensionsCitationsByBook:null,hasAltmetrics:0,numberOfTotalCitations:2,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 21st 2021",dateEndSecondStepPublish:"May 19th 2021",dateEndThirdStepPublish:"July 18th 2021",dateEndFourthStepPublish:"October 6th 2021",dateEndFifthStepPublish:"December 5th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"248271",title:"Dr.",name:"Abdo",middleName:null,surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé",profilePictureURL:"https://mts.intechopen.com/storage/users/248271/images/system/248271.jpg",biography:"Abdo Abou Jaoudé has been teaching for many years and has a passion for researching and teaching mathematics. He is currently an Associate Professor of Mathematics and Statistics at Notre Dame University-Louaizé (NDU), Lebanon. He holds a BSc and an MSc in Computer Science from NDU, and three PhDs in Applied Mathematics, Computer Science, and Applied Statistics and Probability, all from Bircham International University through a distance learning program. He also holds two PhDs in Mathematics and Prognostics from the Lebanese University, Lebanon, and Aix-Marseille University, France. Dr. Abou Jaoudé's broad research interests are in the field of applied mathematics. He has published twenty-three international journal articles and six contributions to conference proceedings, in addition to seven books on prognostics, pure and applied mathematics, and computer science.",institutionString:"Notre Dame University - Louaize",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Notre Dame University – Louaize",institutionURL:null,country:{name:"Lebanon"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"612",title:"Statistical Mechanics",slug:"statistical-mechanics"}],chapters:[{id:"77258",title:"The Paradigm of Complex Probability and Thomas Bayes’ Theorem",doi:"10.5772/intechopen.98340",slug:"the-paradigm-of-complex-probability-and-thomas-bayes-theorem",totalDownloads:1080,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The mathematical probability concept was set forth by Andrey Nikolaevich Kolmogorov in 1933 by laying down a five-axioms system. This scheme can be improved to embody the set of imaginary numbers after adding three new axioms. Accordingly, any stochastic phenomenon can be performed in the set C of complex probabilities which is the summation of the set R of real probabilities and the set M of imaginary probabilities. Our objective now is to encompass complementary imaginary dimensions to the stochastic phenomenon taking place in the “real” laboratory in R and as a consequence to gauge in the sets R, M, and C all the corresponding probabilities. Hence, the probability in the entire set C = R + M is incessantly equal to one independently of all the probabilities of the input stochastic variable distribution in R, and subsequently the output of the random phenomenon in R can be evaluated totally in C. This is due to the fact that the probability in C is calculated after the elimination and subtraction of the chaotic factor from the degree of our knowledge of the nondeterministic phenomenon. We will apply this novel paradigm to the classical Bayes’ theorem in probability theory.",signatures:"Abdo Abou Jaoudé",downloadPdfUrl:"/chapter/pdf-download/77258",previewPdfUrl:"/chapter/pdf-preview/77258",authors:[{id:"248271",title:"Dr.",name:"Abdo",surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé"}],corrections:null},{id:"77284",title:"The Paradigm of Complex Probability and Isaac Newton’s Classical Mechanics: On the Foundation of Statistical Physics",doi:"10.5772/intechopen.98341",slug:"the-paradigm-of-complex-probability-and-isaac-newton-s-classical-mechanics-on-the-foundation-of-stat",totalDownloads:1614,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The concept of mathematical probability was established in 1933 by Andrey Nikolaevich Kolmogorov by defining a system of five axioms. This system can be enhanced to encompass the imaginary numbers set after the addition of three novel axioms. As a result, any random experiment can be executed in the complex probabilities set C which is the sum of the real probabilities set R and the imaginary probabilities set M. We aim here to incorporate supplementary imaginary dimensions to the random experiment occurring in the “real” laboratory in R and therefore to compute all the probabilities in the sets R, M, and C. Accordingly, the probability in the whole set C = R + M is constantly equivalent to one independently of the distribution of the input random variable in R, and subsequently the output of the stochastic experiment in R can be determined absolutely in C. This is the consequence of the fact that the probability in C is computed after the subtraction of the chaotic factor from the degree of our knowledge of the nondeterministic experiment. We will apply this innovative paradigm to Isaac Newton’s classical mechanics and to prove as well in an original way an important property at the foundation of statistical physics.",signatures:"Abdo Abou Jaoudé",downloadPdfUrl:"/chapter/pdf-download/77284",previewPdfUrl:"/chapter/pdf-preview/77284",authors:[{id:"248271",title:"Dr.",name:"Abdo",surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé"}],corrections:null},{id:"78082",title:"Flooding Fragility Model Development Using Bayesian Regression",doi:"10.5772/intechopen.99556",slug:"flooding-fragility-model-development-using-bayesian-regression",totalDownloads:120,totalCrossrefCites:1,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Traditional component pass/fail design analysis and testing protocol drives excessively conservative operating limits and setpoints as well as unnecessarily large margins of safety. Component performance testing coupled with failure probability model development can support selection of more flexible operating limits and setpoints as well as softening defense-in-depth elements. This chapter discuses the process of Bayesian regression fragility model development using Markov Chain Monte Carlo methods and model checking protocol using three types of Bayesian p-values. The chapter also discusses application of the model development and testing techniques through component flooding performance experiments associated with industrial steel doors being subjected to a rising water scenario. These component tests yield the necessary data for fragility model development while providing insight into development of testing protocol that will yield meaningful data for fragility model development. Finally, the chapter discusses development and selection of a fragility model for industrial steel door performance when subjected to a water-rising scenario.",signatures:"Alison Wells and Chad L. Pope",downloadPdfUrl:"/chapter/pdf-download/78082",previewPdfUrl:"/chapter/pdf-preview/78082",authors:[{id:"324562",title:"Prof.",name:"Chad L.",surname:"Pope",slug:"chad-l.-pope",fullName:"Chad L. Pope"},{id:"417835",title:"Dr.",name:"Alison",surname:"Wells",slug:"alison-wells",fullName:"Alison Wells"}],corrections:null},{id:"79141",title:"Markov Chain Monte Carlo in a Dynamical System of Information Theoretic Particles",doi:"10.5772/intechopen.100428",slug:"markov-chain-monte-carlo-in-a-dynamical-system-of-information-theoretic-particles",totalDownloads:102,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In Bayesian learning, the posterior probability density of a model parameter is estimated from the likelihood function and the prior probability of the parameter. The posterior probability density estimate is refined as more evidence becomes available. However, any non-trivial Bayesian model requires the computation of an intractable integral to obtain the probability density function (PDF) of the evidence. Markov Chain Monte Carlo (MCMC) is a well-known algorithm that solves this problem by directly generating the samples of the posterior distribution without computing this intractable integral. We present a novel perspective of the MCMC algorithm which views the samples of a probability distribution as a dynamical system of Information Theoretic particles in an Information Theoretic field. As our algorithm probes this field with a test particle, it is subjected to Information Forces from other Information Theoretic particles in this field. We use Information Theoretic Learning (ITL) techniques based on Rényi’s α-Entropy function to derive an equation for the gradient of the Information Potential energy of the dynamical system of Information Theoretic particles. Using this equation, we compute the Hamiltonian of the dynamical system from the Information Potential energy and the kinetic energy. The Hamiltonian is used to generate the Markovian state trajectories of the system.",signatures:"Tokunbo Ogunfunmi and Manas Deb",downloadPdfUrl:"/chapter/pdf-download/79141",previewPdfUrl:"/chapter/pdf-preview/79141",authors:[{id:"51885",title:"Prof.",name:"Tokunbo",surname:"Ogunfunmi",slug:"tokunbo-ogunfunmi",fullName:"Tokunbo Ogunfunmi"},{id:"422469",title:"MSc.",name:"Manas",surname:"Deb",slug:"manas-deb",fullName:"Manas Deb"}],corrections:null},{id:"78730",title:"Monte Carlo and Medical Physics",doi:"10.5772/intechopen.100121",slug:"monte-carlo-and-medical-physics",totalDownloads:184,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The different codes based on the Monte Carlo method, allows to make simulations in the field of medical physics, so the determination of all the magnitudes of radiation protection namely the absorbed dose, the kerma, the equivalent dose, and effective, what guarantees the good planning of the experiment in order to minimize the degrees of exposure to ionizing radiation, and to strengthen the radiation protection of patients and workers in clinical environment as well as to respect the 3 principles of radiation protection ALARA (As Low As Reasonably Achievable) and which are based on: -Justification of the practice -Optimization of radiation protection -Limitation of exposure.",signatures:"Omaima Essaad Belhaj, Hamid Boukhal and El Mahjoub Chakir",downloadPdfUrl:"/chapter/pdf-download/78730",previewPdfUrl:"/chapter/pdf-preview/78730",authors:[{id:"321054",title:"Prof.",name:"Hamid",surname:"Boukhal",slug:"hamid-boukhal",fullName:"Hamid Boukhal"},{id:"321056",title:"Prof.",name:"El Mahjoub",surname:"Chakir",slug:"el-mahjoub-chakir",fullName:"El Mahjoub Chakir"},{id:"419592",title:"Ph.D. Student",name:"Omaima Essaad",surname:"Belhaj",slug:"omaima-essaad-belhaj",fullName:"Omaima Essaad Belhaj"}],corrections:null},{id:"77562",title:"Reliability and Comparison of Some GEANT4-DNA Processes and Models for Proton Transportation: An Ultra-Thin Layer Study",doi:"10.5772/intechopen.98753",slug:"reliability-and-comparison-of-some-geant4-dna-processes-and-models-for-proton-transportation-an-ultr",totalDownloads:190,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter presents a specific reliability study of some GEANT4-DNA (version 10.02.p01) processes and models for proton transportation considering ultra-thin layers (UTL). The Monte Carlo radiation transport validation is fundamental to guarantee the simulation results accuracy. However, sometimes this is impossible due to the lack of experimental data and, it is then that the reliability evaluation takes an important role. Geant4-DNA runs in an energy range that makes impossible, nowadays, to perform a proper microscopic validation (cross-sections and dynamic diffusion parameters) and allows very limited macroscopic reliability. The chemical damage cross-sections reliability (experiment versus simulation) is a way to verify the consistency of the simulation results which is presented for 2 MeV incident protons beam on PMMA and PVC UTL. A comparison among different Geant4-DNA physics lists for incident protons beams from 2 to 20 MeV, interacting with homogeneous water UTL (2 to 200 nm) was performed. This comparison was evaluated for standard and five other optional physics lists considering radial and depth profiles of deposited energy as well as number of interactions and stopping power of the incident particle.",signatures:"Gabriela Hoff, Raquel S. Thomaz, Leandro I. Gutierres, Sven Muller, Viviana Fanti, Elaine E. Streck and Ricardo M. Papaleo",downloadPdfUrl:"/chapter/pdf-download/77562",previewPdfUrl:"/chapter/pdf-preview/77562",authors:[{id:"299864",title:"Ph.D.",name:"Gabriela",surname:"Hoff",slug:"gabriela-hoff",fullName:"Gabriela Hoff"},{id:"310012",title:"Dr.",name:"Elaine E.",surname:"Streck",slug:"elaine-e.-streck",fullName:"Elaine E. Streck"},{id:"310013",title:"Prof.",name:"Viviana",surname:"Fanti",slug:"viviana-fanti",fullName:"Viviana Fanti"},{id:"418045",title:"Dr.",name:"Raquel S.",surname:"Thomaz",slug:"raquel-s.-thomaz",fullName:"Raquel S. Thomaz"},{id:"418046",title:"Dr.",name:"Leandro I.",surname:"Gutierres",slug:"leandro-i.-gutierres",fullName:"Leandro I. Gutierres"},{id:"418047",title:"Dr.",name:"Sven",surname:"Müller",slug:"sven-muller",fullName:"Sven Müller"},{id:"418048",title:"Prof.",name:"Ricardo M",surname:"Papaleo",slug:"ricardo-m-papaleo",fullName:"Ricardo M Papaleo"}],corrections:null},{id:"80243",title:"Applications of Simulation Codes Based on Monte Carlo Method for Radiotherapy",doi:"10.5772/intechopen.101323",slug:"applications-of-simulation-codes-based-on-monte-carlo-method-for-radiotherapy",totalDownloads:104,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Monte Carlo simulations have been applied to determine and study different parameters that are challenged in experimental measurements, due to its capability in simulating the radiation transport with a probability distribution to interact with electrosferic electrons and some cases with the nucleus from an arbitrary material, which such particle track or history can carry out physical quantities providing data from a studied or investigating quantities. For this reason, simulation codes, based on Monte Carlo, have been proposed. The codes currently available are MNCP, EGSnrc, Geant, FLUKA, PENELOPE, as well as GAMOS and TOPAS. These simulation codes have become a tool for dose and dose distributions, essentially, but also for other applications such as design clinical, tool for commissioning of an accelerator linear, shielding, radiation protection, some radiobiologic aspect, treatment planning systems, prediction of data from results of simulation scenarios. In this chapter will be present some applications for radiotherapy procedures with use, specifically, megavoltage x-rays and electrons beams, in scenarios with homogeneous and anatomical phantoms for determining dose, dose distribution, as well dosimetric parameters through the PENELOPE and TOPAS code.",signatures:"Iury Mergen Knoll, Ana Quevedo and Mirko Salomón Alva Sánchez",downloadPdfUrl:"/chapter/pdf-download/80243",previewPdfUrl:"/chapter/pdf-preview/80243",authors:[{id:"307138",title:"Dr.",name:"Mirko Salomón",surname:"Alva-Sánchez",slug:"mirko-salomon-alva-sanchez",fullName:"Mirko Salomón Alva-Sánchez"},{id:"416560",title:"Dr.",name:"Ana",surname:"Quevedo",slug:"ana-quevedo",fullName:"Ana Quevedo"},{id:"440449",title:"BSc.",name:"Iury",surname:"Mergen Knoll",slug:"iury-mergen-knoll",fullName:"Iury Mergen Knoll"}],corrections:null},{id:"80188",title:"Physical Only Modes Identification Using the Stochastic Modal Appropriation Algorithm",doi:"10.5772/intechopen.101224",slug:"physical-only-modes-identification-using-the-stochastic-modal-appropriation-algorithm",totalDownloads:106,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Many operational modal analysis (OMA) algorithms such as SSI, FDD, IV, … are conceptually based on the separation of the signal subspace and the noise subspace of a certain data matrix. Although this is a trivial problem in theory, in the practice of OMA, this is a troublesome problem. Errors, such as truncation errors, measurement noise, modeling errors, estimation errors make the separation difficult if not impossible. This leads to the appearance of nonphysical modes, and their separation from physical modes is difficult. An engineering solution to this problem is based on the so-called stability diagram which shows alignments for physical modes. This still does not solve the problem since it is rare to find modes stable in the same order. Moreover, nonphysical modes may also stabilize. Recently, the stochastic modal appropriation (SMA) algorithm was introduced as a valid competitor for existing OMA algorithms. This algorithm is based on isolating the modes mode by mode with the advantage that the modal parameters are identified simultaneously in a single step for a given mode. This is conceptually similar to ground vibration testing (GVT). SMA is based on the data correlation sequence which enjoys a special physical structure making the identification of nonphysical modes impossible under the isolating conditions. After elaborating the theory behind SMA, we illustrate these advantages on a simulated system as well as on an experimental case.",signatures:"Maher Abdelghani",downloadPdfUrl:"/chapter/pdf-download/80188",previewPdfUrl:"/chapter/pdf-preview/80188",authors:[{id:"417124",title:"Associate Prof.",name:"Maher",surname:"Abdelghani",slug:"maher-abdelghani",fullName:"Maher Abdelghani"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"10062",title:"Forecasting in Mathematics",subtitle:"Recent Advances, New Perspectives and Applications",isOpenForSubmission:!1,hash:"9a3ad05fef0502040d2a238ad22487c0",slug:"forecasting-in-mathematics-recent-advances-new-perspectives-and-applications",bookSignature:"Abdo Abou Jaoude",coverURL:"https://cdn.intechopen.com/books/images_new/10062.jpg",editedByType:"Edited by",editors:[{id:"248271",title:"Dr.",name:"Abdo",surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3003",title:"Simulated Annealing",subtitle:"Advances, Applications and Hybridizations",isOpenForSubmission:!1,hash:"2922b38cdbb1374af416a22aae979372",slug:"simulated-annealing-advances-applications-and-hybridizations",bookSignature:"Marcos de Sales Guerra Tsuzuki",coverURL:"https://cdn.intechopen.com/books/images_new/3003.jpg",editedByType:"Edited by",editors:[{id:"146384",title:"Dr.",name:"Marcos Sales Guerra",surname:"Tsuzuki",slug:"marcos-sales-guerra-tsuzuki",fullName:"Marcos Sales Guerra Tsuzuki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,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"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,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"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"57158",slug:"correction-to-chemical-composition-and-biological-activities-of-mentha-species",title:"Correction to: Chemical Composition and Biological Activities of Mentha Species",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/57158.pdf",downloadPdfUrl:"/chapter/pdf-download/57158",previewPdfUrl:"/chapter/pdf-preview/57158",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/57158",risUrl:"/chapter/ris/57158",chapter:{id:"54028",slug:"chemical-composition-and-biological-activities-of-mentha-species",signatures:"Fatiha Brahmi, Madani Khodir, Chibane Mohamed and Duez Pierre",dateSubmitted:"June 7th 2016",dateReviewed:"December 19th 2016",datePrePublished:null,datePublished:"March 15th 2017",book:{id:"5612",title:"Aromatic and Medicinal Plants",subtitle:"Back to Nature",fullTitle:"Aromatic and Medicinal Plants - Back to Nature",slug:"aromatic-and-medicinal-plants-back-to-nature",publishedDate:"March 15th 2017",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/5612.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"193281",title:"Dr.",name:"Fatiha",middleName:null,surname:"Brahmi",fullName:"Fatiha Brahmi",slug:"fatiha-brahmi",email:"fatiha.brahmi@univ-bejaia.dz",position:null,institution:{name:"University of Béjaïa",institutionURL:null,country:{name:"Algeria"}}},{id:"199693",title:"Prof.",name:"Khodir",middleName:null,surname:"Madani",fullName:"Khodir Madani",slug:"khodir-madani",email:"madani28dz@yahoo.fr",position:null,institution:null},{id:"199694",title:"Prof.",name:"Pierre",middleName:null,surname:"Duez",fullName:"Pierre Duez",slug:"pierre-duez",email:"pduez@umons.be",position:null,institution:null},{id:"203738",title:"Prof.",name:"Mohamed",middleName:null,surname:"Chibane",fullName:"Mohamed Chibane",slug:"mohamed-chibane",email:"chibanem@yahoo.fr",position:null,institution:null}]}},chapter:{id:"54028",slug:"chemical-composition-and-biological-activities-of-mentha-species",signatures:"Fatiha Brahmi, Madani Khodir, Chibane Mohamed and Duez Pierre",dateSubmitted:"June 7th 2016",dateReviewed:"December 19th 2016",datePrePublished:null,datePublished:"March 15th 2017",book:{id:"5612",title:"Aromatic and Medicinal Plants",subtitle:"Back to Nature",fullTitle:"Aromatic and Medicinal Plants - Back to Nature",slug:"aromatic-and-medicinal-plants-back-to-nature",publishedDate:"March 15th 2017",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/5612.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"193281",title:"Dr.",name:"Fatiha",middleName:null,surname:"Brahmi",fullName:"Fatiha Brahmi",slug:"fatiha-brahmi",email:"fatiha.brahmi@univ-bejaia.dz",position:null,institution:{name:"University of Béjaïa",institutionURL:null,country:{name:"Algeria"}}},{id:"199693",title:"Prof.",name:"Khodir",middleName:null,surname:"Madani",fullName:"Khodir Madani",slug:"khodir-madani",email:"madani28dz@yahoo.fr",position:null,institution:null},{id:"199694",title:"Prof.",name:"Pierre",middleName:null,surname:"Duez",fullName:"Pierre Duez",slug:"pierre-duez",email:"pduez@umons.be",position:null,institution:null},{id:"203738",title:"Prof.",name:"Mohamed",middleName:null,surname:"Chibane",fullName:"Mohamed Chibane",slug:"mohamed-chibane",email:"chibanem@yahoo.fr",position:null,institution:null}]},book:{id:"5612",title:"Aromatic and Medicinal Plants",subtitle:"Back to Nature",fullTitle:"Aromatic and Medicinal Plants - Back to Nature",slug:"aromatic-and-medicinal-plants-back-to-nature",publishedDate:"March 15th 2017",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/5612.