Biochemical properties of eukaryotic and retroviral DNA polymerases.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"8331",leadTitle:null,fullTitle:"Pharmaceutical Formulation Design - Recent Practices",title:"Pharmaceutical Formulation Design",subtitle:"Recent Practices",reviewType:"peer-reviewed",abstract:"Pharmaceutical formulations have evolved from simple and traditional systems to more modern and complex novel dosage forms. Formulation development is a tedious process and requires an enormous amount of effort from many different people. Developing a stable novel dosage form and further targeting it to the desired site inside the body has always been a challenge. The purpose of this book is to bring together scholarly articles that highlight recent developments and trends in pharmaceutical formulation science. Each article has been written by authors specializing in the subject area and hailing from top institutions around the world. The book has been written in a systematic and lucid style explaining all basic concepts and fundamentals in a very simple way. This book aims to serve the need of all individuals involved at any level in the pharmaceutical dosage form development. I sincerely hope that the book will be liked by inquisitive students and learned colleagues.",isbn:"978-1-78985-839-6",printIsbn:"978-1-78985-662-0",pdfIsbn:"978-1-78985-840-2",doi:"10.5772/intechopen.78460",price:119,priceEur:129,priceUsd:155,slug:"pharmaceutical-formulation-design-recent-practices",numberOfPages:164,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"e7b436a5e31db5f48ba1b6220a11848f",bookSignature:"Usama Ahmad and Juber Akhtar",publishedDate:"February 5th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/8331.jpg",numberOfDownloads:18633,numberOfWosCitations:11,numberOfCrossrefCitations:21,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:51,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:83,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 9th 2018",dateEndSecondStepPublish:"September 6th 2018",dateEndThirdStepPublish:"November 5th 2018",dateEndFourthStepPublish:"January 24th 2019",dateEndFifthStepPublish:"March 25th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Integral University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"252107",title:"Dr.",name:"Juber",middleName:null,surname:"Akhtar",slug:"juber-akhtar",fullName:"Juber Akhtar",profilePictureURL:"https://mts.intechopen.com/storage/users/252107/images/system/252107.jpg",biography:"Dr. Juber Akhtar completed his B.Pharm in 2005 from Jamia Hamdard University, New Delhi. In 2007 he completed his M.Pharm with specialization in Pharmaceutics from Manipal University, Karnataka. He obtained his PhD degree from Integral University in 2014. He is currently employed as an Associate Professor at Integral University. He acted as Head of Department from 2014 till 2016. He also has experience of teaching abroad and has served as a Professor at Buraydah College of Dentistry and Pharmacy, KSA. Dr. Akhtar has more than 40 publications in reputed journals and is also editorial member of many esteemed journals. He has supervised a dozen of PhD and M.Pharm students in research projects. Dr. Akhtar is actively involved in research activities and his areas of interest include development of nano particulate drug delivery system for targeting to various organs.",institutionString:null,position:null,outsideEditionCount:null,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1188",title:"Pharmacokinetics",slug:"drug-discovery-pharmacokinetics"}],chapters:[{id:"67588",title:"Preformulation Studies: An Integral Part of Formulation Design",doi:"10.5772/intechopen.82868",slug:"preformulation-studies-an-integral-part-of-formulation-design",totalDownloads:4012,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"When a promising new chemical entity is synthesized, it needs transformation to appropriate formulation in order to show a better and desirable action at appropriate site. Preformulation study is a phase which is initiated once the new molecule is seeded. In a broader way, it deals with studies of physical, chemical, analytical, and pharmaceutical properties related to molecule and provides idea about suitable modification in molecule to show a better performance. Study of these parameters and suitable molecular modification can be linked to generation of effective, safer, stable, and reliable pharmaceutical formulation. Therefore, preformulation study is an approach for generation of pharmaceutical formulation which utilizes knowledge and area application of toxicology, biochemistry, medicinal chemistry, and analytical chemistry. The highlighted chapter is framed with a vision to provide an in-depth knowledge about pharmaceutical formulation development.",signatures:"Pinak Patel",downloadPdfUrl:"/chapter/pdf-download/67588",previewPdfUrl:"/chapter/pdf-preview/67588",authors:[null],corrections:null},{id:"68656",title:"Drug Analysis",doi:"10.5772/intechopen.88739",slug:"drug-analysis",totalDownloads:1710,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Instrumental methods are widely used for the analysis and stability studies of compounds in bulk and pharmaceutical forms. They vary in their sensitivity, techniques and reagents involved. This chapter will overview those different techniques and the application of the analytical methods. It will also describe how to design and develop simple, sensitive and accurate method for routine quality control of specified compound depending on its molecular structure. Quality control and assurance of the analytical process will be discussed. Furthermore, the chapter will describe a number of factors affecting the chemical and physical stability of Pharmaceutical formulations and how to develop stability-indicating methods to qualify and quantify the drug degradation.",signatures:"Shaza W. Shantier",downloadPdfUrl:"/chapter/pdf-download/68656",previewPdfUrl:"/chapter/pdf-preview/68656",authors:[null],corrections:null},{id:"68199",title:"Microcrystalline Cellulose as Pharmaceutical Excipient",doi:"10.5772/intechopen.88092",slug:"microcrystalline-cellulose-as-pharmaceutical-excipient",totalDownloads:3586,totalCrossrefCites:3,totalDimensionsCites:18,hasAltmetrics:1,abstract:"Microcrystalline cellulose (MCC) is a pure partially depolymerized cellulose synthesized from α-cellulose precursor (type Iβ), obtained as a pulp from fibrous plant material, with mineral acids using hydrochloric acid to reduce the degree of polymerization. The MCC can be synthesized by different processes such as reactive extrusion, enzyme mediated, steam explosion, and acid hydrolysis. It is commonly manufactured by spray-drying the neutralized aqueous slurry of hydrolyzed cellulose. The MCC is a valuable additive in pharmaceutical, food, cosmetic, and other industries. MMC obtained from different sources will differ considerably in chemical composition, structural organization, and physicochemical properties (crystallinity, moisture content, surface area and porous structure, molecular weight, etc.). The high demand of microcrystalline cellulose used in pharmaceutical industries has led to the utilization of locally and naturally occurring materials in the production of microcrystalline cellulose. Many studies on the physicochemical properties of locally produced MCC derived from natural sources have been extensively evaluated in the development of a new natural source for MCC as a substitution of wood, the most abundant one.",signatures:"Anis Yohana Chaerunisaa, Sriwidodo Sriwidodo and Marline Abdassah",downloadPdfUrl:"/chapter/pdf-download/68199",previewPdfUrl:"/chapter/pdf-preview/68199",authors:[null],corrections:null},{id:"66222",title:"Bioavailability and Bioequivalence Studies",doi:"10.5772/intechopen.85145",slug:"bioavailability-and-bioequivalence-studies",totalDownloads:3285,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:1,abstract:"In vivo bioavailability studies are performed for new drug to establish essential pharmacokinetic parameters including rate of absorption, extent of absorption, rates of excretion and metabolism and elimination half-life after a single and multiple dose administration. These essential pharmacokinetic parameters are useful in establishing dosage regimens. Bioequivalence used to assess the expected in vivo biological equivalence of two proprietary preparations of drug products. If two drugs are bioequivalent, it means that they are expected to be same for all intents and purposes. In determining bioequivalence between two drugs such as a reference drug or brand and potential to be test drug or marketed generic drug. Pharmacokinetic studies are conducted whereby each of the drugs is administered in a cross over study to healthy volunteer’s subjects. Plasma is obtained at regular intervals and assayed for parent drug or metabolite concentration to compare the two drugs. For comparison purpose of two formulations, the plasma concentration data are used to assess key pharmacokinetic parameters. If 90% confidence interval for the ratio of the geometric least square means of peak plasma concentration, area under curve of test and reference drugs are within 80–125%, then bioequivalence will be established.",signatures:"Divvela Hema Nagadurga",downloadPdfUrl:"/chapter/pdf-download/66222",previewPdfUrl:"/chapter/pdf-preview/66222",authors:[null],corrections:null},{id:"65701",title:"pH-Responsive Microgels: Promising Carriers for Controlled Drug Delivery",doi:"10.5772/intechopen.82972",slug:"ph-responsive-microgels-promising-carriers-for-controlled-drug-delivery",totalDownloads:1275,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The development of a new drug entity is a time-consuming and an expensive process; therefore, the design of new drug delivery systems for an existing drug molecule can significantly improve the safety and efficacy of the drug with improved patient compliance. In recent years, polymeric carriers have been widely investigated and are playing an important role in controlled drug delivery, biomedical applications, and tissue engineering. Microgels are microscopic hydrogels and have attracted much attention as vehicle for drug delivery. Stimuli-responsive MGs are smart drug delivery carriers and have the capability to incorporate and release their host molecules in response to stimuli (pH, ionic strength, and temperature), for targeted drug delivery. Of the many stimuli, alteration in pH is markedly fascinating because of the availability of pH gradients admissible for drug targeting. For example, pH gradients between normal tissues and some pathological sites between the extracellular environment and some cellular compartments, and along the gastrointestinal (GI) tract, are well characterized. Microgels can be fabricated through different methods.",signatures:"Zermina Rashid",downloadPdfUrl:"/chapter/pdf-download/65701",previewPdfUrl:"/chapter/pdf-preview/65701",authors:[null],corrections:null},{id:"67848",title:"Using Microbubbles as Targeted Drug Delivery to Improve AIDS",doi:"10.5772/intechopen.87157",slug:"using-microbubbles-as-targeted-drug-delivery-to-improve-aids",totalDownloads:1290,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"No preventive vaccines are available for the treatment of AIDS. To improve therapy, combinational antiretroviral drugs are given; however some patients develop resistance to particular combinational drug. Microbubble-mediated drug delivery technology solves the problem by reducing systemic dose and toxicity. Microbubbles are bubbles smaller than one millimeter in diameter but larger than one micrometer. The general composition of microbubble is gas core. The mechanism of microbubbles through which its delivery increases is sonoporation, the formation of openings in the vasculature, induced by ultrasound-triggered oscillations and destruction of microbubbles. Rapid isolation strategy of CD4+ cells is mixing blood and glass microbubbles which then bind with the specific target cells to the microbubble carrying specific antibodies on their surface. The target cells will spontaneously float to the top of the blood vial and can be quickly separated. The microbubbles are particularly used in the diagnosis of AIDS because of their cell isolation techniques which is rapid and inexpensive and their small size to pass through capillary for perfusion in tissue This review demonstrates the problems with the current treatment of the disease and shed light on the remarkable potential of microbubbles to provide more effective treatment and prevention for HIV/AIDS by advancing antiretroviral therapy, gene therapy, immunotherapy, vaccinology, and microbicides.",signatures:"Harsha Virsingh Sonaye, Rafik Yakub Shaikh and Chandrashekhar A. Doifode",downloadPdfUrl:"/chapter/pdf-download/67848",previewPdfUrl:"/chapter/pdf-preview/67848",authors:[null],corrections:null},{id:"67502",title:"Nanopharmaceuticals: A Boon to the Brain-Targeted Drug Delivery",doi:"10.5772/intechopen.83040",slug:"nanopharmaceuticals-a-boon-to-the-brain-targeted-drug-delivery",totalDownloads:1573,totalCrossrefCites:3,totalDimensionsCites:8,hasAltmetrics:0,abstract:"Brain is well known for its multifarious nature and complicated diseases. Brain consists of natural barriers that pose difficulty for the therapeutic agents to reach the brain tissues. Blood-brain barrier is the major barrier while blood-brain tumor barrier, blood-cerebrospinal (CSF) barrier and efflux pump impart additional hindrance. Therapeutic goal is to achieve a considerable drug concentration in the brain tissues in order to obtain desired therapeutic outcomes. To overcome the barriers, nanotechnology was employed in the field of drug delivery and brain targeting. Nanopharmaceuticals are rapidly emerging sub-branch that deals with the drug-loaded nanocarriers or nanomaterials that have unique physicochemical properties and minute size range for penetrating the CNS. Additionally, nanopharmaceuticals can be tailored with functional modalities to achieve active targeting to the brain tissues. The magic behind their therapeutic success is the reduced amount of dose and lesser toxicity, whereby localizing the therapeutic agent to the specific site. Different types of nanopharmaceuticals like polymeric, lipidic and amphiphilic nanocarriers were administered into the living organisms by exploiting different routes for improved targeted therapy. Therefore, it is essential to throw light on the properties, mechanism and delivery route of the major nanopharmaceuticals that are employed for the brain-specific drug delivery.",signatures:"Mahira Zeeshan, Mahwash Mukhtar, Qurat Ul Ain, Salman Khan and Hussain Ali",downloadPdfUrl:"/chapter/pdf-download/67502",previewPdfUrl:"/chapter/pdf-preview/67502",authors:[null],corrections:null},{id:"70715",title:"3D Printing in Pharmaceutical Sector: An Overview",doi:"10.5772/intechopen.90738",slug:"3d-printing-in-pharmaceutical-sector-an-overview",totalDownloads:1906,totalCrossrefCites:10,totalDimensionsCites:14,hasAltmetrics:1,abstract:"The pharmaceutical industry is moving ahead at a rapid pace. Modern technology has enabled the development of novel dosage forms for targeted therapy. However, the fabrication of novel dosage forms at industrial scale is limited and the industry still runs on conventional drug delivery systems, especially modified tablets. The introduction of 3D printing technology in the pharmaceutical industry has opened new horizons in the research and development of printed materials and devices. The main benefits of 3D printing technology lie in the production of small batches of medicines, each with tailored dosages, shapes, sizes, and release characteristics. The manufacture of medicines in this way may finally lead to the concept of personalized medicines becoming a reality. 