\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"9894",leadTitle:null,fullTitle:"Advanced Ceramic Materials",title:"Advanced Ceramic Materials",subtitle:null,reviewType:"peer-reviewed",abstract:"This book examines exciting advancements in the field of ceramics, including nanotechnology, clean energy, and tribology as well as fundamental concepts like defects and structure. It is a comprehensive discussion on how today’s ceramics are processed and used in many of today’s critical technologies. It discusses current techniques for synthesizing durable and cost-effective ceramic components with biocompatibility, complexity, and high precision. This book is a comprehensive reference for researchers, engineers, dental clinicians, biologists, academics, and students interested in ceramics.",isbn:"978-1-83881-212-6",printIsbn:"978-1-83881-204-1",pdfIsbn:"978-1-83881-213-3",doi:"10.5772/intechopen.87703",price:119,priceEur:129,priceUsd:155,slug:"advanced-ceramic-materials",numberOfPages:296,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"9adbe58d10d5ca2b61e9ff2b6b138f40",bookSignature:"Mohsen Mhadhbi",publishedDate:"May 5th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/9894.jpg",numberOfDownloads:6500,numberOfWosCitations:0,numberOfCrossrefCitations:11,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:16,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:27,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 29th 2020",dateEndSecondStepPublish:"August 5th 2020",dateEndThirdStepPublish:"October 4th 2020",dateEndFourthStepPublish:"December 23rd 2020",dateEndFifthStepPublish:"February 21st 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"228366",title:"Dr.",name:"Mohsen",middleName:null,surname:"Mhadhbi",slug:"mohsen-mhadhbi",fullName:"Mohsen Mhadhbi",profilePictureURL:"https://mts.intechopen.com/storage/users/228366/images/system/228366.png",biography:"Dr. Mohsen Mhadhbi obtained his Ph.D. from the Faculty of Sciences of Sfax, Tunisia. He is currently an Assistant Professor of Chemistry at the National Institute of Research and Physical-Chemical Analysis, Tunisia. His research interests include nanomaterials, powder technology, ceramics, modeling, and simulations. Dr. Mhadhbi has published works in national and international journals and books. He is a member of various scientific journals and associations and has been an editorial board member for several journals.",institutionString:"National Institute of Research and Physicochemical Analysis",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Tunis El Manar University",institutionURL:null,country:{name:"Tunisia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"155",title:"Ceramics",slug:"ceramics"}],chapters:[{id:"75967",title:"Recent Advances in Ceramic Materials for Dentistry",doi:"10.5772/intechopen.96890",slug:"recent-advances-in-ceramic-materials-for-dentistry",totalDownloads:815,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Dental ceramics constitute a heterogeneous group of materials with desirable optical and mechanical proprieties combined with chemical stability. They are inorganic non-metallic materials used in several applications. These materials are biocompatible to tissue, highly esthetic, with satisfying resistance to tensile and shear stress. Over the past years, several developments in new ceramic materials in dental restoration were achieved, including processing techniques and high mechanical properties. Thus, concepts on the structure and strengthening mechanisms of dental ceramic materials are also discussed. The dental practitioner requires best knowledge concerning indications, limitations, and correct use of started materials. The purpose of this book chapter is to overview advances in new ceramic materials and processes, which are used in dentistry. The properties of these materials are also discussed.",signatures:"Mohsen Mhadhbi, Faïçal Khlissa and Chaker Bouzidi",downloadPdfUrl:"/chapter/pdf-download/75967",previewPdfUrl:"/chapter/pdf-preview/75967",authors:[{id:"228366",title:"Dr.",name:"Mohsen",surname:"Mhadhbi",slug:"mohsen-mhadhbi",fullName:"Mohsen Mhadhbi"},{id:"324375",title:"Dr.",name:"Faïçal",surname:"Khlissa",slug:"faical-khlissa",fullName:"Faïçal Khlissa"},{id:"324535",title:"Dr.",name:"Chaker",surname:"Bouzidi",slug:"chaker-bouzidi",fullName:"Chaker Bouzidi"}],corrections:null},{id:"74215",title:"Ferroelectric Glass-Ceramic Systems for Energy Storage Applications",doi:"10.5772/intechopen.93855",slug:"ferroelectric-glass-ceramic-systems-for-energy-storage-applications",totalDownloads:542,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"An overview of ferroelectric glass ceramics, some literature review and some of the important previous studies were focused in this chapter. Nanocrystalline glass–ceramics containing ferroelectric perovskite-structured phases have been included. All modified glasses having ferroelectric ceramics which prepared by different methods are discussed, that producing nanocrystalline glass–ceramics. Then particular tested to their use as dielectric energy storage materials. These materials exhibit promising dielectric properties, indicating good potential for high energy density capacitors as a result of their nanocrystalline microstructures. The results of the analysis are summarised in this chapter to provide an overview of the energy storage characteristics of the different materials produced during the study.",signatures:"Abdulkarim Ziedan Khalf",downloadPdfUrl:"/chapter/pdf-download/74215",previewPdfUrl:"/chapter/pdf-preview/74215",authors:[{id:"323331",title:"Dr.",name:"Abdulkarim",surname:"Khalf",slug:"abdulkarim-khalf",fullName:"Abdulkarim Khalf"}],corrections:null},{id:"74064",title:"From the Laser Plume to the Laser Ceramics",doi:"10.5772/intechopen.94464",slug:"from-the-laser-plume-to-the-laser-ceramics",totalDownloads:614,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The main stages of preparation of ceramic active elements of solid-state lasers are considered. The physical principles of laser synthesis of nanopowders are described. The features and processes taking place during compaction and compacts sintering are specified. Also we report on the investigation of characteristics of highly transparent ceramics on the basis of nanopowders synthesized in laser plume. It is shown that this approach enables to increase the “orange peel” formation threshold in the ceramics with strongly disordered crystalline structure. It opens the road to relatively simple synthesis technology from oxide materials and application of this ceramics as the gain media with oscillation efficiency higher than 50% and also leads to simplification of the synthesis technology of magnetoactive ceramics and to production of highly transparent YAG samples without the use of sintering heterovalent additives.",signatures:"Vladimir Osipov, Vyacheslav Platonov, Vladislav Shitov and Vladimir Solomonov",downloadPdfUrl:"/chapter/pdf-download/74064",previewPdfUrl:"/chapter/pdf-preview/74064",authors:[{id:"97328",title:"Prof.",name:"Vladimir",surname:"Solomonov",slug:"vladimir-solomonov",fullName:"Vladimir Solomonov"},{id:"328400",title:"Prof.",name:"Vladimir",surname:"Osipov",slug:"vladimir-osipov",fullName:"Vladimir Osipov"},{id:"329374",title:"Dr.",name:"Vecheslav",surname:"Platonov",slug:"vecheslav-platonov",fullName:"Vecheslav Platonov"},{id:"329375",title:"MSc.",name:"Vladislav",surname:"Shitov",slug:"vladislav-shitov",fullName:"Vladislav Shitov"}],corrections:null},{id:"73127",title:"The Investigation on the Fabrication and Characterization of the Multicomponent Ceramics Based on PZT and the Relaxor PZN-PMnN Ferroelectric Materials",doi:"10.5772/intechopen.93534",slug:"the-investigation-on-the-fabrication-and-characterization-of-the-multicomponent-ceramics-based-on-pz",totalDownloads:504,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"This chapter presents the investigation of fabrication and the physical properties of the Pb(Zr1−xTix)O3-Pb(Zn1/3Nb2/3)O3-Pb(Mn1/3Nb2/3)O3 multicomponent ceramics. The multicomponent yPb(Zr1−xTix)O3-(0.925 − y)Pb(Zn1/3Nb2/3)O3-0.075Pb(Mn1/3Nb2/3)O3 (PZT-PZN-PMnN) ceramics were synthesized by conventional solid-state reaction method (MO) combined with the B-site oxide mixing technique (BO). Research results show that the electrical properties of PZT-PZN-PMnN ceramics are optimal at a PZT content of 0.8 mol and Zr/Ti ratio of 48/52. At these contents, the ceramics have the following optimal properties: electromechanical coupling factor, kp = 0.62 and kt = 0.51; piezoelectric constant (d31) of 130 pC/N; mechanical quality factor (Qm) of 1112; dielectric loss (tan δ) of 0.005; high remanent polarization (Pr) of 30.4 μC.cm−2; and low coercive field (EC) of 6.2 kV.cm−1. Investigation of the domain structure of the two ferroelectric phases (tetragonal and rhombohedral) in the ZnO-doped PZT-PZN-PMnN with compositions at near the morphotropic phase boundary is described as follows: the 90 and 180° domains exist in the tetragonal phase, while the 71, 109, and 90° domains are located in the rhombohedral phase, and the widths of these domains were about 100 nm. Besides, the ceramics exhibited excellent temperature stability, which makes them a promising material for high-intensity ultrasound applications.",signatures:"Le Dai Vuong, Vo Thanh Tung and Phan Dinh Gio",downloadPdfUrl:"/chapter/pdf-download/73127",previewPdfUrl:"/chapter/pdf-preview/73127",authors:[{id:"241214",title:"Dr.",name:"Le",surname:"Dai Vuong",slug:"le-dai-vuong",fullName:"Le Dai Vuong"},{id:"326085",title:"Prof.",name:"Vo",surname:"Thanh Tung",slug:"vo-thanh-tung",fullName:"Vo Thanh Tung"}],corrections:null},{id:"73186",title:"Self-Healing of Concrete through Ceramic Nanocontainers Loaded with Corrosion Inhibitors and Microorganisms",doi:"10.5772/intechopen.93514",slug:"self-healing-of-concrete-through-ceramic-nanocontainers-loaded-with-corrosion-inhibitors-and-microor",totalDownloads:415,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Self-healing was considered for repairing of destruction of reinforced concrete on bridges, houses, etc., that comes from corrosion of reinforcement metals as well as cracking in cement. The work was accomplished at producing and assessing through incorporate ceramic nanocontainers loaded with microorganisms. We produced various types of organic and inorganic nanocontainers that were incorporated into the cement that can act as carriers for the transport of bacteria. The microorganisms used in the work are Escherichia coli and Staphylococcus aureus. Precipitation of CaCO3 was observed by both bacteria. As microspheres do not affect the submersion of the mineral by the microorganism, additional studies were carried out to assess the interaction between transmission microsystems and bacterium. The mechanism of self-healing of building materials in this work was based on CaCO3 precipitation, through the ureolytic action of bacteria. When a crack appears in the cement, then the bacterium trapped in a nanocontainers is released and comes into contact with the water. In this way, the microorganism begins to metabolize and precipitate the mineral, in a way that eventually observes healing of the crack. CaCO3 microbial precipitation was based on the breakdown of urea (CO (NH2)2) into CO32− and NH3. Due to the high pK value of the NH3/NH4+ system (pKa = 9.2), the breakdown reaction led to an increase in pH, favoring the release of carbonated ions (CO32−), and in an environment rich in calcium ions (Ca2+), CaCO3 precipitation took place.",signatures:"George Kordas",downloadPdfUrl:"/chapter/pdf-download/73186",previewPdfUrl:"/chapter/pdf-preview/73186",authors:[{id:"306484",title:"Emeritus Prof.",name:"George",surname:"Kordas",slug:"george-kordas",fullName:"George Kordas"}],corrections:null},{id:"73538",title:"New Bismuth Sodium Titanate Based Ceramics and Their Applications",doi:"10.5772/intechopen.93921",slug:"new-bismuth-sodium-titanate-based-ceramics-and-their-applications",totalDownloads:556,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Ferroelectric materials are widely investigated due to their excellent properties and versatile applications. At present, the dominant materials are lead-containing materials, such as Pb (Zr,Ti)O3 solid solutions. However, the use of lead gives rise to environmental concerns, which is the driving force for the development of alternative lead-free ferroelectric materials. (Bi0.5Na0.5)TiO3-based ceramics are considered to be one of the most promising lead-free materials to replace lead-containing ferroelectric ceramics due to their excellent ferroelectric properties, relaxation characteristics, and high Curie point. After decades of efforts, great progress has been made in the phase structure characterization and properties improvement of BNT based ceramics. However, most of the studies on BNT system mainly focuses on its piezoelectric properties and application of piezoelectric sensors and strain actuators, little attention is paid to its ferroelectric properties and related applications. In this chapter, new BNT-based ceramics via composition modification and special focuses on the ferroelectric properties, phase transition behaviors under external fields and related applications, such as application in energy storage, pulsed power supply and pyroelectric detection were proposed.",signatures:"Hengchang Nie, Genshui Wang and Xianlin Dong",downloadPdfUrl:"/chapter/pdf-download/73538",previewPdfUrl:"/chapter/pdf-preview/73538",authors:[{id:"324929",title:"Dr.",name:"Hengchang",surname:"Nie",slug:"hengchang-nie",fullName:"Hengchang Nie"},{id:"332042",title:"Dr.",name:"Genshui",surname:"Wang",slug:"genshui-wang",fullName:"Genshui