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11066",leadTitle:null,title:"The Monte Carlo Methods",subtitle:"Recent Advances, New Perspectives and Applications",reviewType:"peer-reviewed",abstract:"In applied mathematics, the name Monte Carlo is given to the method of solving problems by means of experiments with random numbers. This name, after the casino at Monaco, was first applied around 1944 to the method of solving deterministic problems by reformulating them in terms of a problem with random elements, which could then be solved by large-scale sampling. But, by extension, the term has come to mean any simulation that uses random numbers. Monte Carlo methods have become among the most fundamental techniques of simulation in modern science. This book is an illustration of the use of Monte Carlo methods applied to solve specific problems in mathematics, engineering, physics, statistics, and science in general.",isbn:"978-1-83968-760-0",printIsbn:"978-1-83968-759-4",pdfIsbn:"978-1-83968-761-7",doi:null,price:119,priceEur:129,priceUsd:155,slug:"the-monte-carlo-methods-recent-advances-new-perspectives-and-applications",numberOfPages:232,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"d1488c96b5b4d4909e963b9a91b1632f",bookSignature:"Abdo Abou Jaoudé",publishedDate:"March 9th 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11066.jpg",keywords:null,numberOfDownloads:3492,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfDimensionsCitations:1,numberOfTotalCitations:2,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 21st 2021",dateEndSecondStepPublish:"May 19th 2021",dateEndThirdStepPublish:"July 18th 2021",dateEndFourthStepPublish:"October 6th 2021",dateEndFifthStepPublish:"December 5th 2021",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a year",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:"Abdo Abou Jaoudé is an Associate Professor of Mathematics and Statistics at Notre Dame University-Louaizé. He holds two PhDs in Mathematics and Prognostics from the Lebanese University and Aix-Marseille University. His research interests are in the field of applied mathematics.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"248271",title:"Dr.",name:"Abdo",middleName:null,surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé",profilePictureURL:"https://mts.intechopen.com/storage/users/248271/images/system/248271.jpg",biography:"Abdo Abou Jaoudé has been teaching for many years and has a passion for researching and teaching mathematics. He is currently an Associate Professor of Mathematics and Statistics at Notre Dame University-Louaizé (NDU), Lebanon. He holds a BSc and an MSc in Computer Science from NDU, and three PhDs in Applied Mathematics, Computer Science, and Applied Statistics and Probability, all from Bircham International University through a distance learning program. He also holds two PhDs in Mathematics and Prognostics from the Lebanese University, Lebanon, and Aix-Marseille University, France. Dr. Abou Jaoudé's broad research interests are in the field of applied mathematics. He has published twenty-three international journal articles and six contributions to conference proceedings, in addition to seven books on prognostics, pure and applied mathematics, and computer science.",institutionString:"Notre Dame University - Louaize",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Notre Dame University – Louaize",institutionURL:null,country:{name:"Lebanon"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"612",title:"Statistical Mechanics",slug:"statistical-mechanics"}],chapters:[{id:"77258",title:"The Paradigm of Complex Probability and Thomas Bayes’ Theorem",slug:"the-paradigm-of-complex-probability-and-thomas-bayes-theorem",totalDownloads:1080,totalCrossrefCites:0,authors:[{id:"248271",title:"Dr.",name:"Abdo",surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé"}]},{id:"77284",title:"The Paradigm of Complex Probability and Isaac Newton’s Classical Mechanics: On the Foundation of Statistical Physics",slug:"the-paradigm-of-complex-probability-and-isaac-newton-s-classical-mechanics-on-the-foundation-of-stat",totalDownloads:1614,totalCrossrefCites:0,authors:[{id:"248271",title:"Dr.",name:"Abdo",surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé"}]},{id:"78082",title:"Flooding Fragility Model Development Using Bayesian Regression",slug:"flooding-fragility-model-development-using-bayesian-regression",totalDownloads:120,totalCrossrefCites:1,authors:[{id:"324562",title:"Prof.",name:"Chad L.",surname:"Pope",slug:"chad-l.-pope",fullName:"Chad L. Pope"},{id:"417835",title:"Dr.",name:"Alison",surname:"Wells",slug:"alison-wells",fullName:"Alison Wells"}]},{id:"79141",title:"Markov Chain Monte Carlo in a Dynamical System of Information Theoretic Particles",slug:"markov-chain-monte-carlo-in-a-dynamical-system-of-information-theoretic-particles",totalDownloads:102,totalCrossrefCites:0,authors:[{id:"51885",title:"Prof.",name:"Tokunbo",surname:"Ogunfunmi",slug:"tokunbo-ogunfunmi",fullName:"Tokunbo Ogunfunmi"},{id:"422469",title:"MSc.",name:"Manas",surname:"Deb",slug:"manas-deb",fullName:"Manas Deb"}]},{id:"78730",title:"Monte Carlo and Medical Physics",slug:"monte-carlo-and-medical-physics",totalDownloads:184,totalCrossrefCites:0,authors:[{id:"321054",title:"Prof.",name:"Hamid",surname:"Boukhal",slug:"hamid-boukhal",fullName:"Hamid Boukhal"},{id:"321056",title:"Prof.",name:"El Mahjoub",surname:"Chakir",slug:"el-mahjoub-chakir",fullName:"El Mahjoub Chakir"},{id:"419592",title:"Ph.D. Student",name:"Omaima Essaad",surname:"Belhaj",slug:"omaima-essaad-belhaj",fullName:"Omaima Essaad Belhaj"}]},{id:"77562",title:"Reliability and Comparison of Some GEANT4-DNA Processes and Models for Proton Transportation: An Ultra-Thin Layer Study",slug:"reliability-and-comparison-of-some-geant4-dna-processes-and-models-for-proton-transportation-an-ultr",totalDownloads:190,totalCrossrefCites:0,authors:[{id:"299864",title:"Ph.D.",name:"Gabriela",surname:"Hoff",slug:"gabriela-hoff",fullName:"Gabriela Hoff"},{id:"310012",title:"Dr.",name:"Elaine E.",surname:"Streck",slug:"elaine-e.-streck",fullName:"Elaine E. Streck"},{id:"310013",title:"Prof.",name:"Viviana",surname:"Fanti",slug:"viviana-fanti",fullName:"Viviana Fanti"},{id:"418045",title:"Dr.",name:"Raquel S.",surname:"Thomaz",slug:"raquel-s.-thomaz",fullName:"Raquel S. Thomaz"},{id:"418046",title:"Dr.",name:"Leandro I.",surname:"Gutierres",slug:"leandro-i.-gutierres",fullName:"Leandro I. Gutierres"},{id:"418047",title:"Dr.",name:"Sven",surname:"Müller",slug:"sven-muller",fullName:"Sven Müller"},{id:"418048",title:"Prof.",name:"Ricardo M",surname:"Papaleo",slug:"ricardo-m-papaleo",fullName:"Ricardo M Papaleo"}]},{id:"80243",title:"Applications of Simulation Codes Based on Monte Carlo Method for Radiotherapy",slug:"applications-of-simulation-codes-based-on-monte-carlo-method-for-radiotherapy",totalDownloads:104,totalCrossrefCites:0,authors:[{id:"307138",title:"Dr.",name:"Mirko Salomón",surname:"Alva-Sánchez",slug:"mirko-salomon-alva-sanchez",fullName:"Mirko Salomón Alva-Sánchez"},{id:"416560",title:"Dr.",name:"Ana",surname:"Quevedo",slug:"ana-quevedo",fullName:"Ana Quevedo"},{id:"440449",title:"BSc.",name:"Iury",surname:"Mergen Knoll",slug:"iury-mergen-knoll",fullName:"Iury Mergen Knoll"}]},{id:"80188",title:"Physical Only Modes Identification Using the Stochastic Modal Appropriation Algorithm",slug:"physical-only-modes-identification-using-the-stochastic-modal-appropriation-algorithm",totalDownloads:106,totalCrossrefCites:0,authors:[{id:"417124",title:"Associate Prof.",name:"Maher",surname:"Abdelghani",slug:"maher-abdelghani",fullName:"Maher Abdelghani"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"10062",title:"Forecasting in Mathematics",subtitle:"Recent Advances, New Perspectives and Applications",isOpenForSubmission:!1,hash:"9a3ad05fef0502040d2a238ad22487c0",slug:"forecasting-in-mathematics-recent-advances-new-perspectives-and-applications",bookSignature:"Abdo Abou Jaoude",coverURL:"https://cdn.intechopen.com/books/images_new/10062.jpg",editedByType:"Edited by",editors:[{id:"248271",title:"Dr.",name:"Abdo",surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3003",title:"Simulated Annealing",subtitle:"Advances, Applications and Hybridizations",isOpenForSubmission:!1,hash:"2922b38cdbb1374af416a22aae979372",slug:"simulated-annealing-advances-applications-and-hybridizations",bookSignature:"Marcos de Sales Guerra Tsuzuki",coverURL:"https://cdn.intechopen.com/books/images_new/3003.jpg",editedByType:"Edited by",editors:[{id:"146384",title:"Dr.",name:"Marcos Sales Guerra",surname:"Tsuzuki",slug:"marcos-sales-guerra-tsuzuki",fullName:"Marcos Sales Guerra Tsuzuki"}],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:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"75131",title:"Understanding the Mechanism of Action of Indigenous Target Probiotic Yeast: Linking the Manipulation of Gut Microbiota and Performance in Animals",doi:"10.5772/intechopen.95822",slug:"understanding-the-mechanism-of-action-of-indigenous-target-probiotic-yeast-linking-the-manipulation-",body:'Probiotic are the live microbial feed supplements which provide the beneficial impact on the host by producing the useful metabolites [1]. Many probiotics have been available in the market for improving animal and human health in safe and healthy way. The commercially available probiotic product contains mostly lactic acid bacteria (
Representative scheme of development of target-based probiotic (TBP): The right side covers the main steps involving in the preparation of the TBP, the internal part covers the legalistic evidence of the interrelationship between, host and microbes. The left side covers the mechanistic activity of the TBP; including the improve gut microbial balance which leads to the improve feed digestion resultantly improve host health and production in cost effective manner.
In the situation of high animal feed cost, we must identify the cost-effective probiotic by using the concept of ITP to improve poor quality feed into high quality milk and meat. We had already given the concept of indigenous probiotic yeast our previous book chapter [31]. A clear understanding regarding the proposes guidelines to develop the ITP to improve gut microbiota resultantly improve milk and meat production. This book chapter will discuss the identification of the microbial strain from local ecological breed and its mode of action for preparation of target based probiotic products. We will also support our concept of ITP with our lab conducted experiments.
Yeast is a very useful microorganism with broad range of industrial application, because of their unique genetics and physiology. Yeast cells have many useful metabolites (protein, carbohydrate, vitamins; vitamin B6, thiamin, biotin, riboflavin, nicotinic acid and pantothenic acid and minerals; zinc and magnesium) [10]. The utilization of the naturally prepared yeast would be accelerated in coming years due to the nature-oriented mind set of the consumers. Therefore, research on the isolation of the nutritious rich yeast strains for preparation of probiotic product has rapidly increased [11, 12]. Yeast is an important single cell microorganism, belongs to fungus family and it multiplies by cell division. The genetics and physiology of the yeast are very unique, and, therefore, a broad range of research work in biological sciences is being carried out on this microbe. The yeast cell size is composed of 5 × 10 μm and the size of the baker’s yeast genome is 12.1 Mb containing 16 chromosomes and 5400 coding genes approximately [13]. Members of the order Saccharomycetales are mainly used for the animal probiotics when serves as reliable and economical source of essential amino acids, vitamins, carbohydrates, and minerals from yeast cell. Thiamin, Riboflavin, Niacin and Biotin are present in yeast [14]. The antagonistic ability of the yeast to block bacterial pathogenicity is also makes its very useful [15]. Yeast cell has competition for nutrients, pH changes in the medium, high concentrations of ethanol production, secretion of antibacterial compounds and release of antimicrobial compounds are major antagonistic steps. Yeast cell has many useful fermentation metabolites (protein, vitamins, carbohydrates) which makes it important microbial feed supplement. Yeasts are naturally present (1.3 X 105 yeasts ml-1) inside the rumen fluid [16]. Literature showed that, yeasts (
The role of the probiotic yeast in dairy animal is well studied [25]. They have been extensively used for improve milk yeast and its composition in cost effective manners. The benefits to cost ratio of probiotic yeast is 4:1 in dairy animals. They have also used as preventer against digestive problems, and rumen acidosis.
The main target of the PY used in new born ruminate diet are; (a) improvement in the rumen maturation; (b) stop the pathogenic bacterial growth; (c) establishment of the normal growing animals like microbial flora [26, 27, 28]. Microbial based feed can improve the rumen development during the growing phase of the dairy animals. The new born gut is sterile and have no germ [29]. After 6 months of age the rumen is colonized with diverse microbial flora. PY provides beneficial metabolites and enzymes like thiamine for fast growth of the fungi. The poor fungal growth of the animal fed on PY might be due to the low production of thiamine [30]. At the same time, the animal plays an important role in the maximum colonization of the beneficial microbial population [31]. If there is any imbalance bacterial species, it would result in digestive problems and leads to the economic loss. The establishment of the useful bacterial strains results in the development of strong and balanced rumen which resultantly strong immunity and health condition [32, 33]. PY provide the improve the rumen maturation and its microbial flora is also in strong balance. PY provide the useful bacterial species for feed digestion, like cellulolytic bacterial species and ciliate protozoa [34]. The balance in rumen microbial flora plays a crucial role in feed utilization and could result in better animal productivity [35]. PY remove oxygen from rumen and provides a more anaerobic environment for its growth of key beneficial microbial groups [36]. The newborn gut can easily be modulating by PY. The new born key beneficial microbial
For clear understanding of the ruminal gut microbiota using latest genomic methods to get useful information for preparation of specific probiotics. The ruminants feed consists of concentrate, silage, seasonal fodders etc. There diet mostly contains cellulose, hemicellulose starch and water-soluble carbohydrate. The rumen microbes play an important role in feed digestion. The animal feed is digested inside rumen and then energy is released for animal use. Cow and its microbes are mutually benefiting each other (Figure 2). Rumen is the first and the largest anaerobic chamber of the cow GIT. The temperature inside the rumen chamber is between 38 to 41 oC, with 6-7 pH (depends on feed type). There are three different types of microbes present inside the rumen including, bacteria, fungi and ciliated protozoa [41, 42, 43, 44]. The location and size of the rumen microbes depends on the feed formulation and host genetic. Mostly, bacteria are associated with fibrous feed particles; fungi, protozoa [45, 46]. Some are freely living and some are bound with rumen mucous membrane. 1 ml of the rumen is composed of 109 to 1010 per ml bacteria with 200 different species, 104 to 106 per ml protozoa with 20 different species, and 103 per ml fungi with 20 different species [47]. The rumen bacteria are gram negative 1-2 micrometer in size and cocci, and rod shaped mostly. Rumen bacterial are mostly non-spore producing, facultative anaerobes. 1- 5 % of the bacterial cells in rumen are cellulose digesters [48]. The rumen fungi (gut fungi) also play an important role in fiber digestion by stimulating growth of fibrolytic bacteria [49]. The rumen microbial features are heritable; moreover, animals age, feed and genome plays an important role in the microbial colonization. The composition of the diet describes the type of gut microbial species [50]. Therefore, the rumen microbiota can be manipulated by using the yeast-based probiotic to obtained the useful products. The feed must be targeted for modulating the rumen microbiota (Figure 3).
Major factors effects on the mode of action of probiotic.
A scheme describing the mutually benefits between host microbes.
The modulation of the rumen microbiota is mostly for the enhanced colonization of the fiber digesting microbiota [35, 36]. Literature showed that, animal diet has an important role in the manipulation of the rumen microbiota. Low amount of fibrous feed builds up fast working microbes (fibre-degrading Butyrivibrio fibrisolvens and F. succinogenes) and high amount of fibrous build up slow working fiber degrading microbes
Potential mechanisms of microbial ruminal acidosis: This figure suggested that, the live yeast supply different growth factors (amino acid, peptides, vitamins and organic acids). These growth factors have the knock-on impact of increases the stimulation and metabolism of lactic acid utilizing anaerobic bacteria, such as M. Elsdenii or S. ruminantium (that control the acidosis). Yeast cells has a affinity for sugar which outcompete S.bovis for the utilization of sugar.
A proposed flowsheet to explain mechanistic pathway of IPY: Steps involved in the mode of action of PY and its impact on animal.
A simple scheme proposed to explain mode of action of probiotic yeast in gut: IPY improve carbohydrates, protein and lipid digestion rate by improving the production of cellulolytic, hemi- cellulolytic and proteolytic and lipolytic bacteria and fungi as compare to FPY and no yeast animal.
The gut microbiota can digest the animal feed and produce nutrients for improve host health and well beings. Animal feed and host genetics play important role in shaping and composition of gut microbiota [18]. Same is the case of the rumen microbiota, which is highly variable and is depended on various factors like animal breed, physiology, feed type and geographical location. It has been commonly accepted that commercially available probiotic yeast may not showed equal impact to all animal breeds [65, 66]. The compatibility of PY could be variable among animals. The local prepared yeast probiotic isolated from same ecological niche may have more beneficial impact than any exotic probiotic yeast [3]. The local isolated probiotic yeast may have fast adaptability and colonization in the local rumen ecosystem [24]. The origin of the probiotic strain determines the best prepared probiotic product. The strain selection is the most important step for the development of right probiotic for animal. Being precise during the strain’s selection could yield positive outcomes from the probiotic. The probiotic yeast may use for the rumen microbial manipulation [67]. Different types of PY have been used for improve animal health and production [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68]. Some PY strains produced beneficial results in animals while others did not. The difference of that variable results of PY may be explained by different host and PY associated factors [69, 70, 71]. These factors are; animal age, breed, sex, feeding dose, PY strains isolation source and some unknown factors [3]. The major factors might be the low compatibility of the exotic probiotic yeast strain with animal having diverse biological inheritance and gut microbial composition. The right probiotic strain should be novel, so we must use latest molecular methods to isolate the target specific/local isolated microbial strains. The local isolated and molecular identified probiotic strains may have more impact on local animals in cost effective manners. The probiotic are species specific by targeting the indigenous strains and local dairy farms can get the cost-effective probiotic product for improve milk production and composition.
The main steps involved in the preparation of the breed specific probiotic yeast are as following [3].
Pre-plan ruminate diet for isolation of probiotic yeast
Identification of yeast strain based on the molecular techniques
Probiotic potential of selected yeast strains
In vitro probiotic potential
Safety assessment/In-vivo animal model
The first mode of action of the probiotic yeast is competitive exclusion (CE) [27]. The CE is a probiotic mode of action that involves the colonization of the beneficial microbial strains to GIT tract to reduce the addition of disease-causing microbial flora [18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74]. The ability of probiotic yeast cell to fight with other useless microbial flora can improve growth and function of beneficial microbial flora. The IPY has the indigenous strain, which has the advantage that it drives from animal of interest (Cow). IPY has an environmental modification capability. The concept of co-evolution of host microbial has been seen in case of IPY mode of action. The local strain gains an advantage because of its ability to adjust/modify itself in new environment by producing the antimicrobials e.g (lactic acid) to make its less suitable for its competitors. The FPY has the foreign origin strain, which has the less environmental modification capability less, competition for available nutrients, and mucosal adhesion sites. Second mode of action of the PY is reported as a good pH stabilization. Rumen microbial flora can work under stable pH [75]. Rumen pH is highly affected by animal feed intake and its composition. Ruminants eat different types of feed, like high energy concentrate diet, fodder, and silage. These types of feed have a quick impact on rumen pH. If rumen pH is not stable, the animals may have different types of metabolic diseases [76]. Literature showed that PY has a stabilizing effect on the rumen pH [77, 78]. Some studies reported a rise rumen pH when animal was fed on diet with high energy supplemented with PY. Sometimes, the increased pH might be due to the decreased VFAs inside the rumen [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79]. The lower pH leads to the rumen acidosis, PY can prevent the acidosis condition of the dairy animals [7]. The third proposed mechanism is that yeast cell provides the anaerobic condition inside rumen by removing the oxygen thus facilitated the useful feed digestion microbes [35, 36]. The main microbial flora are bacteria fungi and protozoa. These microbial species have a fiber digestion role by secreting the cellulase and hemicellulase enzymes. Fiber is the main part of the ruminant diet. Therefore, fiber digestion, nature blessed them with unique fibrolytic digestion bacteria (
Based upon the above discussion, we have conducted two research experiments on dairy animals by using the IPY concept to improve the gut health. In experiment 1, eight dairy heifers (87 ± 5 kg and 6–7 months) were divided into two equal groups (control n = 4 and probiotic n = 4)[80]. Control group animals fed on NRC recommended diet and probiotic group animals fed control diet FPY (Yea-Sac1026; 5 g/animal). After 120 days results showed that the FPY significantly affected the serum glucose, and urea levels in dairy heifers [24].