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Akhlasur Rahman, Hasina Khatun, M. Ruhul Amin Sarker, Hosneara Hossain, M. Ruhul Quddus, Khandakar M. Iftekharuddaula and M. Shahjahan Kabir",dateSubmitted:"March 6th 2021",dateReviewed:"March 17th 2021",datePrePublished:"June 10th 2021",datePublished:"December 22nd 2021",book:{id:"11571",title:"Cereal Grains",subtitle:"Volume 2",fullTitle:"Cereal Grains - Volume 2",slug:"cereal-grains-volume-2",publishedDate:"December 22nd 2021",bookSignature:"Aakash Kumar Goyal",coverURL:"https://cdn.intechopen.com/books/images_new/11571.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"97604",title:"Dr.",name:"Aakash K.",middleName:null,surname:"Goyal",slug:"aakash-k.-goyal",fullName:"Aakash K. Goyal"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"338812",title:"Dr.",name:"M. Akhlasur",middleName:null,surname:"Rahman",fullName:"M. 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Ruhul Amin Sarker",slug:"m.-ruhul-amin-sarker",email:"mrasbrri@yahoo.com",position:null,institution:{name:"Bangladesh Rice Research Institute",institutionURL:null,country:{name:"Bangladesh"}}},{id:"340369",title:"Dr.",name:"Khandakar M.",middleName:null,surname:"Iftekharuddaula",fullName:"Khandakar M. Iftekharuddaula",slug:"khandakar-m.-iftekharuddaula",email:"kiftekhar03@yahoo.com",position:null,institution:{name:"Bangladesh Rice Research Institute",institutionURL:null,country:{name:"Bangladesh"}}},{id:"352116",title:"Mr.",name:"M. Ruhul",middleName:null,surname:"Quddus",fullName:"M. Ruhul Quddus",slug:"m.-ruhul-quddus",email:"rquddus265@gmail.com",position:null,institution:{name:"Bangladesh Rice Research Institute",institutionURL:null,country:{name:"Bangladesh"}}},{id:"352118",title:"Dr.",name:"M. Shahjahan",middleName:null,surname:"Kabir",fullName:"M. Shahjahan Kabir",slug:"m.-shahjahan-kabir",email:"kabir.stat@gmail.com",position:null,institution:{name:"Bangladesh Rice Research Institute",institutionURL:null,country:{name:"Bangladesh"}}}]}},chapter:{id:"76501",slug:"enhancing-abiotic-stress-tolerance-to-develop-climate-smart-rice-using-holistic-breeding-approach",signatures:"M. Akhlasur Rahman, Hasina Khatun, M. Ruhul Amin Sarker, Hosneara Hossain, M. Ruhul Quddus, Khandakar M. Iftekharuddaula and M. Shahjahan Kabir",dateSubmitted:"March 6th 2021",dateReviewed:"March 17th 2021",datePrePublished:"June 10th 2021",datePublished:"December 22nd 2021",book:{id:"11571",title:"Cereal Grains",subtitle:"Volume 2",fullTitle:"Cereal Grains - Volume 2",slug:"cereal-grains-volume-2",publishedDate:"December 22nd 2021",bookSignature:"Aakash Kumar Goyal",coverURL:"https://cdn.intechopen.com/books/images_new/11571.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"97604",title:"Dr.",name:"Aakash K.",middleName:null,surname:"Goyal",slug:"aakash-k.-goyal",fullName:"Aakash K. Goyal"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"338812",title:"Dr.",name:"M. Akhlasur",middleName:null,surname:"Rahman",fullName:"M. 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The possibility to prepare nanostructured polymers by self-assembly with reduced post-synthesis processing warrants further study and application of these materials, especially in the field of nanomaterials. The notable applications include in tissue engineering, biosensors, filtration, wound dressings, drug delivery, and enzyme immobilization. In this book, this amazing new area of polymeric nanofibers will be reviewed concerning the state-or-art results of synthesis, spectroscopic characterization and applications. The main goal of this book is to contribute in the rationalization of some important results obtained in this open area of polymeric nanofibers.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"a0e27f82282826770dcb5d3dde15d1b5",bookSignature:"Prof. Gustavo Morari Do Nascimento",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/6852.jpg",keywords:"Nanofibers, Polymers, Composites, Spectroscopy, Characterization, Functionalization, Synthesis, Fire-Retardant, Modified Electrodes, FTIR, Raman, Synchrotron Techniques",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 11th 2018",dateEndSecondStepPublish:"July 2nd 2018",dateEndThirdStepPublish:"August 31st 2018",dateEndFourthStepPublish:"November 19th 2018",dateEndFifthStepPublish:"January 18th 2019",remainingDaysToSecondStep:"4 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento",profilePictureURL:"https://mts.intechopen.com/storage/users/7153/images/system/7153.jpg",biography:"Dr. Gustavo Morari do Nascimento is a professor at the Federal University of ABC, Brazil. He obtained a Ph.D. from the University of São Paulo (USP), Brazil, in 2004. Since completing a postdoctorate at Massachusetts Institute of Technology (MIT), USA, in 2008, Dr. Morari do Nascimento has been working with carbon allotropes, conducting polymers, and conducting polymer-clay nanocomposites. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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In particular this includes reviewing the size, location within the kidney, and the degree of the exophytic nature of the tumour, in robotic-assisted partial nephrectomy. A thorough pre-operative review of the cross-sectional imaging and patient factors needs to be considered in a multi-disciplinary setting. Each hospital uses their own CT protocol, however we perform a pre-contrast and post contrast nephrogenic phase to assess renal mass enhancement. An arterial and delayed excretory phase may also be added for surgical planning. These phases clarify the presence of variant anatomy including feeding vessels to the tumour or accessory renal veins. It also helps demarcate the distance of the tumour from the renal hilum and the collecting system [1]. The anatomical relations play an important role, particularly in hilar dissection, including the presence of the head of the pancreas and part of the duodenum overlying the right renal hilum. The left hilum is in close proximity to the body and tail of the pancreas, with the left colonic flexure bordering the left kidney anteriorly. In nearly 30% of cases more than one renal artery is identified supplying a kidney, often on the right side [2]. The renal arteries run posteriorly from the aorta to the kidneys, due to the orientation of the renal hilum. The arteries split into four anterior and one posterior segmental branches at the renal hilum [3]. The renal arteries sit in the middle at the hilum, with the renal veins anteriorly and the ureters/collecting systems posterior to the artery [4]. Multiple variants in renal artery anatomy have been reported in the literature, thereby highlighting the close attention warranted during the review of preoperative imaging [3, 5].
We use a standardised four robotic arm technique using the for renal surgery the Da Vinci Si Surgical system (Intuitive Surgical Inc., Sunnyvale, CA, USA). Suitable training must be achieved to acquire appropriate robotic skills before performing complex renal surgery. We recommend a modular training programme in keeping with European and British board standards [6, 7].
Ensuring that the early stages of the learning curve are supervised with a mentor is essential to reduce errors and aid development of confidence in robotic skills. Evidence on learning curves vary in robotic-assisted partial nephrectomy (RAPN), with a study reporting 44 case requirement by a laparoscopically trained surgeon, to achieve a warm ischaemia time (WIT) of less than 20 min and an operative time of less than 120 min [8]. An alternative report by another centre identified needing to perform 61–90 cases to reach a trifecta of no significant complications, negative surgical margins and WIT of less than 25 min [9]. Needless to say learning curves can be improved with better training techniques, volume and exposure [10]. WIT was found to decrease to 13 from 20 min, following performing 150 RAPN cases compared to the first 10 cases [11]. Robotic trainees under expert supervision were found to have longer operating and warm ischaemia time, but otherwise no worse outcomes than experts performing robotic partial nephrectomies [12]. In addition the patient-side assistant should be appropriately skilled in handling instruments safely and deploying ligature clips. All cases should be subjected to nephrometry scoring (PADUA and RENAL) and a thorough imaging review preoperatively to predict operative complexities and postoperative complications [13, 14, 15, 16]. We incorporate the PADUA score due to its standardised use across the national nephrectomy register, collected by the British Association of Urological Surgeons.
The authors recommend this operative approach, based on the available disseminated techniques and preference in their experience and training [17, 18, 19, 20, 21, 22, 23, 24]. In order to perform a robotic-assisted partial nephrectomy, the patient is positioned in a lateral decubitus/flank position (Figure 1) on the operative table to aid bowel mobilisation [24]. The operative table is subsequently broken/flexed. This opens the flank, between the costal margin and the iliac crest. A reported variation may include a slight Trendelenburg position and a flat table [23]. The anterior abdomen lies on the edge of the operative table. The upper arm is flexed at the elbow and kept adjacent to the face [21]. We prefer adhesive tape to secure the patient to the bed, at the level of the iliac crest [23]. Additional adhesive tape used at the level of the mid thoracic cavity should be applied with caution to avoid reduced chest expansion, in the context of ventilation. The back can be stabilised using an additional back support attachment with gel pads. The bottom leg in the lateral position is flexed to 90° at the knee, and is separated from the extended top leg using pillows. All pressure points are padded [23]. A nasogastric tube (NGT) is placed in left sided tumours and a urinary catheter is inserted following anaesthetic induction for all cases, and prior to patient positioning [21]. The NGT is removed in recovery.
Full flank patient positioning for left RAPN. Note port site marking made prior to knife to skin.
A consistent surgical team who develop skills progressively with the surgeon, specifically for renal surgery is essential for optimal outcomes. Robotic renal surgery is approached differently from pelvic surgery and cannot instantly be translated.
It is vital that your anaesthetic staff is experienced with patient positioning and moving for robotic renal surgery.
A uniform anaesthetic team will also lead to better pain control in the post-operative phase and consistently enhanced results particularly during the critical on-clamp (WIT) period of partial nephrectomy.
Precise port placement and patient cart position are important for successful outcomes in robotic renal surgery. Unlike in pelvic surgery, the operative field is wider increasing the potential for robot arms to clash. With some basic principles, success can be replicated case after case. As with radical prostatectomy, the ports must be placed with a minimum 8 cm distance apart. However, with different laterality of renal surgery, an additional consideration is placing arm 3 of the patient cart. In the case of right sided renal tumours, arm 3 should be positioned on the left of the cart stem. The reverse is true for left renal surgery.
We recommend marking the skin to plan port positioning. Formation of a skewed cross or upside-down kite shape should be made with the camera port forming the apex. However the reference point should be the subcostal port, as it offers least flexibility in positioning. The camera port, target organ and patient cart should form a straight line, thereby creating adequate triangulation for safe operating. The contralateral operating port will form a horizontal line to the subcostal port, with the camera port bisecting this line in the middle (Figure 2). This should give adequate room for the 4th robotic arm port, which will then complete the kite or cross shape, placed laterally roughly in the anterior axillary line. It is possible that arm 1 (when operating on the right kidney) can hold the ProGrasp™ forceps, rather than arm 3. The robot is then manipulated to dock over the patient’s upper shoulder at an angle of 45 degrees to the kidney.
Port site marking for a right RAPN.
Use of the bariatric ports can be beneficial to achieve greater distance between the robot arms, particularly in smaller patients. This will reduce the potential for robot arm clashing.
Should the arms clash, then ‘burping’ the ports away from each other can create additional room and potentially avoid restricted movement of the instruments, which can severely limit surgical progress. The ports placed under traction, tents the abdominal wall externally, increasing intra-abdominal space to work in [25].
Evidence from a meta-analysis reveals similar surgical outcomes and complications between transperitoneal and retroperitoneal robot-assisted partial nephrectomies. The retroperitoneal approach may have a specific role in selected cases including posterior tumours and in patients with pervious significant transperitoneal surgery. Absence of the need to mobilise bowel and easy access to the hilar vessels, leads to a shorter operative time [26]. However, the choice between retroperitoneal or transperitoneal approach lies based on surgeon’s expertise and patient factors [17].
We recommend a trans-peritoneal approach, particularly in the early phase of the learning curve. This will ensure that adjacent structures can be adequately mobilised away from the kidney. In addition, operative space is optimised when within the peritoneum. This will avoid injury to sensitive structures such as the duodenum on the right and the spleen; tail of the pancreas and duodeno-jejunal junction on the left. The authors recommend using a 0° camera lens in the early learning curve period, unless experienced in 30° downward scope lens from laparoscopic surgery [23]. Use of 30° downward lens has a role in the later stages of dissecting posterior tumours [24]. A pneumoperitoneum of 10–12 mmHg is established. In almost all cases the kidney can be adequately mobilised to expose renal masses to perform a partial nephrectomy successfully in the trans-peritoneal approach. However, some surgeons transferring from retroperitoneal laparoscopic surgery may feel suitably experienced in translating skills to perform retroperitoneal robotic surgery. Guides are available on performing retroperitoneal RAPN [27, 28].
A wide array of instruments and preferences exist in performing a RAPN. The authors perform the procedure with the surgeon holding the EndoWrist® Fenestrated Bipolar Forceps and the EndoWrist® Hot Shears™ monopolar curved scissors in the non-dominant and dominant hand robotic ports respectively. Sharp dissection is performed along the white line of Toldt. Sharp and blunt dissection is used to reflect the large bowel off the anterior surface of Gerota’ fascia [24]. Dissection is directed to the inferior border of Gerota’s fascia in order to locate the ureter. Release of attachments from adjacent structures including liver or spleen may be performed to characterise the planes clearly. The psoas major muscle is used as a landmark to help identify the ureter, similar to a laparoscopic approach. The ureter is then dissected cranially to identify the renal hilum [23]. Specific care should be taken to control, or avoid injury to the gonadal vessels. The additional robotic arm, holding the ProGrasp™ forceps can now be deployed to retract the kidney laterally, thereby creating space to dissect the hilum safely away from sensitive medial structures (such as the duodenum or inferior vena cava). The Force Bipolar™ is a new instrument which combines the ProGrasp™ grasping qualities with bipolar diathermy and may be incorporated instead for efficiency. In right sided tumours, the hilum can be approached from a cranial to caudal direction, enabling earlier access to the renal artery. The Inferior Vena Cava just below the liver can be easily identified and followed caudally to reach the renal pedicle in right sided tumours.