Wang"},{id:"332043",title:"Dr.",name:"Xianlin",surname:"Dong",slug:"xianlin-dong",fullName:"Xianlin Dong"}],corrections:null},{id:"74295",title:"Investigation of Structural, Magnetic and Electrical Properties of Chromium Substituted Nickel Ceramic Nanopowders",doi:"10.5772/intechopen.94941",slug:"investigation-of-structural-magnetic-and-electrical-properties-of-chromium-substituted-nickel-cerami",totalDownloads:322,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Nano-ceramic of NiCrxFe2-xO4 (0.1 ≤ x ≤ 1.0) ferrites were synthesized by citrate-gel auto combustion method. The structural parameter such as lattice parameter, X-ray density, bulk density and porosity variations with Cr doping were studied. The average crystallite size is in the range 8.5–10.5 nm. The surface morphology and elemental analysis was studied with SEM (EDAX) spectrum and the structural information analyzed with FTIR spectra. Magnetic properties were discussed with Cr3+ion concentration. Electrical parameters like dc resistivity and drift mobility were reported with function of temperature and dopent concentration from room temperature to well beyond Curie temperature and explained with hopping mechanism between Fe2+↔Fe3+ ions. The activation energies in ferri and para magnetic regions were investigated. Dielectric parameters like dielectric constant, dielectric loss and ac conductivity were investigated variation with frequency and composition.",signatures:"Rapolu Sridhar, D. Ravinder, J. Laxman Naik, K. Vijaya Kumar, N. Maramu and S. Katlakunta",downloadPdfUrl:"/chapter/pdf-download/74295",previewPdfUrl:"/chapter/pdf-preview/74295",authors:[{id:"289636",title:"Prof.",name:"Ravinder",surname:"Dachepalli",slug:"ravinder-dachepalli",fullName:"Ravinder Dachepalli"},{id:"346605",title:"Dr.",name:"Nyathani",surname:"Maramu",slug:"nyathani-maramu",fullName:"Nyathani Maramu"},{id:"346606",title:"Dr.",name:"Sadhana",surname:"Katlakunta",slug:"sadhana-katlakunta",fullName:"Sadhana Katlakunta"}],corrections:null},{id:"74406",title:"The Effect of Ceramic Wastes on Physical and Mechanical Properties of Eco-Friendly Flowable Sand Concrete",doi:"10.5772/intechopen.95041",slug:"the-effect-of-ceramic-wastes-on-physical-and-mechanical-properties-of-eco-friendly-flowable-sand-con",totalDownloads:378,totalCrossrefCites:4,totalDimensionsCites:5,hasAltmetrics:0,abstract:"This work aims to study the valorization and recycling of ceramic wastes (wall tiles) as a fine aggregate instead of sand in the manufacturing of flowable sand concrete (FSC). For this, the sand is substituted with the ceramic wastes at different dosages (0, 5, 10, 15, 20, and 25% by volume of the sand). The influence of the ceramic wastes addition on the physical (workability, density) and mechanical (compressive, flexural and elastic modulus) properties of FSC was studied. The results show that the use of ceramic waste as partial replacement of sand contributes to reduce the workability, bulk density and improves the mechanical strengths of FSC according to the use of 25% of wall tiles waste.",signatures:"Mohamed Guendouz, Djamila Boukhelkhal, Alexandra Bourdot, Oussama Babachikh and Amine Hamadouche",downloadPdfUrl:"/chapter/pdf-download/74406",previewPdfUrl:"/chapter/pdf-preview/74406",authors:[{id:"323550",title:"Dr.",name:"Mohamed",surname:"Guendouz",slug:"mohamed-guendouz",fullName:"Mohamed Guendouz"},{id:"326866",title:"Dr.",name:"Alexandra",surname:"Bourdot",slug:"alexandra-bourdot",fullName:"Alexandra Bourdot"},{id:"326867",title:"Dr.",name:"Djamila",surname:"Boukhelkhal",slug:"djamila-boukhelkhal",fullName:"Djamila Boukhelkhal"},{id:"338169",title:"Mr.",name:"Oussama",surname:"Babachikh",slug:"oussama-babachikh",fullName:"Oussama Babachikh"},{id:"338170",title:"Mr.",name:"Amine",surname:"Hamadouche",slug:"amine-hamadouche",fullName:"Amine Hamadouche"}],corrections:null},{id:"73232",title:"Ceramics Coated Metallic Materials: Methods, Properties and Applications",doi:"10.5772/intechopen.93814",slug:"ceramics-coated-metallic-materials-methods-properties-and-applications",totalDownloads:723,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Surface coating can allow the bulk materials to remain unchanged, while the surface functionality is engineered to afford a more wanted characteristic. Ceramic coatings are considered as ideal coatings on metal which can significantly improve the surface properties of metal materials including anti-fouling, self-cleaning, corrosion resistance, wear resistance, oil/water separation and biocompatibility. Furthermore, various techniques have been utilized to fabricate a range of different ceramic coatings with more desirable properties on metal materials, which make the materials widely used in service environment. This chapter focus will be on the types, fabrication methods, surface properties and applications of ceramics coated metal materials.",signatures:"Dongmian Zang and Xiaowei Xun",downloadPdfUrl:"/chapter/pdf-download/73232",previewPdfUrl:"/chapter/pdf-preview/73232",authors:[{id:"324466",title:"M.D.",name:"Xiaowei",surname:"Xun",slug:"xiaowei-xun",fullName:"Xiaowei Xun"},{id:"325574",title:"Dr.",name:"Dongmian",surname:"Zang",slug:"dongmian-zang",fullName:"Dongmian Zang"}],corrections:null},{id:"73977",title:"Nanostructured Multilayer Composite Coatings for Cutting Tools",doi:"10.5772/intechopen.94363",slug:"nanostructured-multilayer-composite-coatings-for-cutting-tools",totalDownloads:435,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The chapter deals with the specific features concerning the application of wear-resistant coatings to improve the performance properties of ceramic cutting tools. The paper discusses the theoretical background associated with the specific operation conditions and wear of ceramic cutting tools and influencing the choice of the compositions and structures of wear-resistant coatings. The studies were focused on the application of the Ti-(Ti,Al)N-(Zr,Nb,Ti,Al)N multilayer composite coating with a nanostructured wear-resistant layer, as well as the (Cr,Al,Si)N–(DLC–Si)–DLC–(DLC–Si) and (Cr,Al,Si)N–DLC composite coatings in order to improve the cutting properties of ceramic tools. The chapter presents the results of the comparative cutting tests for the tools with the coatings under study, uncoated tools, and tools with the Ti-(Ti,Al)N commercial coating. The wear mechanisms typical for ceramic cutting tools with coatings of various compositions have been investigated.",signatures:"Sergey Grigoriev, Alexey Vereschaka, Marina Volosova, Caterina Sotova, Nikolay Sitnikov, Filipp Milovich and Nikolay Andreev",downloadPdfUrl:"/chapter/pdf-download/73977",previewPdfUrl:"/chapter/pdf-preview/73977",authors:[{id:"196459",title:"Dr.",name:"Alexey",surname:"Vereschaka",slug:"alexey-vereschaka",fullName:"Alexey Vereschaka"},{id:"207607",title:"Dr.",name:"Nikolay",surname:"Sitnikov",slug:"nikolay-sitnikov",fullName:"Nikolay Sitnikov"},{id:"264336",title:"Dr.",name:"Catherine",surname:"Sotova",slug:"catherine-sotova",fullName:"Catherine Sotova"},{id:"329434",title:"Prof.",name:"Sergey",surname:"Grigoriev",slug:"sergey-grigoriev",fullName:"Sergey Grigoriev"},{id:"329437",title:"Dr.",name:"Filipp",surname:"Milovich",slug:"filipp-milovich",fullName:"Filipp Milovich"},{id:"329438",title:"Dr.",name:"Nikolay",surname:"Andreev",slug:"nikolay-andreev",fullName:"Nikolay Andreev"},{id:"330235",title:"Dr.",name:"Marina",surname:"Volosova",slug:"marina-volosova",fullName:"Marina Volosova"}],corrections:null},{id:"74485",title:"Three-Dimensionally Ordered Macroporous-Mesoporous Bioactive Glass Ceramics for Drug Delivery Capacity and Evaluation of Drug Release",doi:"10.5772/intechopen.95290",slug:"three-dimensionally-ordered-macroporous-mesoporous-bioactive-glass-ceramics-for-drug-delivery-capaci",totalDownloads:449,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Bioactive glass ceramics (BGCs) have been used in orthopedic and dentistry due to having better osteoconductive and osteostimulative properties. This study aimed to evaluate and compare the drug release properties of two different BGCs; 45S5 and S53P4. The BGCs were composed with four phases of SiO2 – CaO – Na2O – P2O5 system, synthesized by sol–gel method using dual templates; a block-copolymer as mesoporous templates and polymer colloidal crystals as macroporous templates, called three-dimensionally ordered macroporous-mesoporous bioactive glass ceramics (3DOM-MBGCs). In vitro bioactivity test performed by soaking the 3DOM-MBGCs in simulated body fluid (SBF) at 37°C. The results indicated that, the 45S5 have the ability to grow hydroxyapatite-like layer on the surfaces faster than S53P4. Gentamicin drug was used to examine in vitro drug release properties in phosphate buffer solution (PBS). The amount of drug release was quantified through UV/Vis spectroscopy by using o-phthaldialdehyde reagent. S53P4 showed high drug loading content. The outcome of drug release in PBS showed that both S53P4 and 45S5 exhibited a slowly continuous gentamicin release. The resultant drug release profiles were fitted to the Peppas-Korsmeyer model to establish the predominant drug release mechanisms, which revealed that the kinetics of drug release from the glasses mostly dominated by Fickian diffusion mechanism.",signatures:"Reedwan Bin Zafar Auniq, Namon Hirun and Upsorn Boonyang",downloadPdfUrl:"/chapter/pdf-download/74485",previewPdfUrl:"/chapter/pdf-preview/74485",authors:[{id:"328197",title:"Assistant Prof.",name:"Upsorn",surname:"Boonyang",slug:"upsorn-boonyang",fullName:"Upsorn Boonyang"},{id:"338371",title:"Dr.",name:"Namon",surname:"Hirun",slug:"namon-hirun",fullName:"Namon Hirun"},{id:"338373",title:"Mrs.",name:"Reedwan",surname:"Bin-Zafar Auniq",slug:"reedwan-bin-zafar-auniq",fullName:"Reedwan Bin-Zafar Auniq"}],corrections:null},{id:"75213",title:"Challenges in Rietveld Refinement and Structure Visualization in Ceramics",doi:"10.5772/intechopen.96065",slug:"challenges-in-rietveld-refinement-and-structure-visualization-in-ceramics",totalDownloads:749,totalCrossrefCites:3,totalDimensionsCites:5,hasAltmetrics:0,abstract:"The most common and basic characterization in the field of material science is the almighty X-ray diffraction (XRD). In every institute, every research report and every manuscript, concerning material properties, the X-ray diffraction pattern is essentially found. Although the basis of these works relies on the fact that X-ray diffraction pattern was found to be matching with some structure in a database, the in depth significance of the various characteristic diffraction manifestations of various physical characters are rarely discussed. Most of the researchers (especially beginners) are either not aware of the prowess of X-ray based characterizations, or have not been introduced to it properly or may be sometimes they are not interested in its results at all. The decreased interest (later) in the results from such studies might be for not being productive enough for time spending or non-effectiveness in justifying the motivation of the work. The former two are more related to the availability and accessibility of study material for the development of core concepts. Most of the institutes always do not have access to the span-wide scientific literature and the researchers joining these institutions are partly affected. In this context the effective open-access and free availability of intech-open, it is prudent to at least attempt to accumulate, assimilated and aggregate the concepts related to X-ray diffraction in a single package. 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Saleh",coverURL:"https://cdn.intechopen.com/books/images_new/9873.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"144691",title:"Prof.",name:"Hosam M.",middleName:null,surname:"Saleh",slug:"hosam-m.-saleh",fullName:"Hosam M. Saleh"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11867",leadTitle:null,title:"Echocardiography",subtitle:null,reviewType:"peer-reviewed",abstract:"\r\n\tAlthough the diagnosis and overall survival of patients with various cardiac diseases have improved in the last years, there still remains a significant proportion of patients with unfavorable prognoses. The evaluation of these patients necessitates effective imaging techniques in both diagnosis and long-term follow-up. Even though Cardiac Magnetic Resonance imaging is currently the imaging modality of choice for tissue characterization, advanced echocardiography represents a modern alternative. Speckle tracking echocardiography can be used to assess myocardial deformation at both segmental and global levels. Since distinct myocardial pathologies affect deformation differently, information about the underlying tissue can be offered by strain imaging. Echocardiography advances also show promising results in the improvement of diagnostic accuracy, management, and follow-up and a major advantage of echocardiography over other imaging modalities is the ability to use it in real-time, in the cardiac catheterization laboratory, allowing for the performance of imaging immediately before, during, and after interventional procedures. Furthermore, the prevalence of adult congenital heart disease continues to grow due to advances in surgical and diagnostic techniques. Echocardiography has proven to be a useful tool in the diagnosis and follow-up of these patients, both after percutaneous and surgical procedures, and its utility has expanded significantly due to the development of better technology. In addition, stress echocardiography could be useful in the evaluation of several cardiac diseases and should be preferred over other imaging modalities due to the lower cost, wider availability, and radiation-free nature.