That means, we had a proof of positive impact of PFY on animal health. We had isolated the yeast from dairy animals fed on yeast. After careful assessment of the probiotic potential, we conducted another experiment to determine the impact of FPY Vs IPY on the health of lactating dairy cattle. Mix breed (
Items | Feeding regime | p-Value | |
---|---|---|---|
Control2 | FPY3 | ||
Before treatment4 | 30.10 ± *0.711 | 31.14 ± 0.974 | 0.012 |
After treatment5 | 33.34 ± 0.432 | 29.23 ± 0.494 | 0.01 |
Before treatment | 62.67 ± 4.04 | 60.86 ± 2.80 | 0.605 |
After treatment | 63.31 ± 2.60 | 65.47 ± 2.84 | 0.600 |
Blood serum metabolites (Means ± SEM) in dairy heifers fed on control and foreign probiotic yeast.
n = 4 per treatment.
Control feed without yeast.
Probiotic feed compose of control feed supplemented with 2.5×10 07 cfu/g commercially available probiotic yeast (Yac-Sac1026) at the rate of 5 g per animal/day * ± Standard error of the mean.
Before treatment (day 0).
After treatment (day 120).
Parameters | Feeding regime | ||
---|---|---|---|
Control2 | IPY3 | FPY4 | |
Before treatment5 | 14.55 ± *0.57 | 14.18 ± 0.21 | 15.54 ± 0.32 |
After treatment6 | 14.18a ± 0.58 | 12.31b ± 0.22 | 13.68ab ± 0.90 |
Before treatment | 75.70 ± 1.24 | 73.99 ± 2.51 | 75.08 ± 2.30 |
After treatment | 73.84b ± 0.71 | 77.42a ± 1.28 | 78.97a ± 0.54 |
Effect of indigenous Vs foreign probiotic yeast on blood parameters (Means ± SEM) in lactating dairy cattle.
n = 3 per treatment.
Control feed without yeast.
LAB-Probiotic feed compose of control feed supplemented with 3.13 × 1007 cfu/g laboratory produces probiotic yeast (QAUSC03) at the rate of 8 g/day/animal.
COM-Probiotic feed compose of control feed supplemented with 2.5×10 07 cfu/g commercially probiotic yeast (Yac-Sac1026) at the rate of 10g/day/animal.
Before treatment (day 0).
After treatment (day 120) * ± SEM = standard error of the mean.
a,b Values on the same row with different superscripts differ significantly (P < 0.05).
We highlighted that improved animal health condition might be due to improved digestive enzymes produced from well propagated IPY. The VFAs have a capability to reduce the triglycerol and cholesterol in liver cells and might be change the animal lipid profile. Results of the ruminal gut microflora showed that the average, beneficial
Total Lactococcus count (CFU/g) in the ruminal gut of dairy heifers fed on control feed (control, ♦; no yeast) or commercial probiotic feed (COM-P, ■; control feed plus commercial yeast) (n = 4).
Total Enterococcus count (CFU/g) in the ruminal gut of dairy heifers fed on control feed (control, ♦; no yeast) or commercial probiotic feed (COM-P, ■; control feed plus commercial yeast) (n = 4).
It can be concluded IPY improves the, gut health, and wellbeing of lactating dairy cattle in cost effective manner. IPY strain may adopt well in the cattle gut than FPY [80].
Ruminants of developing and developed countries have different types of gut microbiota due to their living standard, feeding type, their managemental style. Although from above discussion we have a clear understanding that the interlink between gut microbiota and fiber digestion plays a key role for obtaining maximum profit from dairy animals. Therefore, the PY must be target specific which give maximum outcomes in cost effective manners. For animals of specific geographical region, a unique and precise YP must be designed by isolating the local yeast strains from that population, only then maximum beneficial outputs can be obtained. The reason beings, compactivity of the local strains with normal microbiota of the rumen ecosystem (Figure 9).
Target based Probiotic Preparation strategy: This figure showed probiotic preparation of by using the local animal GIT tract as preparation of local yeast probiotic. Interlinked factors involved in the application of probiotics in the ruminant’s nutrition.
The recommendations are outlined as follows;
Pre-plane feed formulation for the manipulation of the rumen microbiota to digest the fibrous feed
Identification of breed specific probiotic strains with same target.
Whole genome sequencing of the probiotic strains as well as animal for maximum outputs
Mode of action of the probiotic should studied well for understanding of the useful and useless probiotic.
Angiogenesis is a process that is important to the growth of cancers. It refers to when new blood vessels sprout from existing ones. This multi-step process is imperative to the physiological maintenance of the body such as tissue repair [1]. It is also thought to be a critical process that tumours depend on for the delivery of oxygen and nutrients, in order to facilitate growth and progression [2]. Both pro-angiogenic factors and anti-angiogenic factors play a role in modulating tumour neovascularisation. Notably, vascular endothelial growth factors (VEGF) and catecholaminergic signalling pathways have been shown to be key factors in angiogenesis, invasion and metastases [3]. Investigations into catecholaminergic signalling from the sympathetic nervous system have shown to increase VEGF and matrix metalloprotease (MMP) levels, promoting tumour growth, invasion and metastasis [4]. Since tumour angiogenesis requires the up-regulation of these factors, anti-angiogenic agents have now been developed. A multitude of trials have investigated the effect of anti-angiogenic agents on the progression of cancer as well as combination therapies to improve the current standard of care. However, not all patients respond to these, leading to studies that aim at elucidating the mechanisms of resistance.
Angiogenesis is considered to be a fundamental event in tumour progression and metastatic dissemination and is [2] regulated by numerous endogenous factors that stimulate or inhibit neovascularisation [3]. One of the most studied pathways is the vascular endothelial growth factor (VEGF) family of ligands and their receptors [5]. In humans and mice, the VEGF family consists of 5 members: VEGF-A, -B, -C, -D and placental growth factor (PIGF). These ligands demonstrate variable specificity for the three VEGF receptors (VEGFR1, VEGFR2, VEGFR3) [3, 5]. The predominant member of the VEGF family involved in tumourigenesis is VEGF-A and will be referred to as simply ‘VEGF’ from herein.
One of the most important stimuli for tumour angiogenesis is hypoxia, which can occur when a rapidly growing tumour exceeds the ability of the local vasculature to supply its needs. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor, made up of two DNA binding proteins (HIF-1
Binding of VEGF to the extracellular domain of VEGFR2 causes receptor dimerisation and phosphorylation of the receptor on tyrosine residues within the intracellular domain (Figure 1) [11]. The Y1054 and Y1059 residues, which lie within the kinase domain, become phosphorylated in response to VEGF stimulation. These positively regulate the intrinsic kinase activity of the intracellular domain and signal to phospholipase-Cγ (PLCγ), which in turn leads to VEGFR2 internalisation [12]. The Y1175 and Y1214 residues lie in the carboxyl terminal tail. These residues become highly phosphorylated in response to VEGF. Y1214 signalling leads to endothelial cell migration and Y1175 signalling leads to PLCγ and extracellular related kinase 1/2 (ERK1/2) activation that is required for DNA synthesis and cell proliferation [13]. Activation of ERK1/2 requires the Ras-Raf-MEK-ERK1/2 signalling cascade but may also require the PLCγ/PKC/PKD pathway [14]. The roles of Y951 and Y996 residues, which lie in the kinase insert region, have not been definitively determined, but Y951 phosphorylation has been shown to increase endothelial cell migration and proliferation via both the PLC-γ and PI3K pathways [15].
Signalling from VEGFR2. The signalling cascades downstream of VEGFR2 have been the best studied and are illustrated here. VEGF binding to VEGFR2 induces dimerisation of VEGFR2 and phosphorylation of tyrosine residues (indicated by the four-digit numbers in the illustration). Pathways activated include the Ras-Raf-MEK-ERK pathway, PLCγ/PKC pathway and the PI3K/Akt pathway. Activation of downstream signalling from VEGF receptors exerts control over multiple processes required for angiogenesis including endothelial cell proliferation, migration, tube formation and vascular permeability.
According to the established dogma, VEGF released by tumours stimulates the growth of new vessels in the following way. The VEGF diffuses through the tissue and activates endothelial cells located in local blood vessels. Firstly, VEGF receptor activation induces the selection of sprouting endothelial cells. Proteinases such as urokinase-type plasminogen activator, uPA, and members of the matrix metalloproteinase (MMP) family mediates the dissolution of the vascular basement membrane and extracellular matrix to facilitate the infiltration of sprouting endothelial cells into the surrounding tissue [16]. Next, endothelial proliferation, migration and branching allows for the formation of new vessels. This is followed by sprout fusion and lumen formation where vessels fuse together to form a network. Finally, there is perfusion and maturation. This is where the stabilisation of new blood vessels forms a functionally perfused system, which is mediated by the recruitment of pericytes to surround the newly formed endothelial tubes; recruitment of pericytes prevents further endothelial cell proliferation and migration and also suppresses vessel leakage [17].
Multiple possible mechanisms exist regarding immunosuppressive effects of VEGF on the tumour microenvironment. Firstly, due to the effect of VEGF on tumour vasculature, T cell migration from lymph nodes to the microenvironment may be impaired. Furthermore, the ability of T cells to migrate through vessels is negatively affected by VEGF through the down regulation of vascular endothelial selectins, adhesion molecules and promotion of Fas ligand expression. Secondly, VEGF binding to its receptor on myeloid derived suppressor cells within the tumour microenvironment results in STAT 3 signalling, with subsequent promotion of Treg cells and the down regulation of tumour specific T cells [18]. Additionally, the binding of VEGF to VEGFR2 has effects including reduced activation of cytotoxic CD8+ and CD4+ T cells, as well as the upregulation of inhibitory receptors including PD1 and CTLA4 [19]. The interaction of VEGF with VEGFR may also upregulate the programmed death ligand 1 (PDL1) on dendritic cells (DCs) [20]. Furthermore, the binding of VEGF to VEGFR1 on dendritic cells has the effect of inhibiting dendritic cell maturation [20].
Given the key role VEGF is proposed to play in tumour angiogenesis, it is unsurprising that it has become a major drug target. Various drugs designed to inhibit VEGF signalling have been developed, including VEGF neutralising antibodies (e.g. bevacizumab), novel fusion proteins which bind pro-angiogenic growth factors (e.g. aflibercept) and VEGF receptor tyrosine kinase inhibitors (e.g. sunitinib) [5, 21]. Such agents have shown promise in the treatment of several malignancies, including mCRC, metastatic renal cell carcinoma (mRCC), metastatic lung cancer, hepatocellular carcinoma (HCC) and pancreatic neuroendocrine tumours (PNET) [22].
Bevacizumab (Avastin®) is a recombinant humanised monoclonal antibody that binds to the VEGF-A isoform of human VEGF specifically and prevents the VEGF from activating the VEGF receptor [23].
Trials with bevacizumab as a single agent in metastatic colorectal cancer (mCRC) failed to demonstrate activity, but early Phase I trials demonstrated that it has the potential to be combined with many chemotherapy agents [24]. In the advanced setting, several randomised Phase II and III clinical trials clearly demonstrated that bevacizumab improves response rates (ORR), progression free survival (PFS) and overall survival (OS) in mCRC, when added to standard chemotherapy in the first line setting [25, 26], and the second line setting [27] (Table 1). In February 2004, the US Food and Drug Administration (FDA) approved bevacizumab for the treatment of mCRC in combination with 5-fluorouracil-based chemotherapy regimens based on a pivotal Phase III study which demonstrated significant PFS and OS survival benefit [25]. Of clinical importance, bevacizumab in combination with a fluoropyrimidine has also demonstrated efficacy in elderly patients with mCRC [26].
Studies investigating bevacizumab in metastatic colorectal cancer in the first line.
Despite these data, only a small proportion of patients benefit from the addition of bevacizumab, and furthermore, some studies have demonstrated only an increase in PFS, with no increase in ORR or OS (Table 1) [28]. Additionally, even those who respond initially to bevacizumab combined with chemotherapy will inevitably develop resistance and relapse [29].
In the setting of colorectal liver-only metastasis (CRLM), it has been well demonstrated that preoperative chemotherapy improves outcome and metastatectomy rates [30]. With this in mind, and on the basis that bevacizumab can improve ORR, several groups set out to evaluate its role in the preoperative CRLM setting. Findings from a small non-randomised controlled trial of neoadjuvant conventional chemotherapy with bevacizumab in high-risk CRLM patients alluded to an improvement of CRC liver metastasis rate to 40% [31]. Data from retrospective, inter-trial studies have also suggested that the addition of bevacizumab to chemotherapy significantly improves pathological response in CRLM compared to when chemotherapy is administered alone [32]. Subgroup post hoc analyses extracted from large randomised controlled trials of unselected patients have failed to show significant improvements in resection rates with the addition of bevacizumab [33]. Without prospective randomised trials however, it is difficult to make conclusions regarding the efficacy of chemotherapy versus chemotherapy combined with bevacizumab in the CRLM setting.
The role of continuing bevacizumab beyond first progression in advanced colorectal cancer has also been examined. The results of two non-randomised observational cohort studies (BRiTE and ARIES) demonstrated a significant correlation between the use of bevacizumab beyond progression and substantial improvement in OS [34, 35]. Benefit of treatment beyond progression following first line treatment was later confirmed in a prospective randomised trial [36].
The efficacy of bevacizumab has also been evaluated in the adjuvant setting in CRC patients. Two large randomised studies compared survival between the following arms: adjuvant chemotherapy alone for 6 months versus adjuvant chemotherapy in combination with bevacizumab for 6 months (followed by bevacizumab alone for 6 months). Both studies demonstrated that at 1 year there was an improvement in PFS in the bevacizumab arm. However, no significant difference in OS was observed between treatment arms when assessed at 3 or 5 years [37, 38]. In fact, an analysis at 5 years in the AVANT study demonstrated a possible detrimental effect on survival with the addition of bevacizumab, documenting a higher number of relapses and deaths due to disease progression [37].
Bevacizumab in combination with cytotoxic chemotherapy has also shown significant clinical efficacy in other tumour types.
In advanced non-squamous non-small cell lung cancer (NSCLC), two randomised controlled phase III trials demonstrated significant benefit in PFS when bevacizumab was added to platinum-based doublet chemotherapy [39, 40], but only one study reported an increase in OS [40]. To further understand this discrepancy, a recent meta-analysis pooling data from several studies including the aforementioned two, deduced a modest but significant improvement in OS [41]. More recently in metastatic non-squamous NSCLC, the Impower150 phase 3 clinical trial investigated treatment with bevacizumab plus platinum doublet chemotherapy with or without the PDL1 inhibitor atezolizumab. Treatment with atezolizumab, bevacizumab and chemotherapy compared with bevacizumab and chemotherapy resulted in a significant improvement in PFS at 6 months (66.9% vs. 36.5%) and at 12 months (56.1% vs. 18%) [42]. In an interim analysis of OS, an improvement was again seen (Table 2) [42].
Studies investigating anti-VEGF agents in NSCLC and RCC.
In advanced ovarian cancer, in the first- and second-line settings, the efficacy of bevacizumab has been assessed when added to platinum-based chemotherapy doublets. Two pivotal first line phase III studies utilising the same chemotherapy doublet (ICON7/AGO-OVAR and GOG-0218 trials) demonstrated a significant improvement in PFS [43]. An updated survival analysis failed to show a significant survival benefit [43].
Bevacizumab has been investigated in glioblastoma multiforme (GBM), in the recurrent setting following first line treatment with temozolamide and radiation therapy. In this setting bevacizumab monotherapy is ineffective, however in combination with lomustine it has resulted in improvement in PFS but not OS [44]. Bevacizumab has also been investigated in the first line setting with chemoradiation in a large randomised placebo controlled trial, but failed to improve outcomes [45].
Earlier phase III trials in RCC have demonstrated efficacy of bevacizumab in combination with sorafenib, sunitinib and interferon alpha (Table 2). More recently, bevacizumab has been combined with atezolizumab in metastatic RCC. A phase III randomised trial confirmed significant improvement in PFS for bevacizumab combined with atezolizumab compared with sunitinib monotherapy but mature OS data are still awaited [46].
Despite such encouraging results, bevacizumab has thus far failed to make a significant impact in several other indications, including metastatic breast cancer (mBC), melanoma, pancreatic cancer and prostate cancer. Interestingly, in breast cancer, pooled data from four large clinical trials demonstrated that it neither prolonged OS, nor delayed disease progression significantly, leading the FDA to revoke its initial approval of bevacizumab for mBC [47]. The variation in impact that bevacizumab has, not only across tumour types, but also within a single tumour type, is curious and needs to be better understood.
Ramucirumab is a fully human IgG1 monoclonal antibody that binds to the extracellular domain of VEGFR-2, blocking VEGF from activating the receptor [48]. Clinical efficacy and tolerability have been demonstrated in a number of preclinical studies and more recently in phase III trials. In the refractory metastatic gastric and gastro-oesophageal junction (GOJ) adenocarcinoma setting, ramucirumab significantly improved median OS compared with placebo but this only represented an absolute improvement of 1.4 months [49]. In the second line setting of advanced gastric and GOJ adenocarcinoma, the combination of ramucirumab and paclitaxel has become standard treatment based on the results of the pivotal RAINBOW trial showing significant improvement in OS compared with paclitaxel and placebo [50]. Ramucirumab has not shown benefit in the first line setting including combination with chemotherapy [51].
Ramucirumab has also been investigated in metastatic NSCLC but does not yet have an established role for this indication. After progression on first line platinum based chemotherapy, there was a small but statistically significant benefit in median OS of ramucirumab added to docetaxel [52]. Early results of the RELAY phase 3 clinical trial investigating ramucirumab in combination with erlotinib in the first line setting of metastatic EGFR mutated NSCLC have indicated an improvement in PFS however formal publication of the study findings are awaited.
Ramucirumab has also been investigated in urothelial cancers. In a phase III trial of ramucirumab plus docetaxel compared with docetaxel plus placebo in patients with advanced urothelial carcinoma who had received platinum-based chemotherapy, there was a statistically significant improvement in median PFS (4.07 months vs. 2.76 months) [53].
Aflibercept is a recombinant fusion protein that binds to VEGF-A, VEGF-B and placental growth factor (PLGF), all of which have been implicated in angiogenesis and/or the survival of newly formed blood vessels [54]. As it binds to additional pro-angiogenic targets (compared to bevacizumab which binds only VEGF-A), aflibercept may provide further anti-angiogenic effects compared to targeting VEGF-A alone. In preclinical studies, it demonstrated a broad range of anti-tumour and anti-angiogenic activity both alone and in combination with chemotherapy, which was also observed in phase I clinical trials [55]. Recently, a large randomised phase III clinical trial (VELOUR) in advanced CRC patients, receiving second line therapy, demonstrated that the addition of aflibercept to systemic chemotherapy significantly improved outcomes compared to chemotherapy alone [56]. Based on this data, aflibercept was recently approved for use in the second line setting in mCRC when given in combination with chemotherapy. Importantly, results from a subanalysis of VELOUR showed that there was no significant impact of prior exposure to bevacizumab, illustrating the benefit that it provides as a multiple angiogenic factor trap, in a setting where resistance to bevacizumab may have developed [57].