Hilar dissection requires sensitive movements to adequately expose all renal vessels (one at a time) to allow for application of clamps later in the operation. This enables precise control in case of unexpected haemorrhage. We recommend clamping the main renal artery early in the learning curve, rather than attempting to selectively clamp more distal segmental branches. Near-infrared fluorescence imaging system with indocyanine green is an available technology allowing identification of intraoperative parenchymal perfusion, thereby enabling selective vessel clamping for limiting ischaemia to the tumour alone. It has been shown to improve early functional outcomes, with better preservation of glomerular filtration rate of the resected kidney on renal scan with Tc 99 m-DTPA [29]. Once the main artery is exposed, a short sling can be placed and held in place by a suitable arterial clip (to the rubber sling ends alone), we use a Weck® Hem-o-lok® ligating clip.
At this stage exposure of the renal tumour proceeds by incising Gerota’s fascia and ‘defatting’ the kidney adequately, preferably along the renal capsular plane. This will enable adequate exposure of the renal tumour and mobilise the kidney to achieve a wide surgical field to perform the excision. The drop-in ultrasound probe is introduced and manipulated by the surgeon using the ProGrasp™ forceps to distinguish tumour margins [17]. The tumour is marked superficially on the renal capsule with the Hot Shears™ curved monopolar diathermy scissors, leaving a 5 mm margin for oncological outcomes.
All accessory equipment is introduced through the assistant port, including the arterial clamps. Two absorbable monofilament sutures such as Poliglecaprone, e.g. Monocryl® 3–0 and two absorbable braided sutures such as Polyglactin, e.g. 0-Vicryl®, cut to size are strategically positioned in the abdomen for easy access during renorrhaphy.
At this stage a brief ‘time-out’ ensures that the surgeon and the surgical team are aware of the ensuing critical element of the operation—sometimes known as ‘on-clamp time’. This provides ample opportunity to ensure that there is adequate insufflation gas in the tanks, that additional sutures are readily available and that the anaesthetist is prepared for potential haemorrhage. At this stage it is recommended to re-review the CT images to ensure that the shape of the renal mass can be translated to the operative field. The authors do not recommend the usage of Mannitol in view of its limited evidence in minimising loss of renal function post operatively in humans [30].
To minimise the dangers associated with, the next step is performed after unanimous readiness of the theatre staff. A Scanlan® Reliance Bulldog Clamp (Scanlan® International, St. Paul, MN, USA) is applied to the renal artery, in selected cases this is followed by another on the renal vein [23]. Satinsky clamp is an option in the rare difficult dissections when bleeding from the renal pedicle impairs ability to clamp the vessels with a bulldog clamp [31]. The clamping marks the triggering of a stopwatch, to measure warm ischaemic time.
The tumour is excised with consideration of surgical margins, with the assistant surgeon ensuring the field is adequately exposed by suctioning away blood. The sliding-clip renorrhaphy principle is applied to close the renal defect, in multiple layers. The deep layer of the renorrhaphy is performed with the poliglecaprone 3–0 suture, with a Weck® Hem-o-lok® ligating clip already attached at one end. A continuous suture runs through the base of the defect closing any open collecting system and small vessels. If arterial bleeds are detected these can be closed individually with additional monofilament sutures to ensure meticulous haemostasis. Once the continuous running poliglecaprone suture is applied, a Hem-o-lok® clip is applied to the needle end. Traction is applied to the needle end to snug the clip down against the renal capsule, bringing the renal defect together. Larger defects will require multiple sutures. We use an early ‘off-clamp’ technique after the deep sliding-clip renorraphy is complete, in the order of release of renal vein, followed by the artery, where the vein has been clamped. This reduces the warm ischaemic time. We do not use a bolster. At this stage haemostasis is adequate to complete the superficial sliding-clip renorrhaphy suture with a large polyglactin suture. In this layer, clips are applied at every throw through the renal capsule to further close the defect. A second locking clip can be applied above every previous clip on the sliding suture to prevent slipping. Use of adjuncts to haemostasis is not essential but may provide added security and further minimise blood loss. This may be in the form of Floseal®, Surgicel® or Evicel®. The hilum and excision site are carefully inspected following this step, to ensure haemostasis is achieved. We recommend closing Gerota’s fascia, which may minimise difficulty in future renal surgery from scarring [24]. An intra-abdominal drain is inserted through the lateral port. The specimen is removed using an endocatch pouch, inserted through the assistant’s port.
A ‘time-out’ is taken to assess the tumour excision, the associated renal defect and the plan for renorraphy prior to the on-clamp time, will in our experience lead to better planning and a potentially safer procedure.
Use of intraoperative doppler ultrasound is widely recommended for use in partial nephrectomy.
Plan your incision on the Gerota’s fascia carefully will help with closure after. Practice often on simulators to ensure that your suturing skills are adequate to perform renorrhaphy under the pressure of limited time, whilst the clamp clock is ticking.
An apron of Perinephric fat can be placed behind the posterior surface of the kidney, to anteriorly displace the kidney. This improves access to posterior and lateral tumours. If there is inadequate Perinephric fat, tonsil swabs can be placed instead.
This is our summarised technique that is performed in our practice, which can be adopted by departments interested in developing a robotic partial nephrectomy service.
Both EAU and AUA guidelines advise minimally invasive surgery if possible, however advise caution if perioperative, oncological or functional outcomes are at risk of compromise [32, 33]. In fact, EAU recommend partial nephrectomy over radical in patients with T1 tumours, even if an open approach is warranted. Any approach for PN is valid based on the surgeons skill and preference.
The EAU advise that despite the similar cancer specific survival and recurrence free survival for pT1 tumours in the comparison of partial versus radical nephrectomy; partial nephrectomy is still the ideal treatment in view of minimising impairment to renal function and preventing metabolic and cardiovascular disorders in the long term. Retrospective studies have revealed no difference in long term overall and cancer specific survival between laparoscopic and open partial nephrectomies [34, 35].
Prospective comparison of robotic-assisted versus open partial nephrectomy found significant improvement in estimated blood loss and length of stay in the cohort undergoing RAPN. Early and short term complications, operative time and warm ischaemia time were similar between both approaches [36]. Robotic-assisted surgery was found be superior to laparoscopic PN with regards to conversion to open, conversion to radical nephrectomy, warm ischaemia time and length of stay. This meta-analysis of 23 studies also concluded no difference in short term postoperative complications, operative time, estimated blood loss and positive margins [37].
We describe a few developing technologies which may be of interest to urologists.
Reconstruction and navigation technology appears to have an emerging role in both preoperative and intraoperative planning and operative assistance. A diverse group of 108 urologists of various training experience changed their views to feel an RAPN over a radical nephrectomy was indicated from 47–75% of the 20 complex cases reviewed following a re-review of the CT scan with three dimensional reconstruction of the renal units [38].
Hyperaccuracy three dimensional (HA3D) is an emerging technology allowing three dimensional reconstructions, enabling virtual mapping of the in-vivo structures with the reconstructed model during the partial nephrectomy. A small sample sized study in complex renal tumours (PADUA >10), using this HA3D technology enabled intraoperative management of the pedicle as preoperatively planned in 90% of the cases [39]. The accuracy of the arterial reconstruction enabled preoperative simulation of vascular ischaemia by selective clamping. This enabled reduction of global ischaemia from 81–24% with the use of the HA3D technology [39].
Near-infrared fluorescence (NIRF) technology using an intravenous contrast medium (e.g. Indocyanine green) enables identification of the segmental vessels perfusing the renal tumour, by switching between white light and fluorescence enhanced views intraoperatively [40]. NIRF RAPN has been found to have a lower loss in renal scan confirmed renal function in the operated unit and a lower reduction in Glomerular Filtration Rate (GFR of 8%)compared to standard RAPN without selective vessel clamping. In three of the 15 NIRF RAPN cases, selective clamping was converted to standard clamping as incomplete ischaemia of the tumour was identified. This demonstrates NIFRs growing benefit over non-NIFR selective clamping.
Urologists participating in a study on 3D (Three Dimensional) printed models of the kidney, favoured its use in preoperative planning, patient counselling and surgical training [41]. The authors report maximal benefit of these models in patients with complex renal vasculature [42].
Our technique offers a standardised approach to aspiring urologists in performing robotic-assisted partial nephrectomies. We expect urologists to have the appropriate level of training and supervision prior to performing this procedure. We highlight a variety of tips and tricks that have benefitted our team in performing safer and easier surgery. We describe the stance of guidelines of robotic surgery in partial nephrectomies. We highlight emerging technologies which may become incorporated into the future practice of robotic surgery.
Humans are persistently exposed to various chemical and physical agents that have the potential to damage genomic DNA, such as, irradiation (IR), ultraviolet (UV) light, reactive oxygen species (ROS), et cetera [1]. The integrity and survival of a cell is critically dependent on genome stability and mammalian cells have established multiple pathways to repair different types of target DNA lesions to safeguard the genome from deleterious consequences of various kinds of stresses [2]. The significance of the DNA repair in the protection of genomic stability is highlighted by the fact that many proteins/factors involved have been preserved through evolution [3].
DNA damage, induced by endogenous and exogenous agents, is a common event and must undergo a variety of DNA damage repair in order to ensure the faithful transfer of genetic information during cell division [3]. Four main DNA polymerases are involved with nuclear DNA replication: DNA polymerase α, β, δ and ε [1] (Figure 1). DNA repair pathways, which are also recognized as guardians of the genome, protect cells from numerous damages leading to DNA breaks [4]. Failure to restore DNA lesions or inappropriate repair of DNA damage give rise to genomic instability, which is a hallmark of cancer. Remarkably, mild and massive DNA damage are differentially integrated into the cellular signaling networks and, in consequence, provoke different cell fate decisions. After mild damage, the cellular response is cell cycle arrest, DNA repair, and cell survival, whereas severe damage, drives the cell death response. The inability of the DNA damage response (DDR) to repair following endogenous and exogenous insults can lead to (i) an accumulation of errors in genomic DNA, (ii) subsequent malignant transformation, (iii) cancer progression and (iv) further impairment of the DNA repair capacity. DNA repair mechanisms comprise the detection and deletion (excision) of the lesion, the rejoining of DNA ends and the restoration of the complementary sequence based on a DNA template.
Sub-cellular localization of eukaryotic and retroviral DNA polymerases.
Since cancer cells typically have many mutations compared to a non-cancer cell, it was proposed that one of the earliest changes in the development of a cancer cell is a mutation that increases the spontaneous mutation rate [5]. The presence of a “mutator phenotype” could increase the acquisition of alterations that could lead to enhanced drug resistance limiting the effectiveness of anti-cancer drug treatment.
Viral infection is characterized by the high genetic variability found in virus populations [6]. This phenomenon is attributed to the inaccuracy of the replication machinery that is unique to the viral life cycle. Virulence, pathogenesis and the ability to develop effective antiretroviral drugs and vaccines are largely dependent on genetic diversity in viruses [7]. Retroviruses are RNA viruses that replicate through a DNA intermediate in a process catalyzed by the viral reverse transcriptase (RT) in cytoplasm (Figure 1) [7]. Human immunodeficiency virus type 1 (HIV-1), the etiological agent of AIDS, exhibits exceptionally high mutation frequencies [8]. The accepted explanations for the inaccuracy of HIV-1 RT are the relatively low fidelity of the enzyme during DNA synthesis and the deficiency of intrinsic proofreading activity. A strong mutator phenotype is also observed for herpes viral DNA polymerase mutants with reduced intrinsic 3′ → 5′ exonuclease activity [9].
Mitochondrial DNA (mtDNA) alterations have been associated with various human diseases with impaired mitochondrial function [10]. Mitochondrial DNA polymerase γ (pol γ) is responsible for replication of mtDNA and is implicated in all repair processes (Figure 1) [11]. Mitochondrial DNA is prone to mutations, since it is localized near the inner mitochondrial membrane in which reactive oxygen species are generated. Additionally, mtDNA lacks histone protection and the highly efficient DNA repair mechanisms [12]. The mutation rate of mtDNA is estimated to be about 20–100-fold higher than that of nuclear DNA [13]. The mutagenic mechanisms were shown to be replication errors caused by mis insertion (as a result of a dNTP excess), or decreased proofreading efficiency [14, 15].
Thus, in various compartments of the cell, enhanced DNA replication fidelity is a vital activity for the preservation of genomic stability for many organisms.
Genomic integrity of the cell is crucial for the successful transmission of genetic information to the offspring and its survival [16]. DNA is constantly being damaged. Essentially, DNA lesions can occur in two major ways, affecting either a single-stranded break (SSB) or double-stranded (DSB) or mono-adducts and inter-strand crosslinks, respectively. To combat this, eukaryotes have developed complex DNA damage repair (DDR) pathways (Figure 2). The active pathways for DNA repair are base excision repair (BER), nucleotide excision repair (NER), and mismatch repair MMR for SSB repair, whereas homologous recombination (HR) and non-homologous end-joining (NHEJ) for DSB repair [16]. Nucleotide excision repair (NER) removes a variety of helix-distorting lesions such as typically induced by UV irradiation, whereas base excision repair (BER) targets oxidative base modifications. Mismatch repair (MMR) scans for nucleotides that have been erroneously inserted during replication. The most deleterious types of damage in DNA are DSBs that are typically induced by IR and resolved either by NHEJ or by HR, whereas RECQ helicases assume various roles in genome maintenance during recombination repair and replication.
DNA damage and repair mechanisms. Various DNA damaging agents cause a range of DNA lesions with different outcomes at both the genomic and cellular levels. Each are corrected by a specific DNA repair mechanism, namely, base-excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR)/non-homologous end-joining (NHEJ) or mismatch repair (MMR).