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art novel imaging techniques by focusing on the most important evidence-based developments in this area.
Genetic polymorphism is the existence of at least two variants with respect to gene sequences, chromosome structure, or a phenotype (gene sequences and chromosomal variants are seen at the frequency of 1% or higher), typical of a polymorphism, rather than the focus being on rare variants [1].
The human genome comprises 6 billion nucleotides of DNA packaged into two sets of 23 chromosomes, one set inherited from each parent. The probability of polymorphic DNA in humans is great due to the relatively large size of human genome. Genomic variability includes a wide range of variations from single base pair change, many base pairs, and repeated sequences [2].
Single nucleotide polymorphisms are the most common type of genetic variations in humans [3], due to their abundance across the human genome; single nucleotide polymorphisms (SNPs) have become important genetic markers for mapping human diseases, population genetics, and evolutionary studies. SNPs have become very important since technologies for DNA sequencing have become feasible and widely available. Advance continues at a rapid rate [4].
A major step forward in genome identification is the discovery of about 30–90% of the genome which is constituted by regions of repetitive DNA which are highly polymorphic in nature [5]. Polymorphic tandem repeated sequences have emerged as important genetic markers and initially, variable number tandem repeats (VNTRs) were used in DNA fingerprinting. In recent years, evidence has been accumulated for the involvement of VNTR repeats in a wide spectrum of pathological states [6].
Throughout the past years, scientists have believed that genes strictly came in two copies in a genome. However, with the recent advancement in molecular technology, discoveries have revealed substantial segments of DNA, ranging in size from thousands to millions of DNA bases that could vary in copy number. Such copy number variations (or CNVs) encompass gene copies, newly discovered CNVs are important sources of genomic diversity [7, 8].
The development and use of DNA-based molecular markers is one of the most significant developments in the field of molecular genetics that facilitate the study of genetic variations in health and diseases [5].
This chapter reviews the DNA-based genetic markers and their application in medicine, with a particular emphasis on common DNA-based genetic markers, including single nucleotide polymorphisms and short tandem repeats (STRs).
Genomic variability at DNA level can be present in many forms including: single nucleotide polymorphisms, variable number of tandem repeats (e.g., mini- and microsatellites), transposable elements (e.g., Alu repeats), structural alterations, and copy number variations. It can occur in the nucleus or mitochondria. Two major sources: (1) mutations that may result as chance processes or have been induced by external agents such as radiation and (2) recombination. Once formed, it can be inherited, allowing its inheritance to be tracked from parent to child [3].
The genomes of humans may be divided into different parts based on known functional properties; the coding and noncoding regions mostly do not code for protein [2, 9]. The coding regions contain DNA sequences which determine primarily the amino acid sequences of the proteins for which they code. Noncoding DNA generally containing DNA sequences with no function has not yet been discovered or possibly no function exists [10]; such sequences may be either single copy or exist as multiple copies called repetitive DNA [10]. Indeed, regions of DNA that do not code for proteins tend to have more polymorphisms. Recently, there has been substantial progress in understanding genome content which centered on discovered protein-coding genes which considered a functional DNA sequence moving away for discoveries of many repeat families, and various copy number variations encompass gene copies leading to dosage imbalance that plays an important role in genome structure, evolution, and diversity [11, 12]. “The Human Genome Project has revealed that humans have only 20,000–30,000 structural genes (protein-coding genes) (International Human Genome Sequencing Consortium, 2004)” [13].
Single base change is “high-density natural sequence variations in human genome” [14]. SNPs are mostly formed when errors occur (substitution, insertion and deletion). SNPs are prominent sources of variation in human genome and serve as excellent genetic markers. Some regions of the genome are richer in SNPs than others. SNPs may occur within gene sequences or in intergenic sequences. SNPs mostly are located in noncoding regions of the genome and have mostly no direct known impact on the phenotype of an individual but their role till now remains elusive, and depending on where SNPs occurs, it might have different consequences at the phenotypic level [3].
It is a type of DNA variation in which a specific nucleotide sequence of various lengths ranging from one to several 100 base pairs is inserted or deleted. Indels are widely spread across the genome. Some authors consider one base pair as SNPs or repeat insertion/deletion as indels.
DNA repeats can be classified as interspersed repeats or tandem repeats. This can comprise over two-thirds of the human genome [15]. Interspersed repeats are dispersed across the genome within gene sequences or intergenic and include retro (pseudo) genes and transposons. Tandem repeats or variable number tandem repeats (≥2 bp in length) that are adjacent to each [16] can involve as few as two copies or many thousands of copies. Centromeres and telomeres largely comprise tandem repeats. Despite increasing evidence on the functionality of DNA repeats, their biologic role is still elusive and under frequent debate [11]. Tandem repeats are organized in a head-to-tail orientation; based on the size of each repeat unit, satellite repeats can be further divided into macrosatellites, minisatellites, and microsatellites [17]. Some of these repeats are described as follows: macrosatellites, with sequence repeats longer than 100 bp, are the largest of the tandem DNA repeats, located on one or multiple chromosomes [11], minisatellites, stretches of DNA, are characterized by moderate length patterns, 10–100 bp usually less than 50 bp [9, 18], and microsatellites also known as short tandem repeats (STRs) repeat units of less than 10 bp, [3].
Structural and copy number variations (CNVs) are another frequent source of genome variability [6, 19, 20]. The term CNVs therefore encompasses previously introduced terms such as large-scale copy number variants (LCVs) [19], copy number polymorphisms (CNPs) [20], and intermediate-sized variants (ISVs) [21]. Some currently used terms are structural variations; a genomic alteration (e.g., an inversion) that involves segments of DNA > 1 kb, copy number polymorphisms; a duplication or deletion event involving >1 kb of DNA [22], intermediate-sized structural variant; and a structural variant that is ∼8–40 kb in size, this can refer to a CNVs or a balanced structural rearrangement (e.g., an inversion) [21].
The development and use of molecular methods for the detection of DNA molecular markers is one of the most significant progresses in the field of molecular genetics. Mapping the human genome requires a set of genetic markers to which we can relate the position of genes. Some of these markers are genes, others SNPs and VNTRs. Molecular markers can be used to mark in genomes for various purposes such as mapping human diseases, pharmacogenetics, and human identification.
Single base pair change leads to single nucleotide variant, probably accounting for many genetic conditions caused by single gene or multiple genes. SNPs represent the major source of human genomic variability. Due to the lack of knowledge on exact SNP number, it is difficult to give a direct estimate of the number of the SNPs in the human genome but in different public and private data bases, more than 5 million have been recorded and about 4 million validated [23]. “The data from the Human Genome project revealed that that human nucleotide sequence differs every 1000-1500 bases from one individual to another” [24]. “The SNP Map working group observed that two haploid genomes differ at 1 nucleotide per 1331 bp”. Over 60,000 however are within genes and some of them associated with diseases [2].
Single nucleotide polymorphisms within protein-coding regions either synonymous polymorphisms; those that do not have any effect on the organism and are said to be selectively silent as the substitution causes no amino acid change in the protein produced (silent mutation) or nonsynonymous substitution results in change in encoded amino acids either missense mutation; change the protein through codon alteration or nonsense mutation results in a chain termination codon [3].
Single nucleotide polymorphisms within a coding sequence cause genetic diseases including sickle cell anemia. SNPs responsible for a disease can also occur in any genetic region that can
Another important group of SNPs is the one that alters the primary structure of a protein involved in drug metabolism; these SNPs are targets for pharmacogenetics studies.
However, some SNPs are not causative, some SNPs are in close association with, and therefore segregate with, a disease-causing sequence so, the presence of SNP correlates with the presence or an increased risk of developing the disease; these SNPs are useful in diagnostics, disease prediction, and other applications [3].
Single nucleotide polymorphisms can be used as genetic markers for constructing high genetic maps and to carry out association studies related to diseases because of their abundance and the availability of high throughput analysis technologies. SNPs have become an important application in the development and research of genetic markers [14].
There are numerous strategies that can be implemented to new single nucleotide variant (SNVs) discoveries; the most common and well-known method is by direct sequencing and in comparison to a puplic or other sequence date base [25, 26] or locus specific amplification of target genomic region followed by sequence comparison [27, 28]; prescreening prior to sequence determination is needed. SNV detection encompasses two broad areas: (1) scanning DNA sequences for previously unknown polymorphisms and (2) screening (genotyping) individuals for known polymorphisms. Scanning for new SNVs can be further classified to two different types of approaches, the first one being the global (or random approach) and the other one being the regional (targeted approach) [14]. There are certain methods which have been developed for using SNVs randomly in the genome; “such as representation shotgun sequencing [14, 29], primer-ligation-mediated PCR [14, 30] and degenerate oligonucleotide–primed PCR” [14, 31].
Haplotypes are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual SNPs and may therefore provide increased diagnostic accuracy in some cases [32].
Microsatellites are short tandem repeats (STRs), repeat units, or motifs of less than 10 bp; because of high variability, microsatellite loci are often used in forensics, population genetics, and genetic genealogy. Significant associations were demonstrated between microsatellite variants and many diseases [15].
Depending on the search algorithm, there are approximately 700,000–1,000,000 microsatellite loci which are 2–6 bp long in the human reference genome [33, 34]. Di- and tetra-nucleotides constitute about 75% of microsatellites, with the remaining loci containing tri-, penta, and hexanucleotide. Within genes, STRs are nonrandomly distributed across protein-coding sequences, untranslated regions (UTRs), and introns. STRs containing dinucleotide repeat units that are much more abundant in the regulatory or UTR regions than in other genomic regions. In the coding regions of the genes, repeats mostly have either trimeric or hexameric repeat unit, likely as a result of selection against frameshift mutations [34, 35]. “The mutation rates of STRs often lie between 103 and 106 per cell generation which is 10- to 105-fold higher than the average mutation rates observed in nonrepeated regions of the genome”[36, 37].
“Polymorphism of tandem repeats within protein-coding regions reveals that tandem repeat variation is an important source of variation in many proteins, many of this variation is of significant impact on protein function. Tandem repeats has been associated with a number of diseases and phenotypic conditions, changes in the protein products of genes, leading to diseases, other tandem repeat polymorphisms in noncoding regions are known to modify function through their impact on gene regulation”. “These polymorphisms can arise from events such as unequal crossover, replication slippage or double-strand break repair” [38].
Variations in the STR length play a significant role in modulating gene expression and STRs are likely to be general regulatory elements; regulatory STRs manifest significant polymorphism because of their high intrinsic mutation rate [15].
There are examples for distinctive phenotypic changes and diseases that are directly associated with the increases or decreases of microsatellite repeat arrays; for example, considering Huntington disease gene, triplet nucleotide mutations, the mutation that causes the disease, is an expansion of CAG repeats from the normal range of 11–14 copies to abnormal range of at least 38 copies. The extra CAG repeats that causes extra glutamine is produced [9] and there are more than 40 neurological diseases in humans, such as spinocerebellar ataxia with polyglutamine tracts, which are caused by microsatellite motif length changes in trinucleotide arrays [39].