Several small molecule inhibitors of VEGF receptor tyrosine kinase activity now have an established role in the treatment of certain tumour types, including mRCC, HCC and advanced CRC. These small molecule inhibitors readily diffuse through the cell membrane to compete for ATP binding to the intracellular tyrosine kinase domain of VEGF receptor 2.
Sunitinib is an orally active multi-kinase inhibitor, which targets VEGFR1–3, PDGFR
In terms of outcome in the clinical setting, sunitinib initially showed efficacy, as a single agent, for second-line therapy in single-arm, Phase II studies in mRCC [61]. Patients treated with sunitinib showed promising outcomes in terms of ORR, response duration, PFS and OS. A pivotal Phase III study was subsequently conducted comparing sunitinib with interferon-α as a first-line treatment in mRCC, which demonstrated improved OS, PFS and ORR in the sunitinib arm [62]. Based on such data, sunitinib was approved by the FDA in 2006 for the first line treatment of mRCC. Other TKI’s, with similar target specificity (sorafenib, pazopanib, cabozantinib and axitinib) also have activity in mRCC. Combination with immunotherapeutic agents has also shown promising results and we are seeing the treatment algorithm for mRCC change rapidly. In a recent landmark phase 3 trial of advanced RCC in the first line setting, axitinib was combined with the PD1 inihibitor pembrolizumab and compared with sunitinib monotherapy (KEYNOTE-426). The results are promising with a significant improvement in PFS and ORR with axitinib and pembrolizumab, however more mature OS data are awaited [63].
The role of such TKIs has also being evaluated in mCRC. The anti-tumour and anti-angiogenic effects of sunitinib have been well documented in a series of CRC xenograft tumour models [64]. In the clinical setting, however, sunitinib employed either as a single agent or with combination chemotherapy, has failed to demonstrate favourable outcome, both for ORR and PFS [65].
Recently, another TKI called regorafenib has created a lot of interest in advanced CRC. This agent inhibits VEGFR1-3, PDGFR
Regorafenib also has clinical utility in gastrointestinal stromal tumours (GIST) where it is currently employed in the third line setting after imatinib and sunitinib. This indication followed from a phase 3 randomised trial, demonstrating significantly improved PFS for regorafenib compared with placebo (4.8 months vs. 0.9 months) [69]. There was no significant difference in OS, however this trial did allow for crossover which likely impacted on this finding [69].
Regorafenib has FDA approval for second line treatment of HCC following the positive results of the phase 3 RESORCE clinical trial. Compared with placebo, regorafenib demonstrated survival benefit [70].
Early phase clinical trials have demonstrated that bevacizumab, in combination with systemic cytotoxic chemotherapy, can potentiate treatment efficacy when given concomitantly [71]. In fact, in most clinical settings, with the exception of ovarian cancer where bevacizumab has been observed to have single agent activity [72], bevacizumab has only shown significant activity when it is combined with cytotoxic chemotherapy and the same is true for aflibercept [21].
It has been well-established that the tumour vasculature is dysfunctional and leaky, resulting in enhanced interstitial fluid pressure and thus preventing effective delivery of chemotherapy [73]. Evidence from preclinical studies showed that bevacizumab can ‘normalise’ the chaotic tumour vasculature, achieving reduced vessel tortuosity, reduced leakiness and reduced interstitial fluid pressure. Based on these studies, it was proposed that bevacizumab works in combination with chemotherapy to improve chemotherapy delivery [71, 73], which is now a widely accepted notion amongst many clinicians.
However, this concept is also highly controversial, with some work even refuting the normalisation hypothesis. For example, one group demonstrated that bevacizumab persistently reduced both tumour perfusion and chemotherapy delivery when NSCLC patients were treated with bevacizumab-containing chemotherapy [74]. Therefore, other potential explanations for synergy between bevacizumab and chemotherapy must be considered. Current alternative theories based mostly on preclinical data include: (1) direct synergy between the anti-angiogenic effects of bevacizumab and potential anti-angiogenic effects of chemotherapy [75], (2) targeting of VEGF signalling directly in cancer cells by bevacizumab [21], (3) chemotherapy may inhibit resistance to bevacizumab, because chemotherapy suppresses the tumour recruitment of myeloid cells that have been implicated in resistance to bevacizumab [76], (4) bevacizumab may prevent tumour rebound that may occur during breaks in chemotherapy [76].
It should be noted that vessel normalisation facilitated by anti-angiogenic agents may provide therapeutic benefit through other mechanisms, which are independent of chemotherapy delivery. For example, in glioblastoma patients, vessel normalisation induced by single agent VEGF-targeted therapy may prolong survival due to other effects, such as oedema control or improved tumour oxygenation [77].
There are two other curious observations that have yet to be properly explained. Firstly, the synergistic effect of adding bevacizumab to chemotherapy does not occur in all tumour types. For example, the addition of bevacizumab does not lead to improvements in outcome in advanced breast cancer [78]. Secondly, VEGFR TKIs show single agent activity without the need for co-administration of chemotherapy [21].
Recent insight into these two curious observations has been reported. A study examining both clinical and mouse tumour tissue specimens demonstrated that tumour types utilising a vasculature surrounded by a well-developed stroma (e.g. mCRC, NSCLC) respond better to bevacizumab when it is added to chemotherapy as opposed to tumour types that utilise a vasculature without a well-developed intervening stromal component (e.g. mRCC, PNET) which respond better to VEGF TKIs alone [79]. This suggests that tumour cell interactions with different stromal components may influence response to different anti-angiogenic agents and how they synergise with concomitant drugs. However, there is still much work to be done in order to understand the mechanisms involved.
A series of pre-clinical studies have shown that the use of anti-angiogenic agents along with immune checkpoint inhibitors (ICI) as a combination therapy has a synergistic and enhanced effect on the tumour when compared to either ICI therapy or anti-angiogenic therapy alone. Immunotherapy has emerged as a promising treatment option for many cancer types, offering hope for patients with the demonstration of improved outcomes including durable responses in some. Unfortunately, there are still many patients that either have short lived responses to such therapies or none at all. To overcome resistance mechanisms, combinations of immunotherapy with other treatments including VEGF inhibitors are being explored.
Since 2013, pre-clinical investigations in mice with various tumours have indicated that the combination of ICI and anti-angiogenic agents results in prolonged overall survival [80]. It has been observed that the VEGF can cause the upregulation of immune checkpoint molecules such as PD-1 and as a result, the use of anti-VEGF agents has been seen to reduce the expression of PD-1 on cytotoxic T lymphocytes [81]. Thus, the combination of using both anti-VEGF agents as well as anti-PD-1 agents could have a synergistic effect on inhibiting further tumour development [81]. Through the encouraging findings of pre-clinical investigations, many clinical studies have recently or are still in the process of investigating this.
There are a multitude of clinical studies supporting the role of bevacizumab in the positive immune modulation of the tumour microenvironment and its beneficial effects when combined with the immune checkpoint PD1/PDL1 and CTLA4 inhibitors. In a study investigating melanoma patients treated with ipilimumab plus bevacizumab versus ipilimumab alone, the results showed that the combination therapy increased circulating CD4+ and CD8+ T cells compared with ipilimumab monotherapy [82]. The investigation showed that there was a greater median overall survival in patients undergoing combination therapy (25.1 months) compared to those who underwent the ipilimumab alone treatment (10.1 months) [82]. Furthermore, a separate study of patients with RCC investigating the effect that bevacizumab plus atezolizumab had versus bevacizumab alone found that the combination therapy demonstrated a reduction in neovasulature-related gene expression and decreased microvascular density. The treatment was also associated with an increased tumour infiltration of CD8+ T cells as demonstrated by immunohistochemical staining of cells [83]. This study also demonstrated that MHC Class I is upregulated as a result of the treatment and that both intratumoural CD8+ T cells and macrophages increased as well.
In a phase II study involving patients with RCC, as compared with sunitinib monotherapy, atezolizumab and bevacizumab demonstrated improvements in PFS in patients with an immunosuppressive tumour microenvironment [84]. Whilst it was also discovered that the use of atezolizumab failed to generate an anti-tumour immune response (possibly due to myeloid-induced immune suppression), the addition of bevacizumab to atezolizumab was found to be able to overcome this suppression [84].
Both pre-clinical and clinical studies have shown that anti-angiogenic agents and immunomodulatory therapies have a synergistic affect in reducing tumour growth and a multitude of clinical trials are currently investigating this synergy further. Thus, there is promise in the use of a combination therapy with anti-angiogenic agents and immunomodulatory agents to improve on patient prognosis.
In view of the variable outcomes seen in the clinic, there is a need for the development of validated predictive biomarkers of response for anti-angiogenic therapy. In this way, patients who will derive benefit from such agents could be appropriately selected, whilst those that will not derive benefit (either at the outset or during therapy) could be selected for alternative, more effective therapy. Such a strategy would not only improve clinical outcomes but would also reduce the unnecessary burden of (a) toxicity to the patient, and (b) cost to the economy. Despite extensive international research in this field, there is currently no biomarker which predicts benefit or resistance to anti-angiogenic agents that is approved for routine clinical practice. The following are amongst several which have been investigated in the clinical setting.
Circulating biomarkers are an attractive tool for patients and clinicians as ‘liquid biopsies’ are relatively non-invasive and easy to perform, as compared with tissue biopsies of tumour with associated risks and potential technical difficulties depending on tumour site. VEGF levels have been studied as a potential biomarker with high levels associated with poorer outcomes [85]. Findings regarding its utility as a predictive biomarker have been more inconsistent [85]. An analysis of four randomised phase 3 trials investigated circulating VEGF level as a prognostic and predictive biomarker in mCRC, lung cancer and RCC which included bevacizumab in the treatment regimen. Tumour specimens were also tested for VEGF level. This found that higher baseline circulating VEGF levels were associated with poorer clinical outcomes but levels did not predict response to bevacizumab [86]. There is early evidence from small and exploratory studies to suggest soluble VEGFR-1, with higher levels being associated with poorer outcomes with anti-angiogenic treatments, however larger studies are required to confirm these findings [87].
Other potential circulating biomarkers have also been investigated. In mCRC, elevated IL-8 levels at baseline were associated with a shorter PFS in patients treated with chemotherapy (FOLFIRI) and bevacizumab [88]. Elevated LDH and neutrophil levels have been found to independently predict poorer survival in patients treated with chemotherapy plus bevacizumab [89]. A promising predictive biomarker for response to bevacizumab based therapy in CRC appears to be circulating endothelial cells, with studies showing that patients with lower circulating endothelial cells at baseline undergoing treatment with bevacizumab based therapy had improved PFS [90].
Levels of VEGF expression in a tumour could be a determinant of responsiveness to anti-VEGF therapy. Some small studies have demonstrated a relationship between baseline VEGF expression and response, however these findings have not been consistently replicated in large clinical trials and are often more informative as prognostic rather than predictive biomarkers [91]. Data from more recent prospective studies, however, have shown more consistency in the use of VEGF as a biomarker. A large randomised trial in patients with advanced breast cancer treated with bevacizumab demonstrated a significant association between high circulating levels of VEGF and survival benefit [78]. VEGF expression in tumours was investigated in the large phase III clinical trial of bevacizumab plus chemotherapy in mCRC, but this failed to predict outcomes [92].
There are multiple reasons why using VEGF expression as a biomarker could be problematic: (1) advanced tumours express numerous pro-angiogenic factors in addition to VEGF which could confer resistance to bevacizumab irrespective of the amount of VEGF produced [93], (2) differences in the intensity of VEGF expression might be too small to be clinically relevant, (3) hypoxia, which is promoted by anti-angiogenic therapy, is an important inducer of VEGF expression and might, therefore, lead to increased VEGF production in the presence of bevacizumab treatment; indeed, anti-angiogenic agents have been shown to induce expression of VEGF even in tumour naïve hosts [94], (4) variations in methodology across centres (including sample handling, the use of different scoring systems and non-validated antibodies) have a significant effect on biomarker trial results [95], (5) it is very challenging to standardise cut-offs for low and high VEGF levels, due to: (a) different methods used to measure VEGF at different centres and (b) differences in biology that occur between racial groups, tumour types and different stages of disease [95].
Studies which have investigated other single circulating factors (such as FGF2, and r soluble VEGFR2) have also yielded contradictory and unsatisfactory conclusions [96]. Interestingly, however, recent clinical work in mRCC patients treated with anti-angiogenic TKIs suggests that profiling multiple circulating factors in the blood could have a more powerful prognostic and predictive role than assessing levels of single factors alone [97]. In this study, when patients with mRCC were treated with the TKI pazopanib, a biomarker signature of six factors (HGF, interleukin 6 and interleukin 8, osteopontin, VEGF and TIMP1) was able to distinguish a sub-group of patients that derived a significantly greater overall survival benefit from this agent.
Polymorphisms in VEGF or VEGF receptors have been proposed to predict outcome from anti-angiogenic therapy. As these are generally binary in nature, they are attractive biomarkers since they may be easier to measure and apply prospectively. In metastatic breast cancer, polymorphisms in VEGF and VEGFR2 were analysed in several retrospective subset analyses in patients treated with chemotherapy, with or without bevacizumab. Two polymorphisms within the VEGF promoter/5′ untranslated region, VEGF alleles −2578AA and −1154AA, were significantly associated with improved OS in the bevacizumab plus paclitaxel group when compared to the −2578CA/−2578CC and −1154GA/−1154GG alleles. In contrast, they did not have prognostic power for OS in the chemotherapy-only arm [98]. The predictive power of the −2578AA and −1154AA VEGF alleles was also reported in a retrospective subset analysis of patients with metastatic colorectal cancer that received either FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus bevacizumab or XELIRI (capecitabine and irinotecan) plus bevacizumab [99].
More recently, the role of VEGFR1 polymorphisms was studied in a large meta-analysis pooling DNA data from two phase III trials in patients with advanced pancreatic cancer treated with bevacizumab. VEGFR1 −1213AC/−1213CC alleles were significantly associated with poor outcome in patients receiving bevacizumab when compared to VEGFR1 −1213AA alleles [100]. To understand how this VEGFR1 polymorphism functionally affects VEGFR1 expression and how it might explain its correlation with poor outcome in patients receiving bevacizumab, Lambrechts and colleagues performed an
Functional clinical imaging, taking into account tumour vasculature or metabolic activity by utilising CT, MRI or PET scanning, either prior to commencing treatment or following brief exposure of patients to therapy, may be a useful tool for predicting response or resistance to anti-angiogenic therapy [102]. For conventional cytotoxic chemotherapy, imaging has been employed to assess therapy response based on change in tumour size, as defined by RECIST (Response Evaluation Criteria In Solid Tumours). However, biological agents, such as bevacizumab and TKIs, may be cytostatic in terms of their mechanism of action, thus size may not be the only parameter that needs to be considered when assessing response and outcome. Examination of various parameters such as blood flow and tumour morphology may provide additional important predictive information.
Several studies have examined pre-treatment levels of tumour perfusion and whether they can predict outcome. For example, enhanced levels of vessel perfusion at baseline (measured by contrast-assisted tumour enhancement) in mRCC patients treated with VEGF TKIs has been shown to predict for response and survival [103].
Early alterations in features of the tumour vasculature on imaging after a short period of therapy have also been shown to be associated with response and outcome. For example, in studies of mRCC patients treated with anti-angiogenic TKIs, response criteria that measured both a significant reduction in tumour vascular perfusion and a significant reduction in tumour size were more predictive of outcome compared to change in lesion size alone [104].
Although the use of the above radiological criteria may seem promising as predictors of response and outcome, there are associated challenges that need to be considered before incorporating them into clinical practice. These include, (a) diversity in the methodologies used to assess potential surrogate radiological biomarkers of response between studies and across centres, and (b) insufficient comprehension of how certain radiological features correlate with the underlying tumour biology.
Currently, the efficacy of any anti-neoplastic therapy is assessed by several outcome measures, which include (a) effective downsizing of tumours on clinical imaging (to facilitate curative surgery or consolidative radiotherapy for localised disease and to reduce the symptomatic burden of disease in the metastatic setting), (b) prolongation of the interval where a patient is either disease-free or progression-free, and (c) prolongation of survival.
Conventional assessment of residual tumour volume after cytotoxic chemotherapy has traditionally been performed with the use of size-based criteria (overall response rate, ORR, by RECIST). This was based on evidence that there is good correlation between radiological information and residual viable tumour (pathological response) and good correlation with progression-free (PFS) and overall survival (OS) in patients treated with cytotoxic chemotherapy [105]. However, with the advent of biological therapies, such as bevacizumab, the value of utilising RECIST on its own as a surrogate for outcome has been questioned and new imaging criteria have been proposed [102].
For anti-angiogenic therapy employed in advanced malignant disease, retrospective clinical meta-analyses have (a) highlighted the pitfalls and limitations of using RECIST alone in the assessment of response and progression, and (b) highlighted a disassociation of RECIST from time-related endpoints of PFS and OS [105].
This curiosity was provoked by several large randomised clinical trials investigating the effect of adding bevacizumab to conventional chemotherapy in different tumour types. These have consistently demonstrated that significant improvements in PFS and OS were incongruent with modest increases in ORRs [25, 28, 40]. In their CRC meta-analysis, Grothey and colleagues specifically examined the impact of tumour response to bevacizumab (ORR) on treatment benefit (PFS, OS) and concluded that patients who did not attain a positive response according to RECIST (i.e. stable disease) in fact showed significant benefit from bevacizumab, which was of the same magnitude as responding patients (i.e. complete or partial response) [105].
Moreover, similar concepts have consistently featured in several Phase I and II clinical trials employing antiangiogenic agents, and other molecular targeted therapies. These studies corroborate that there is little value in utilising ORR alone, particularly in predicting whether an agent will ultimately have truly meaningful effects on pathological response or in prolonging survival [106]. The underlying reason for these incongruent observations with bevacizumab and other molecular targeted therapies may be because such agents are cytostatic rather than cytotoxic [107].
There has been growing interest in how the appearance of lesions on clinical imaging can be utilised to accurately assess the effect of bevacizumab on tumour volume and how this appearance may correlate with other clinical end-points. In a small retrospective colorectal liver only metastasis (CRLM) patient cohort treated with bevacizumab and chemotherapy, Chun and colleagues demonstrated that novel morphological response criteria predicted more accurately for OS and pathological response than RECIST (Figure 2) [108]. This was subsequently validated in a larger patient population which included patients who were treated with and without bevacizumab [109]. Not only were the morphological response criteria superior to RECIST in predicting major pathological response and OS, further analyses confirmed that the morphological response criteria did not correlate with responses measured according to RECIST. Moreover, there was a significantly higher incidence of optimal responses (measured by morphological response criteria) in the patient cohort receiving bevacizumab with chemotherapy compared to the chemotherapy alone cohort [109]. These data suggest that (a) morphological response criteria and RECIST measure different biological parameters, and (b) the use of morphological response criteria represents a more sensitive tool for measuring tumour response and time-related endpoints of survival for bevacizumab. Similar findings were reported in a retrospective study of non-small cell lung cancer patients treated with bevacizumab and concomitant chemotherapy [110].