A low fidelity of DNA synthesis in various compartments of the cell by main replicative DNA polymerases leads to genomic instability (mutator phenotype) [17]. The errors produced during DNA synthesis could result from three fidelity determining processes: a) nucleotide misinsertion into the nascent DNA, b) lack of exonucleolytic proofreading activity, that is, the mechanism to identify and excise incorrect nucleotide incorporated during DNA synthesis, and c) extension of mismatched 3′-termini of DNA (Table 1) [18].
Biochemical properties of cellular DNA polymerases | |||
---|---|---|---|
Function | 3′ → 5′ exonuclease | Proofreading | |
Nuclear DNA polymerases | |||
α | primase | no | no |
β | repair | no | no |
δ | Lagging DNA synthesis, repair | yes | yes |
ε | Leading DNA synthesis, repair | yes | yes |
Mitochondrial DNA polymerase | |||
γ | DNA synthesis | yes | yes |
Retroviral DNA polymerase | |||
HIV-1 RT | DNA synthesis | no | no |
Biochemical properties of eukaryotic and retroviral DNA polymerases.
Incorrectly repaired DNA lesions can lead to mutations, genomic instability, changes in the regulation of cellular functions, progression of cancer and premature aging. Cells can repair the large variety of DNA lesions through a variety of sophisticated DNA-repair machineries, recognizing and activating battery of proteins/factors for the repair of damaged DNA. DNA replication is a complex process influenced by numerous proteins/factors. The most important part of the DNA damage response is the activation of tumor repressor p53 protein [18].
The p53 represents a major factor for the maintenance of genome stability and for the suppression of cancer [19, 20]. The p53 protein is commonly referred to as the “
Under normal conditions within the cell, p53 is maintained at low levels by the E3 Ubiquitin ligase MDM2, mediating p53 proteasomal degradation [23]. In response to exposure to various endogenous and exogenous stress signals (such as DNA damage, oncogene activation, hypoxia, and nutrient depletion), the protein is stabilized and functionally activated by a series of post-translational modifications (
In response to various endogenous and exogenous stress signals, the activated p53 arrests the cell cycle until the DNA damage is repaired thereby preventing the cancer. If the DNA damage cannot be repaired apoptosis occurs for eliminating cells that contained excessive and irreparable damaged DNA.
p53 exhibits the functional heterogeneity in its basal (non-induced) state and under various p53 inducible circumstances [20]. Increasing evidences suggest various “non-transcriptional functions” of p53, that can contribute to tumor suppressor activity [25]. p53 may modulate DNA repair through processes, which are independent of its transactivation function. p53 is actively transported between the nucleus and cytoplasm. Furthermore, p53 translocate to mitochondria [26]. p53 can directly interact with DNA repair related cellular factors [27]. The origin, duration, intensity of the stress signals, the interaction with other cellular or viral proteins, and stress-mediated subcellular localization of p53 determines the outcome of the p53 response, namely, its pro- or anti-survival functions [28]. p53 protein executes multi-compartmental functions in the cell by either numerous p53-regulated proteins or by its intrinsic biochemical activities [28].
The functioning of the eukaryotic genome relies on effective and accurate DNA replication and repair [2]. DNA replication in the nucleus of eukaryotic cells employs DNA polymerases (pols) α, β, δ, and ϵ, that are the key enzymes required to maintain the integrity of the genome under all these circumstances [1, 3]. However, the maintenance of genomic integrity is complicated by the fact that the genome is persistently challenged by a variety of endogenous and exogenous DNA-damaging factors [4]. DNA lesion can block DNA replication, which can lead to double-strand breaks (DSB) or alter base coding potential, leading to mutations. The accumulation of damage in DNA can affect gene expression leading to the malfunction of many cellular processes [4]. Various DNA repair systems operate in cells to remove DNA lesions, and several proteins are known to be the key components of these repair systems.
The presence of p53 was demonstrated in different nuclear compartments and suggested that the p53 population not engaged in transcriptional regulation could exert functions other than induction of growth arrest or apoptosis and directly participate in processes of repair [25]. p53 mediating various activities are correlated with the levels of the p53 protein in the cells [27, 29]. The non-genotoxic stress may include a long-lasting, moderate accumulation of p53 in nucleus. Conversely, acute genotoxic stress may induce rapid and transient accumulation of very high levels of p53 with preferential activation of target genes involved in apoptosis [29]. There is a possibility that both transcriptional and transcription-independent pathways act in synergy thereby amplifying the potency of involvement of p53 in DNA repair.
p53 localized in cell nuclei in response to replication stress actively participate in various processes of DNA repair and DNA recombination via its ability to interact with components of the repair and recombination machinery and by its various biochemical activities [30, 31]. Both
The C-terminal 30 amino acids of p53 were shown to recognize several DNA damage-related structures.
In addition, full range of various intrinsic biochemical features of the p53 protein support its possible roles in DNA repair. After DNA damage: (a) p53 is able to recognize and bind sites of DNA damage, such as ssDNA and dsDNA ends [33, 34], (b) p53 catalyzes DNA and RNA strand transfer and promotes the annealing of complementary DNA and RNA single-strands [35, 36], (c) p53 binds insertion/deletion mismatches and bulges [37], (d) p53 binds to three-stranded heteroduplex joints and four-stranded Holliday junction DNA structures with localization specifically at the junction, suggesting that p53 directly participates in recombination repair [38], (e) it can bind DNA in a non-sequence-specific manner [39], (f) p53 exhibits a Mg2+ dependent 3′ → 5′ exonuclease activity [40, 41, 42, 43].
Noticeably, the same central region within p53, where tumorigenic mutations are clustered, recognizes DNA sequence specifically, is required for junction-specific binding of heteroduplex joints and is necessary and sufficient for the 3′ → 5′ exonuclease activity on DNA [28]. In addition to p53’s biochemical activities, numerous reports on physical and functional protein interactions further strengthened the proposal of a direct role of p53 in BER, NER, and DSB repair.
Oxidative DNA damage is largely repaired by the BER pathway. p53 might directly facilitate BER mainly via association with BER components. Wtp53 directly enhanced BER activity measured both
The cellular response depends on the dose of genotoxic agent introduced to the cells. Increasing doses of genotoxic agents cause the accumulation of activated p53 that determines the onset of BER or apoptosis. Low doses of DNA damaging agent resulted in the enhancement of p53-dependent BER activity whereas high levels induced different p53 post-translational modifications that down regulate BER pathway and instead provoked an apoptotic response [29]. The quantitative changes in p53 protein level were associated with qualitative changes in p53 phosphorylation status. In all, this may indicate that increasing doses of genotoxic agents cause the accumulation of activated p53 that determines the onset of BER or apoptosis.
NER is an important DNA repair process that detects and eliminates lesions including both chemical alteration and structural distortion of the DNA helix (
Pathogenic mutations in the GG components XPC and DDB2 (XPE) result in xeroderma pigmentosum (XP) a disease characterized by increased UV-sensitivity and skin cancer incidence [46]. Conversely, mutation in TC genes result in Cockayne’s syndrome that is characterized by neurological abnormalities but no increase in skin cancer incidence. Some NER proteins, particularly the GG damage recognition proteins, can decide a cell’s fate by triggering the initiation of the repair pathway or by signaling apoptosis [46]. Therefore, if the GG pathway is defective, neither DNA repair nor apoptosis occurs, resulting in a cancer cell containing high levels of UV-induced mutations that does not undergo apoptosis. How this non-transcriptional function of p53 contributes to tumor suppression is unclear.
DNA mismatch repair (MMR) is an important DNA repair pathway, which facilitates removal of incorrect nucleotides incorporated during replication. p53 facilitates excision of incorrect nucleotides produced from the error prone nature of DNA polymerases and misincorporation of the incorrect base [25]. Mismatched bases can be either a G/T or A/C pair. To initiate MMR a nick in the DNA either 5′ or 3′ to the mismatch must occur. Proteins that bind the mismatch in humans are
Mutator phenotypes (with the potential for cancer progression) have been reported for cells that lack a proofreading 3′ → 5′ exonuclease activity associated with the DNA polymerase [54]. Excision of incorrectly polymerized nucleotides by exonucleases is an imperious mechanism diminishing the errors during DNA polymerization [55]. Certain organisms with a deficiency of exonucleolytic proofreading, have an increased susceptibility to cancer, especially under conditions of stress. Because the misincorporation of non-complementary dNTPs during DNA replication represents a chief mechanism of gene mutation [56], the removal of the wrong nucleotides from DNA is critical for genomic stability. The intrinsic limited accuracy of DNA polymerases and the imbalance of intracellular dNTP pools are the two most important factors responsible for DNA replication errors [57, 58]. The proofreading for such replication errors by the 3′ → 5′ exonuclease activity associated with the DNA replication machinery is extremely important in reduction of the occurrence of mutations. Interestingly, the mammalian DNA pol α, an enzyme considered to be responsible for the lagging strand replication [59], lacks the 3′ → 5′ exonuclease proof-reading activity and is prone to making replication errors [60].
Three steps, base selection, exonucleolytic proofreading, and DNA elongation, ensure the high fidelity of DNA replication. wtp53 exhibits an intrinsic 3′ → 5′ exonuclease activity. wtp53, co-located with the DNA replication machinery [61], specifically interacts with pol α and has been shown to preferentially eliminate mismatched nucleotides from DNA with its 3′ → 5′ exonuclease activity, thereby enhancing the DNA replication fidelity of pol α
Hydroxyurea (HU), an inhibitor of ribonucleotide reductase involved in the
The functional interaction of DNA polymerase and exonuclease activity was observed with p53/pol-prim complex. p53-containing DNA pol-prim complex excised preferentially a 3′-mispaired primer end over a paired one and replaced it with a correctly paired nucleotide [63]. In contrast, a pol-prim complex containing the hot spot mutant p53R248H did not display exonuclease activity and did not elongate a mispaired 3′-end, representing that the p53 exonuclease from the p53/pol-prim complex was indispensable for the subsequent elongation of the primer by DNA polymerase. These findings support the view that p53 might fulfill a proofreading function for pol-prim and suggest that the defect in proofreading function of p53 may contribute to genetic instability associated with cancer development and progression [63].
DSBs are the most severe type of DNA damage, and these DSBs generated at the replication fork are repaired by two principal repair pathways: homology-based repair (HR) and non-homologous end-joining (NHEJ) [25, 31]. Furthermore, replication blocking lesions such as bulky adducts are subject to HR repair, thereby rescuing the replication fork. HR is considered the most error-free pathway, because sister chromatids are the preferred template, however, it can also produce genetic instability upon up- or down-regulation [25].
Depending on the type and quality of the DSB repair pathway involved, the repair process may end up with deletions, loss of heterozygosity, and chromosomal translocations which may accelerate the multistep process of tumorigenesis. p53 can control HR
p53 prevents the accumulation of DSBs at stalled-replication forks induced by UV or hydroxyurea (HU) treatment. When DNA replication is blocked, p53 becomes phosphorylated on serine 15 and associates with key enzymes of HR such as, Rad51, and Rad54 [68, 69]. Notably, during replication arrest p53 remains inactive in transcriptional transactivation, further supporting the direct involvement in HR regulatory functions unrelated to transcriptional transactivation activities.
p53 preferentially represses HR between certain mispaired DNA sequences. p53 specifically recognizes preformed heteroduplex joints structurally resembling early recombination intermediates, when comprising these mispairings [68]. p53 is able to attack DNA by 3′–5′ exonuclease activity principally during Rad51-mediated strand transfer and to display a DNA substrate preference for heteroduplex recombination intermediates with a further enhancement of the exonucleolytic activity for mispaired as compared to correctly paired heteroduplex DNA [38].
Highlighting the significance of p53 DNA interactions in the regulation of strand exchange events, p53 inhibits branch migration of Holliday junctions (HJs) [25, 31]. p53 recognizes this HJs -like structure and controls the generation and branch migration of the replication fork as well as its resolution, to prevent error-prone DSB repair and to cause replication pausing until the DNA lesion is repaired.
Mammalian cells repair the majority of double-strand breaks by NHEJ [69, 70] which is regarded as principally inaccurate process. The role of p53 in NHEJ remains unclear. p53 has an inhibitory effect on error-prone NHEJ but not error-free NHEJ [71], thereby suppressing genomic instability arising from low-fidelity repair. Remarkably, after the exposure to IR, DSB rejoining increases with loss of wtp53function. Inhibition of in vitro end-joining was observed with the oncogenic mutant p53(175H), whereas the phosphorylation-mimicking mutant p53(15D) failed to inhibit, thereby providing evidence for possible role of phosphorylated p53 in the regulation of NHEJ [72].
Various
Under normal conditions a basal pool of p53 is retained intra-cellular, with the distribution of p53 between the different subcellular compartments dependent on the cellular stress milieu [28]. Indeed, wtp53 occurs in cytoplasm in a subset of human tumor cells such as breast cancers, colon cancers and neuroblastoma [73, 74, 75]. Shuttling between nucleus and cytoplasm not only regulates protein localization, but also often impacts on protein function.
p53, localized in the cytoplasmic lysates of non-stressed p53-proficient cell lines [e.g. LCC2, HCT116 (p53+/+)] exerts an inherent 3′ → 5′ exonuclease activity displaying identical biochemical functions characteristic for recombinant wtp53 [76, 77]: 1) it removes 3′-terminal nucleotides from various nucleic acid substrates: ssDNA, dsDNA, and RNA/DNA template-primers, 2) it hydrolyzes ssDNA in preference to dsDNA substrate, 3) it shows a marked preference for excision of a mismatched vs. correctly paired 3′ terminus with RNA/DNA and DNA/DNA substrates, 4) it excises nucleotides from nucleic acid substrates independently from DNA polymerase, 6) it fulfills the requirements for proofreading function; acts coordinately with the exonuclease-deficient viral DNA polymerases.