Testing candidate genes for polymorphisms in exons, promoters, splice sites, or other regulatory regions will have to be done using SNP testing, because it is the most common polymorphisms and more likely responsible for phenotypic variations. For complex phenotypic traits and candidate loci, single-loci SNP analyses present less information due to the bi-allelic nature of the markers, as compared to the multi-allelic microsatellites. However, performing haplotype frequency may improve the accuracy [40]. Recently, polymorphic tandem repeated sequences and coy number variations have emerged as important sources of genomic diversity that facilitate the study of genetic variations in health and diseases.
Different forms of DNA-based molecular markers can be tracked using a variety of techniques. Some of these techniques include RFLPs with Southern blots and polymerase chain reactions (PCRs). Recently great advances in methodology for DNA polymorphisms detection using real time PCR, hybridization techniques using DNA microarray chips, genome sequencing each technique has its own advantage and disadvantage.
DNA digestion with restriction enzyme endonuclease cuts DNA at a specific sequence pattern known as a restriction endonuclease recognition site. Thus, the alleles differ in length and can be distinguished by gel electrophoresis, which can arise from a number of genetic events including point mutation in restriction sites, mutation that creates a new restriction site, insertion, deletion, and repeated sequences. The first polymorphic RFLP was described in 1980. RFLPs were the original DNA targets used for human identification, parentage testing, and gene mapping.
The method of hybridization of DNA with probes is called Southern blotting, after the name of the inventor, Southern [41]. RFLP requires relatively large amounts of DNA. Hence, it cannot be performed with the samples degraded by environmental factors and also takes longer time to get the results [42, 43]. PCR-RFLP is now replaced to avoid using Southern blot.
In-vitro amplification of particular DNA sequences with the help of specifically chosen primers and DNA polymerase enzyme is done. The amplified fragments are separated electrophonically and detected by different staining methods. Real-time PCR useful modification of PCR can detect polymorphisms by various methodologies using real-time PCR chemistries, for example, TaqMan assay or molecular beacons.
Genomic array technology is a type of hybridization analysis allowing simultaneous study of large numbers of targets or samples. In 1987, macroarray evolved into the microarray. Tens of thousands of targets can be screened simultaneously in a very small area. Automated depositing systems (arrayers) can place thousands of spots on glass substrate of the size of a microscope slide (chip) with spotting representative sequences of each gene in triplicate, simultaneous screening of the entire human genome on a single chip. This technique facilitates the process of identifying specific homozygous and heterozygous alleles, by comparing the disparity of hybridization of the target DNA with each redundant probe. Microarray is also used to characterize genetic diversity and drug responses, to identify new drug targets, and to assess the toxicological properties of chemicals and pharmaceuticals [44].
Since technologies for rapid DNA sequencing have become available they are now widely used. There is a great progression for the detection of single nucleotide variants (SNVs) by direct sequencing, but intermediate-sized (from 50 bp to 50 kb) structural variants (SVs) remain a challenge. Such variants are too small to detect with cytogenetic methods but too large to reliably discover with short-read DNA sequencing. Recent high-quality genome assemblies using long-read sequencing have revealed that each human genome has approximately 20,000 structural variants, spanning 10 million base pairs, more than twice the number of bases affected by SNVs. New long-read sequencing approaches are needed to meet this challenge, as short-read sequencing technologies only detect 20% of the SVs present in the human genome [45, 46, 47, 48].
DNA-based molecular markers are such powerful tools for mapping human diseases and discover many multifactorial diseases and disorders.
Genetic mapping and linkage: The mapping of the human genome has made possible to develop a haplotype map in order to better define human SNV variability. The haplotype map or HapMap will be a tool for the detection of human genetic variation that can affect health and diseases [23]. The HapMap project is far more useful because it will reduce the number of SNVs required to examine the entire genome for association with a phenotype or diseases from the 10 million SNPs that are expected to exist to approximately tag 500,000 SNPs [38]. The first large-scale effort to produce a human genetic map was performed mainly using RFLP; other several projects are underway to identify more markers in humans and to make this data publicly available to scientists worldwide. Many groups that are involved in these massive efforts through DNA polymorphisms discovery resource include the SNP consortium (TSC) http://snp.cshl.org [49, 50]. The reason for the current enormous interest in SNPs is the hope that they could be used as markers to identify genes that predispose individuals to common, multifactorial disorders by using linkage disequilibrium (LD) mapping.
“The HapMap Project (http://hapmap.ncbi.nlm.nih.gov/), and other approaches, such as genome wide association studies, have been widely reported for complex polygenic diseases, with some interesting novel genes affecting disease susceptibility now identified. Genome Wide Association; the GWAS has now been used for a large range of traits and diseases e.g. baldness and eye color” [51, 52].
The identification of genes affecting complex trait is a very difficult task. For many complex traits, the observable variation is quantitative, and loci affecting such traits are generally termed quantitative trait loci (QTL). (SNVs) can be used as genetic markers for constructing high-density genetic maps and to carry out association studies related to complex traits and diseases [14].
Individual response to a drug is governed by many factors such as genetics, age, sex, environment, and disease. The influence of genetic factors on the response of a drug is a known fact. Polymorphic STRs, together with SNPs and CNVs, can explain variability in response to pharmacotherapy because of their prevalence in the human genome and their functional role as regulators of gene expression and its applications. Pharmacogenetics is the study of the influence of genetics factors on drug response and metabolism. The science of pharmacogenetics when applied can be used to evade adverse drug reactions, predict toxicity and therapeutic failure, and refine therapeutic efficiency and improve clinical outcomes [53].
Establishing an individual’s identity is one of the uses of DNA sequence information that highlights uniqueness of a particular sample [5], also known as genetic fingerprinting; DNA typing and DNA profiling are molecular genetic methods that enable the identification of individuals using hair, blood, semen, or other biological samples, based on unique patterns in their DNA. This uniqueness in each individual is the basis of human identification at the DNA level, forensic identification, determination of genetic variation, determination of family relationship, and one important instance is identifying good genetic matches for organ or marrow donation. When first described in 1984 by British scientist Alec Jeffreys, the technique used was minisatellites; these sequences are unique to each individual, with the exception of identical twins. Different DNA fingerprinting methods exist, using either restriction fragment length polymorphism (RFLP) or PCR or both. More than 200 RFLP loci have been described in human DNA. Initially, forensic medicine used minisatellite testing; however, this method requires a large amount of material and yield low-quality results especially when only little amount of materials are available. Nowadays, in most forensic samples, the study of DNA is usually performed by microsatellite analysis. The most useful microsatellite for human identification is those with a greater number of alleles, smaller size, higher frequency of heterozygotes (higher than 90%), and low frequency of mutations [43]. Among others, the microsatellite DNA marker has been the most widely used, due to its easy use by simple PCR, followed by a denaturing gel electrophoresis [40]. Each person has some STRs that were inherited from the father and some from mother, useful in paternity testing but however no person has STRs that are identical to those of either parent. The uniqueness of an individual’s STR provides the scientific marker of identity and hence is helpful in forensic identification [54]. Genomic and mitochondrial are two types of DNA which are used in forensic sciences. The genomic DNA is found in the nucleus of each cell in the human body and represents a DNA source for most forensic applications. Mitochondrial DNA (mt DNA) is another source of material that can be used; various biological samples such as hair, bones, and teeth that lack nucleate cellular materials can be analyzed with mt DNA [43, 55].
“Majority of the length of the human Y chromosome is inherited as a single block in linkage from father to male offspring as a haploid entity. DNA genetic markers on the human Y chromosome are valuable tools for understanding human evolution, migration and for tracing relationships among males” [43, 56]. “Chromosome X specific STRs is used in the identification and the genomic studies of different ethnic groups worldwide, because the small size of X-chromosome STR alleles; about 100–350 nucleotides, it is relatively easy to be amplified and detected with high sensitivity” [43].
DNA typing becomes the method of choice for engraftment monitoring, donor cells are examined by following donor polymorphisms in the recipient blood and bone marrow. Although RFLP can efficiently differentiate donor and recipient cells, the detection of RFLP requires the use of southern blot methods, which is too labor intensive and has limited sensitivity for this application, in comparison with small minisatellites or microsatellites that are easily detected by PCR amplification, because of increased rapidity and the 0.5–1% sensitivity achievable with PCR. Sensitivity can be raised to 0.01% using Y-STR, but this approach is limited to that transplant from sex mismatched donor recipient pairs preferably from a female donor to a male recipient [2].
Nowadays, DNA fingerprinting is used as a tool for designing “personalized” medical treatments for cancer patients.
Single nucleotide polymorphisms (SNPs) have become an important application in the development and research of genetic diseases or other phenotypic traits. Haplotypes are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual SNPs and may therefore provide increased diagnostic accuracy in some cases.
Polymorphic tandem repeated sequences have emerged as important genetic markers and initially, variable number tandem repeats (VNTRs) were used in DNA fingerprinting; in recent years, evidence has been accumulated for the involvement of VNTR repeats in a wide spectrum of pathological states.
The new global CNV map will transform medical research in four main areas: detection for genes underlying common diseases, study of familial genetic conditions, exclude variation found in unaffected individuals, helping researchers to target the region that might be involved and the data generated will also contribute to a more accurate and complete human genome reference sequence used by all biomedical scientists. Currently, approximately 2000 CNVs have been described; there could be thousands more CNVs in the human population. About 100 CNVs were detected in each genome tested with the average size being 250,000 bases (an average gene is 60,000 bases). With advanced molecular technologies more CNVs will be discovered and more DNA samples from worldwide populations are examined.
Recently, there has been substantial progress in understanding genome content which centered on protein-coding genes which considered a functional DNA sequence moving away for many discoveries, many repeat families, and various copy number variations that play an important role in genome structure, evolution, and diversity. Additional efforts are being placed to develop strategies that would overcome the obstacles in alignment next-generation sequencing data. “Future precision medicine efforts will direct to connect genotypes to phenotypes and distinguish common, from rare or potentially disease linked variants. New long-read sequencing approaches are needed to meet this challenge.”
Other important applications of genetic polymorphism knowledge are improving health care through gene therapy, discovery of new drugs and drug targets, and upgradation of the discovery processes with advanced technologies.
Advances in molecular technologies, DNA sequencing technology, and microarray, coupled with novel, efficient computational analysis tools, have made it possible to analyze sequence-based experimental data, more discoveries, and development at a rapid rate.
The author declares that there is no conflict of interest.
The cellular microenvironment of metastatic solid tumors is composed of heterogeneous malignant cells and other supporting nonmalignant cells such as cancer-associated fibroblasts, angiogenic endothelial cells, mesenchymal stem cells, and pericytes, along with lymphoid and myeloid immune cells. The latter includes B- and T-cells, dendritic cells, and tumor-associated macrophages (TAMs).
TAMs form a major component of the tumor microenvironment (TME) and likely are the most abundant cell [1, 2, 3]. Macrophages, which are differentiated from monocytes, are heterogeneous and belong to the inherent myeloid cells present in TME. The roles and phenotypes of macrophages depend on their homeostatic and pathological microenvironment. Macrophages can aid in enhancing immunity by clearing cellular debris and tumor cells, as well as boosting adaptive immunity [4, 5]. In contrast, continued or prolonged activation of macrophages can result in a dysregulated host immune defense, ultimately resulting in pathogenetic outcomes [4].
Macrophages can release soluble factors such as cytokines and stimulate the complement system, contributing to inflammation [6]. In the case of a large tumor volume, the microenvironment can have low oxygen tension and acidic pH to create conditions that are identical to tissue damage seen in inflammatory conditions [7, 8]. In turn, the macrophages within an inflammatory microenvironment can initiate mechanisms to repair the “damaged tissue.” These include triggers to initiate neoangiogenesis, tissue remodeling, and removal of dead and damaged cells as well as promoting immunosuppression [8, 9, 10, 11]. In this regard, tumor growth can behave as an aberrant but complex interaction between tumor cells, immune system, and stromal cells in which proliferating and dying cells coexist similar to a wound [8, 9, 12].
The prognostic value of TAM infiltration in several different kinds of cancer, such as breast [13], lung [14], prostate [15], and gastric [16], has been demonstrated in various studies. Other studies reported on a correlation between TAM density and poor prognosis [17, 18]. Zhao et al. have also demonstrated that increased penetration of TAMs correlated with poor prognosis and reduced patient survival in breast cancer [19]. Further subset analysis has shown differential prognostic association between M1 and M2 macrophage phenotypes. A high M1 phenotype density has been shown to correlate with better prognosis due to the pro-inflammatory role of this subtype. In contrast, predominance of M2 phenotype correlated with a poorer overall survival as found in gastric cancer, partly due to their anti-inflammatory property, including increased regulatory T-cells [20].