Morphological response criteria on contrast-enhanced CT (CECT) scans as a predictor of outcome (i) and (ii) CECT performed in a 43-year old patient before and after 10 cycles of bevacizumab containing chemotherapy demonstrating an optimal response (OR). (i) Before therapy, the liver metastasis presented with profound heterogeneous attenuation, a hyperattenuated peripheral rim and a thick, poorly defined tumour-liver interface (‘group 3’ metastasis). (ii) After therapy, the same liver metastasis shows complete resolution of these features (i.e. it is homogeneous, of low attenuation, with a thin, sharply defined tumor-liver interface). Change in size of lesion is minimal. (iii) and (iv) CECT of the liver performed in a 67-year old patient before and after 2 cycles of bevacizumab-containing chemotherapy demonstrating a partial response (PR). (iii) Before therapy, the liver metastas is presented with features of a ‘group 3’ metastasis. (iv) After therapy, the same liver metastasis shows moderate resolution of these features (i.e. it has a moderate degree of heterogeneous attenuation, a moderately defined tumor-liver interface with a slight hyperattenuating peripheralrim (‘group 2’ metastasis)). (v) and (vi) CECT of the liver performed in a 56-year old patient before and after 2 cycles of bevacizumab-containing chemotherapy demonstrating an absent response (AR). (v) Before therapy, the liver metastasis presented with features of a ‘group 3’ metastasis. (vi) After therapy, the same liver metastas is shows a decrease in tumour size without change in attenuation or tumour-liver interface (‘group 3’ metastasis). Changes in tumour morphology on CECT have been shown to correlate more significantly with survival than the use of RECIST citeria in CRLM patients treated with bevacizumab-containing chemotherapy.
Radiological assessment alone may not accurately reflect response to therapy because simple, unidimensional imaging parameters may overestimate or underestimate downstaging of tumour burden [111]. Furthermore, in the case of adding anti-angiogenic therapy to chemotherapy, although it has been suggested that proposed morphological imaging characteristics can accurately predict tumour response and clinical outcome, such scoring methods have not yet been validated for conventional use in clinical practice and may also be too subjective. Scoring of pathological response may therefore be a better alternative or perhaps an adjunct in assessing residual viable tumour. Moreover, in the case of preoperative chemotherapy or radiotherapy in settings such as rectal cancer and oesophageal cancer, pathological response has also been shown to correlate significantly to disease-free survival (DFS) and OS [112].
Several methodologies incorporating various parameters for scoring pathological response in resected CRLMs, treated with and without bevacizumab, have been proposed. It is still not clear from the current literature which of these classification methods may be superior.
Microscopic assessment of the percentage residual viable tumour on haematoxylin & eosin-stained sections of resected tissue has been employed as a predominant parameter in assessing the efficacy of different pre-operative chemotherapy regimens in tumour types such as oesophageal, gastric and rectal adenocarcinomas [113]. Based on this methodology, Ribero and colleagues modified this scoring system for application in CRLMs treated preoperatively, with or without bevacizumab [114]. A semi-quantitative estimation of the percentage area of residual viable tumour cells relative to total tumour surface area within each CRLM metastasis was made with the analysis of four tumour cell viability subsets (<25%, 25–49%, 50–75%, >75%). This retrospective study confirmed that the addition of bevacizumab to chemotherapy yielded an incrementally greater decrease in residual viable cells within these CRLMs in comparison to those treated with chemotherapy alone but no correlation with imaging, or other clinical end-points, was made [114].
Mandard and colleagues were one of the first to establish a five-point histological scoring system for pathological response. This was based on cytological and stromal changes on haematoxylin & eosin-stained sections of primary oesophageal squamous cell carcinomas treated with chemoradiotherapy prior to resection [115]. Tumour response was scored according to five tumour regression grades (TRG1-5) based on the proportion of fibrosis to viable tumour cells. Later, this TRG scoring system was modified for its application in CRLMs receiving different chemotherapy backbones prior to liver resection (Figure 3A–E) [116]. Correlation analyses have demonstrated a significant association of major histological responders with increased survival.
Tumour regression grade (TRG) scoring system as a component of measuring pathological response in treated CRLMs. (A–E) TRG as scored on haematoxylin and eosin sections of CRLMs based on the proportion of fibrosis to viable tumour cells. The five TRGs shown in this cartoon roughly illustrate the different proportions of fibrosis (fibrils) to tumour cells (black areas). (A) TRG1. There is an absence of viable tumour cells and large amounts of fibrosis. (B) TRG2. The presence of viable tumour cells is rare and they are scattered throughout the fibrosis. (C) TRG3. There is the presence of more residual tumour cells but fibrosis predominates. (D) TRG4. Residual cancer cells predominate over fibrosis. (E) TRG5. There are no signs of tumour regression. The percentage of the CRLM surface area occupied by necrosis is also incorporated as a parameter for pathological response (grey areas). 3 main pathological response groups: TRG1-2: major response (MjHR), TRG3: partial response (PHR), TRG4-5: no histological response (NHR).
Similar retrospective studies using the TRG in CRLMs were undertaken to see whether adding bevacizumab to chemotherapy would further increase pathological response rate, without necessarily increasing radiographic response rate, after liver resection. Indeed, several retrospective analyses demonstrated that a significantly increased percentage of patients treated with bevacizumab achieved a major pathological response and a significantly higher percentage area of tumour necrosis compared to chemotherapy-only treated patients [117]. Furthermore, the extent of pathological response correlated significantly with long-term-outcomes such as 3- and 5-year overall survival.
As is the case with most cancer therapeutics, drug resistance is considered to be a major factor that limits the efficacy of anti-angiogenic agents. Two ‘modes’ of resistance to anti-angiogenic therapy are currently recognised: intrinsic resistance, whereby the tumour fails to respond to the therapy from the outset, and acquired resistance, whereby the tumour develops means to evade the therapy after a period of response [21, 29, 118]. It is important to realise that resistance to anti-angiogenic therapy may be attributable to either the tumour cells themselves or due to interactions with their microenvironment. In terms of specific mechanisms mediating resistance to anti-angiogenic therapy, several have been proposed.
Pre-clinical work has demonstrated that although anti-angiogenic agents thwart the growth of newly established tumour vessels, they are less effective against more mature blood vessels, indicating that they may be less dependent on VEGF (Figure 4A) [29]. This may be due to PDGF secretion mediating pericyte recruitment, allowing young vessels to mature and survive [119]. Co-inhibition of VEGF and PDGF has been shown to generate significant anti-angiogenic and anti-tumour effects than with VEGF inhibition alone [120].
Proposed mechanisms of resistance to anti-angiogenic therapy. (A–F) The potential mechanisms that tumours can utilise to evade anti-angiogenic therapy. (A) Vessel heterogeneity. Tumours can contain vessels that are at different stages of maturation making some more sensitive to therapy than others. For example, here the top vessel is immature and is abolished by therapy (grey), whilst the bottom one is mature and remains viable (red). (B) Alternative proangiogenic signalling pathway scan affect the susceptibility of vessels to therapy. Here, tumour cells (blue) have up-regulated an alternative pro-angiogenic growth factor to facilitate persistent blood vessel growth and survival despite VEGF blockade. (C) Stromal cells infiltrating into of the tumour, such as myeloid progenitors (black) or fibroblasts (green), can also mediate resistance by releasing pro-angiogenic growth factors or by physically incorporating into vessels. (D) Tumour cell adaptation to stress. Subpopulations of cancer cells in the tumour (blue) can survive the hypoxic conditions and nutrient shortage resulting from vascular destruction by employing different adaptation mechanisms. (E) Alternative tumour vascularisation mechanisms. Apart from sprouting angiogenesis, tumours may utilise alternative mechanisms to recruit a vascular supply. In intussusceptive microvascular growth, new vessels are generated by the fission of pre-existing vessels. Glomeruloid angiogenesis is where tight nests of vessels, resembling the renal glomerulus, are formed. Vasculogenic mimicry is a process whereby tumour cells can create vascular-like structures themselves (blue) which are perfused as they become continuous with the host vasculature (red). In looping angiogenesis, contractile myofibroblasts (green) pull host vessels (red) out of the surrounding parenchymal tissue (pink region). Vessel co-option is a process whereby invading tumour cells engulf pre-existing vessels (red) in the normal parenchyma (pink region). (F) Selection of aggressive cells. Therapy alters the biology of the tumour cells in that they become more invasive and/or facilitate accelerated growth of metastases.
Alternative pro-angiogenic signalling pathways may allow tumour vascularisation to proceed when VEGF signalling is blocked (Figure 4B) [29]. A large body of preclinical work has identified candidate pathways that may provide such an alternative pro-angiogenic stimulus. These include fibroblast growth factors 1 and 2 (FGF1 and FGF2) [121], hepatocyte growth factor (HGF) [122] and epidermal growth factor (EGF) [123]. Most of the above preclinical work suggests that, by inhibiting both VEGF signalling and the candidate pathway, improvements in the anti-tumour efficacy can be seen. Therefore, targeting multiple pro-angiogenic pathways may prove more beneficial than employing agents that inhibit VEGF signalling alone.
Preclinical data suggest that cells in the tumour stroma, including fibroblasts, neutrophils, macrophages and myeloid progenitors, mediate resistance to VEGF-targeted agents (Figure 4C) [124]. For example, tumour-derived granulocyte-colony stimulating factor (G-CSF) mobilises myeloid cells from bone marrow, and is believed to promote pro-angiogenic Bv8 signalling by myeloid cells, which in tumours may confer resistance to anti-VEGF treatment [125]. Immunohistochemistry studies in human tumours showed expression of Bv8 in tumour-infiltrating neutrophils, which were seen in around 15% of breast carcinomas [126].
It is presumed that the inhibition of tumour vascularisation by anti-angiogenic agents will lead to a reduction in oxygen and nutrients available to the tumour thus causing retardation of tumour growth. However, tumours may develop a number of survival mechanisms enabling them to adapt to such hostile conditions (Figure 4D).
Some studies have suggested that anti-angiogenic therapy leads to metabolic reprogramming of tumour cells, allowing them to adapt to reduced vascular supply. Preclinical studies have demonstrated that treatment with anti-VEGF antibodies can lead to tumour cells relying on anaerobic metabolism and the glycolytic pathway for ATP [127]. Furthermore, the withdrawal of anti-angiogenic therapy has been shown to cause an increase in lipid metabolism, leading to a rebound in tumour growth [127].
Tumours treated with anti-angiogenic agents may also adapt to survive by activation of autophagy. Autophagy can occur in response to treatment related stressors such as hypoxia and occurs when organelles and proteins in the cell are degraded and recycled by lysosomes [128]. Autophagy-mediating molecules such as BNIP3 have been identified in GBM tumour cells after exposure (a) to hypoxic conditions in vitro, (b) to bevacizumab therapy in vivo or (c) to bevacizumab therapy in human tumours [129]. Furthermore, a recent study has reported that when MDA-MB-231 breast cancer cells were treated with an agent that induced autophagy, they exhibited increased invasiveness [130].
It is becoming clear that many solid tumours contain relatively rare subpopulations of cancer stem cells. These are clones of tumour cells that are able to sustain self-renewal and can tolerate hostile environments [131]. Furthermore, it has been proposed that hypoxia induced by anti-angiogenic therapy can (a) select for CSCs, and (b) maintain the niche that supports the survival of CSCs [132]. Conceivably, these persistent clones of CSCs may render the tumour more invasive and metastatic and may also lead to antiangiogenic therapy resistance [133].
Anti-angiogenic therapy has been proposed to induce hypoxic tumour microenvironments, enhancing the aggressiveness of tumour cells (Figure 4F) [134]. This may help explain why the response to anti-angiogenic therapy is often transient as anti-angiogenic agents can cause initial reductions in tumour burden and a prolonged PFS, but with minimal or no improvement in OS [118]. Anti-angiogenic agents have demonstrated an ability to select for more aggressive cancer cells and enhance tumour cell invasion, growth and metastasis [135]. Moreover, it is now well accepted that some GBM patients with tumours treated with bevacizumab show an increase in tumour invasiveness [136].
Despite the dogma that tumours primarily employ VEGF-dependent sprouting angiogenesis, emerging evidence now exists for alternative tumour vascularisation mechanisms, including: intussusceptive microvascular growth (IMG) (sometimes known merely as ‘intussusception’), glomeruloid angiogenesis, vascular mimicry (also sometimes called ‘vasculogenic mimicry’), looping angiogenesis, and vessel co-option (also sometimes called ‘vascular co-option’) (Figure 4E) [21]. These mechanisms may occur by alternative signalling pathways that may not be inhibited by VEGF-targeted therapies.
Intussusception is a mechanism whereby pre-existing vessels split into two daughter vessels without the need for endothelial cell proliferation and sprouting (Figure 4E). It has been observed in embryonic development and within experimental tumours recovering from anti-angiogenic therapy and radiotherapy [137]. The molecular mechanisms that control this process are still not well understood.
Vascular mimicry (VM) is a process observed in clinical and preclinical studies whereby tumour cells differentiate into vascular-like structures themselves [138] (Figure 4E). It has been shown that basic fibroblast growth factor (bFGF) and VEGF, are incapable of inducing VM channels and networks in poorly aggressive melanoma cell lines, suggesting that VM channel formation maybe be independent of these classical pro-angiogenic growth factors [139]. However, further mechanistic detail is lacking.
Vessel co-option is the process whereby, when a tumour invades, existing local vessels become directly incorporated into the tumour (Figure 4E). Histopathological studies have indicated that colorectal and breast cancer liver metastases may utilise vessel co-option [140, 141].
Vessel co-option has been shown to mediate resistance to VEGF inhibitors in mouse models of melanoma metastasis to the brain and in mouse models of glioblastoma multiforme, and has been observed in glioblastoma patients who have progressed on anti-VEGF therapy [142, 143, 144]. Recently, it has been demonstrated that vessel co-option plays a role in mediating resistance to anti-angiogenic therapy in colorectal cancer liver metastases [145].
In tumour samples obtained from primary lung cancer patients, gene expression arrays have been utilised to identify pathways differentially expressed between angiogenic tumours and vessel co-opting tumours [146]. Stromal expression of thrombospondin-1 appeared to be up regulated in angiogenic tumours, whilst in vessel co-option tumours, there was increased expression of genes involved in oxidative phosphorylation in primary [146]. Surprisingly, no differences in classic hypoxia or angiogenesis related genes were found between angiogenic and non-angiogenic tumours.
In a glioma rat model of breast cancer brain and lung metastasis, co-opted blood vessels were seen in early-stage tumours and these vessels were found to overexpress angiopoietin-2, a natural antagonist of angiopoietin-1 [147]. As these tumours grew to become more hypoxic, VEGF was upregulated at the hypoxic tumour periphery and stimulated angiogenesis [147]. These observations suggest that a transition from vessel co-option to angiogenesis, or vice versa, may be dependent on the relative expression of pro-angiogenic growth factors (angiopoeitin-1, VEGF) and anti-angiogenic factors (angiopoeitin-2).
Cell adhesion molecules have been implicated in facilitating the process of vessel co-option. In a preclinical brain metastasis model, Carbonell et al. demonstrated that the β1 integrin subunit in breast cancer and lymphoma cells facilitates (a) tumour cell adhesion to the vascular basement membrane of existing brain vessels, (b) tumour cell invasion and (c) the process of vessel co-option [148]. When the function of the β1 integrin subunit was blocked, adhesion to vessels was attenuated and brain metastasis colonies failed to become established and grow [148].
Furthermore, the L1 cell adhesion molecule (L1CAM) has been shown to be involved in vessel co-option in the brain [149]. The ability of cancer cells to co-opt blood vessels was suppressed when L1CAM expression was depleted using shRNA. Conversely, when L1CAM was overexpressed, tumour cells demonstrated enhanced adherence to the outer surface of vessels and tumour growth alongside them. Although such mechanisms are likely to be more specific for vessel co-option in the brain, similar mechanisms may be at work during vessel co-option at other anatomical sites.
Tumour vascularisation is modulated by the complex interplay of several endogenous factors and processes that can be up-regulated or downregulated, depending on the tumour microenvironment and the treatment pressures that are imposed on it. A multitude of studies have shown that the majority of solid tumours exhibit an overexpression of VEGF, one of the key drivers of sprouting angiogenesis. As a result, various anti-angiogenic therapies targeting VEGF or VEGFR have now been developed and are used conventionally in the clinic. Compellingly, recent pre-clinical and clinical studies using anti-angiogenic agents in combination with immunotherapies (e.g. ICI’s), have demonstrated a synergistic effect in reducing tumour growth. This highlights that there is promise, not only in incorporating anti-angiogenic therapy in the management of most cancers, but also in combining such agents with immunomodulatory agents.
However, as is the case with many cancer treatments, drug resistance can limit the efficacy of these agents. Trials of VEGF-targeted therapies in advanced malignancies have not consistently demonstrated beneficial outcomes in terms of tumour response and survival. Importantly, only a proportion of patients benefit from anti-angiogenic therapy, control of tumour growth is generally transient, there remains significant risk for therapeutic toxicity and we are still challenged by the burden of health costs.
Limited clinical outcomes with anti-angiogenic therapies are felt to be driven by either intrinsic or acquired resistance mechanisms, and several of these have now been proposed. In this chapter, we have reviewed the most commonly used anti-angiogenic agents in the clinic and have highlighted the spectrum of mechanisms that may be involved in therapeutic resistance. However, despite the plethora of pre-clinical and clinical studies that have been undertaken, these mechanisms are yet to be entirely elucidated. Importantly, the clinically relevant mechanisms that mediate such resistance to anti-angiogenic therapy are poorly understood and we still do not have means to select patients who will benefit from these agents. Furthermore, there has been a rapid expansion in the development of multiple next generation anti-vascular agents, but there is still little clarity regarding important biological pathways that may affect their efficacy.
The data supporting the role of candidate biomarkers for response and resistance to anti-angiogenic therapies thus far have been generated from basic research, retrospective studies and limited prospective correlative studies. As such there remains a crucial need for substantial research of clinically relevant predictive biomarkers with the use of large, prospective randomised trials. This could also provide a platform for longitudinal and frequent biospecimen collection in order to further interrogate the mechanisms involved in tumour vascularisation and therapeutic resistance over time.
This is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
",metaTitle:"Publishing Process Steps and Descriptions",metaDescription:"This is a brief overview of the main steps involved in publishing with InTechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Publishing Process Manager who will be your single point of contact and lead you through all the described steps below.",metaKeywords:null,canonicalURL:"page/publishing-process-steps",contentRaw:'[{"type":"htmlEditorComponent","content":"1. SEND YOUR PROPOSAL
\\n\\nPlease complete the publishing proposal form. The completed form should serve as an overview of your future Compacts, Monograph or Edited Book. Once submitted, your publishing proposal will be sent for evaluation, and a notice of acceptance or rejection will be sent within 10 to 30 working days from the date of submission.
\\n\\n2. SUBMIT YOUR MANUSCRIPT
\\n\\nAfter approval, you will proceed in submitting your full-length manuscript. 50-130 pages for compacts, 130-500 for Monographs & Edited Books.Your full-length manuscript must follow IntechOpen's Author Guidelines and comply with our publishing rules. Once the manuscript is submitted, but before it is forwarded for peer review, it will be screened for plagiarism.
\\n\\n3. PEER REVIEW RESULTS
\\n\\nExternal reviewers will evaluate your manuscript and provide you with their feedback. You may be asked to revise your draft, or parts of your draft, provide additional information and make any other necessary changes according to their comments and suggestions.
\\n\\n4. ACCEPTANCE AND PRICE QUOTE
\\n\\nIf the manuscript is formally accepted after peer review you will receive a formal Notice of Acceptance, and a price quote.
\\n\\nThe Open Access Publishing Fee of your IntechOpen Compacts, Monograph or Edited Book depends on the volume of the publication and includes: project management, editorial and peer review services, technical editing, language copyediting, cover design and book layout, book promotion and ISBN assignment.
\\n\\nWe will send you your price quote and after it has been accepted (by both the author and the publisher), both parties will sign a Statement of Work binding them to adhere to the agreed upon terms.
\\n\\nAt this step you will also be asked to accept the Copyright Agreement.
\\n\\n5. LANGUAGE COPYEDITING, TECHNICAL EDITING AND TYPESET PROOF
\\n\\nYour manuscript will be sent to Straive, a leader in content solution services, for language copyediting. You will then receive a typeset proof formatted in XML and available online in HTML and PDF to proofread and check for completeness. The first typeset proof of your manuscript is usually available 10 days after its original submission.
\\n\\nAfter we receive your proof corrections and a final typeset of the manuscript is approved, your manuscript is sent to our in house DTP department for technical formatting and online publication preparation.