Viruses exploits their cellular host for their successful replication, they utilize cell proteins for multiple purposes during their intracellular replication [78]. Since viral infection evokes cellular stress, the infected cells harbor stabilized activated p53 and manipulate p53’s guardian role. Interestingly, increased p53 levels have been noted following infection of cells with various viruses including retrovirus-human immunodeficiency virus [79], which exhibits exceptionally high genetic variability [6], due to the low fidelity of the replication apparatus that is exclusive to the retroviral life cycle.
Reverse transcriptase (RT) of HIV-1 is responsible for the conversion of the viral genomic ssRNA into the proviral DNA in the cytoplasm [7]. The lack of intrinsic 3′ → 5′ exonuclease activity, the formation of 3′-mispaired DNA and the subsequent extension of this DNA were shown to be determinants for the low fidelity of HIV-1 RT [80]. p53 can proofread for HIV-1 RT, increasing the fidelity of DNA synthesis by excising incorrectly polymerized nucleotides from RNA/DNA and DNA/DNA temple-primers in the direct exonuclease assay, when first binding to a 3′-terminus and during ongoing DNA synthesis
DNA polymerase (pol) γ is the sole DNA polymerase that is responsible for replication and repair of mtDNA [81]. It is well established that defects in mtDNA replication lead to mitochondrial dysfunction and disease [56, 60]. Mutations in mtDNA can arise from exogenous sources, from endogenous oxidative stress, or as spontaneous errors of replication during either DNA synthesis or repair events [82]. Mitochondrial DNA is replicated by DNA polymerase γ in concert with replisome accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, the multifunctional mitochondrial transcription factor A (TFAM) with important roles in mtDNA replication and initiating factors.
A high frequency of mutations within mtDNA, resulting in mitochondrial dysfunctions, is an important source of various diseases including cancer and human aging [81, 82]. To verify mtDNA integrity, cells hold various DNA damage response pathway(s) comprising mtDNA replication/repair preservation programs that either preclude or repair damage [83]. The mutagenic mechanisms were shown to be replication errors formed by either pol γ during DNA synthesis by incorporation of incorrect nucleotide or produced due to the presence of unbalanced dNTP concentrations, or by diminished proofreading efficiency. MtDNA is not protected by histones and mtDNA repair is ineffective [81]. Furthermore, a potentially important source of replication infidelity is damage due to ROS. pol γ, was demonstrated to stably misincorporate highly mutagenic 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) opposite template adenine in a complete DNA synthesis reaction
Because of the susceptibility of mtDNA to oxidative damage and replication errors, it is vital to protect mtDNA genomic stability to preserve health. Mitochondrial localization of p53 was observed in non-stressed and stressed cells [26]. Mitochondrial p53 (mit-p53) levels are proportional to total p53 levels, and the majority of p53 was present inside the intra-mitochondrial compartment-matrix, in which mtDNA is located [85]. The mit-p53 physically and functionally interacts with both, mtDNA and pol γ [86].
Notably, with the exception of NER, components of these nuclear DNA repair pathways are also shared in mtDNA maintenance. Several studies illustrated the participation of p53 in mtDNA repair:
53 enhances mitochondrial BER (mtBER) through direct interaction with the repair complex in mouse liver and cancer cells [87]. p53 modulates mtBER through the stimulation of the nucleotide incorporation step.
p53 interacts physically with human mtSSB (HmtSSB)
Intra-mitochondrial p53 provides an error-repair proofreading function for pol γ by excision of misincorporated nucleotides [89]. The p53 in mitochondria may affect the accuracy of DNA synthesis by acting as an external proofreader, thus reducing the production of polymerization errors.
In addition to having a critical role in preservation of genome integrity, alterations in the expression, and function of DNA repair proteins are a major facilitator of tumor responses to chemo- and radiotherapy, commonly functioning by inducing DNA damage in tumor cells. Nucleoside analogs, clinically active in cancer chemotherapy (
The cytotoxic activity of gemcitabine (2′2’-difluorodeoxycitidine, dFdC) was strongly correlated with the amount of dFdCMP incorporated into cellular DNA [92]. The p53 protein recognizes dFdCMP-DNA in whole cells, as evidenced by the fact that p53 protein rapidly accumulated in the nuclei of the gemcitabine treated ML-1 cells [93]. Although, the excision of the dFdCMP from the 3′-end of the DNA was slower than the excision of mismatched nucleotides in whole cells with wtp53 (ML-1) and not detectable in CEM cells harboring mutant p53. ML-1 cells were more sensitive to the cytotoxic effect of the drugs compared to the p53-null or mutant cells. The recognition of the incorporated NAs in DNA by wtp53 did not confer resistance to gemcitabine, but may have facilitated the apoptotic cell death process. It was reported that treatment with gemcitabine resulted in an increased production of DNA-dependent protein kinase (DNA-PK) and p53 complex in nucleus, that interacts with the gemcitabine-containing DNA [93, 94]. DNA-PK and p53 sensor complex may serve as a mechanism to activate the pro-apoptosis function of p53. Apparently, the prolonged existence of the NA-stalled DNA end induced the kinase activity, which subsequently phosphorylated p53 and activated the downstream pathways leading to apoptosis.
Remarkably, p53 present in complex with DNA-PK exhibited 3′ → 5′ exonuclease activity with mismatched DNA, however the active p53 was unable of excising efficiently the incorporated drug from NA-DNA construct containing gemcitabine at the 3′-end [94]. Notably, the specific effects of gemcitabine exposure appeared to vary depending on the duration of treatment and upon the cell line.
It should be pointed out, that wtp53 in ML-1 cells removed the purine nucleoside analog fludarabine (F-ara-A) more efficiently than gemcitabine [93]. Further studies are needed to assess the role of p53 in cellular response to various anti-cancer purine and pyrimidine NA-induced DNA damage.
HIV-1 RT readily utilizes many NAs and the incorporation of nucleoside RT inhibitors (NRTIs) into the 3′-end of viral DNA leads to chain termination of viral DNA synthesis in cytoplasm [88, 95]. p53 protein in the cytoplasm excises the incorporated NAs during both RNA-dependent and DNA-dependent DNA polymerization reactions, although less efficiently than the mismatched nucleotides; longer incubation times were required for excision of the terminally incorporated analogs [96]. The data suggest that p53 in cytoplasm may act as an external proofreader for NA incorporation and confer cellular resistance mechanism to the anti-viral compounds.
Pol γ is unique among the cellular replicative DNA polymerases as it is sensitive to inhibition by nucleoside analogue reverse transcriptase inhibitors (NRTIs) used in the treatment of HIV, which can cause an induced mitochondrial toxicity [97]. Acquired mitochondrial toxicity occurs as a consequence of incorporation of NA into mtDNA or inhibition of mtDNA replication or both. A terminally incorporated NA may be removed by p53 in mitochondria [97]. The removal of the incorporated NA by p53 exonuclease, indicates that the presence of the cellular component-p53 in mitochondria may be important in defining the cytotoxicity of NAs toward mitochondrial replication, thus affecting risk–benefit approach (NA toxicity versus viral inhibition) [98, 99]. Apparently, the presence of p53 in mitochondria may be important, as the excision of the mispair and NA by p53 is favorable event for mitochondrial function.
p53 is a multifunctional protein with positive and negative effects. In general, drug resistance that occurs in cancer chemotherapy and antiviral therapy is a negative event that will decrease the efficacy of the treatment. The recognition and removal of NA from drug-containing DNAs by p53 exonuclease activity in various compartments of the cell may play a role in decreasing drug activity, leading to various biological outcomes: 1)the excision of the incorporated NA from DNA in nucleus may confer resistance to the drugs (negative effect) [93]; 2)the removal of the NA by p53 from DNA incorporated by HIV-1 RT in cytoplasm may confer resistance to the drugs by non-viral mechanism (negative effect) [96] and 3)the excision of NAs from mitochondrial DNA may decrease the potential for chain termination and host toxicity (positive effect) [97].
The genome is constantly under attack from extrinsic and intrinsic damaging agents. Uracil (dU) mis-incorporation in DNA is an intrinsic factor resulting in genomic instability and DNA mutations. The excessive levels of genomic uracil in DNA can modify gene expression by interfering with promoter binding and transcription inhibition, can change transcriptional stalling, or induce DNA strand breaks leading to apoptosis. The factors that influence uracil levels in DNA are cytosine deamination, de novo thymidylate (dTMP) biosynthesis, salvage dTMP biosynthesis, and DNA repair. Furthermore, mis-incorporation occurs when DNA polymerases incorporate dUTP into DNA, in place of dTTP, and the rate of misincorporation is believed to be determined by the intracellular dUTP:dTTP ratio [100, 101]. The enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase), which facilitates the conversion of dUTP to dUMP further utilized by thymidylate synthase (TS) for synthesis of dTMP, avoids mis-incorporation of dU into DNA in nucleus by decreasing the dUTP/dTTP ratio [101]. The misincorporation of dU, as a result of accumulation of dUTP, plays a critical role in cytotoxicity mediated by TS inhibitors, such as the commonly used anticancer drug 5-fluorouracil (5-FU) [102]. DNA directed cytotoxicity of chemotherapeutic agents (e.g.5-FU) not only depends on accumulation of dUTP, but may also be determined by the efficiency of the DNA repair mechanisms (e.g. excision repair) which preclude the incidence of the mistake.
Pol γ in mitochondria is incapable to readily correct U:A mismatches [11]. HIV-1 RT in the cytoplasm of HIV-infected cells efficiently inserts the non-canonical dUTP into the proviral DNA and extends the dU-terminated DNA [103]. The misincorporation of dUTP leads to mutagenesis, and to down-regulation of viral gene expression [104].
Within the context of error-correction events, p53 as a DNA binding protein, contributes an external proofreading function; upon excision of the dU, the p53 dissociates, thus letting the transfer of the substrate with the correct 3′-terminus to DNA polymerase and renewal of DNA synthesis.
The biochemical data show that the procession of U:A and mismatched U:G lesions enhances in the presence of recombinant or endogenous cytoplasmic or mitochondrial p53 [105]. p53 in cytoplasm can participate through the intermolecular pathway in a dU-damage-associated repair mechanism by its ability to remove preformed 3′-terminal dUs, thus preventing further extension of 3’ dU-terminated primer during DNA synthesis by HIV-1 RT. Similarly, p53 in mitochondria can function as an exonuclease/proofreader for pol γ by either decreasing the incorporation of non-canonical dUTP into DNA or by promoting the excision of incorporated dU from nascent DNA, thus expanding the spectrum of DNA damage sites exploited for proofreading as a trans-acting protein [106].
During genomic DNA replication another form of replication errors arises during the incorporation of nucleotides carrying the correct base, but the wrong sugar at substantial rates [107]. DNA polymerases often incorporate ribonucleoside triphosphates (rNTPs) into DNA because of the much higher concentration of rNTPs than that of dNTPs in the cellular nucleotide pool. Indeed, more than 106 rNMPs are incorporated during one round of replication of a mammalian genome [107]. Newly incorporated rNMPs destabilize DNA and pose a major threat to genome integrity due to their reactive 2’OH group. The inserted rNs are the most abundant non-canonical nucleotides in the genome. Failure of rN removal is associated with genome instability in the form of mutagenesis, replication stress, DNA breaks, and chromosomal rearrangements. The aberrant accumulation of rNs in the genome leads to human diseases including Aicardi–Goutières syndrome (AGS), the severe autoimmune disease, and tumorigenesis [108]. Mammalian cells have developed strategies to prevent persistent rN accumulation. In eukaryotes, rNs embedded into DNA are primarily repaired by RNase H2-initiated repair pathway. Ribonucleotide excision repair (RER) may be directly coupled to replication and results in rapid post-replicative repair of rNMPs [108]. Remarkably, exonuclease-proficient yeast and human DNA polymerases can proofread incorporated rNs, albeit inefficiently [107].
Recent studies have demonstrated the importance of p53 in 3′-terminal RER pathway through a functional collaboration with HIV-1 RT, acting in a coordinated manner to attain higher fidelity. p53, functioning as a trans-acting proofreader in cytoplasm, can decrease the stable incorporation of rNs, into DNA by HIV-1 RT [109]. p53 can influence events needed for RER by possessing the compatible biochemical properties: p53 is pertinent in the correction of replication errors produced by HIV-1 RT during distinct steps of rN incorporation through intermolecular pathway: by removal pre-existing 3′-terminal rN; by reducing rN incorporation; by preventing extension of a 3′ rN-terminated primer, by attenuating stable incorporation of rNs. Thus, p53, functioning as a trans-acting proofreader in cytoplasm, can decrease the stable incorporation of rNs.
The fact that p53 in cytoplasm can edit an incorrect sugar irrespective of the nature of base, expands the role of p53 as a proofreader in the repair of replication errors by removing both a base mismatch and an incorrect sugar.
Mammalian cells have evolved multiple strategies to safeguard the genetic information to prevent the fixation of genetic damage induced by endogenous and exogenous mutagens [16]. p53 protein plays a crucial role in the regulation of cell fate determination in response to a variety of cellular stresses. p53 may exert the functional heterogeneity in its non-induced and in its activated state [16]. Remarkably, DNA repair transcription-independent functions of wtp53, contributing to tumor suppression, were found to protect cells from DNA damage independently of the transcription-mediated functions of p53 [25]. Thus, a more comprehensive understanding of how p53 transcription- independent functions are induced in response to a variety of cellular insults is vital. This report focuses on direct roles of p53 in DNA repair during DNA replication in various compartments of the cell. Apparently, p53 has more than one contributions to DNA replication fidelity, which could depend on sub-cellular localization of p53, on the type and incidence of replication obstacles, on the levels of p53 protein [28].
p53 is able to elicit a spectrum of different effective DNA repair pathways in nucleus, cytoplasm and mitochondria (Figure 4). Within the nucleus, p53 regulates different repair mechanisms, in response to endogenous and exogenous replicative stress
p53 functions in DNA repair. p53 under both normal and stress conditions, can help cellular and viral DNA polymerases to promote the repair of DNA in various cellular compartments. The result of p53 activation depends on many variables, including the extent of the stress or damage. In this model, basal p53 activity or that induced by stress signals elicits the protector responses that support the repair of genotoxic damage by various pathways.