Malignant transformation is associated with an “angiogenic switch,” marked by an increase in the number of new blood vessels [21, 22]. Macrophages also appear to be important players in angiogenesis. TAMs may stimulate the tumor neovascularization by producing angiogenic factors. Leek et al. have shown a positive relationship between high vascular grade and increased macrophage infiltration in breast carcinoma, which leads to reduced disease-free survival and overall survival [23]. TAMs residing in hypoxic tumor areas have increased expression of vascular endothelial growth factor A (VEGFA) [24]. This correlates with TAM-mediated induction of metalloproteinases (MMPs), contributing to increased tumor angiogenesis, which is consistent with findings of TAMs as major source of MMP9 in a mouse model of human ovarian cancer [25]. Chen et al. have shown that a hypoxic TME can be crucial for preferential polarization of recruited macrophages into M2 subtype [26]. These recruited M2 macrophages significantly enhance tumor neovascularization while protecting the cancer cells of the immune system.
Macrophages that express high levels of tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS), or major histocompatibility complex (MHC) class II molecules have been considered antitumorigenic. Expression of high levels of arginase-1 (ARG1), interleukin (IL)-10, CD163, CD204, or CD206 by macrophages has been associated with pro-tumorgenic behavior [27]. Macrophage polarization is an area of intense immunological research [28, 29, 30]. In a conventional dualistic approach, M1 macrophages refer to macrophages activated through lipopolysaccharide (LPS) or the polarizing cytokine interferon gamma (INFγ) [31, 32]. These are identified by the expression of “M1 marker genes” such as
However, macrophages can express both ARG1 and NOS2 simultaneously, suggesting the inadequacy of the strict dichotomous model to address layers of complexity. This dualistic model has been replaced by a spectrum model, wherein M1 and M2 are thought to represent ends of a continuum. Heterogeneity in the microenvironment along with other development factors must be considered for TAM phenotyping. Metabolic changes within the TME have significant potential to change polarization of macrophages. It has been shown that oxidative pathways result in M2 polarized macrophages, whereas M1 macrophages depend more on glycolysis [6, 32].
Breast cancer ranks as the second most common cancer type worldwide with higher incidence being seen in African Americans and Hispanics. Lifetime risk of breast cancer remains at one in every eight women equating to about 13% of American women developing breast cancer in their lifetime. It is estimated that in 2022, approximately 288,000 new cases of invasive breast cancer will be diagnosed in women within the United States and over 43,000 will die from their breast cancer (SEER database; http://cancer.gov).
Triple-negative breast cancer (TNBC) refers to tumors lacking expression of estrogen receptor (ER), progesterone receptor (PR), and receptor tyrosine-protein kinase erbB-2 (HER2), all of which are molecular targets of therapeutic agents, ensuring TNBC remains difficult to treat. Chemotherapy remains the mainstay for standard of care treatment of TNBC, with preferential use of platinum compounds in BRCA1/2 mutated breast cancer that are triple-negative. About 10–20% of all diagnosed breast cancers are triple-negative. TNBCs will often present with higher grade tumors that clinically correlate with a poorer outcome as compared to other breast cancer subtypes. In particular, patients with TNBC tend to present with clinically more advanced disease in the form of larger tumors and a higher burden of nodal involvement. This is reflective of their inherently aggressive nature [33]. Despite responses to treatment, these cancers can present with earlier relapses involving the visceral sites [34, 35, 36, 37, 38, 39]. Despite multi-agent systemic treatment, fewer that 30% of patients with metastatic breast cancer survive longer than 5 years and virtually no patient with metastatic TNBC will be alive after that [40, 41]. Despite a higher risk of recurrence for TNBC, better clinical and pathological initial response to chemotherapy has been seen in TNBC compared to other breast tumors, an interesting but paradoxical contrast [41, 42]. In a large majority of residual TNBCs that persist after initial chemotherapy, there may be targetable pathway alterations that could serve as therapeutic targets [41, 43]. Use of poly ADP ribose polymerase (PARP) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, mitogen-activated protein (MAP) kinase (MEK) inhibitors, heat-shock protein 90 (HSP90) inhibitors, histone deacetylase inhibitors, etc., are notable examples [41]. Some of these interventions have been approved by the US Food and Drug Administration (FDA) and others remain investigational. The standard of care for TNBC remains multiagent chemotherapy; however, use of PARP inhibitors (such as olaparib) and immune checkpoint inhibitors (such as pembrolizumab) have recently been incorporated as part of adjuvant or neoadjuvant potentially curative options approved in certain settings [39, 44, 45, 46, 47]. Unfortunately, TNBC patients display remarkable clinical diversity, making treatment decisions challenging, as seen with the recent voluntary withdrawal of the expedited approval of atezolizumab in combination with chemotherapy against metastatic TNBC, despite initial approval for use in this setting. In summary, TNBC remains a major unmet need in contemporary cancer medicine.
Immunotherapy has been of interest and a focus for the development of therapeutics for many years. Clinical trials have yielded mixed results. Vaccine trials have exploited the idea of increasing immune system engagement by increasing tumor recognition by the immune system but without consistent results. Active engagement of the immune system using immunotherapies continues to be both of clinical and investigational interest [41].
TNBCs are known to have genomic instability and have been shown to have higher degree of tumor-infiltrating lymphocytes [48] along with increased expression of programmed cell death ligand 1 (PD-L1) in comparison with other breast tumor types [49, 50]. Immune tolerance regulation has been linked to PD-L1 and its receptor programmed cell death protein 1 (PD-1). PD-1 is a receptor expressed on the surface of cells, like T-cells in the adaptive immune environment. These cells can then bind to either PD-L1 or PD-L2 which can be found on both tumor cells and tumor-infiltrating cells. This can in turn induce inhibition and depletion of T-cells which limits the tumor cell clearance and allows the tumor cells to evade innate and adaptive immune mechanisms [51, 52, 53]. Therefore, inhibition of immune checkpoints can reverse the immunosuppressive environment to promote an effective local immune response [54, 55].
TNBC has been shown to harbor mutations and tumor-infiltrating lymphocytes, along with a higher expression of PD-L1, making immunotherapy an attractive therapeutic approach [56, 57, 58]. In KEYNOTE-012, a phase 1b study, the PD-1 inhibitor pembrolizumab was evaluated as monotherapy for TNBC patients whose tumors expressed PD-L1. An overall response rate of 19% was seen in the study with one complete response. There were four partial responses seen, and 29% of patients had stable disease on treatment [59]. KEYNOTE-086 further explored the use of pembrolizumab in patients with metastatic TNBC. This study characterized patients by treatment history for their metastatic disease as well as PD-L1 expression on tumor cells [53, 60]. Progression-free survival (PFS) was similar with an overall response of 4.7% in both PD-L1 positive and negative previously treated patients of Cohort A in this study. Cohort B consisted of untreated patients with positive PD-L1 expression and showed a higher overall response rate of 23.1% [53]. KEYNOTE-119 evaluated advanced TNBC patients with 1:1 randomization to single-agent pembrolizumab vs. physician choice of chemotherapy and failed to meet its primary endpoint [61]. KEYNOTE-522, a prospective randomized trial evaluating neoadjuvant and adjuvant pembrolizumab for patients with TNBC assigned to pembrolizumab plus chemotherapy and placebo plus chemotherapy in a 2:1 ratio, showed a pathological complete response of 64.8% vs. 51.2% between the two groups. Patients with early TNBC who had received pembrolizumab with neoadjuvant chemotherapy had a significantly higher complete pathological response compared to the group that received placebo with neoadjuvant chemotherapy [62, 63]. Atezolizumab, a monoclonal antibody targeting PD-L1, was the first immune checkpoint inhibitor to be approved in combination with Nab-paclitaxel for unresectable locally advanced and metastatic TNBC expressing PD-L1 [64]. Approval was withdrawn when results of IMpassion131 showed failure to meet the primary endpoint of PFS superiority compared to the frontline treatment. Additionally, there was no survival advantage seen in the PD-L1 positive population nor in the intention to treat population. In fact, the study investigators observed a negative trend for overall survival [65], highlighting the urgent need for new treatment options.
As immunotherapies targeting co-stimulatory blockade move to the forefront of cancer therapeutics, it becomes increasingly important to understand the contribution of inflammatory cells to tumor progression and their potential use for targeted therapy. As discussed earlier, TAMs are critical components of the TME in many solid tumors, including breast cancers, and play key roles in facilitating tumor progression and metastases [30]. This pro-tumor effect of TAM appears to be mediated by increased proliferation of tumor cells, angiogenesis, matrix remodeling, and the sustained release of growth factors and cytokines within the TME. Although both phenotypic and functional heterogeneity are well documented for the macrophage lineage, and the activation state can be clearly defined as a spectrum (see Section 1.2.), here we will utilize two distinct states of polarized activation to demonstrate macrophage targeting in translational experiments. Specifically, the classically activated (M1) macrophage acts in response to IFNγ and/or LPS, and the release of IL-12, IL-23, and tumor necrosis factor (TNF), resulting in efficient antigen presentation and antitumor activity. The alternatively activated (M2) macrophage was originally discovered to respond to IL-4 [66] and can be characterized by low IL-12 and high IL-10 expression, dampened inflammation, increased parasite clearance, tissue remodeling, and promotion of tumor progression [30].
Macrophage dysregulation is central to the pathogenesis of human TNBC. Given that TAMs are influenced by their TME, it becomes important to explore how disease-specific changes in TNBC, specifically the large TAM population within the TME, can be selectively exploited for clinical applications. Thus, a main goal of this book chapter is to provide a few recent selected examples of basic and applied research programs that study TAM biology in the setting of TNBC, toward bringing discoveries and new mechanistic insights into translational applications.
Here, we have highlighted four specific examples of reversal of immune subversion in TNBC and targeted cellular imaging in vivo of TAMs in preclinical models of disease, namely:
Attenuating TNBC with a lysosome-targeted DNA nanodevice [67] (Figure 1A).
Ligand-directed targeting a vitamin D receptor in the cell surface of TAMs in a TNBC model for tumor ablation and immune subversion reversal [39] (Figure 1B).
Magnetic resonance imaging (MRI) of superparamagnetic iron oxide nanoparticle (SPION)-loaded TAMs in vivo in an isogenic mouse model of TNBC (Figure 1C) [68].
Controlling TNBC dormancy through differentially activated TAM-derived exosomes and their cargo (Figure 1D) [69].
Selected examples of targeting TAMs in TNBC for therapeutic or imaging applications in pre-clinical models of disease. (A) Administration of E64, an inhibitor or cysteine proteases, conjugated to DNA, leads to selective autophagocytosis and lysosomal uptake, where cysteine protease activity is blocked selectively, enabling TAMs to display tumor antigens and activate CD8+ T cells for anti-tumor activity [
Cui et al. recently reported a novel approach to exploit the known lysosomal trapping phenomenon of DNA-based agents [67]. Nucleic acid therapies seem to be preferentially trafficked to the lysosome via the endo-lysosomal pathway [70, 71]. Rather than reinvent the wheel—re-engineer the nucleic acid—for alternative organelle targeting, the authors identified lysosomal functions that could be co-opted for an antitumor effect, specifically that an increase in cysteine protease activity in lysosomes diminishes antigen presentation on M2 macrophages, avoiding T-cell activation and tumor immunity [67].
Cui and team [67] completed a proteomic analysis of M1 and M2 macrophages to identify distinct markers of tumorigenesis associated with M2 polarization. In addition to validating known mitochondrial and adhesion proteins, the M2 macrophage-specific profile included a panel of elevated lysosomal proteins, findings confirmed in TAM samples from TNBC patients. Specific deletion of transcription factor EB (TFEB), a regulator of the concerted network of lysosomal enzymes responsible for degrading proteins [72] and transcriptional regulation of autophagosome-lysosome fusion and function [73], resulted in delayed tumor growth and decreased lysosomal activity, likely caused by increased antigen presentation by TAMs and the recruitment of CD8+ T-cells [67].