\\n\\nAdditionally, you will be asked to provide a profile picture (face or chest-up portrait photograph) and a short summary of the book which is required for the book cover design.
\\n\\n6. INVOICE PAYMENT
\\n\\nThe invoice is generally paid by the author, the author’s institution or funder. The payment can be made by credit card from your Author Panel (one will be assigned to you at the beginning of the project), or via bank transfer as indicated on the invoice. We currently accept the following payment options:
\\n\\nIntechOpen will help you complete your payment safely and securely, keeping your personal, professional and financial information safe.
\\n\\n7. ONLINE PUBLICATION, PRINT AND DELIVERY OF THE BOOK
\\n\\nIntechOpen authors can choose whether to publish their book online only or opt for online and print editions. IntechOpen Compacts, Monographs and Edited Books will be published on www.intechopen.com. If ordered, print copies are delivered by DHL within 12 to 15 working days.
\\n\\nIf you feel that IntechOpen Compacts, Monographs or Edited Books are the right publishing format for your work, please fill out the publishing proposal form. For any specific queries related to the publishing process, or IntechOpen Compacts, Monographs & Edited Books in general, please contact us at book.department@intechopen.com
\\n"}]'},components:[{type:"htmlEditorComponent",content:'1. SEND YOUR PROPOSAL
\n\nPlease complete the publishing proposal form. The completed form should serve as an overview of your future Compacts, Monograph or Edited Book. Once submitted, your publishing proposal will be sent for evaluation, and a notice of acceptance or rejection will be sent within 10 to 30 working days from the date of submission.
\n\n2. SUBMIT YOUR MANUSCRIPT
\n\nAfter approval, you will proceed in submitting your full-length manuscript. 50-130 pages for compacts, 130-500 for Monographs & Edited Books.Your full-length manuscript must follow IntechOpen's Author Guidelines and comply with our publishing rules. Once the manuscript is submitted, but before it is forwarded for peer review, it will be screened for plagiarism.
\n\n3. PEER REVIEW RESULTS
\n\nExternal reviewers will evaluate your manuscript and provide you with their feedback. You may be asked to revise your draft, or parts of your draft, provide additional information and make any other necessary changes according to their comments and suggestions.
\n\n4. ACCEPTANCE AND PRICE QUOTE
\n\nIf the manuscript is formally accepted after peer review you will receive a formal Notice of Acceptance, and a price quote.
\n\nThe Open Access Publishing Fee of your IntechOpen Compacts, Monograph or Edited Book depends on the volume of the publication and includes: project management, editorial and peer review services, technical editing, language copyediting, cover design and book layout, book promotion and ISBN assignment.
\n\nWe will send you your price quote and after it has been accepted (by both the author and the publisher), both parties will sign a Statement of Work binding them to adhere to the agreed upon terms.
\n\nAt this step you will also be asked to accept the Copyright Agreement.
\n\n5. LANGUAGE COPYEDITING, TECHNICAL EDITING AND TYPESET PROOF
\n\nYour manuscript will be sent to Straive, a leader in content solution services, for language copyediting. You will then receive a typeset proof formatted in XML and available online in HTML and PDF to proofread and check for completeness. The first typeset proof of your manuscript is usually available 10 days after its original submission.
\n\nAfter we receive your proof corrections and a final typeset of the manuscript is approved, your manuscript is sent to our in house DTP department for technical formatting and online publication preparation.
\n\nAdditionally, you will be asked to provide a profile picture (face or chest-up portrait photograph) and a short summary of the book which is required for the book cover design.
\n\n6. INVOICE PAYMENT
\n\nThe invoice is generally paid by the author, the author’s institution or funder. The payment can be made by credit card from your Author Panel (one will be assigned to you at the beginning of the project), or via bank transfer as indicated on the invoice. We currently accept the following payment options:
\n\nIntechOpen will help you complete your payment safely and securely, keeping your personal, professional and financial information safe.
\n\n7. ONLINE PUBLICATION, PRINT AND DELIVERY OF THE BOOK
\n\nIntechOpen authors can choose whether to publish their book online only or opt for online and print editions. IntechOpen Compacts, Monographs and Edited Books will be published on www.intechopen.com. If ordered, print copies are delivered by DHL within 12 to 15 working days.
\n\nIf you feel that IntechOpen Compacts, Monographs or Edited Books are the right publishing format for your work, please fill out the publishing proposal form. For any specific queries related to the publishing process, or IntechOpen Compacts, Monographs & Edited Books in general, please contact us at book.department@intechopen.com
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. In the Engineering side, Digital Signal Processing, Computer Architecture, Electronics Devices, Digital Filtering and Engineering Management.\nApart from his Academic Interest and activities he loves sport especially, Cricket, Football, Snooker and Squash. He plays cricket for Esbjerg city in the second division team as an opener wicket keeper batsman. He is a very good player of squash but has not played squash since his arrival in Denmark.",institutionString:null,institution:null},{id:"611",title:"Prof.",name:"T",middleName:null,surname:"Nagarajan",slug:"t-nagarajan",fullName:"T Nagarajan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universiti Teknologi Petronas",country:{name:"Malaysia"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:6675},{group:"region",caption:"Middle and South America",value:2,count:5955},{group:"region",caption:"Africa",value:3,count:2459},{group:"region",caption:"Asia",value:4,count:12718},{group:"region",caption:"Australia and Oceania",value:5,count:1017},{group:"region",caption:"Europe",value:6,count:17720}],offset:12,limit:12,total:134177},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"0",sort:"dateEndThirdStepPublish"},books:[{type:"book",id:"11369",title:"RNA Viruses",subtitle:null,isOpenForSubmission:!0,hash:"52f8a3a1486912beae40b34ac557fed3",slug:null,bookSignature:"Ph.D. Yogendra Shah",coverURL:"https://cdn.intechopen.com/books/images_new/11369.jpg",editedByType:null,editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11027",title:"Basics of Hypoglycemia",subtitle:null,isOpenForSubmission:!0,hash:"98ebc1e36d02be82c204b8fd5d24f97a",slug:null,bookSignature:"Dr. Alok Raghav",coverURL:"https://cdn.intechopen.com/books/images_new/11027.jpg",editedByType:null,editors:[{id:"334465",title:"Dr.",name:"Alok",surname:"Raghav",slug:"alok-raghav",fullName:"Alok Raghav"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11124",title:"Next-Generation Textiles",subtitle:null,isOpenForSubmission:!0,hash:"093f9e26bb829b8d414d13626aea1086",slug:null,bookSignature:"Dr. Hassan Ibrahim",coverURL:"https://cdn.intechopen.com/books/images_new/11124.jpg",editedByType:null,editors:[{id:"90645",title:"Dr.",name:"Hassan",surname:"Ibrahim",slug:"hassan-ibrahim",fullName:"Hassan Ibrahim"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11610",title:"New Insights in Herbicide Science",subtitle:null,isOpenForSubmission:!0,hash:"eb3830b8176caf3d1fd52c32313c5168",slug:null,bookSignature:"Ph.D. Kassio Ferreira Mendes",coverURL:"https://cdn.intechopen.com/books/images_new/11610.jpg",editedByType:null,editors:[{id:"197720",title:"Ph.D.",name:"Kassio",surname:"Ferreira Mendes",slug:"kassio-ferreira-mendes",fullName:"Kassio Ferreira Mendes"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11561",title:"Zeolite From Wastes - New Perspectives on Innovative Resources and Their Valorization Process",subtitle:null,isOpenForSubmission:!0,hash:"3ed0dfd842de9cd1143212415903e6ad",slug:null,bookSignature:"Dr. Claudia Belviso",coverURL:"https://cdn.intechopen.com/books/images_new/11561.jpg",editedByType:null,editors:[{id:"61457",title:"Dr.",name:"Claudia",surname:"Belviso",slug:"claudia-belviso",fullName:"Claudia Belviso"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11709",title:"Type 1 Diabetes Mellitus",subtitle:null,isOpenForSubmission:!0,hash:"cc0e61f864a2a8a9595f4975ce301f70",slug:null,bookSignature:"Dr. Shilpa Mehta and Dr. Resmy Palliyil Gopi",coverURL:"https://cdn.intechopen.com/books/images_new/11709.jpg",editedByType:null,editors:[{id:"342545",title:"Dr.",name:"Shilpa",surname:"Mehta",slug:"shilpa-mehta",fullName:"Shilpa Mehta"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11517",title:"Phase Change Materials - Technology and Applications",subtitle:null,isOpenForSubmission:!0,hash:"1b7a5f2631db5e49399539ade1edf264",slug:null,bookSignature:"Dr. Manish K Rathod",coverURL:"https://cdn.intechopen.com/books/images_new/11517.jpg",editedByType:null,editors:[{id:"236035",title:"Dr.",name:"Manish",surname:"Rathod",slug:"manish-rathod",fullName:"Manish Rathod"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11451",title:"Molecular Docking - Recent Advances",subtitle:null,isOpenForSubmission:!0,hash:"8c918a1973786c7059752b28601f1329",slug:null,bookSignature:"Dr. Erman Salih Istifli",coverURL:"https://cdn.intechopen.com/books/images_new/11451.jpg",editedByType:null,editors:[{id:"179007",title:"Dr.",name:"Erman Salih",surname:"Istifli",slug:"erman-salih-istifli",fullName:"Erman Salih Istifli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11732",title:"Multiple Pregnancy - New Insights",subtitle:null,isOpenForSubmission:!0,hash:"70396c6f5f2928c422c1eaf6d33c6269",slug:null,bookSignature:"Prof. Hassan S Abduljabbar",coverURL:"https://cdn.intechopen.com/books/images_new/11732.jpg",editedByType:null,editors:[{id:"68175",title:"Prof.",name:"Hassan",surname:"Abduljabbar",slug:"hassan-abduljabbar",fullName:"Hassan Abduljabbar"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11682",title:"Rare Diseases - Recent Advances",subtitle:null,isOpenForSubmission:!0,hash:"ad68db8a4109ae3acc0d3f001a2f4fde",slug:null,bookSignature:"Dr. John Kanayochukwu Nduka",coverURL:"https://cdn.intechopen.com/books/images_new/11682.jpg",editedByType:null,editors:[{id:"107866",title:"Dr.",name:"John Kanayochukwu",surname:"Nduka",slug:"john-kanayochukwu-nduka",fullName:"John Kanayochukwu Nduka"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11664",title:"Recent Advances in Sensing Technologies for Environmental Control and Monitoring",subtitle:null,isOpenForSubmission:!0,hash:"cf1ee76443e393bc7597723c3ee3e26f",slug:null,bookSignature:"Dr. Toonika Rinken and Dr. Kairi Kivirand",coverURL:"https://cdn.intechopen.com/books/images_new/11664.jpg",editedByType:null,editors:[{id:"24687",title:"Dr.",name:"Toonika",surname:"Rinken",slug:"toonika-rinken",fullName:"Toonika Rinken"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11636",title:"Neuroplasticity - Visual Cortex Reorganization From Neurons to Maps",subtitle:null,isOpenForSubmission:!0,hash:"b306ce94998737c764d08736e76d60e1",slug:null,bookSignature:"Dr. Alyssa A Brewer and Dr. Brian Barton",coverURL:"https://cdn.intechopen.com/books/images_new/11636.jpg",editedByType:null,editors:[{id:"115304",title:"Dr.",name:"Alyssa",surname:"Brewer",slug:"alyssa-brewer",fullName:"Alyssa Brewer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:38},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:12},{group:"topic",caption:"Business, Management and Economics",value:7,count:7},{group:"topic",caption:"Chemistry",value:8,count:22},{group:"topic",caption:"Computer and Information Science",value:9,count:23},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:15},{group:"topic",caption:"Engineering",value:11,count:65},{group:"topic",caption:"Environmental Sciences",value:12,count:10},{group:"topic",caption:"Immunology and Microbiology",value:13,count:15},{group:"topic",caption:"Materials Science",value:14,count:24},{group:"topic",caption:"Mathematics",value:15,count:11},{group:"topic",caption:"Medicine",value:16,count:114},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:6},{group:"topic",caption:"Neuroscience",value:18,count:4},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:9},{group:"topic",caption:"Physics",value:20,count:9},{group:"topic",caption:"Psychology",value:21,count:10},{group:"topic",caption:"Robotics",value:22,count:2},{group:"topic",caption:"Social Sciences",value:23,count:9},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:4}],offset:12,limit:12,total:410},popularBooks:{featuredBooks:[{type:"book",id:"10858",title:"MOOC (Massive Open Online Courses)",subtitle:null,isOpenForSubmission:!1,hash:"d32f86793bc72dde32532f509b1ec5b0",slug:"mooc-massive-open-online-courses-",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/10858.jpg",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10195",title:"Serotonin and the CNS",subtitle:"New Developments in Pharmacology and Therapeutics",isOpenForSubmission:!1,hash:"7ed9d96da98233a885bd2869a8056c36",slug:"serotonin-and-the-cns-new-developments-in-pharmacology-and-therapeutics",bookSignature:"Berend Olivier",coverURL:"https://cdn.intechopen.com/books/images_new/10195.jpg",editors:[{id:"71579",title:"Prof.",name:"Berend",middleName:null,surname:"Olivier",slug:"berend-olivier",fullName:"Berend Olivier"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10755",title:"Corporate Governance",subtitle:"Recent Advances and Perspectives",isOpenForSubmission:!1,hash:"ffe06d1d5c4bf0fc2e63511825fe1257",slug:"corporate-governance-recent-advances-and-perspectives",bookSignature:"Okechukwu Lawrence Emeagwali and Feyza Bhatti",coverURL:"https://cdn.intechopen.com/books/images_new/10755.jpg",editors:[{id:"196317",title:"Associate Prof.",name:"Okechukwu Lawrence",middleName:null,surname:"Emeagwali",slug:"okechukwu-lawrence-emeagwali",fullName:"Okechukwu Lawrence Emeagwali"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11120",title:"Environmental Impact and Remediation of Heavy Metals",subtitle:null,isOpenForSubmission:!1,hash:"9e77514288e7394f1e6cd13481af3509",slug:"environmental-impact-and-remediation-of-heavy-metals",bookSignature:"Hosam M. Saleh and Amal I. Hassan",coverURL:"https://cdn.intechopen.com/books/images_new/11120.jpg",editors:[{id:"144691",title:"Prof.",name:"Hosam M.",middleName:null,surname:"Saleh",slug:"hosam-m.-saleh",fullName:"Hosam M. Saleh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10901",title:"Grapes and Wine",subtitle:null,isOpenForSubmission:!1,hash:"5d7f2aa74874444bc6986e613ccebd7c",slug:"grapes-and-wine",bookSignature:"Antonio Morata, Iris Loira and Carmen González",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg",editors:[{id:"180952",title:"Prof.",name:"Antonio",middleName:null,surname:"Morata",slug:"antonio-morata",fullName:"Antonio Morata"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11080",title:"Engineering Principles",subtitle:"Welding and Residual Stresses",isOpenForSubmission:!1,hash:"6c07a13a113bce94174b40096f30fb5e",slug:"engineering-principles-welding-and-residual-stresses",bookSignature:"Kavian Omar Cooke and Ronaldo Câmara Cozza",coverURL:"https://cdn.intechopen.com/books/images_new/11080.jpg",editors:[{id:"138778",title:"Dr.",name:"Kavian",middleName:"Omar",surname:"Cooke",slug:"kavian-cooke",fullName:"Kavian Cooke"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11332",title:"Essential Oils",subtitle:"Advances in Extractions and Biological Applications",isOpenForSubmission:!1,hash:"742e6cae3a35686f975edc8d7f9afa94",slug:"essential-oils-advances-in-extractions-and-biological-applications",bookSignature:"Mozaniel Santana de Oliveira and Eloisa Helena de Aguiar Andrade",coverURL:"https://cdn.intechopen.com/books/images_new/11332.jpg",editors:[{id:"195290",title:"Ph.D.",name:"Mozaniel",middleName:null,surname:"Santana De Oliveira",slug:"mozaniel-santana-de-oliveira",fullName:"Mozaniel Santana De Oliveira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11029",title:"Hepatitis B",subtitle:null,isOpenForSubmission:!1,hash:"609701f502efc3538c112ff47a2c2119",slug:"hepatitis-b",bookSignature:"Luis Rodrigo",coverURL:"https://cdn.intechopen.com/books/images_new/11029.jpg",editors:[{id:"73208",title:"Prof.",name:"Luis",middleName:null,surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9537",title:"Human Rights in the Contemporary World",subtitle:null,isOpenForSubmission:!1,hash:"54f05b93812fd434f3962956d6413a6b",slug:"human-rights-in-the-contemporary-world",bookSignature:"Trudy Corrigan",coverURL:"https://cdn.intechopen.com/books/images_new/9537.jpg",editors:[{id:"197557",title:"Dr.",name:"Trudy",middleName:null,surname:"Corrigan",slug:"trudy-corrigan",fullName:"Trudy Corrigan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11371",title:"Cerebral Circulation",subtitle:"Updates on Models, Diagnostics and Treatments of Related Diseases",isOpenForSubmission:!1,hash:"e2d3335445d2852d0b906bb9750e939f",slug:"cerebral-circulation-updates-on-models-diagnostics-and-treatments-of-related-diseases",bookSignature:"Alba Scerrati, Luca Ricciardi and Flavia Dones",coverURL:"https://cdn.intechopen.com/books/images_new/11371.jpg",editors:[{id:"182614",title:"Dr.",name:"Alba",middleName:null,surname:"Scerrati",slug:"alba-scerrati",fullName:"Alba Scerrati"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11012",title:"Radiopharmaceuticals",subtitle:"Current Research for Better Diagnosis and Therapy",isOpenForSubmission:!1,hash:"f9046d6f96148b285e776f384991120d",slug:"radiopharmaceuticals-current-research-for-better-diagnosis-and-therapy",bookSignature:"Farid A. Badria",coverURL:"https://cdn.intechopen.com/books/images_new/11012.jpg",editors:[{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9974",title:"E-Learning and Digital Education in the Twenty-First Century",subtitle:null,isOpenForSubmission:!1,hash:"88b58d66e975df20425fc1dfd22d53aa",slug:"e-learning-and-digital-education-in-the-twenty-first-century",bookSignature:"M. Mahruf C. Shohel",coverURL:"https://cdn.intechopen.com/books/images_new/9974.jpg",editors:[{id:"94099",title:"Dr.",name:"M. Mahruf C.",middleName:null,surname:"Shohel",slug:"m.-mahruf-c.-shohel",fullName:"M. Mahruf C. Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:4431},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"10858",title:"MOOC (Massive Open Online Courses)",subtitle:null,isOpenForSubmission:!1,hash:"d32f86793bc72dde32532f509b1ec5b0",slug:"mooc-massive-open-online-courses-",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/10858.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:1677,editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10195",title:"Serotonin and the CNS",subtitle:"New Developments in Pharmacology and Therapeutics",isOpenForSubmission:!1,hash:"7ed9d96da98233a885bd2869a8056c36",slug:"serotonin-and-the-cns-new-developments-in-pharmacology-and-therapeutics",bookSignature:"Berend Olivier",coverURL:"https://cdn.intechopen.com/books/images_new/10195.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:1337,editors:[{id:"71579",title:"Prof.",name:"Berend",middleName:null,surname:"Olivier",slug:"berend-olivier",fullName:"Berend Olivier"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10755",title:"Corporate Governance",subtitle:"Recent Advances and Perspectives",isOpenForSubmission:!1,hash:"ffe06d1d5c4bf0fc2e63511825fe1257",slug:"corporate-governance-recent-advances-and-perspectives",bookSignature:"Okechukwu Lawrence Emeagwali and Feyza Bhatti",coverURL:"https://cdn.intechopen.com/books/images_new/10755.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:1309,editors:[{id:"196317",title:"Associate Prof.",name:"Okechukwu Lawrence",middleName:null,surname:"Emeagwali",slug:"okechukwu-lawrence-emeagwali",fullName:"Okechukwu Lawrence Emeagwali"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11120",title:"Environmental Impact and Remediation of Heavy Metals",subtitle:null,isOpenForSubmission:!1,hash:"9e77514288e7394f1e6cd13481af3509",slug:"environmental-impact-and-remediation-of-heavy-metals",bookSignature:"Hosam M. Saleh and Amal I. Hassan",coverURL:"https://cdn.intechopen.com/books/images_new/11120.