In the cytoplasm, p53 may contribute effective proofreading for exonuclease-deficient DNA polymerases (
Within the mitochondria, various studies illustrated the participation of p53 in mtDNA repair in a variety of systems: a)p53 enhances BER through direct interaction with the repair complex in mouse liver and cancer cells [87]. b) Intra-mitochondrial p53 provides an error-repair proofreading function for pol γ by excision of misincorporated nucleotides [89]. c)p53 is proficient of hydrolyzing the 8-oxo-7,8-dihydro-2′-deoxy-guanosine (8-oxodG) present at the 3′-end of DNA, a well-known marker of oxidative stress [88]. d)p53 regulates mtDNA copy number, which may impact mitochondrial and cellular functions [112].
Therapeutic strategies based on p53 are particularly interesting because they exploit the cancer cell’s intrinsic genome instability and predisposition to cell death-apoptosis [90, 91]. The role of p53 is predominantly relevant with respect to the development of anticancer and antiviral therapies. Removal of drugs by 3′ → 5′ exonuclease activity may also facilitate resistance to anti-cancer or anti-viral treatments. Clinical drug resistance limits the efficacy of these compounds. Uncovering the mechanisms, which are responsible for DNA repair of NA-induced DNA damage will have therapeutic value. The p53 protein is able to remove incorporated NA. The stress induced activation of p53 that occurs during anti-cancer or anti-viral therapy has negative and positive effects. p53 may remove incorporated therapeutic NAs from DNA or trigger apoptosis. More studies regarding functions of p53 in genome integrity and cancer evolution may facilitate drug screening and better design of therapeutic approaches.
The functional interaction between p53 and DNA polymerase may have important consequences for the maintenance of genomic integrity and in the development of p53- targeted clinical therapies. Further assessments are required to establish the role of p53 in DNA replication and the significance of these functions in various cellular compartments and treatment responses. Studies on the biology of various mutant p53 isoforms and their interaction with the factors involved in DNA repair and apoptosis, will be relevant to establish whether the direct involvement of p53 in DNA repair is a tumor suppressor function of this important anti-oncogene. Characterization of exonuclease-deficient H115N mutant p53 revealed that although exonuclease-mutant H115N p53 can induce cell cycle arrest more efficiently than wild-type p53, its ability to produce apoptosis in DNA damaged cells is markedly impaired [113]. By utilizing various function-mutant p53 isoforms, more studies must be conducted on the biology of mutant p53 forms and their interaction with the factors involved in DNA repair and apoptosis, in order to recognize the molecular mechanisms that mediate p53-dependent control of DNA replication by cellular and viral DNA polymerases.
p53 has a dual role in response to therapy, as exonuclease that by excision of incorporated anti-cancer drugs may confer resistance to drugs or as mediator of cell death induced by chemotherapy [93]. p53, by removal of the incorporated NA, could confer a cellular resistance mechanism to the antiviral compounds. Finally, the excision of NAs from mitochondrial DNA may decrease the potential for chain termination and host toxicity. These features could serve as a template for the development of p53-targeting therapies.
The control of the viral mutation rate could be a practical anti-retroviral strategy. The mutagenic capacity of a low fidelity DNA polymerase will be decreased through increase in exonuclease concentration or exonuclease targeting (increase in local p53 concentration). It is important to further elucidate the molecular mechanisms involved in governing fidelity not only at a molecular level (
A major issue in the future would be to characterize the cellular and biological functions of p53 in mitochondria in response to various stresses. There are many missing links about the biological functions of mitochondrial p53 that are required to be investigated. Whether p53 defines the percent of mutated mtDNA (heteroplasmy in a cell)? Uncovering the mechanisms by which pol γ-mediated mtDNA mutations and depletion are manifested in cells in the absence and presence of p53 is significant step in understanding underlying causes for mtDNA–related diseases. Depletion and mutation of mtDNA may lead to cellular respiratory dysfunction and release of reactive oxidative species, resulting in cellular damage [99]. Future NAs should provide higher specificity for HIV-RT and lower incorporation by pol γ to diminish mitochondrial toxicity. Whether the effective targeting of p53 in mitochondria by error-correction functions, may result in decrease of mitochondrial toxicity in response to conventional anti-viral therapies? Understanding how p53 can be imported into mitochondria, will be important and could contribute toward the design of new therapies for various diseases.
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El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/5612.jpg",editedByType:"Edited by",editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5494",title:"Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis",subtitle:null,isOpenForSubmission:!1,hash:"7b3b6a2700d7fd0511770bf77290a422",slug:"chinese-medical-therapies-for-diabetes-infertility-silicosis-and-the-theoretical-basis",bookSignature:"Xing-Tai Li",coverURL:"https://cdn.intechopen.com/books/images_new/5494.jpg",editedByType:"Edited by",editors:[{id:"73821",title:"Dr.",name:"Xing-Tai",middleName:null,surname:"Li",slug:"xing-tai-li",fullName:"Xing-Tai Li"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2975",title:"Complementary Therapies for the Contemporary Healthcare",subtitle:null,isOpenForSubmission:!1,hash:"604c4ba43197c3ba1506c55c763d4ca7",slug:"complementary-therapies-for-the-contemporary-healthcare",bookSignature:"Marcelo Saad and Roberta de Medeiros",coverURL:"https://cdn.intechopen.com/books/images_new/2975.jpg",editedByType:"Edited by",editors:[{id:"51991",title:"Prof.",name:"Marcelo",middleName:null,surname:"Saad",slug:"marcelo-saad",fullName:"Marcelo Saad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"542",title:"A Compendium of Essays on Alternative Therapy",subtitle:null,isOpenForSubmission:!1,hash:"a805c1d2d8449dcecd52eb7a48d2e6b1",slug:"a-compendium-of-essays-on-alternative-therapy",bookSignature:"Arup Bhattacharya",coverURL:"https://cdn.intechopen.com/books/images_new/542.jpg",editedByType:"Edited by",editors:[{id:"66982",title:"Dr.",name:"Arup",middleName:null,surname:"Bhattacharya",slug:"arup-bhattacharya",fullName:"Arup Bhattacharya"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"643",title:"Recent Advances in Theories and Practice of Chinese Medicine",subtitle:null,isOpenForSubmission:!1,hash:"499a7fabf489d2502de4616a4c7f3da0",slug:"recent-advances-in-theories-and-practice-of-chinese-medicine",bookSignature:"Haixue Kuang",coverURL:"https://cdn.intechopen.com/books/images_new/643.jpg",editedByType:"Edited by",editors:[{id:"44740",title:"Prof.",name:"Haixue",middleName:null,surname:"Kuang",slug:"haixue-kuang",fullName:"Haixue Kuang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:13,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"61866",doi:"10.5772/intechopen.76139",title:"Plants Secondary Metabolites: The Key Drivers of the Pharmacological Actions of Medicinal Plants",slug:"plants-secondary-metabolites-the-key-drivers-of-the-pharmacological-actions-of-medicinal-plants",totalDownloads:8735,totalCrossrefCites:52,totalDimensionsCites:132,abstract:"The vast and versatile pharmacological effects of medicinal plants are basically dependent on their phytochemical constituents. Generally, the phytochemical constituents of plants fall into two categories based on their role in basic metabolic processes, namely primary and secondary metabolites. Primary plant metabolites are involved in basic life functions; therefore, they are more or less similar in all living cells. On the other hand, secondary plant metabolites are products of subsidiary pathways as the shikimic acid pathway. In the course of studying, the medicinal effect of herbals is oriented towards the secondary plant metabolites. Secondary plant metabolites played an important role in alleviating several aliments in the traditional medicine and folk uses. In modern medicine, they provided lead compounds for the production of medications for treating various diseases from migraine up to cancer. Secondary plant metabolites are classified according to their chemical structures into various classes. In this chapter, we will be presenting various classes of secondary plant metabolites, their distribution in different plant families and their important medicinal uses.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Rehab A. Hussein and Amira A. El-Anssary",authors:[{id:"212117",title:"Dr.",name:"Rehab",middleName:null,surname:"Hussein",slug:"rehab-hussein",fullName:"Rehab Hussein"},{id:"221140",title:"Dr.",name:"Amira",middleName:null,surname:"El-Anssary",slug:"amira-el-anssary",fullName:"Amira El-Anssary"}]},{id:"64851",doi:"10.5772/intechopen.80348",title:"Herbal Medicines in African Traditional Medicine",slug:"herbal-medicines-in-african-traditional-medicine",totalDownloads:14014,totalCrossrefCites:25,totalDimensionsCites:45,abstract:"African traditional medicine is a form of holistic health care system organized into three levels of specialty, namely divination, spiritualism, and herbalism. The traditional healer provides health care services based on culture, religious background, knowledge, attitudes, and beliefs that are prevalent in his community. Illness is regarded as having both natural and supernatural causes and thus must be treated by both physical and spiritual means, using divination, incantations, animal sacrifice, exorcism, and herbs. Herbal medicine is the cornerstone of traditional medicine but may include minerals and animal parts. The adjustment is ok, but may be replaced with –‘ Herbal medicine was once termed primitive by western medicine but through scientific investigations there is a better understanding of its therapeutic activities such that many pharmaceuticals have been modeled on phytochemicals derived from it. Major obstacles to the use of African medicinal plants are their poor quality control and safety. Traditional medical practices are still shrouded with much secrecy, with few reports or documentations of adverse reactions. However, the future of African traditional medicine is bright if viewed in the context of service provision, increase of health care coverage, economic potential, and poverty reduction. Formal recognition and integration of traditional medicine into conventional medicine will hold much promise for the future.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Ezekwesili-Ofili Josephine Ozioma and Okaka Antoinette Nwamaka\nChinwe",authors:[{id:"191264",title:"Prof.",name:"Josephine",middleName:"Ozioma",surname:"Ezekwesili-Ofili",slug:"josephine-ezekwesili-ofili",fullName:"Josephine Ezekwesili-Ofili"},{id:"211585",title:"Prof.",name:"Antoinette",middleName:null,surname:"Okaka",slug:"antoinette-okaka",fullName:"Antoinette Okaka"}]},{id:"54028",doi:"10.5772/67291",title:"Chemical Composition and Biological Activities of Mentha Species",slug:"chemical-composition-and-biological-activities-of-mentha-species",totalDownloads:7440,totalCrossrefCites:12,totalDimensionsCites:41,abstract:"The genus Mentha L. (Lamiaceae) is distributed all over the world and can be found in many environments. Mentha species, one of the world’s oldest and most popular herbs, are widely used in cooking, in cosmetics, and as alternative or complementary therapy, mainly for the treatment of gastrointestinal disorders like flatulence, indigestion, nausea, vomiting, anorexia, and ulcerative colitis. Furthermore, it is well documented that the essential oil and extracts of Mentha species possess antimicrobial, fungicidal, antiviral, insecticidal, and antioxidant properties. The economic importance of mints is also evident; mint oil and its constituents and derivatives are used as flavoring agents throughout the world in food, pharmaceutical, herbal, perfumery, and flavoring industry. To provide a scientific basis for their traditional uses, several studies have been conducted to determine the chemical composition of mints and assess their biological activities. This chapter describes the therapeutic effects and uses of Mentha species and their constituents, particularly essential oils and phenolic compounds; some additional biological activities will also be considered.",book:{id:"5612",slug:"aromatic-and-medicinal-plants-back-to-nature",title:"Aromatic and Medicinal Plants",fullTitle:"Aromatic and Medicinal Plants - Back to Nature"},signatures:"Fatiha Brahmi, Madani Khodir, Chibane Mohamed and Duez Pierre",authors:[{id:"193281",title:"Dr.",name:"Fatiha",middleName:null,surname:"Brahmi",slug:"fatiha-brahmi",fullName:"Fatiha Brahmi"},{id:"199693",title:"Prof.",name:"Khodir",middleName:null,surname:"Madani",slug:"khodir-madani",fullName:"Khodir Madani"},{id:"199694",title:"Prof.",name:"Pierre",middleName:null,surname:"Duez",slug:"pierre-duez",fullName:"Pierre Duez"},{id:"203738",title:"Prof.",name:"Mohamed",middleName:null,surname:"Chibane",slug:"mohamed-chibane",fullName:"Mohamed Chibane"}]},{id:"58270",doi:"10.5772/intechopen.72437",title:"Toxicity and Safety Implications of Herbal Medicines Used in Africa",slug:"toxicity-and-safety-implications-of-herbal-medicines-used-in-africa",totalDownloads:3323,totalCrossrefCites:14,totalDimensionsCites:36,abstract:"The use of herbal medicines has seen a great upsurge globally. In developing countries, many patronize them largely due to cultural acceptability, availability and cost. In developed countries, they are used because they are natural and therefore assumed to be safer than allopathic medicines. In recent times, however, there has been a growing concern about their safety. This has created a situation of ambivalence in discussions regarding their use. Some medicinal plants are intrinsically toxic by virtue of their constituents and can cause adverse reactions if inappropriately used. Other factors such as herb-drug interactions, lack of adherence to good manufacturing practice (GMP), poor regulatory measures and adulteration may also lead to adverse events in their use. Many in vivo tests on aqueous extracts largely support the safety of herbal medicines, whereas most in vitro tests on isolated single cells mostly with extracts other than aqueous ones show contrary results and thus continue the debate on herbal medicine safety. It is expected that toxicity studies concerning herbal medicine should reflect their traditional use to allow for rational discussions regarding their safety for their beneficial use. While various attempts continue to establish the safety of various herbal medicines in man, their cautious and responsible use is required.