The cysteine proteinase inhibitor E64 [74] was then selected to develop a therapeutic agent with the same effect as TFEB depletion [67]. Increased lysosomal cysteine protease activity is known to improve antigen cross-presentation [75], so E64, a specific inhibitor of cysteine proteases [76], was conjugated to a 38 base pair DNA sequence that could be picked up by scavenger receptors on TAMs for autophagolysosome processing [67]. The benefits of this approach would be twofold: 1) direct antitumor activity from immunomodulation [77] and 2) to sensitize cells to cancer drugs [78].
Trafficking of the E64-DNA compound to lysosomes was confirmed with a fluorescent reporter [67]. E64-DNA inhibited cysteine protease activity specifically, which increased antigen presentation and CD8+ T-cell recruitment [77]. When tested in the E0771 TNBC tumor model, E64-DNA was able to selectively target TAMs, internalize via scavenger receptors, and localize to lysosomes. Further analyses revealed M2 macrophages were preferentially targeted. After E64-DNA administration, tumor growth was hampered, and the number of CD8+ T effector cells increased, as did markers of both T-cell proliferation and activation. Further investigation confirmed that E64-DNA acts on the M2 macrophage population to reduce cysteine protease activity, which facilitates antigen presentation on the TAM cells, leading to activation of CD8+ T-cells and slowed tumor growth [67].
Finally, in addition to this nascent antitumor immunomodulatory activity, E64-DNA enhanced chemosensitivity, and combination therapy with E64-DNA and cyclophosphamide led to longer-term efficacy and tumor regression. The increase in tumor cell death provides a ready supply of antigens TAM presentation leading to antitumor immunity [67]. This report exemplifies the potential of exploiting what some might originally write off as a negative (lysosomal trapping of nucleic acids) to counterintuitively engineer an organelle-specific DNA conjugate for affecting lysosomal functions toward immunotherapeutic applications.
The use of oncolytic viruses to selectively target cancer cells is fairly widespread. Multiple viruses have been selected or engineered for specific purposes, often tumor cell destruction with minimal impact to nonmalignant tissues. Some of the most common—and clinically advanced—are adenoviruses [79, 80] and adeno-associated viruses [81]. AAVP is a unique hybrid AAV and bacteriophage (phage) vector first described in 2006 [82]. AAVP contains cis-elements from AAV within the single-stranded phage genome that facilitates tumor-targeted delivery of a transgene cassette for noninvasive tumor imaging and/or therapy [82]. Unlike mammalian viruses that are conventionally used for gene therapy, AAVP has been extensively characterized and has several safety features built into the vector design, such as: (i) targeting peptides to ensure receptor-mediated transduction and tumor-specific gene expression, (ii) well-characterized fate of the genome (concatemerization and integration of intact genomes) [82], and (iii) the ability to avoid neutralization, as proven in repeat dose studies using pet dogs with spontaneous tumors [83] and several mouse models, including transgenic tumor models with intact immune systems [82, 84]. Receptor-mediated AAVP internalization is required for transduction, eliminating off-target effects, even during phage particle clearance through the reticuloendothelial system (RES), sparing healthy tissues while a strong promoter drives the transgene expression of the within tumors. In the following section, we report one translational approach utilizing AAVP to selectively target the TAM population for theranostic gene delivery.
A recently reported study describing the identification and validation of the CSSTRESAC (single letter amino acid code) peptide and its receptor, a novel TAM biomarker, is summarized here. Staquicini et al. devised a combinatorial peptide library-based screening that allowed the identification of peptides selectively targeting the TAM-rich TME of mammary tumors [39]. Assuming that peptides binding to mammary tumors in vivo, but not to the corresponding breast cancer cells (BCCs) in vitro, would selectively target the TME, an in vivo combinatorial selection was performed by injecting a naive CX7C (C, cysteine; X, any residue) phage peptide library into EF43.
Peptide affinity chromatography and mass spectrometry identified protein disulfide-isomerase A3 (PDIA3) and vitamin D-binding protein (DBP) as targets of CSSTRESAC on the surface of TAMs. Because the CSSTRESAC phage bound specifically to the CD11b+ F4/80+ TAM population, and because PDIA3 was validated as its receptor, PDIA3 expression on the surface of TAMs was investigated. TAMs were isolated from EF43.
Homing of CSSTRESAC phage to the tumors in two aggressive breast cancer models [86, 87] was robust and specific, and, when displayed on AAVP to deliver the Herpes simplex virus
Importantly, upon binding, the CSSTRESAC peptide—alone or displayed on phage—induced the expression of pro-inflammatory cytokines IL-6, TNF, and IL-1β in CD11b+ F4/80+ TAMs, reverting from an M2-rich macrophage population toward an inflammatory TME reminiscent of classical M1 macrophages and further inhibiting tumor growth (Figure 2A) [39]. Collectively, these data confirm the binding specificity of the CSSTRESAC peptide to the TME, specifically the M2 macrophage population expressing PDIA3 on the cell surface, and the potential for an immunoregulatory response that shifts the cytokine profile toward an inflammatory M1 population and further induces antitumor activity.
Immunomodulation roles of CSSTRESAC and ferumoxytol remain untapped. (A) The CSSTRESAC peptide alone or displayed on phage/AAVP functions in an immunoregulatory role in TAMs in an EF43.
Extrapolating from publicly available datasets, high
Breast cancer patients undergo a series of imaging studies in order to diagnose disease, monitor disease progression, and evaluate responses to therapy. The presence of TAMs in the microenvironment of TNBC, in particular, promotes tumor growth and metastasis formation. Accordingly, a method of imaging this cell population specifically would be of clinical interest, particularly relating to response to immunotherapies utilized in these patients. Sillerud et al. recently reported one such approach, wherein an iron (Fe) nanoparticle is selectively phagocytosed by TAMs in mouse models of breast cancer for visualization by MRI [68]. A decrease in signal is detectable with T2-weighted MRI, and the spatial and temporal dynamics of particle uptake can be quantified and monitored [68].
Ferumoxytol is a superparamagnetic iron oxide nanoparticle (SPION) that has been approved by the FDA for patients with iron-deficient anemia. Its off-label use as a contrast agent for MRI has been studied for almost two decades in parallel with its role as an iron replacement therapy [91, 92, 94, 95, 96]. Importantly, a multicenter study found ferumoxytol was generally well tolerated and safe for administration [93].
More importantly, both M1 and M2 macrophages—but not tumor cells—can internalize ferumoxytol [97]. When combined with work done to validate ferumoxytol uptake and detection in lymphomas and sarcomas, known to have CD68+ and CD163+ TAM populations, ferumoxytol can function as an “imaging biomarker for TAM” [98]. When in a macrophage-rich TME, ferumoxytol might also induce some cytotoxicity and M1 macrophage polarization, making the tumor more susceptible to immunotherapeutic agents [99, 100, 101] (Figure 2B). Yet another application of clinical importance would be to use MRI to image ferumoxytol-containing TAMs as a surrogate for tumor localization. Specifically, on T2-weighted MRI, ferumoxytol produces a decrease in signal, darkening dramatically from a hyperintense image at baseline [68].
The EF43.
Breast cancer cells (BCCs) preferentially disseminate to the bone marrow (BM) [105]. The BM niche contributes to the survival of BCCs by allowing their transition into dormancy [106]. Dormant BCCs can remain undetected for extended periods by acquiring a cancer stem cell (CSC) phenotype [107]. Cancer stem cells (CSCs) share properties with nonmalignant stem cells such as self-renewal, cell cycle quiescence, and drug resistance [108]. Reactivation of dormant BCCs/CSCs in BM is associated with poor patient prognosis and results in cancer resurgence [109, 110]. Targeting dormant BCCs/CSCs is challenging because current treatments mostly target the active cycling cells [111]. Additionally, dormant BCCs home to the endosteal niche of the BM close to endogenous hematopoietic stem cells (HSCs) and utilize strategies similar to those of the endogenous HSCs to survive and remain dormant [105, 112]. More importantly, the method of survival includes the marrow microenvironment with macrophages comprising a major component of the supporting cells. Thus, any treatment aimed to eliminate the BCCs can also target the survival and/or function of the HSCs found within the same niche. This could result in disruption of hematopoietic activity, which will affect the individual’s immune system and other organ functions that require immune competence. Hence, it is imperative to elucidate the precise mechanisms of communication between cells in the BM microenvironment and BCCs to understand how dormancy is achieved and how the same microenvironment can reverse the dormant phase. Such understanding will lead to effective methods to selectively eliminate malignant stem cells without harm to the endogenous HSCs.
The BM is a complex organ composed of various niches that aid in hematopoietic activity and maintain dormancy [112, 113, 114]. The cellular component of the BM niche includes mesenchymal stem cells, fibroblasts, and macrophages, all contributing to the survival of BCC dormancy [69, 115, 116]. Intercellular communication between BM niche cells and BCCs is fundamental for BC dormancy [105]. The interaction between components of the BM niche and BCCs can be direct through intercellular communication such as gap junctions and/or contact-independent, which involves soluble and insoluble factors such as cytokines and microvesicles (i.e. exosomes). Both forms of the aforementioned interactions facilitate and maintain BC dormancy [116, 117]. Disrupting these interactions can reverse the dormant phenotype of BCCs resulting in cancer recurrence [115, 118, 119]. The next section addresses the role of macrophages in BC dormancy and provides evidence supporting that intercellular communication between the niche and BCCs is essential for dormancy.
BCCs recruit macrophages to the TME by upregulating chemokines such as C-C motif chemokine ligand 2 (CCL2) [120]. Recruited macrophages have been shown to modulate BC dormancy or reversal. For instance, Ma et al. demonstrated that a macrophage subset expressing high levels of CD204 and IL-4 receptor facilitated BC metastasis to the bone [121]. Depletion of this macrophage subset halted BCC proliferation [121]. Depletion of CD11b+ VEGFRhigh CCR2high macrophages prevented extravasation and growth of BCCs within the lungs [122]. This macrophage subset is significantly present in lungs with BC metastasis compared to healthy lungs [122]. Although these findings are related to BC metastasis to the lung, it is plausible that a similar mechanism is occurring upon BC metastasis to the BM or bone.
Endogenous BM-derived macrophages have a crucial role in BC dormancy and can be polarized into M1 or M2 phenotype depending on microenvironmental cues [69]. Classically activated macrophages (M1) exert antitumor response in BC, whereas alternatively activated (M2) macrophages employ a pro-tumorigenic effect [123]. However, with respect to dormancy, M2 macrophages maintain cycling quiescence whereas M1 macrophages can reverse dormancy [69]. Such polarization has been demonstrated when the toll-like receptor was activated, suggesting that infectious agents that activate these receptors could be a method to reverse dormancy.
M1 macrophages facilitate reversed dormancy by releasing microvesicles that promote NF-κB signaling in quiescent BCCs to mediate cell cycle activation (Figure 3) [69]. As a result, M1-derived microvesicles sensitized BCCs to chemotherapy by reducing BCC stemness. Conversely, M2 macrophages form gap junctions with CSCs to support dormancy and chemoresistance of BC in BM [69]. Mechanistically, the polarization of M2 macrophages into an M1 phenotype was shown to be mediated by LPS, which activated toll-like receptor 4 signaling. This study showed the role of contact-dependent and contact-independent interactions between BCCs and macrophages in BC dormancy.
Left panel shows the bone marrow cavity and the predominant region for dormant breast cancer cells within the endosteal niche. The established dormant phenotype is highlighted in boxed region, which is enlarged. The latter shows M2 macrophage sustaining gap junctional-mediated dormancy. Activation of M2 macrophages to M1 type release microvesicles to reverse dormancy.
In TNBC cells, macrophage polarization toward an M2 phenotype is facilitated by the oncogene multiple copies in T-cell malignancy-1 (MCT-1) [124]. Silencing of MCT-1 in TNBC reduced overall tumor volume and the total number of M2 macrophages within the TME [124]. Interestingly, MCT-1 enhances mammosphere formation in TNBC cells through IL-6 signaling. Blockade of IL-6 signaling with the IL-6 receptor (IL-6R) monoclonal antibody tocilizumab reduced mammosphere formation and downregulated MCT-1 expression [124]. Another strategy to target MCT-1 expression was shown by miRNA-34a reducing stemness in TNBC cells and prevented M2 polarization. Macrophage polarization in the TME can also be mediated by oncometabolites such as lactate which enhance BCC proliferation through the ERK/STAT3 signaling pathway [125]. Pharmacological inhibition of ERK/STAT3 with selumetinib and stattic, respectively, abrogated lactate levels within the TME and prevented macrophage polarization to M2 phenotype [125]. Collectively, these studies provided evidence of the importance of macrophage polarization in BC dormancy and reversal.