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:847,editors:[{id:"144691",title:"Prof.",name:"Hosam M.",middleName:null,surname:"Saleh",slug:"hosam-m.-saleh",fullName:"Hosam M. Saleh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10901",title:"Grapes and Wine",subtitle:null,isOpenForSubmission:!1,hash:"5d7f2aa74874444bc6986e613ccebd7c",slug:"grapes-and-wine",bookSignature:"Antonio Morata, Iris Loira and Carmen González",coverURL:"https://cdn.intechopen.com/books/images_new/10901.jpg",publishedDate:"June 15th 2022",numberOfDownloads:2273,editors:[{id:"180952",title:"Prof.",name:"Antonio",middleName:null,surname:"Morata",slug:"antonio-morata",fullName:"Antonio Morata"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11080",title:"Engineering Principles",subtitle:"Welding and Residual Stresses",isOpenForSubmission:!1,hash:"6c07a13a113bce94174b40096f30fb5e",slug:"engineering-principles-welding-and-residual-stresses",bookSignature:"Kavian Omar Cooke and Ronaldo Câmara Cozza",coverURL:"https://cdn.intechopen.com/books/images_new/11080.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:591,editors:[{id:"138778",title:"Dr.",name:"Kavian",middleName:"Omar",surname:"Cooke",slug:"kavian-cooke",fullName:"Kavian Cooke"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11332",title:"Essential Oils",subtitle:"Advances in Extractions and Biological Applications",isOpenForSubmission:!1,hash:"742e6cae3a35686f975edc8d7f9afa94",slug:"essential-oils-advances-in-extractions-and-biological-applications",bookSignature:"Mozaniel Santana de Oliveira and Eloisa Helena de Aguiar Andrade",coverURL:"https://cdn.intechopen.com/books/images_new/11332.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:515,editors:[{id:"195290",title:"Ph.D.",name:"Mozaniel",middleName:null,surname:"Santana De Oliveira",slug:"mozaniel-santana-de-oliveira",fullName:"Mozaniel Santana De Oliveira"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11029",title:"Hepatitis B",subtitle:null,isOpenForSubmission:!1,hash:"609701f502efc3538c112ff47a2c2119",slug:"hepatitis-b",bookSignature:"Luis Rodrigo",coverURL:"https://cdn.intechopen.com/books/images_new/11029.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:413,editors:[{id:"73208",title:"Prof.",name:"Luis",middleName:null,surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9537",title:"Human Rights in the Contemporary World",subtitle:null,isOpenForSubmission:!1,hash:"54f05b93812fd434f3962956d6413a6b",slug:"human-rights-in-the-contemporary-world",bookSignature:"Trudy Corrigan",coverURL:"https://cdn.intechopen.com/books/images_new/9537.jpg",publishedDate:"June 8th 2022",numberOfDownloads:2194,editors:[{id:"197557",title:"Dr.",name:"Trudy",middleName:null,surname:"Corrigan",slug:"trudy-corrigan",fullName:"Trudy Corrigan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"11371",title:"Cerebral Circulation",subtitle:"Updates on Models, Diagnostics and Treatments of Related Diseases",isOpenForSubmission:!1,hash:"e2d3335445d2852d0b906bb9750e939f",slug:"cerebral-circulation-updates-on-models-diagnostics-and-treatments-of-related-diseases",bookSignature:"Alba Scerrati, Luca Ricciardi and Flavia Dones",coverURL:"https://cdn.intechopen.com/books/images_new/11371.jpg",publishedDate:"June 23rd 2022",numberOfDownloads:341,editors:[{id:"182614",title:"Dr.",name:"Alba",middleName:null,surname:"Scerrati",slug:"alba-scerrati",fullName:"Alba Scerrati"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"11043",title:"Endometriosis",subtitle:"Recent Advances, New Perspectives and Treatments",isOpenForSubmission:!1,hash:"7baf1c70b11d41400bb9302ae9411ca4",slug:"endometriosis-recent-advances-new-perspectives-and-treatments",bookSignature:"Giovana Ap. Gonçalves",coverURL:"https://cdn.intechopen.com/books/images_new/11043.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"185930",title:"Associate Prof.",name:"Giovana",middleName:null,surname:"Gonçalves",slug:"giovana-goncalves",fullName:"Giovana Gonçalves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10536",title:"Campylobacter",subtitle:null,isOpenForSubmission:!1,hash:"c4b132b741dd0a2ed539b824ab63965f",slug:"campylobacter",bookSignature:"Guillermo Tellez-Isaias and Saeed El-Ashram",coverURL:"https://cdn.intechopen.com/books/images_new/10536.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"73465",title:"Dr.",name:"Guillermo",middleName:null,surname:"Téllez",slug:"guillermo-tellez",fullName:"Guillermo Téllez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10798",title:"Starch",subtitle:"Evolution and Recent Advances",isOpenForSubmission:!1,hash:"f197f6062c1574a9a90e50a369271bcf",slug:"starch-evolution-and-recent-advances",bookSignature:"Martins Ochubiojo Emeje",coverURL:"https://cdn.intechopen.com/books/images_new/10798.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"11083",title:"Hazardous Waste Management",subtitle:null,isOpenForSubmission:!1,hash:"d553bd4f6f1c4b115ca69bd19faac7dc",slug:"hazardous-waste-management",bookSignature:"Rajesh Banu Jeyakumar, Kavitha Sankarapandian and Yukesh Kannah Ravi",coverURL:"https://cdn.intechopen.com/books/images_new/11083.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"218539",title:"Dr.",name:"Rajesh Banu",middleName:null,surname:"Jeyakumar",slug:"rajesh-banu-jeyakumar",fullName:"Rajesh Banu Jeyakumar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10848",title:"Tribology of Machine Elements",subtitle:"Fundamentals and Applications",isOpenForSubmission:!1,hash:"3c4ca4c4692ca8d4fa749b4ae81ec1fa",slug:"tribology-of-machine-elements-fundamentals-and-applications",bookSignature:"Giuseppe Pintaude, Tiago Cousseau and Anna Rudawska",coverURL:"https://cdn.intechopen.com/books/images_new/10848.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"18347",title:"Prof.",name:"Giuseppe",middleName:null,surname:"Pintaude",slug:"giuseppe-pintaude",fullName:"Giuseppe Pintaude"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10856",title:"Crude Oil",subtitle:"New Technologies and Recent Approaches",isOpenForSubmission:!1,hash:"8d0a7ca35b3de95b295dc4eab39a087e",slug:"crude-oil-new-technologies-and-recent-approaches",bookSignature:"Manar Elsayed Abdel-Raouf and Mohamed Hasan El-Keshawy",coverURL:"https://cdn.intechopen.com/books/images_new/10856.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"102626",title:"Prof.",name:"Manar",middleName:null,surname:"Elsayed Abdel-Raouf",slug:"manar-elsayed-abdel-raouf",fullName:"Manar Elsayed Abdel-Raouf"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9625",title:"Spinocerebellar Ataxia",subtitle:"Concepts, Particularities and Generalities",isOpenForSubmission:!1,hash:"365a7025fd46eb45de2549bdd9d50b98",slug:"spinocerebellar-ataxia-concepts-particularities-and-generalities",bookSignature:"Patricia Bozzetto Ambrosi",coverURL:"https://cdn.intechopen.com/books/images_new/9625.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"221787",title:"Dr.",name:"Patricia",middleName:null,surname:"Bozzetto Ambrosi",slug:"patricia-bozzetto-ambrosi",fullName:"Patricia Bozzetto Ambrosi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10905",title:"Plant Defense Mechanisms",subtitle:null,isOpenForSubmission:!1,hash:"84ad5b27dde5f01dc76087d0fd6fa834",slug:"plant-defense-mechanisms",bookSignature:"Josphert Ngui Kimatu",coverURL:"https://cdn.intechopen.com/books/images_new/10905.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"224171",title:"Prof.",name:"Josphert N.",middleName:null,surname:"Kimatu",slug:"josphert-n.-kimatu",fullName:"Josphert N. Kimatu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10686",title:"Natural Gas",subtitle:"New Perspectives and Future Developments",isOpenForSubmission:!1,hash:"581763788a6a59e653a9d1d9b5a42d79",slug:"natural-gas-new-perspectives-and-future-developments",bookSignature:"Maryam Takht Ravanchi",coverURL:"https://cdn.intechopen.com/books/images_new/10686.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"2416",title:"Dr.",name:"Maryam",middleName:null,surname:"Takht Ravanchi",slug:"maryam-takht-ravanchi",fullName:"Maryam Takht Ravanchi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10988",title:"Railway Transport Planning and Manageme",subtitle:null,isOpenForSubmission:!1,hash:"5cb54cc53caedad9ec78372563c82e2c",slug:"railway-transport-planning-and-management",bookSignature:"Stefano de Luca, Roberta Di Pace and Chiara Fiori",coverURL:"https://cdn.intechopen.com/books/images_new/10988.jpg",editedByType:"Edited by",publishedDate:"June 28th 2022",editors:[{id:"271061",title:"Prof.",name:"Stefano",middleName:null,surname:"de Luca",slug:"stefano-de-luca",fullName:"Stefano de Luca"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"158",title:"Metals and Nonmetals",slug:"metals-and-nonmetals",parent:{id:"14",title:"Materials Science",slug:"materials-science"},numberOfBooks:123,numberOfSeries:0,numberOfAuthorsAndEditors:3072,numberOfWosCitations:5859,numberOfCrossrefCitations:3269,numberOfDimensionsCitations:7336,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"158",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"9926",title:"Magnesium Alloys Structure and Properties",subtitle:null,isOpenForSubmission:!1,hash:"a6d1a99f4befe885857743f77e81524c",slug:"magnesium-alloys-structure-and-properties",bookSignature:"Tomasz Tański and Paweł Jarka",coverURL:"https://cdn.intechopen.com/books/images_new/9926.jpg",editedByType:"Edited by",editors:[{id:"15700",title:"Prof.",name:"Tomasz Arkadiusz",middleName:null,surname:"Tański",slug:"tomasz-arkadiusz-tanski",fullName:"Tomasz Arkadiusz Tański"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10700",title:"Titanium Dioxide",subtitle:"Advances and Applications",isOpenForSubmission:!1,hash:"d9448d83caa34d90fd58464268c869a0",slug:"titanium-dioxide-advances-and-applications",bookSignature:"Hafiz Muhammad Ali",coverURL:"https://cdn.intechopen.com/books/images_new/10700.jpg",editedByType:"Edited by",editors:[{id:"187624",title:"Dr.",name:"Hafiz Muhammad",middleName:null,surname:"Ali",slug:"hafiz-muhammad-ali",fullName:"Hafiz Muhammad Ali"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6832",title:"Ruthenium",subtitle:"An Element Loved by Researchers",isOpenForSubmission:!1,hash:"9a3be4dd6035f78add07d239b8eae379",slug:"ruthenium-an-element-loved-by-researchers",bookSignature:"Hitoshi Ishida",coverURL:"https://cdn.intechopen.com/books/images_new/6832.jpg",editedByType:"Edited by",editors:[{id:"210140",title:"Dr.",name:"Hitoshi",middleName:null,surname:"Ishida",slug:"hitoshi-ishida",fullName:"Hitoshi Ishida"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10388",title:"Heavy Metals",subtitle:"Their Environmental Impacts and Mitigation",isOpenForSubmission:!1,hash:"ac4f5b254442e9f19a8c609453a83915",slug:"heavy-metals-their-environmental-impacts-and-mitigation",bookSignature:"Mazen Khaled Nazal and Hongbo Zhao",coverURL:"https://cdn.intechopen.com/books/images_new/10388.jpg",editedByType:"Edited by",editors:[{id:"214815",title:"Dr.",name:"Mazen",middleName:null,surname:"Nazal",slug:"mazen-nazal",fullName:"Mazen Nazal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9912",title:"Advanced Aluminium Composites and Alloys",subtitle:null,isOpenForSubmission:!1,hash:"c7c20182f3241e13162b011fac7efdd6",slug:"advanced-aluminium-composites-and-alloys",bookSignature:"Leszek A. Dobrzański",coverURL:"https://cdn.intechopen.com/books/images_new/9912.jpg",editedByType:"Edited by",editors:[{id:"15880",title:"Prof.",name:"Leszek A.",middleName:null,surname:"Dobrzański",slug:"leszek-a.-dobrzanski",fullName:"Leszek A. Dobrzański"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10506",title:"Liquid Metals",subtitle:null,isOpenForSubmission:!1,hash:"a1c30d83631953e1c8905554d937bb10",slug:"liquid-metals",bookSignature:"Samson Jerold Samuel Chelladurai, S. Gnanasekaran and Suresh Mayilswamy",coverURL:"https://cdn.intechopen.com/books/images_new/10506.jpg",editedByType:"Edited by",editors:[{id:"247421",title:"Dr.",name:"Samson Jerold Samuel",middleName:null,surname:"Chelladurai",slug:"samson-jerold-samuel-chelladurai",fullName:"Samson Jerold Samuel Chelladurai"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10629",title:"Advances in High-Entropy Alloys",subtitle:"Materials Research, Exotic Properties and Applications",isOpenForSubmission:!1,hash:"eef8e329dc2559a9dbe5f1522ec690e3",slug:"advances-in-high-entropy-alloys-materials-research-exotic-properties-and-applications",bookSignature:"Jiro Kitagawa",coverURL:"https://cdn.intechopen.com/books/images_new/10629.jpg",editedByType:"Edited by",editors:[{id:"210570",title:"Prof.",name:"Jiro",middleName:null,surname:"Kitagawa",slug:"jiro-kitagawa",fullName:"Jiro Kitagawa"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9991",title:"Iron Ores",subtitle:null,isOpenForSubmission:!1,hash:"f1b2c288312233e1be62cd01c7e74fec",slug:"iron-ores",bookSignature:"Volodymyr Shatokha",coverURL:"https://cdn.intechopen.com/books/images_new/9991.jpg",editedByType:"Edited by",editors:[{id:"111000",title:"Dr.",name:"Volodymyr",middleName:null,surname:"Shatokha",slug:"volodymyr-shatokha",fullName:"Volodymyr Shatokha"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10412",title:"Transition Metal Compounds",subtitle:"Synthesis, Properties, and Application",isOpenForSubmission:!1,hash:"bd7287b801dc0ac77e01f66842dc1d99",slug:"transition-metal-compounds-synthesis-properties-and-application",bookSignature:"Sajjad Haider and Adnan Haider",coverURL:"https://cdn.intechopen.com/books/images_new/10412.jpg",editedByType:"Edited by",editors:[{id:"110708",title:"Dr.",name:"Sajjad",middleName:null,surname:"Haider",slug:"sajjad-haider",fullName:"Sajjad Haider"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10201",title:"Post-Transition Metals",subtitle:null,isOpenForSubmission:!1,hash:"cc7f53ff5269916e3ce29f65a51a87ae",slug:"post-transition-metals",bookSignature:"Mohammed Muzibur Rahman, Abdullah Mohammed Asiri, Anish Khan, Inamuddin and Thamer Tabbakh",coverURL:"https://cdn.intechopen.com/books/images_new/10201.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",middleName:null,surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10432",title:"Casting Processes and Modelling of Metallic Materials",subtitle:null,isOpenForSubmission:!1,hash:"2c5c9df938666bf5d1797727db203a6d",slug:"casting-processes-and-modelling-of-metallic-materials",bookSignature:"Zakaria Abdallah and Nada Aldoumani",coverURL:"https://cdn.intechopen.com/books/images_new/10432.jpg",editedByType:"Edited by",editors:[{id:"201670",title:"Dr.",name:"Zak",middleName:null,surname:"Abdallah",slug:"zak-abdallah",fullName:"Zak Abdallah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editedByType:"Edited by",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:123,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"37067",doi:"10.5772/35482",title:"Fourier Transform Infrared Spectroscopy for Natural Fibres",slug:"fourier-transform-infrared-spectroscopy-for-natural-fibres",totalDownloads:9257,totalCrossrefCites:162,totalDimensionsCites:394,abstract:null,book:{id:"2270",slug:"fourier-transform-materials-analysis",title:"Fourier Transform",fullTitle:"Fourier Transform - Materials Analysis"},signatures:"Mizi Fan, Dasong Dai and Biao Huang",authors:[{id:"104647",title:"Prof.",name:"Mizi",middleName:null,surname:"Fan",slug:"mizi-fan",fullName:"Mizi Fan"}]},{id:"60680",doi:"10.5772/intechopen.76082",title:"Environmental Contamination by Heavy Metals",slug:"environmental-contamination-by-heavy-metals",totalDownloads:16133,totalCrossrefCites:180,totalDimensionsCites:391,abstract:"The environment and its compartments have been severely polluted by heavy metals. This has compromised the ability of the environment to foster life and render its intrinsic values. Heavy metals are known to be naturally occurring compounds, but anthropogenic activities introduce them in large quantities in different environmental compartments. This leads to the environment’s ability to foster life being reduced as human, animal, and plant health become threatened. This occurs due to bioaccumulation in the food chains as a result of the nondegradable state of the heavy metals. Remediation of heavy metals requires special attention to protect soil quality, air quality, water quality, human health, animal health, and all spheres as a collection. Developed physical and chemical heavy metal remediation technologies are demanding costs which are not feasible, time-consuming, and release additional waste to the environment. This chapter summarises the problems related to heavy metal pollution and various remediation technologies. A case study in South Africa mines were also used.",book:{id:"6534",slug:"heavy-metals",title:"Heavy Metals",fullTitle:"Heavy Metals"},signatures:"Vhahangwele Masindi and Khathutshelo L. Muedi",authors:[{id:"225304",title:"Dr.",name:"Vhahangwele",middleName:null,surname:"Masindi",slug:"vhahangwele-masindi",fullName:"Vhahangwele Masindi"},{id:"241403",title:"M.Sc.",name:"Khathutshelo",middleName:"Lilith",surname:"Muedi",slug:"khathutshelo-muedi",fullName:"Khathutshelo Muedi"}]},{id:"46243",doi:"10.5772/57255",title:"Corrosion Inhibitors – Principles, Mechanisms and Applications",slug:"corrosion-inhibitors-principles-mechanisms-and-applications",totalDownloads:13693,totalCrossrefCites:40,totalDimensionsCites:159,abstract:null,book:{id:"3817",slug:"developments-in-corrosion-protection",title:"Developments in Corrosion Protection",fullTitle:"Developments in Corrosion Protection"},signatures:"Camila G. Dariva and Alexandre F. Galio",authors:[{id:"169261",title:"Dr.",name:"Camila",middleName:"G.",surname:"Dariva",slug:"camila-dariva",fullName:"Camila Dariva"},{id:"170138",title:"Dr.",name:"Alexandre",middleName:"Ferreira",surname:"Galio",slug:"alexandre-galio",fullName:"Alexandre Galio"}]},{id:"44359",doi:"10.5772/56197",title:"Microstructure and Mechanical Properties of High Strength Two-Phase Titanium Alloys",slug:"microstructure-and-mechanical-properties-of-high-strength-two-phase-titanium-alloys",totalDownloads:10278,totalCrossrefCites:55,totalDimensionsCites:127,abstract:null,book:{id:"3494",slug:"titanium-alloys-advances-in-properties-control",title:"Titanium Alloys",fullTitle:"Titanium Alloys - Advances in Properties Control"},signatures:"J. Sieniawski, W. Ziaja, K. Kubiak and M. Motyka",authors:[{id:"101690",title:"Associate Prof.",name:"Maciej",middleName:null,surname:"Motyka",slug:"maciej-motyka",fullName:"Maciej Motyka"},{id:"109232",title:"Prof.",name:"Jan",middleName:null,surname:"Sieniawski",slug:"jan-sieniawski",fullName:"Jan Sieniawski"}]},{id:"46882",doi:"10.5772/58534",title:"Additive Manufacturing of Al Alloys and Aluminium Matrix Composites (AMCs)",slug:"additive-manufacturing-of-al-alloys-and-aluminium-matrix-composites-amcs-",totalDownloads:10093,totalCrossrefCites:52,totalDimensionsCites:117,abstract:null,book:{id:"3844",slug:"light-metal-alloys-applications",title:"Light Metal Alloys Applications",fullTitle:"Light Metal Alloys Applications"},signatures:"Diego Manfredi, Flaviana Calignano, Manickavasagam Krishnan,\nRiccardo Canali, Elisa Paola Ambrosio, Sara Biamino, Daniele Ugues,\nMatteo Pavese and Paolo Fino",authors:[{id:"16648",title:"Dr.",name:"Diego",middleName:null,surname:"Manfredi",slug:"diego-manfredi",fullName:"Diego Manfredi"},{id:"18978",title:"Dr.",name:"Matteo",middleName:null,surname:"Pavese",slug:"matteo-pavese",fullName:"Matteo Pavese"},{id:"19187",title:"Dr.",name:"Sara",middleName:null,surname:"Biamino",slug:"sara-biamino",fullName:"Sara Biamino"},{id:"19188",title:"Dr.",name:"Elisa",middleName:null,surname:"Ambrosio",slug:"elisa-ambrosio",fullName:"Elisa Ambrosio"},{id:"19189",title:"Dr.",name:"Paolo",middleName:null,surname:"Fino",slug:"paolo-fino",fullName:"Paolo Fino"},{id:"170227",title:"Dr.",name:"Flaviana",middleName:null,surname:"Calignano",slug:"flaviana-calignano",fullName:"Flaviana Calignano"},{id:"170228",title:"MSc.",name:"Riccardo",middleName:null,surname:"Canali",slug:"riccardo-canali",fullName:"Riccardo