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Merlin L.K. Mensah, Gustav Komlaga, Arnold D. Forkuo, Caleb\nFirempong, Alexander K. Anning and Rita A. Dickson",authors:[{id:"190435",title:"Dr.",name:"Caleb",middleName:null,surname:"Firempong",slug:"caleb-firempong",fullName:"Caleb Firempong"},{id:"212111",title:"Dr.",name:"Gustav",middleName:null,surname:"Komlaga",slug:"gustav-komlaga",fullName:"Gustav Komlaga"},{id:"217045",title:"Dr.",name:"Arnold Forkuo",middleName:null,surname:"Donkor",slug:"arnold-forkuo-donkor",fullName:"Arnold Forkuo Donkor"},{id:"217049",title:"Prof.",name:"Merlin Lincoln Kwao",middleName:null,surname:"Mensah",slug:"merlin-lincoln-kwao-mensah",fullName:"Merlin Lincoln Kwao Mensah"},{id:"217488",title:"Dr.",name:"Alexander K.",middleName:null,surname:"Anning",slug:"alexander-k.-anning",fullName:"Alexander K. Anning"},{id:"223959",title:"Prof.",name:"Akosua Rita",middleName:null,surname:"Dickson",slug:"akosua-rita-dickson",fullName:"Akosua Rita Dickson"}]},{id:"26489",doi:"10.5772/28224",title:"Alternative and Traditional Medicines Systems in Pakistan: History, Regulation, Trends, Usefulness, Challenges, Prospects and Limitations",slug:"alternative-and-traditional-medicines-systems-in-pakistan-history-regulation-trends-usefulness-chall",totalDownloads:9179,totalCrossrefCites:8,totalDimensionsCites:20,abstract:null,book:{id:"542",slug:"a-compendium-of-essays-on-alternative-therapy",title:"A Compendium of Essays on Alternative Therapy",fullTitle:"A Compendium of Essays on Alternative Therapy"},signatures:"Shahzad Hussain, Farnaz Malik, Nadeem Khalid, Muhammad Abdul Qayyum and Humayun Riaz",authors:[{id:"73162",title:"Dr.",name:"Shahzad",middleName:null,surname:"Hussain",slug:"shahzad-hussain",fullName:"Shahzad Hussain"},{id:"82266",title:"Dr.",name:"Farnaz",middleName:null,surname:"Malik",slug:"farnaz-malik",fullName:"Farnaz Malik"},{id:"124185",title:"Dr.",name:"Humayun",middleName:null,surname:"Riaz",slug:"humayun-riaz",fullName:"Humayun Riaz"},{id:"124186",title:"Mr.",name:"Muhammad Abdul",middleName:null,surname:"Qayyum",slug:"muhammad-abdul-qayyum",fullName:"Muhammad Abdul Qayyum"},{id:"125340",title:"Mr.",name:"Nadeem",middleName:null,surname:"Khalid",slug:"nadeem-khalid",fullName:"Nadeem Khalid"}]}],mostDownloadedChaptersLast30Days:[{id:"64851",title:"Herbal Medicines in African Traditional Medicine",slug:"herbal-medicines-in-african-traditional-medicine",totalDownloads:13973,totalCrossrefCites:25,totalDimensionsCites:45,abstract:"African traditional medicine is a form of holistic health care system organized into three levels of specialty, namely divination, spiritualism, and herbalism. The traditional healer provides health care services based on culture, religious background, knowledge, attitudes, and beliefs that are prevalent in his community. Illness is regarded as having both natural and supernatural causes and thus must be treated by both physical and spiritual means, using divination, incantations, animal sacrifice, exorcism, and herbs. Herbal medicine is the cornerstone of traditional medicine but may include minerals and animal parts. The adjustment is ok, but may be replaced with –‘ Herbal medicine was once termed primitive by western medicine but through scientific investigations there is a better understanding of its therapeutic activities such that many pharmaceuticals have been modeled on phytochemicals derived from it. Major obstacles to the use of African medicinal plants are their poor quality control and safety. Traditional medical practices are still shrouded with much secrecy, with few reports or documentations of adverse reactions. However, the future of African traditional medicine is bright if viewed in the context of service provision, increase of health care coverage, economic potential, and poverty reduction. Formal recognition and integration of traditional medicine into conventional medicine will hold much promise for the future.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Ezekwesili-Ofili Josephine Ozioma and Okaka Antoinette Nwamaka\nChinwe",authors:[{id:"191264",title:"Prof.",name:"Josephine",middleName:"Ozioma",surname:"Ezekwesili-Ofili",slug:"josephine-ezekwesili-ofili",fullName:"Josephine Ezekwesili-Ofili"},{id:"211585",title:"Prof.",name:"Antoinette",middleName:null,surname:"Okaka",slug:"antoinette-okaka",fullName:"Antoinette Okaka"}]},{id:"61866",title:"Plants Secondary Metabolites: The Key Drivers of the Pharmacological Actions of Medicinal Plants",slug:"plants-secondary-metabolites-the-key-drivers-of-the-pharmacological-actions-of-medicinal-plants",totalDownloads:8695,totalCrossrefCites:52,totalDimensionsCites:131,abstract:"The vast and versatile pharmacological effects of medicinal plants are basically dependent on their phytochemical constituents. Generally, the phytochemical constituents of plants fall into two categories based on their role in basic metabolic processes, namely primary and secondary metabolites. Primary plant metabolites are involved in basic life functions; therefore, they are more or less similar in all living cells. On the other hand, secondary plant metabolites are products of subsidiary pathways as the shikimic acid pathway. In the course of studying, the medicinal effect of herbals is oriented towards the secondary plant metabolites. Secondary plant metabolites played an important role in alleviating several aliments in the traditional medicine and folk uses. In modern medicine, they provided lead compounds for the production of medications for treating various diseases from migraine up to cancer. Secondary plant metabolites are classified according to their chemical structures into various classes. In this chapter, we will be presenting various classes of secondary plant metabolites, their distribution in different plant families and their important medicinal uses.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Rehab A. Hussein and Amira A. El-Anssary",authors:[{id:"212117",title:"Dr.",name:"Rehab",middleName:null,surname:"Hussein",slug:"rehab-hussein",fullName:"Rehab Hussein"},{id:"221140",title:"Dr.",name:"Amira",middleName:null,surname:"El-Anssary",slug:"amira-el-anssary",fullName:"Amira El-Anssary"}]},{id:"77433",title:"Extraction of Bioactive Compounds from Medicinal Plants and Herbs",slug:"extraction-of-bioactive-compounds-from-medicinal-plants-and-herbs",totalDownloads:1041,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Human beings have relied on herbs and medicinal plants as sources of food and remedy from time immemorial. Bioactive compounds from plants are currently the subject of much research interest, but their extraction as part of phytochemical and/or biological investigations present specific challenges. Herbalists or scientists have developed many protocols of extraction of bioactive ingredients to ensure the effectiveness and the efficacy of crude drugs that were used to get relief from sickness. With the advent of new leads from plants such as morphine, quinine, taxol, artemisinin, and alkaloids from Voacanga species, a lot of attention is paid to the mode of extraction of active phytochemicals to limit the cost linked to the synthesis and isolation. Thus, the extraction of active compounds from plants needs appropriate extraction methods and techniques that provide bioactive ingredients-rich extracts and fractions. The extraction procedures, therefore, play a critical role in the yield, the nature of phytochemical content, etc. This chapter aims to present, describe, and compare extraction procedures of bioactive compounds from herbs and medicinal plants.",book:{id:"10356",slug:"natural-medicinal-plants",title:"Natural Medicinal Plants",fullTitle:"Natural Medicinal Plants"},signatures:"Fongang Fotsing Yannick Stéphane, Bankeu Kezetas Jean Jules, Gaber El-Saber Batiha, Iftikhar Ali and Lenta Ndjakou Bruno",authors:[{id:"224515",title:"Dr.",name:"Fongang Fotsing",middleName:null,surname:"Yannick Stéphane",slug:"fongang-fotsing-yannick-stephane",fullName:"Fongang Fotsing Yannick Stéphane"},{id:"227816",title:"Dr.",name:"Bankeu Kezetas",middleName:null,surname:"Jean Jules",slug:"bankeu-kezetas-jean-jules",fullName:"Bankeu Kezetas Jean Jules"},{id:"227817",title:"Prof.",name:"Lenta Ndjakou",middleName:null,surname:"Bruno",slug:"lenta-ndjakou-bruno",fullName:"Lenta Ndjakou Bruno"},{id:"349790",title:"Prof.",name:"Gaber",middleName:null,surname:"El-Saber Batiha",slug:"gaber-el-saber-batiha",fullName:"Gaber El-Saber Batiha"},{id:"357350",title:"Dr.",name:"Iftikhar",middleName:null,surname:"Ali",slug:"iftikhar-ali",fullName:"Iftikhar Ali"}]},{id:"26491",title:"Homeopathy: Treatment of Cancer with the Banerji Protocols",slug:"homeopathy-treatment-of-cancer-with-the-banerji-protocols",totalDownloads:53814,totalCrossrefCites:1,totalDimensionsCites:2,abstract:null,book:{id:"542",slug:"a-compendium-of-essays-on-alternative-therapy",title:"A Compendium of Essays on Alternative Therapy",fullTitle:"A Compendium of Essays on Alternative Therapy"},signatures:"Prasanta Banerji and Pratip Banerji",authors:[{id:"79939",title:"Dr",name:"Prasanta",middleName:null,surname:"Banerji",slug:"prasanta-banerji",fullName:"Prasanta Banerji"},{id:"79943",title:"Dr.",name:"Pratip",middleName:null,surname:"Banerji",slug:"pratip-banerji",fullName:"Pratip Banerji"}]},{id:"54028",title:"Chemical Composition and Biological Activities of Mentha Species",slug:"chemical-composition-and-biological-activities-of-mentha-species",totalDownloads:7432,totalCrossrefCites:12,totalDimensionsCites:41,abstract:"The genus Mentha L. (Lamiaceae) is distributed all over the world and can be found in many environments. Mentha species, one of the world’s oldest and most popular herbs, are widely used in cooking, in cosmetics, and as alternative or complementary therapy, mainly for the treatment of gastrointestinal disorders like flatulence, indigestion, nausea, vomiting, anorexia, and ulcerative colitis. Furthermore, it is well documented that the essential oil and extracts of Mentha species possess antimicrobial, fungicidal, antiviral, insecticidal, and antioxidant properties. The economic importance of mints is also evident; mint oil and its constituents and derivatives are used as flavoring agents throughout the world in food, pharmaceutical, herbal, perfumery, and flavoring industry. To provide a scientific basis for their traditional uses, several studies have been conducted to determine the chemical composition of mints and assess their biological activities. This chapter describes the therapeutic effects and uses of Mentha species and their constituents, particularly essential oils and phenolic compounds; some additional biological activities will also be considered.",book:{id:"5612",slug:"aromatic-and-medicinal-plants-back-to-nature",title:"Aromatic and Medicinal Plants",fullTitle:"Aromatic and Medicinal Plants - Back to Nature"},signatures:"Fatiha Brahmi, Madani Khodir, Chibane Mohamed and Duez Pierre",authors:[{id:"193281",title:"Dr.",name:"Fatiha",middleName:null,surname:"Brahmi",slug:"fatiha-brahmi",fullName:"Fatiha Brahmi"},{id:"199693",title:"Prof.",name:"Khodir",middleName:null,surname:"Madani",slug:"khodir-madani",fullName:"Khodir Madani"},{id:"199694",title:"Prof.",name:"Pierre",middleName:null,surname:"Duez",slug:"pierre-duez",fullName:"Pierre Duez"},{id:"203738",title:"Prof.",name:"Mohamed",middleName:null,surname:"Chibane",slug:"mohamed-chibane",fullName:"Mohamed Chibane"}]}],onlineFirstChaptersFilter:{topicId:"991",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81738",title:"How Do Extraction Methods and Biotechnology Influence Our Understanding and Usages of Ginsenosides?: A Critical View and Perspectives",slug:"how-do-extraction-methods-and-biotechnology-influence-our-understanding-and-usages-of-ginsenosides-a",totalDownloads:14,totalDimensionsCites:0,doi:"10.5772/intechopen.103863",abstract:"Ginseng saponins, aka ginsenosides, are bioactive phytochemicals from Panax species. Panax comes from the Greek word “panakos,” which means “cure-all.” Owing to their involvement in the creation of numerous medications and nutritional supplements, ginseng saponins play an essential part, especially in the pharmaceutical sector. The main ginsenosides (i.e., Rb1, Rb2, Rc, Rd and Rf) are extracted using a variety of extraction methods, although from a limited number of Panax species. However, more than ca 1000 unique ginsenosides and 18 Panax species have been reported so far, thus demonstrating our present challenge in better understanding of the potential medicinal uses of these compounds. Moreover, ginsenoside production and extraction methods are both time-consuming and inefficient, which has stimulated the development of several efficient extraction and biotechnological technologies to speed up these processes. In this chapter, we highlighted the need to expand the cutting-edge research approaches involving these unique ginsenosides to better understand their biological activities and discover new bioactive ginsenosides as well. The main objective of this chapter is to discuss the undiscovered aspects and limitations of the current biotechnological and extraction technologies, eventually to provide a platform for the production of these unique ginsenosides.",book:{id:"10539",title:"Ginseng - Modern Aspects of the Famed Traditional Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/10539.jpg"},signatures:"Christophe Hano, Duangjai Tungmunnithum, Samantha Drouet, Mohamed Addi, Saikat Gantait and Jen-Tsung Chen"},{id:"78426",title:"Ginseng: Pharmacological Action and Phytochemistry Prospective",slug:"ginseng-pharmacological-action-and-phytochemistry-prospective",totalDownloads:139,totalDimensionsCites:0,doi:"10.5772/intechopen.99646",abstract:"Ginseng, the root of Panax species is a well-known conventional and perennial herb belonging to Araliaceae of various countries China, Korea, and Japan that is also known as the king of all herbs and famous for many years worldwide. It is a short underground rhizome that is associated with the fleshy root. Pharmacognostic details of cultivation and collection with different morphological characters are discussed. Phytocontent present is saponins glycosides, carbohydrates, polyacetylenes, phytosterols, nitrogenous substances, amino acids, peptides, vitamins, volatile oil, minerals, and enzymes details are discussed. The main focusing of the bioactive constituent of ginseng is ginsenosides are triterpenoid saponin glycosides having multifunctional