As stated earlier, the chemokine CCL2 is crucial in macrophage recruitment to the TME. Thus, efforts to prevent macrophage recruitment and polarization in the TME aimed to target the chemoattractant CCL2. However, although preclinical studies showed promising results and effectively abrogated macrophage recruitment to the TME, anti-CCL2 antibodies failed in clinical studies [126]. Therefore, studies need to be conducted to develop strategies to target macrophage recruitment or polarization into M2 phenotype to inhibit tumor progression.
Macrophages are key to the behavior of tumors and metastatic dissemination. TNBC, while missing specific targetable markers amenable to treatment, is rife with a potentially vulnerable population of macrophages, M2 polarized macrophages in particular. This population in primary tumor sites can be specifically and selectively targeted to (1) induce antitumor immunity and drug sensitivity, (2) produce a theranostic gene for imaging and treatment of the TAM population, and (3) image TAMs in TNBC for diagnosis or assessing response to therapy. Furthermore, M2 macrophages interact with non-hematopoietic cells in BM to maintain cellular quiescence/dormancy, which can be selectively repolarized to an M1 type population to reverse tumor cell quiescence/dormancy and enable systemic therapy.
This work was supported by grant awards from Metavivor Foundation and New Jersey Commission on Cancer Research.
FIS, RP, and WA are inventors on a pending patent application related to the CSSTRESAC peptide and associated technology. They are entitled to royalty payments from licensing or commercialization. RP and WA are founders and equity stockholders of PhageNova Bio, which has licensed this IP. RP is the Chief Scientific Officer and a paid consultant for PhageNova Bio. These conflicts are managed by Rutgers, The State University of New Jersey. The remaining authors declare no conflicts of interest.
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.
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MRI is commonly used once treating brain, prostate cancers, ankle and foot. The Magnetic Resonance Imaging (MRI) images are usually liable to suffer from noises such as Gaussian noise, salt and pepper noise and speckle noise. So getting of brain image with accuracy is very extremely task. An accurate brain image is very necessary for further diagnosis process. During this chapter, a median filter algorithm will be modified. Gaussian noise and Salt and pepper noise will be added to MRI image. A proposed Median filter (MF), Adaptive Median filter (AMF) and Adaptive Wiener filter (AWF) will be implemented. The filters will be used to remove the additive noises present in the MRI images. The noise density will be added gradually to MRI image to compare performance of the filters evaluation. 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Particularly in the case of motor imagery BCIs, users may need several training sessions before they learn how to generate desired brain activity and reach an acceptable performance. A typical training protocol for such BCIs includes execution of a motor imagery task by the user, followed by presentation of an extending bar or a moving object on a computer screen. In this chapter, we discuss the importance of a visual feedback that resembles human actions, the effect of human factors such as confidence and motivation, and the role of embodiment in the learning process of a motor imagery task. Our results from a series of experiments in which users BCI-operated a humanlike android robot confirm that realistic visual feedback can induce a sense of embodiment, which promotes a significant learning of the motor imagery task in a short amount of time. We review the impact of humanlike visual feedback in optimized modulation of brain activity by the BCI users.",book:{id:"6610",slug:"evolving-bci-therapy-engaging-brain-state-dynamics",title:"Evolving BCI Therapy",fullTitle:"Evolving BCI Therapy - Engaging Brain State Dynamics"},signatures:"Maryam Alimardani, Shuichi Nishio and Hiroshi Ishiguro",authors:[{id:"11981",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Ishiguro",slug:"hiroshi-ishiguro",fullName:"Hiroshi Ishiguro"},{id:"231131",title:"Dr.",name:"Maryam",middleName:null,surname:"Alimardani",slug:"maryam-alimardani",fullName:"Maryam Alimardani"},{id:"231134",title:"Dr.",name:"Shuichi",middleName:null,surname:"Nishio",slug:"shuichi-nishio",fullName:"Shuichi Nishio"}]}],mostDownloadedChaptersLast30Days:[{id:"29764",title:"Underlying Causes of Paresthesia",slug:"underlying-causes-of-paresthesia",totalDownloads:193437,totalCrossrefCites:3,totalDimensionsCites:7,abstract:null,book:{id:"1069",slug:"paresthesia",title:"Paresthesia",fullTitle:"Paresthesia"},signatures:"Mahdi Sharif-Alhoseini, Vafa Rahimi-Movaghar and Alexander R. Vaccaro",authors:[{id:"91165",title:"Prof.",name:"Vafa",middleName:null,surname:"Rahimi-Movaghar",slug:"vafa-rahimi-movaghar",fullName:"Vafa Rahimi-Movaghar"}]},{id:"63258",title:"Anatomy and Function of the Hypothalamus",slug:"anatomy-and-function-of-the-hypothalamus",totalDownloads:4646,totalCrossrefCites:6,totalDimensionsCites:12,abstract:"The hypothalamus is a small but important area of the brain formed by various nucleus and nervous fibers. Through its neuronal connections, it is involved in many complex functions of the organism such as vegetative system control, homeostasis of the organism, thermoregulation, and also in adjusting the emotional behavior. The hypothalamus is involved in different daily activities like eating or drinking, in the control of the body’s temperature and energy maintenance, and in the process of memorizing. It also modulates the endocrine system through its connections with the pituitary gland. Precise anatomical description along with a correct characterization of the component structures is essential for understanding its functions.",book:{id:"6331",slug:"hypothalamus-in-health-and-diseases",title:"Hypothalamus in Health and Diseases",fullTitle:"Hypothalamus in Health and Diseases"},signatures:"Miana Gabriela Pop, Carmen Crivii and Iulian Opincariu",authors:null},{id:"57103",title:"GABA and Glutamate: Their Transmitter Role in the CNS and Pancreatic Islets",slug:"gaba-and-glutamate-their-transmitter-role-in-the-cns-and-pancreatic-islets",totalDownloads:3576,totalCrossrefCites:4,totalDimensionsCites:10,abstract:"Glutamate and gamma-aminobutyric acid (GABA) are the major neurotransmitters in the mammalian brain. Inhibitory GABA and excitatory glutamate work together to control many processes, including the brain’s overall level of excitation. The contributions of GABA and glutamate in extra-neuronal signaling are by far less widely recognized. In this chapter, we first discuss the role of both neurotransmitters during development, emphasizing the importance of the shift from excitatory to inhibitory GABAergic neurotransmission. The second part summarizes the biosynthesis and role of GABA and glutamate in neurotransmission in the mature brain, and major neurological disorders associated with glutamate and GABA receptors and GABA release mechanisms. The final part focuses on extra-neuronal glutamatergic and GABAergic signaling in pancreatic islets of Langerhans, and possible associations with type 1 diabetes mellitus.",book:{id:"6237",slug:"gaba-and-glutamate-new-developments-in-neurotransmission-research",title:"GABA And Glutamate",fullTitle:"GABA And Glutamate - New Developments In Neurotransmission Research"},signatures:"Christiane S. Hampe, Hiroshi Mitoma and Mario Manto",authors:[{id:"210220",title:"Prof.",name:"Christiane",middleName:null,surname:"Hampe",slug:"christiane-hampe",fullName:"Christiane Hampe"},{id:"210485",title:"Prof.",name:"Mario",middleName:null,surname:"Manto",slug:"mario-manto",fullName:"Mario Manto"},{id:"210486",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Mitoma",slug:"hiroshi-mitoma",fullName:"Hiroshi Mitoma"}]},{id:"35802",title:"Cross-Cultural/Linguistic Differences in the Prevalence of Developmental Dyslexia and the Hypothesis of Granularity and Transparency",slug:"cross-cultural-linguistic-differences-in-the-prevalence-of-developmental-dyslexia-and-the-hypothesis",totalDownloads:3625,totalCrossrefCites:2,totalDimensionsCites:7,abstract:null,book:{id:"673",slug:"dyslexia-a-comprehensive-and-international-approach",title:"Dyslexia",fullTitle:"Dyslexia - A Comprehensive and International Approach"},signatures:"Taeko N. Wydell",authors:[{id:"87489",title:"Prof.",name:"Taeko",middleName:"N.",surname:"Wydell",slug:"taeko-wydell",fullName:"Taeko Wydell"}]},{id:"58597",title:"Testosterone and Erectile Function: A Review of Evidence from Basic Research",slug:"testosterone-and-erectile-function-a-review-of-evidence-from-basic-research",totalDownloads:1373,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Androgens are essential for male physical activity and normal erectile function. Hence, age-related testosterone deficiency, known as late-onset hypogonadism (LOH), is considered a risk factor for erectile dysfunction (ED). This chapter summarizes relevant basic research reports examining the effects of testosterone on erectile function. Testosterone affects several organs and is especially active on the erectile tissue. The mechanism of testosterone deficiency effects on erectile function and the results of testosterone replacement therapy (TRT) have been well studied. Testosterone affects nitric oxide (NO) production and phosphodiesterase type 5 (PDE-5) expression in the corpus cavernosum through molecular pathways, preserves smooth muscle contractility by regulating both contraction and relaxation, and maintains the structure of the corpus cavernosum. Interestingly, testosterone deficiency has relationship to neurological diseases, which leads to ED. Testosterone replacement therapy is widely used to treat patients with testosterone deficiency; however, this treatment might also induce some problems. Basic research suggests that PDE-5 inhibitors, L-citrulline, and/or resveratrol therapy might be effective therapeutic options for testosterone deficiency-induced ED. Future research should confirm these findings through more specific experiments using molecular tools and may shed more light on endocrine-related ED and its possible treatments.",book:{id:"5994",slug:"sex-hormones-in-neurodegenerative-processes-and-diseases",title:"Sex Hormones in Neurodegenerative Processes and Diseases",fullTitle:"Sex Hormones in Neurodegenerative Processes and Diseases"},signatures:"Tomoya Kataoka and Kazunori Kimura",authors:[{id:"219042",title:"Ph.D.",name:"Tomoya",middleName:null,surname:"Kataoka",slug:"tomoya-kataoka",fullName:"Tomoya Kataoka"},{id:"229066",title:"Prof.",name:"Kazunori",middleName:null,surname:"Kimura",slug:"kazunori-kimura",fullName:"Kazunori Kimura"}]}],onlineFirstChaptersFilter:{topicId:"18",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82953",title:"Early Visual Areas are Activated during Object Recognition in Emerging Images",slug:"early-visual-areas-are-activated-during-object-recognition-in-emerging-images",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105756",abstract:"Human observers can reliably segment visual input and recognise objects. However, the underlying processes happen so quickly that they normally cannot be captured with fMRI. We used Emerging Images (EI), which contains a hidden object and extends the process of recognition, to investigate the involvement of early visual areas (V1, V2 and V3) and lateral occipital complex (LOC) in object recognition. The early visual areas were located with a retinotopy scan and the LOC with a localiser. The participants (N=8) then viewed an EI, followed by the hidden object’s silhouette (disambiguation), and then, the EI was repeated. BOLD responses before and after disambiguation were compared. The retinotopy parameters were used to back-project the BOLD response onto the visual field, creating spatially detailed maps of the activity change. V1 and V2 (but not V3) showed stronger response after disambiguation, while there was no difference in the LOC. The back-projections revealed no distinct pattern or changes in activity on object location, indicating that the activity in V1 and V2 is not specific for voxels corresponding to the object location. We found no difference before and after disambiguation in the LOC, which may be repetition suppression counteracting the effect of recognition.",book:{id:"11374",title:"Sensory Nervous System - Computational Neuroimaging Investigations of Topographical Organization in Human Sensory Cortex",coverURL:"https://cdn.intechopen.com/books/images_new/11374.jpg"},signatures:"Marleen Bakker, Hinke N. Halbertsma, Nicolás Gravel, Remco Renken, Frans W. Cornelissen and Barbara Nordhjem"},{id:"82931",title:"Neuroinflammation in Traumatic Brain Injury",slug:"neuroinflammation-in-traumatic-brain-injury",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105178",abstract:"Neuroinflammation following traumatic brain injury (TBI) is an important cause of secondary brain injury that perpetuates the duration and scope of disease after initial impact. This chapter discusses the pathophysiology of acute and chronic neuroinflammation, providing insight into factors that influence the acute clinical course and later functional outcomes. Secondary injury due to neuroinflammation is described by mechanisms of action such as ischemia, neuroexcitotoxicity, oxidative stress, and glymphatic and lymphatic dysfunction. Neurodegenerative sequelae of inflammation, including chronic traumatic encephalopathy, which are important to understand for clinical practice, are detailed by disease type. Prominent research topics of TBI animal models and biomarkers of traumatic neuroinflammation are outlined to provide insight into the advances in TBI research. We then discuss current clinical treatments in TBI and their implications in preventing inflammation. To complete the chapter, recent research models, novel biomarkers, and future research directions aimed at mitigating TBI will be described and will highlight novel therapeutic targets. Understanding the pathophysiology and contributors of neuroinflammation after TBI will aid in future development of prophylaxis strategies, as well as more tailored management and treatment algorithms. This topic chapter is important to both clinicians