Canali"},{id:"170229",title:"MSc.",name:"Manickavasagam",middleName:null,surname:"Krishnan",slug:"manickavasagam-krishnan",fullName:"Manickavasagam Krishnan"}]}],mostDownloadedChaptersLast30Days:[{id:"70661",title:"Bioremediation Techniques for Polluted Environment: Concept, Advantages, Limitations, and Prospects",slug:"bioremediation-techniques-for-polluted-environment-concept-advantages-limitations-and-prospects",totalDownloads:2538,totalCrossrefCites:9,totalDimensionsCites:24,abstract:"Environmental pollution has been rising in the past few decades due to increased anthropogenic activities. Bioremediation is an attractive and successful cleaning technique to remove toxic waste from polluted environment. Bioremediation is highly involved in degradation, eradication, immobilization, or detoxification diverse chemical wastes and physical hazardous materials from the surrounding through the all-inclusive and action of microorganisms. The main principle is degrading and converting pollutants to less toxic forms. Bioremediation can be carried out ex-situ and in-situ, depending on several factors, which include but not limited to cost, site characteristics, type, and concentration of pollutants. Hence, appropriate bioremediation technique is selected. Additionally, the major methodologies to develop bioremediation are biostimulation, bioaugmentation, bioventing, biopiles, and bioattenuation provided the environmental factors that decide the completion of bioremediation. Bioremediation is the most effective, economical, eco-friendly management tool to manage the polluted environment. All bioremediation techniques have its own advantage and disadvantage because it has its own specific applications.",book:{id:"9343",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",title:"Trace Metals in the Environment",fullTitle:"Trace Metals in the Environment - New Approaches and Recent Advances"},signatures:"Indu Sharma",authors:[{id:"301262",title:"Associate Prof.",name:"Indu",middleName:null,surname:"Sharma",slug:"indu-sharma",fullName:"Indu Sharma"}]},{id:"60680",title:"Environmental Contamination by Heavy Metals",slug:"environmental-contamination-by-heavy-metals",totalDownloads:16114,totalCrossrefCites:178,totalDimensionsCites:384,abstract:"The environment and its compartments have been severely polluted by heavy metals. This has compromised the ability of the environment to foster life and render its intrinsic values. Heavy metals are known to be naturally occurring compounds, but anthropogenic activities introduce them in large quantities in different environmental compartments. This leads to the environment’s ability to foster life being reduced as human, animal, and plant health become threatened. This occurs due to bioaccumulation in the food chains as a result of the nondegradable state of the heavy metals. Remediation of heavy metals requires special attention to protect soil quality, air quality, water quality, human health, animal health, and all spheres as a collection. Developed physical and chemical heavy metal remediation technologies are demanding costs which are not feasible, time-consuming, and release additional waste to the environment. This chapter summarises the problems related to heavy metal pollution and various remediation technologies. A case study in South Africa mines were also used.",book:{id:"6534",slug:"heavy-metals",title:"Heavy Metals",fullTitle:"Heavy Metals"},signatures:"Vhahangwele Masindi and Khathutshelo L. Muedi",authors:[{id:"225304",title:"Dr.",name:"Vhahangwele",middleName:null,surname:"Masindi",slug:"vhahangwele-masindi",fullName:"Vhahangwele Masindi"},{id:"241403",title:"M.Sc.",name:"Khathutshelo",middleName:"Lilith",surname:"Muedi",slug:"khathutshelo-muedi",fullName:"Khathutshelo Muedi"}]},{id:"59905",title:"Synthesis of Silver Nanoparticles",slug:"synthesis-of-silver-nanoparticles",totalDownloads:6825,totalCrossrefCites:9,totalDimensionsCites:18,abstract:"Nanoparticles of noble metals, especially the silver nanoparticles, have been widely used in different fields of science. Their unique properties, which can be incorporated into biosensor materials, composite fibers, cosmetic products, antimicrobial applications, conducting materials and electronic components, make them a very important subject to be studied by chemistry, biology, healthcare, electronic and other related branches. These unique properties depend upon size and shape of the silver nanoparticles. Different preparation methods have been reported for the synthesis of the silver nanoparticles, such as electron irradiation, laser ablation, chemical reduction, biological artificial methods, photochemical methods and microwave processing. This chapter aims to inform the synthesis methods of the silver nanoparticles.",book:{id:"6552",slug:"silver-nanoparticles-fabrication-characterization-and-applications",title:"Silver Nanoparticles",fullTitle:"Silver Nanoparticles - Fabrication, Characterization and Applications"},signatures:"Remziye Güzel and Gülbahar Erdal",authors:[{id:"226613",title:"Dr.",name:"Remziye",middleName:null,surname:"Güzel",slug:"remziye-guzel",fullName:"Remziye Güzel"},{id:"240772",title:"MSc.",name:"Gülbahar",middleName:null,surname:"Erdal",slug:"gulbahar-erdal",fullName:"Gülbahar Erdal"}]},{id:"71326",title:"Stability of Metal Complexes",slug:"stability-of-metal-complexes",totalDownloads:2314,totalCrossrefCites:7,totalDimensionsCites:11,abstract:"The stability of coordination complex is an important factor that decides the stability and reactivity of a metal complex. The stability of metal complex is governed by two different aspects such as thermodynamic and kinetic stabilities. The correlation between stability and reactivity of coordination compounds has been described in this chapter. This chapter also enlists the factors influencing the stability of metal complexes such as the nature of metal ions, ligands, bonding between metal ions and ligands, etc. In addition, the methods available for the determination of stability constants are given in detail.",book:{id:"9190",slug:"stability-and-applications-of-coordination-compounds",title:"Stability and Applications of Coordination Compounds",fullTitle:"Stability and Applications of Coordination Compounds"},signatures:"Senthilkumar Muthaiah, Anita Bhatia and Muthukumar Kannan",authors:null},{id:"60518",title:"Synthetic Methods for Titanium Dioxide Nanoparticles: A Review",slug:"synthetic-methods-for-titanium-dioxide-nanoparticles-a-review",totalDownloads:5208,totalCrossrefCites:29,totalDimensionsCites:53,abstract:"Titanium dioxide (TiO2) semiconductor nanoparticles are one kind of important and promising photocatalysts in photocatalysis because of their unique optical and electronic properties. Their properties, which are determined by the preparation method, are very crucial in photocatalysis. In this chapter, an overview was carried out on the different methods that are used or have been used to prepare titanium dioxide nanoparticles. There are various methods that can be used to synthesize TiO2 and the most commonly used methods include sol-gel process, chemical vapor deposition (CVD) and hydrothermal method among others. This review will focus on selected preparation methods of titanium dioxide photocatalyst.",book:{id:"6426",slug:"titanium-dioxide-material-for-a-sustainable-environment",title:"Titanium Dioxide",fullTitle:"Titanium Dioxide - Material for a Sustainable Environment"},signatures:"Pardon Nyamukamba, Omobola Okoh, Henry Mungondori,\nRaymond Taziwa and Simcelile Zinya",authors:[{id:"196100",title:"Dr.",name:"Raymond",middleName:null,surname:"Taziwa",slug:"raymond-taziwa",fullName:"Raymond Taziwa"},{id:"219920",title:"Prof.",name:"Omobola",middleName:null,surname:"Okoh",slug:"omobola-okoh",fullName:"Omobola Okoh"},{id:"226567",title:"Dr.",name:"Pardon",middleName:null,surname:"Nyamukamba",slug:"pardon-nyamukamba",fullName:"Pardon Nyamukamba"},{id:"239758",title:"Mr.",name:"Simcelile",middleName:null,surname:"Zinya",slug:"simcelile-zinya",fullName:"Simcelile Zinya"}]}],onlineFirstChaptersFilter:{topicId:"158",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81781",title:"Experimental Investigation of Mechanical and Wear Behaviour of AZ91 Magnesium Hybrid Composite Materials",slug:"experimental-investigation-of-mechanical-and-wear-behaviour-of-az91-magnesium-hybrid-composite-mater",totalDownloads:6,totalDimensionsCites:0,doi:"10.5772/intechopen.104703",abstract:"In recent years, emerging requisite for advanced materials gave a path for hybrid composites. Magnesium metal matrix composites are gaining more interest and a better substitute for heavier steel, aluminium, titanium and even for plastic based materials. At present the AZ91 magnesium alloy is most widely in transport vehicle industry. However, the application of AZ91 magnesium alloys are limited due to several negative effects such as poor creep resistance, wear resistance and inferior corrosion resistance when it is exposed to atmospheric conditions. Future to improve the strength, better corrosion resistance and wear resistance are important for their extend applications of exciting alloy AZ91. The main objective of the present investigation is to achieve above mentioned properties. The AZ91 alloy was reinforced with titanium dioxide/0.5% graphene and with titanium/0.5% graphene in varying weight percentage (1%, 2%) by stir casting technique. These combinations are called hybrid metal matrix composite of materials such as AZ91 + 1%Ti +0.5% Gr (A1), AZ91 + 2%Ti +0.5% Gr (A2), AZ91 + 1%TiO2 + 0.5% Gr (B1) and AZ91 + 2%TiO2 + 0.5% Gr (B2) alloys. The following experiments such as tensile, compressive, hardness and wear tests have been carried out to find all the properties from the newly developed hybrid metal matrix composite of materials and compared with AZ91. Wear tests have been carried out by pin on disc tribometer for both dry and wet sliding condition under 20 N,40 N,60 N, and 80 N. The results indicated the AZ91–1%TiO2–0.5%Gr having high wear resistance compared to other three combinations as well as AZ91. The present experimental investigations of hybrid metal matrix composite of materials have wear resistance in the order of B1 > A2 > A1 > B2 > AZ91 and AZ91–2%TiO2–0.5% Gr showed good tensile strength and hardness. The enhanced these properties were discussed in this paper.",book:{id:"11208",title:"Current Trends in Magnesium (Mg) Research",coverURL:"https://cdn.intechopen.com/books/images_new/11208.jpg"},signatures:"Palanivel Mathiazhagan and S. Jayabharathy"},{id:"81709",title:"New-Age Al-Cu-Mn-Zr (ACMZ) Alloy for High Temperature-High Strength Applications: A Review",slug:"new-age-al-cu-mn-zr-acmz-alloy-for-high-temperature-high-strength-applications-a-review",totalDownloads:17,totalDimensionsCites:0,doi:"10.5772/intechopen.104533",abstract:"One of the prime challenges with age hardened Al-Cu alloys is the strength degradation at high temperatures (above ∼250°C) due to the coarsening of strengthening θ′ precipitates and associated metastable θ′ → stable θ phase transformation. A recent discovery suggests that micro-alloying with Manganese (Mn) and Zirconium (Zr) can synergistically restrict θ′ precipitate coarsening, thereby rendering an excellent high temperature stability for Al-Cu-Mn-Zr (ACMZ) alloys. The θ′ precipitates are stabilized primarily from the reduction of interfacial energy by preferential solute segregation (Mn & Zr) at θ′ precipitate/α-Al matrix interfaces. The Al-Cu-Mn-Zr alloys thereby exhibit excellent high temperature hardness and tensile properties (yield and ultimate tensile strength) in addition to superior fatigue life and creep resistance. This newly developed Al-Cu-Mn-Zr alloys also showed excellent hot tearing resistance compared to the conventional cast Al-Cu alloys so much so that it meets the industrial standards as well. These alloys also have promising manufacturing possibility by additive route. Overall, Al-Cu-Mn-Zr alloys offer great potential for the automotive industry because of their unprecedented high temperature performance which should enable engineers to build light weight passenger vehicles leading to a safer and greener environment.",book:{id:"10847",title:"Aluminium Alloys - Design and Development of Innovative Alloys, Manufacturing Processes and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10847.jpg"},signatures:"Samarendra Roy and Shibayan Roy"},{id:"81342",title:"Magnesium Borates: The Relationship between the Characteristics, Properties, and Novel Technologies",slug:"magnesium-borates-the-relationship-between-the-characteristics-properties-and-novel-technologies",totalDownloads:25,totalDimensionsCites:0,doi:"10.5772/intechopen.104487",abstract:"Magnesium borates are compounds including mainly magnesium (Mg), boron (B) oxygen (O), and hydrogen (H). Magnesium borates are traditionally famous for their strong thermoluminescence, mechanical and thermal features due to their high elasticity coefficient, corrosion, and heat resistance. Because of being beneficial, especially in the applications such as thermoluminescence and X-ray screening, and ease of synthesis, magnesium borates are produced by using different experimental procedures exhibiting different characteristics. Main traditional synthesis techniques can be classified as liquid state and solid-state synthesis methods. With the help of novelties in synthesis technology, new techniques are beginning to emerge in magnesium borate syntheses such as hybrid synthesis, ultrasound, microwave, and capping agent addition. The strengthened characteristics of the compounds would lead to new applications such as stomach cancer chemotherapy and wastewater treatment. In this chapter, it is aimed to make a comparison between the characteristics of synthesized magnesium borates and their properties. In addition, new types of magnesium borates obtained by various synthetic techniques are expected to be useful for industrial applications such as space technology, radiation dosimetry, X-ray screening, ion batteries, and hydrocarbon reaction catalysis. Such classification of properties and the synthesis techniques will enlighten the relationship between the characteristics and novel applications of magnesium borates.",book:{id:"11208",title:"Current Trends in Magnesium (Mg) Research",coverURL:"https://cdn.intechopen.com/books/images_new/11208.jpg"},signatures:"Fatma Tugce Senberber Dumanli"},{id:"81125",title:"Magnesium Alloys for Sustainable Weight-Saving Approach: A Brief Market Overview, New Trends, and Perspectives",slug:"magnesium-alloys-for-sustainable-weight-saving-approach-a-brief-market-overview-new-trends-and-persp",totalDownloads:20,totalDimensionsCites:0,doi:"10.5772/intechopen.102777",abstract:"In the transportation sector, weight-saving strategies emphasize greenhouse gas reductions by improving fuel efficiency. Furthermore, it is a fact that consumers appreciate less-consuming vehicles. Lighter battery electric vehicles (BEV) mean higher travel distance covered with the same battery charge. Still, the fuel range of BEV is today not a secondary issue for choosing an e-vehicle as a unique family vehicle. Weight-saving strategies are also a priority for hydrogen gas-fuelled vehicles. Until hydrogen fuel for the transport sector is not produced at affordable costs in fully renewable pathways, increased fuel efficiency is critical for the product appeal. Magnesium is an environmentally compatible and biodegradable material with a similar density to structural plastics. On the contrary, plastics are responsible for nonbiodegradable microplastics in deep-marine environments when not recycled or correctly treated at their end of life. Due to the costly usage of lightweight materials, priority is given to activities to reduce costs by developing new materials and increasing the affordability of manufacturing costs. In this chapter, magnesium is presented from much perspective point of view: we will base it on comprehension of the past, considering the present, but with some ambition to propel hearts over today’s obstacles.",book:{id:"11208",title:"Current Trends in Magnesium (Mg) Research",coverURL:"https://cdn.intechopen.com/books/images_new/11208.jpg"},signatures:"Fabrizio D’Errico, Martin Tauber and Michael Just"},{id:"80372",title:"Application of the Aluminothermic Reduction Process for Magnesium Removal in Aluminum Scrap",slug:"application-of-the-aluminothermic-reduction-process-for-magnesium-removal-in-aluminum-scrap",totalDownloads:16,totalDimensionsCites:0,doi:"10.5772/intechopen.102407",abstract:"Magnesium is considered as impurity element in aluminum recycled for obtaining some cast alloys, with low concentration Mg, because at 0.1 wt% results in fragility, fractures, and defects. This research applies the aluminothermic reduction process to decrease magnesium content in aluminum cans by adding ZnO, to produce reaction products solid-state (Al2O3, MgO and MgAl2O4), and there is a possibility to obtain Al-Zn alloy. The conditions of the process were, melting temperature (750, 800, 850°C) and stirring velocity (200, 250, 300 rpm). The Mg and Zn contents were measured for chemical analysis and scrap generated from every process was analyzed by X-ray diffraction. The results show how the aluminothermic reduction decreased Mg from 0.93 to 0.06 wt% and increased zinc up to 5.52wt % in the molten metal. Therefore, this process can be used to remove Mg and can also prevent the generation of polluting gases into the environment.",book:{id:"10847",title:"Aluminium Alloys - Design and Development of Innovative Alloys, Manufacturing Processes and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10847.jpg"},signatures:"Rocio Maricela Ochoa Palacios, Citlaly Castillo Rodriguez, Jesus Torres Torres, Perla Janet Resendiz Hernandez and Alfredo Flores Valdes"},{id:"80920",title:"Drilling of 7075 Aluminum Alloys",slug:"drilling-of-7075-aluminum-alloys",totalDownloads:51,totalDimensionsCites:0,doi:"10.5772/intechopen.102864",abstract:"Aluminum alloy (Al 7075) has been increasingly used as structural components in automotive and aerospace industry due to their low density, high strength and good corrosion resistance compared with other metals. To manufacture and assemble the components, drilling operations are often conducted. However, Al 7075 is ductile and soft, which causes difficulty in drilling, resulting in material adhesion, high tool wear, short tool life and poor hole quality. As a result of the poor hole quality, there is a high percentage of part rejection, which can increase the manufacturing time and cost. This chapter discusses challenges and techniques to drill Al 7075 in terms of the cutting parameters and drilling conditions to prolong the tool life and achieve good hole quality. Drilling experiments on Al 7075-T6 (heat-treated) were conducted using carbide cutting tools at various cutting parameters. Reducing cutting speed and increasing feed rate resulted in reducing tool wear, whereas a reduction in surface roughness, hence improved machined surface finish, was found when both cutting speed and feed rate were reduced in drilling Al 7075-T6. Producing good hole quality is vital during the drilling process to ensure a good assembly and product service performance.",book:{id:"10847",title:"Aluminium Alloys - Design and Development of Innovative Alloys, Manufacturing Processes and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10847.jpg"},signatures:"Aishah Najiah Dahnel, Mohamad Noor Ikhwan Naiman, Muhammad Azim Mirza Mohd Farid, Ahmad Faris Abdul Rahman and Nur Munirah Meera Mydin"}],onlineFirstChaptersTotal:13},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:129,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:106,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:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",keywords:"Anthropic effects, Overexploitation, Biodiversity loss, Degradation, Inadequate Management, SDGs adequate practices"},{id:"38",title:"Pollution",scope:"\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment"},{id:"41",title:"Water Science",scope:"