pharmacological activities including anticancer, anti-inflammatory, antimicrobial, antioxidant and many more will be discussed. Ginseng is helpful in the treatment of microbial infection, inflammation, oxidative stress, diabetes, and obesity. Nanoparticles and nanocomposite film technologies had developed in it as novel drug delivery for cancer, inflammation, and neurological disorder. Multifaceted ginseng will be crucial for future development. This chapter review pharmacological, phytochemical, and pharmacognostic studies of this plant.",book:{id:"10539",title:"Ginseng - Modern Aspects of the Famed Traditional Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/10539.jpg"},signatures:"Shuchi Dave Mehta, Priyanka Rathore and Gopal Rai"},{id:"76168",title:"Ginseng in Hair Growth and Viability",slug:"ginseng-in-hair-growth-and-viability",totalDownloads:214,totalDimensionsCites:0,doi:"10.5772/intechopen.96962",abstract:"The hair follicle is the unique organ that has the capacity of undergoing cyclic transformations following periods of growth (anagen), regression (catagen), and rest (telogen) regenerating itself to restart the cycle. The dynamic capacity of hair to growth and rest enables mammals to control hair growth and length in different body side and to change their coats. Unlike what is observed in many animals in which the pelage synchronously passes from one phase of the cycle to other all stages of growth cycle are simultaneously found in the human pelage, the growth pattern is a mosaic where the hair cycling staging of one hair root is completely independent of it nearest hair follicle, meaning that each follicular unit (FU) can contain follicles in different stages at any given time. A variety of factors, such as nutritional status, hormones, exposure to radiations, chemotherapy or radiotherapy, environmental pollution or drugs may affect hair growth, and affects the number of hairs, this progressive hair loss has a cosmetic and social impact that often significantly affects social and psychological well-being of the patient that suffers from this hair loss. Although a number of therapies, such as finasteride and minoxidil, are approved medications, a wide variety of classes of phytochemicals and natural products, including those present in ginseng are being testing. The purpose of this chapter is to focus on study the potential of ginseng and its metabolites in hair loss.",book:{id:"10539",title:"Ginseng - Modern Aspects of the Famed Traditional Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/10539.jpg"},signatures:"Mirecki-Garrido Mercedes, Santana-Farré Ruymán, Guedes-Hernandez Noelia, Jimenez-Acosta Francisco and Lorenzo-Villegas Dionisio L."},{id:"75231",title:"Bioinformatics Exploration of Ginseng: A Review",slug:"bioinformatics-exploration-of-ginseng-a-review",totalDownloads:166,totalDimensionsCites:1,doi:"10.5772/intechopen.96167",abstract:"Ginseng contains an extraordinarily complex mixture of chemical constituents that can vary with the species used, the place of origin, and the growing conditions. Various computational analyses which include genomics, transcriptomics, proteomics and bioinformatics have been used to study ginseng plant. A genome-scale metabolic network offers a holistic view of ginsenoside biosynthesis, helps to predict genes associated with the production of pharmacologically vital dammarane-type ginsenosides, and provides insight for improving medicinal values of ginseng by genomics-based breeding. The draft genomic architecture of tetraploid P. ginseng cultivar (cv.) Chunpoong (ChP) by de novo genome assembly, was found to be 2.98 Gbp and consist of 59,352 annotated genes. Presently, bioinformatics exploration of ginseng includes studies on its P-glycoproteins, the impact of cytochrome P-450 on ginseng pharmacokinetics, as well as target prediction and differential gene expression network analyses. This study applauded Betasitosterol and Daucosterin as ginseng bioactive constituents that have several potential pharmacological effects in human, by modulating several proteins which include androgen receptor, HMG-CoA reductase, interlukin-2, and consequently impact the signaling cascade of several kinases such as mitogen-activated protein kinases (MAPKs), as well as many transcription factors such as polycomb protein SUZ12.",book:{id:"10539",title:"Ginseng - Modern Aspects of the Famed Traditional Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/10539.jpg"},signatures:"Toluwase Hezekiah Fatoki"}],onlineFirstChaptersTotal:4},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"May 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",isOpenForSubmission:!0,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"11",title:"Cell Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/11.jpg",isOpenForSubmission:!0,editor:{id:"133493",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/133493/images/3091_n.jpg",biography:"Prof. Dr. Angel Catalá \r\nShort Biography Angel Catalá was born in Rodeo (San Juan, Argentina). He studied \r\nchemistry at the Universidad Nacional de La Plata, Argentina, where received aPh.D. degree in chemistry (Biological Branch) in 1965. From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",isOpenForSubmission:!0,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}}},{id:"13",title:"Plant Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/13.jpg",isOpenForSubmission:!0,editor:{id:"332229",title:"Prof.",name:"Jen-Tsung",middleName:null,surname:"Chen",slug:"jen-tsung-chen",fullName:"Jen-Tsung Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/332229/images/system/332229.png",biography:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung, Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture. Dr. Chen\\'s research interests include bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. He has published more than ninety scientific papers and serves as an editorial board member for Plant Methods, Biomolecules, and International Journal of Molecular Sciences.",institutionString:"National University of Kaohsiung",institution:{name:"National University of Kaohsiung",institutionURL:null,country:{name:"Taiwan"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:43,paginationItems:[{id:"81796",title:"Apoptosis-Related Diseases and Peroxisomes",doi:"10.5772/intechopen.105052",signatures:"Meimei Wang, Yakun Liu, Ni Chen, Juan Wang and Ye Zhao",slug:"apoptosis-related-diseases-and-peroxisomes",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"The Metabolic Role of Peroxisome in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81723",title:"Peroxisomal Modulation as Therapeutic Alternative for Tackling Multiple Cancers",doi:"10.5772/intechopen.104873",signatures:"Shazia Usmani, Shadma Wahab, Abdul Hafeez, Shabana Khatoon and Syed Misbahul Hasan",slug:"peroxisomal-modulation-as-therapeutic-alternative-for-tackling-multiple-cancers",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"The Metabolic Role of Peroxisome in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81638",title:"Aging and Neuropsychiatric Disease: A General Overview of Prevalence and Trends",doi:"10.5772/intechopen.103102",signatures:"Jelena Milić",slug:"aging-and-neuropsychiatric-disease-a-general-overview-of-prevalence-and-trends",totalDownloads:14,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81566",title:"New and Emerging Technologies for Integrative Ambulatory Autonomic Assessment and Intervention as a Catalyst in the Synergy of Remote Geocoded Biosensing, Algorithmic Networked Cloud Computing, Deep Learning, and Regenerative/Biomic Medicine: Further Real",doi:"10.5772/intechopen.104092",signatures:"Robert L. Drury",slug:"new-and-emerging-technologies-for-integrative-ambulatory-autonomic-assessment-and-intervention-as-a-",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Autonomic Nervous System - Special Interest Topics",coverURL:"https://cdn.intechopen.com/books/images_new/10835.jpg",subseries:{id:"12",title:"Human Physiology"}}}]},overviewPagePublishedBooks:{paginationCount:11,paginationItems:[{type:"book",id:"7264",title:"Calcium and Signal Transduction",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7264.jpg",slug:"calcium-and-signal-transduction",publishedDate:"October 24th 2018",editedByType:"Edited by",bookSignature:"John N. Buchholz and Erik J. Behringer",hash:"e373a3d1123dbd45fddf75d90e3e7c38",volumeInSeries:1,fullTitle:"Calcium and Signal Transduction",editors:[{id:"89438",title:"Dr.",name:"John N.",middleName:null,surname:"Buchholz",slug:"john-n.-buchholz",fullName:"John N. Buchholz",profilePictureURL:"https://mts.intechopen.com/storage/users/89438/images/6463_n.jpg",biography:"Full Professor and Vice Chair, Division of Pharmacology, Loma Linda University, School of Medicine. He received his B.S. Degree in Biology at La Sierra University, Riverside California (1980) and a PhD in Pharmacology from Loma Linda University School of Medicine (1988). Post-Doctoral Fellow at University of California, Irvine, College of Medicine 1989-1992 with a focus on autonomic nerve function in blood vessels and the impact of aging on the function of these nerves and overall blood vessel function. Twenty years of research funding and served on NIH R01 review panels, Editor-In-Chief of Edorium Journal of Aging Research. Serves as a peer reviewer for biomedical journals. Military Reserve Officer serving with the 100 Support Command, 100 Troop Command, 40 Infantry Division, CA National Guard.",institutionString:null,institution:{name:"Loma Linda University",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"6925",title:"Endoplasmic Reticulum",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6925.jpg",slug:"endoplasmic-reticulum",publishedDate:"April 17th 2019",editedByType:"Edited by",bookSignature:"Angel Català",hash:"a9e90d2dbdbc46128dfe7dac9f87c6b4",volumeInSeries:2,fullTitle:"Endoplasmic Reticulum",editors:[{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}}]},{type:"book",id:"6924",title:"Adenosine Triphosphate in Health and Disease",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6924.jpg",slug:"adenosine-triphosphate-in-health-and-disease",publishedDate:"April 24th 2019",editedByType:"Edited by",bookSignature:"Gyula Mozsik",hash:"04106c232a3c68fec07ba7cf00d2522d",volumeInSeries:3,fullTitle:"Adenosine Triphosphate in Health and Disease",editors:[{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",institutionURL:null,country:{name:"Hungary"}}}]},{type:"book",id:"8008",title:"Antioxidants",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/8008.jpg",slug:"antioxidants",publishedDate:"November 6th 2019",editedByType:"Edited by",bookSignature:"Emad Shalaby",hash:"76361b4061e830906267933c1c670027",volumeInSeries:5,fullTitle:"Antioxidants",editors:[{id:"63600",title:"Prof.",name:"Emad",middleName:null,surname:"Shalaby",slug:"emad-shalaby",fullName:"Emad Shalaby",profilePictureURL:"https://mts.intechopen.com/storage/users/63600/images/system/63600.png",biography:"Dr. Emad Shalaby is a professor of biochemistry on the Biochemistry Department Faculty of Agriculture, Cairo University. He\nreceived a short-term scholarship to carry out his post-doctoral\nstudies abroad, from Japan International Cooperation Agency\n(JICA), in coordination with the Egyptian government. Dr.\nShalaby speaks fluent English and his native Arabic. He has 77\ninternationally published research papers, has attended 15 international conferences, and has contributed to 18 international books and chapters.\nDr. Shalaby works as a reviewer on over one hundred international journals and is\non the editorial board of more than twenty-five international journals. He is a member of seven international specialized scientific societies, besides his local one, and\nhe has won seven prizes.",institutionString:"Cairo University",institution:{name:"Cairo University",institutionURL:null,country:{name:"Egypt"}}}]}]},openForSubmissionBooks:{paginationCount:3,paginationItems:[{id:"11675",title:"Advances in Skeletal Muscle Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/11675.jpg",hash:"e1d9662c334dd78ab35bfb57c3bf106e",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"April 19th 2022",isOpenForSubmission:!0,editors:[{id:"281317",title:"Dr.",name:"Fabio",surname:"Iannotti",slug:"fabio-iannotti",fullName:"Fabio Iannotti"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11677",title:"New Insights in Mammalian Endocrinology",coverURL:"https://cdn.intechopen.com/books/images_new/11677.jpg",hash:"c59dd0f87bbf829ca091c485f4cc4e68",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 5th 2022",isOpenForSubmission:!0,editors:[{id:"321396",title:"Prof.",name:"Muhammad Subhan",surname:"Qureshi",slug:"muhammad-subhan-qureshi",fullName:"Muhammad Subhan Qureshi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11676",title:"Recent Advances in Homeostasis",coverURL:"https://cdn.intechopen.com/books/images_new/11676.jpg",hash:"63eb775115bf2d6d88530b234a1cc4c2",secondStepPassed:!1,currentStepOfPublishingProcess:2,submissionDeadline:"June 10th 2022",isOpenForSubmission:!0,editors:[{id:"203015",title:"Dr.",name:"Gaffar",surname:"Zaman",slug:"gaffar-zaman",fullName:"Gaffar Zaman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},onlineFirstChapters:{paginationCount:4,paginationItems:[{id:"81821",title:"Pneumococcal Carriage in Jordanian Children and the Importance of Vaccination",doi:"10.5772/intechopen.104999",signatures:"Adnan Al-Lahham",slug:"pneumococcal-carriage-in-jordanian-children-and-the-importance-of-vaccination",totalDownloads:1,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Streptococcal Infections",coverURL:"https://cdn.intechopen.com/books/images_new/10828.jpg",subseries:{id:"3",title:"Bacterial Infectious Diseases"}}},{id:"81813",title:"Schistosomiasis: Discovery of New Molecules for Disease Treatment and Vaccine Development",doi:"10.5772/intechopen.104738",signatures:"Andressa Barban do Patrocinio",slug:"schistosomiasis-discovery-of-new-molecules-for-disease-treatment-and-vaccine-development",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"New Horizons for Schistosomiasis Research",coverURL:"https://cdn.intechopen.com/books/images_new/10829.jpg",subseries:{id:"5",title:"Parasitic Infectious Diseases"}}},{id:"81644",title:"Perspective Chapter: Ethics of Using Placebo Controlled Trials for Covid-19 Vaccine Development in Vulnerable Populations",doi:"10.5772/intechopen.104776",signatures:"Lesley Burgess, Jurie Jordaan and Matthew Wilson",slug:"perspective-chapter-ethics-of-using-placebo-controlled-trials-for-covid-19-vaccine-development-in-vu",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"SARS-CoV-2 Variants - 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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