and basic and translational scientists, with the goal of improving patient outcomes in this common disease.",book:{id:"11367",title:"Traumatic Brain Injury",coverURL:"https://cdn.intechopen.com/books/images_new/11367.jpg"},signatures:"Grace Y. Kuo, Fawaz Philip Tarzi, Stan Louie and Roy A. Poblete"},{id:"82876",title:"Oxygen Tissue Levels as an Effectively Modifiable Factor in Alzheimer’s Disease Improvement",slug:"oxygen-tissue-levels-as-an-effectively-modifiable-factor-in-alzheimer-s-disease-improvement",totalDownloads:10,totalDimensionsCites:0,doi:"10.5772/intechopen.106331",abstract:"Despite the advance in biochemistry, there are two substantial errors that have remained for at least two centuries. One is that oxygen from the atmosphere passes through the lungs and reaches the bloodstream, which distributes it throughout the body. Another major mistake is the belief that such oxygen is used by the cell to obtain energy, by combining it with glucose. Since the late nineteenth century, it began to be published that the gas exchange in the lungs cannot be explained by diffusion. Even Christian Bohr suggested that it looked like a cellular secretion. But despite experimental evidence to the contrary and based only on theoretical models, the dogma that our body takes the oxygen it contains inside from the air around it has been perpetuated to this day. The oxygen levels contained in the human body are high, close to 99%, and the atmosphere only contains between 19 and 21%. The hypothesis that there is a supposed oxygen concentrating mechanism has not been experimentally proven to date, after almost two centuries. The mistaken belief, even among neurologists, that our body takes oxygen from the atmosphere is widespread, even though there is no experimental basis to support it, just theoretical models. Our finding that the human body can take oxygen from the water it contains, not from the air around it, like plants, comes to mark a before and after in biology in general, and the CNS is no exception. Therefore, establishing the true origin of the oxygen present within our body and brain will allow us to better understand the physio pathogenesis of neurodegenerative diseases.",book:{id:"11637",title:"Neuropsychology of Dementia",coverURL:"https://cdn.intechopen.com/books/images_new/11637.jpg"},signatures:"Arturo Solís Herrera"},{id:"82859",title:"Impact of Hypoxia on Astrocyte Induced Pathogenesis",slug:"impact-of-hypoxia-on-astrocyte-induced-pathogenesis",totalDownloads:6,totalDimensionsCites:0,doi:"10.5772/intechopen.106263",abstract:"Astrocytes are the most abundant cells of the central nervous system. These cells are of diverse types based on their function and structure. Astrocyte activation is linked mainly with microbial infections, but long-term activation can lead to neurological impairment. Astrocytes play a significant role in neuro-inflammation by activating pro-inflammatory pathways. Activation of interleukins and cytokines causes neuroinflammation resulting in many neurodegenerative disorders such as stroke, growth of tumours, and Alzheimer’s. Inflammation of the brain hinders neural circulation and compromises blood flow by affecting the blood–brain barrier. So the oxygen concentration is lowered, causing brain hypoxia. Hypoxia leads to the activation of nuclear factor kappa B (NFkB) and hypoxia-inducible factors (HIF), which aggravates the inflammatory state of the brain. Hypoxia evoked changes in the blood–brain barrier, further complicating astrocyte-induced pathogenesis.",book:{id:"10744",title:"Astrocytes in Brain Communication and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10744.jpg"},signatures:"Farwa Munir, Nida Islam, Muhammad Hassan Nasir, Zainab Anis, Shahar Bano, Shahzaib Naeem, Atif Amin Baig and Zaineb Sohail"},{id:"82839",title:"Neurophysiology of Emotions",slug:"neurophysiology-of-emotions",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.106043",abstract:"Emotions are automatic and primary patterns of purposeful cognitive-behavioral organizations. They have three main functions: coordination, signaling, and information. First, emotions coordinate organs and tissues, thus predisposing the body to peculiar responses. Scholars have not reached a consensus on the plausibility of emotion-specific response patterns yet. Despite the limitations, data support the hypothesis of specific response patterns for distinct subtypes of emotions. Second, emotional episodes signal the current state of the individual. Humans display their state with verbal behaviors, nonverbal actions (e.g., facial movements), and neurovegetative signals. Third, emotions inform the brain for interpretative and evaluative purposes. Emotional experiences include mental representations of arousal, relations, and situations. Every emotional episode begins with exposure to stimuli with distinctive features (i.e., elicitor). These inputs can arise from learning, expressions, empathy, and be inherited, or rely on limited aspects of the environment (i.e., sign stimuli). The existence of the latter ones in humans is unclear; however, emotions influence several processes, such as perception, attention, learning, memory, decision-making, attitudes, and mental schemes. Overall, the literature suggests the nonlinearity of the emotional process. Each section outlines the neurophysiological basis of elements of emotion.",book:{id:"11742",title:"Neurophysiology",coverURL:"https://cdn.intechopen.com/books/images_new/11742.jpg"},signatures:"Maurizio Oggiano"},{id:"82172",title:"Neuroimaging in Common Neurological Diseases Treated by Anticoagulants",slug:"neuroimaging-in-common-neurological-diseases-treated-by-anticoagulants",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.105128",abstract:"Stroke imaging/Cerebral Venous sinus thrombosis/Arterial dissecting disease in Head and Neck regions/Neurocomplication of anticoagulation therapy. Nowsday, anticoagulant drugs are common drugs used in daily practice for patients in neurology clinic. Anticoagulant treatment used for treated symptomatic patients as well as for prophylaxis therapy in asymptomatic patients. The purpose of this chapter based on the review of essential neuroimaging in the most common neurological conditions that benefit from treatment with anticoagulant drugs such as ischemic stroke, cerebral venous sinus thrombosis, and arterial dissecting disease of head and neck arteries and will be enclosed with neuroimaging in case of neurocomplication by anticoagulant therapy.",book:{id:"11742",title:"Neurophysiology",coverURL:"https://cdn.intechopen.com/books/images_new/11742.jpg"},signatures:"Pipat Chiewvit"}],onlineFirstChaptersTotal:12},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:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:333,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:126,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,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:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:13,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",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:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"August 17th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!0,editor:{id:"205604",title:"Dr.",name:"Tomas",middleName:null,surname:"Jarzembowski",slug:"tomas-jarzembowski",fullName:"Tomas Jarzembowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKriQAG/Profile_Picture_2022-06-16T11:01:31.jpg",biography:"Tomasz Jarzembowski was born in 1968 in Gdansk, Poland. He obtained his Ph.D. degree in 2000 from the Medical University of Gdańsk (UG). After specialization in clinical microbiology in 2003, he started studying biofilm formation and antibiotic resistance at the single-cell level. In 2015, he obtained his D.Sc. degree. His later study in cooperation with experts in nephrology and immunology resulted in the designation of the new diagnostic method of UTI, patented in 2017. He is currently working at the Department of Microbiology, Medical University of Gdańsk (GUMed), Poland. Since many years, he is a member of steering committee of Gdańsk branch of Polish Society of Microbiologists, a member of ESCMID. He is also a reviewer and a member of editorial boards of a number of international journals.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorTwo:{id:"484980",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Garbacz",slug:"katarzyna-garbacz",fullName:"Katarzyna Garbacz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003St8TAQAZ/Profile_Picture_2022-07-07T09:45:16.jpg",biography:"Katarzyna Maria Garbacz, MD, is an Associate Professor at the Medical University of Gdańsk, Poland and she is head of the Department of Oral Microbiology of the Medical University of Gdańsk. She has published more than 50 scientific publications in peer-reviewed journals. She has been a project leader funded by the National Science Centre of Poland. Prof. Garbacz is a microbiologist working on applied and fundamental questions in microbial epidemiology and pathogenesis. Her research interest is in antibiotic resistance, host-pathogen interaction, and therapeutics development for staphylococcal pathogens, mainly Staphylococcus aureus, which causes hospital-acquired infections. Currently, her research is mostly focused on the study of oral pathogens, particularly Staphylococcus spp.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. 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Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:755,paginationItems:[{id:"310674",title:"Dr.",name:"Pravin",middleName:null,surname:"Kendrekar",slug:"pravin-kendrekar",fullName:"Pravin Kendrekar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/310674/images/system/310674.jpg",biography:"Dr. Pravin Kendrekar, MSc, MBA, Ph.D., is currently a visiting scientist at the Lipid Nanostructure Laboratory, University of Central Lancashire, England. He previously worked as a post-doctoral fellow at the Ben-Gurion University of Negev, Israel; University of the Free State, South Africa; and Central University of Technology Bloemfontein, South Africa. He obtained his Ph.D. in Organic Chemistry from Nagaoka University of Technology, Japan. He has published more than seventy-four journal articles and attended several national and international conferences as speaker and chair. Dr. Kendrekar has received many international awards. He has several funded projects, namely, anti-malaria drug development, MRSA, and SARS-CoV-2 activity of curcumin and its formulations. He has filed four patents in collaboration with the University of Central Lancashire and Mayo Clinic Infectious Diseases. His present research includes organic synthesis, drug discovery and development, biochemistry, nanoscience, and nanotechnology.",institutionString:"Visiting Scientist at Lipid Nanostructures Laboratory, Centre for Smart Materials, School of Natural Sciences, University of Central Lancashire",institution:null},{id:"428125",title:"Dr.",name:"Vinayak",middleName:null,surname:"Adimule",slug:"vinayak-adimule",fullName:"Vinayak Adimule",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428125/images/system/428125.jpg",biography:"Dr. Vinayak Adimule, MSc, Ph.D., is a professor and dean of R&D, Angadi Institute of Technology and Management, India. He has 15 years of research experience as a senior research scientist and associate research scientist in R&D organizations. He has published more than fifty research articles as well as several book chapters. He has two Indian patents and two international patents to his credit. Dr. Adimule has attended, chaired, and presented papers at national and international conferences. He is a guest editor for Topics in Catalysis and other journals. He is also an editorial board member, life member, and associate member for many international societies and research institutions. His research interests include nanoelectronics, material chemistry, artificial intelligence, sensors and actuators, bio-nanomaterials, and medicinal chemistry.",institutionString:"Angadi Institute of Technology and Management",institution:null},{id:"284317",title:"Prof.",name:"Kantharaju",middleName:null,surname:"Kamanna",slug:"kantharaju-kamanna",fullName:"Kantharaju Kamanna",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284317/images/21050_n.jpg",biography:"Prof. K. Kantharaju has received Bachelor of science (PCM), master of science (Organic Chemistry) and Doctor of Philosophy in Chemistry from Bangalore University. He worked as a Executive Research & Development @ Cadila Pharmaceuticals Ltd, Ahmedabad. He received DBT-postdoc fellow @ Molecular Biophysics Unit, Indian Institute of Science, Bangalore under the supervision of Prof. P. Balaram, later he moved to NIH-postdoc researcher at Drexel University College of Medicine, Philadelphia, USA, after his return from postdoc joined NITK-Surthakal as a Adhoc faculty at department of chemistry. Since from August 2013 working as a Associate Professor, and in 2016 promoted to Profeesor in the School of Basic Sciences: Department of Chemistry and having 20 years of teaching and research experiences.",institutionString:null,institution:{name:"Rani Channamma University, Belagavi",country:{name:"India"}}},{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"436430",title:"Associate Prof.",name:"Mesut",middleName:null,surname:"Işık",slug:"mesut-isik",fullName:"Mesut Işık",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/436430/images/19686_n.jpg",biography:null,institutionString:null,institution:{name:"Bilecik University",country:{name:"Turkey"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a scientist and Principal Investigator at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering the lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via artificial intelligence-based analyses of exosomal Raman signatures. Dr. Paul also works on spatial multiplex immunofluorescence-based tissue mapping to understand the immune repertoire in lung cancer. Dr. Paul has published in more than sixty-five peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award and the 2022 AAISCR-R Vijayalaxmi Award for Innovative Cancer Research. He is a senior member of the Institute of Electrical and Electronics Engineers (IEEE) and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. 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