Examples of gene therapy studies combining the enzyme/prodrug and Cx restoration approaches.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"977",leadTitle:null,fullTitle:"Understanding Tuberculosis - Global Experiences and Innovative Approaches to the Diagnosis",title:"Understanding Tuberculosis",subtitle:"Global Experiences and Innovative Approaches to the Diagnosis",reviewType:"peer-reviewed",abstract:"Mycobacterium tuberculosis is a disease that is transmitted through aerosol. This is the reason why it is estimated that a third of humankind is already infected by Mycobacterium tuberculosis. The vast majority of the infected do not know about their status. Mycobacterium tuberculosis is a silent pathogen, causing no symptomatology at all during the infection. In addition, infected people cannot cause further infections. Unfortunately, an estimated 10 per cent of the infected population has the probability to develop the disease, making it very difficult to eradicate. Once in this stage, the bacilli can be transmitted to other persons and the development of clinical symptoms is very progressive. Therefore the diagnosis, especially the discrimination between infection and disease, is a real challenge. 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The intended purpose of the book will be to extend the circle of users of the Kalman filter by considering it not as a means of theoretical analysis, but rather as a powerful tool for the design of a technical system. The editor accumulated experience of using suboptimal KF in various aerospace applications and would wish to share it with the pool of potential users and like-minded specialists. Instead of the formal programming of the recursive KF equations some simple and robust sub-optimal forms are proposed. For example, developed by the editor, suboptimal (KBF), with bounded grows of memory (FBGM) and its steady-state form- the time-invariant filter with constant coefficients is aimed to be considered. This allows the developer to use the KBF not only for system state estimation but for control as well. Proceeding in this way developer can be guaranteed the filter stability and robustness in many practically uncertain situations when the statistic characteristics of system disturbances and measured errors are not entirely known. A guaranteed approach with using an equivalent white noise is also aimed to be considered. Some representative examples from typical aerospace systems (the editor’s main professional field) are intended to be presented. Summarizing the above, it can be emphasized that when implementing the KF it is always useful to replace the art of programming with the experience of designing conventional robust systems having an idealistic estimate of maximum (best) of achievable performance. This would prevent the system's real-time computer from many possible situations with “empty “computations and even to the divergence of the computational process. It can also show that the filter is not a magic mill and cannot achieve the desired performance if it cannot be achieved in principle, better that it can be “promised” by the KF quadratic criterion minimum, or if some state vector components are not observable and controllable.
",isbn:"978-1-80356-576-7",printIsbn:"978-1-80356-575-0",pdfIsbn:"978-1-80356-577-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"4c3e68adcaeaa44f9fbfe9bb19bdd55b",bookSignature:"Dr. Yuri Kim",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11504.jpg",keywords:"Separation Theorem, Extended Kalman Filter, Covariance Matrix, Riccati Equation, FBGM, Analytical Implementation Forms, Physical Implementation Forms, Steady State Filter, Inertial Navigation System, Global Positioning System, Controllability, Multisensory Navigation",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 15th 2022",dateEndSecondStepPublish:"June 2nd 2022",dateEndThirdStepPublish:"August 1st 2022",dateEndFourthStepPublish:"October 20th 2022",dateEndFifthStepPublish:"December 19th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Prof. Y.V. Kim is a Doctor of Technical Science, having a broad and wealthy international scientific, engineering, and teaching experience, obtained in the former USSR, Israel, and Canada. He has many scientific publications and implemented inventions dedicated to Aerospace GN&C.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"316140",title:"Dr.",name:"Yuri",middleName:null,surname:"Kim",slug:"yuri-kim",fullName:"Yuri Kim",profilePictureURL:"https://mts.intechopen.com/storage/users/316140/images/system/316140.jpg",biography:"Yuri Kim\n24 Buttenut, Gatineau, QC, Canada\nTel : 1-(514)- 466-1033, e-mail: yurikim@hotmail.ca\n\nHIGHLIGHTS OF QUALIFICATIONS:\n\nExperienced scientist, engineer and manager with internationally recognized achievements in area of Aerospace Avionics, (GN&C); Analysis, design (HW&SW), integration, testing and operation for various aerospace platforms and missions. \n\nGained a broad experience in preparation of technical documents for Joint (Industry-Customer) State Commissions for the acceptance (commissioning) of Aerospace Avionics, Navigation and Special application experimental equipment for further serial production, and operational support. Last works have been dedicated to R&D projects developing new Satellite Navigation Control Technology and customer support of Canadian satellites Control system design.\n\n\nACADEMIC DEGREES:\n\n 1991 *Doctor of Technical Science Diploma in Aerospace Vehicles Guidance \n Navigation and Control \n Scientific Council of State Institute of Automatic Systems, Ministry of Aviation\n Industry of USSR, Moscow\n (Recognized by Canadian Professional Counsel of Engineers) \n1982 * Senior Scientific Fellow Diploma in Gyroscopes and Navigation systems \n Capital Certification Commission of Scientists, Ministry of High Education of\n USSR, Moscow.\n (Recognized by Canadian Professional Counsel of Engineers)\n1974 * Candidate of Technical Science Diploma in Aerospace Navigation\n and Control Systems (Accredited as Ph.D by York University, Toronto.)\n Scientific Council of Moscow Aviation Institute, Moscow.\n1970 * Engineer Electromechanic Diploma in Gyro and Navigation systems,\n Faculty of Flight Apparatuses Control Systems, Moscow Aviation Institute, \n Moscow (Accredited as between Masters Degree and Bachelor Degree by\n York University, Toronto).\n1965 * Radio and TV Systems Technician Certificate, Dnepropetrovsk Technical School \n of preparation of technical specialists for Soviet Army, Military Aviation and \n Navy.\n\nMILITARY EDUCATION:\n\n1970 * Engineer in ballistic rocket control system, Military Faculty of MAI, last rank senior engineer-lieutenant (in reserve)\n\n\n\nEMPLOYMENT HISTORY:\nA. GOVERNMENT\n\nAt present - Canadian Space Agency, Space Science and Technology Division, David Florida Laboratory\n\n Senior Aerospace System engineer \n\n° Performing, developing and supporting phases of design, testing, commissioning and \n operation for space vehicle orbit and attitude control systems, in particular: Tecsas, Scope, \n J2Sat, Small satellite, M3Msat, Cassiopea, Neossat, RCM, PCW\n\n° Reviewing and commenting on Attitude Control systems design documentations, related to \n all phases of system development commissioning and operation\n \n° Supporting Aerospace Industry R&D projects funding by CSA (STDP) as Scientific\n Authority, in particular: Microwheel (Dynacon), LOCOOS (NGC), PCW (Bristol)\n\n° Providing expertise on new initiatives for Space Exploration and Utilization regarding \n Attitude and Orbital Control and possible development of Canadian space launcher\n\n° Developing basic mathematical (Simulink/Matlab) simulator for developing the \n requirements and expected performance of AODCS for new space vehicles\n\n° Developing new basic technology (based on Kalman Filter) for satellite attitude\n determination and sensor calibration, developing of FF test-bed equipment and GPS \n navigation in environment of CSA laboratory, developing of methods of ACS sensors\n calibration, measuring and compensation of satellite residual magnetic moment, experimental determination of satellite inertia matrix during ACS integration tests\n\n° Interacting with Space Industry and Universities in the problems, related to development of \n new methods and systems for space vehicle attitude and orbit determination and control\n \n° Sharing with International Aerospace community CSA achievements and experience in\n development of new technologies and methods for space vehicle attitude and orbit \n determination and control through publications, presentations and participation in scientific\n conferences, meetings and symposiums as well as maintaining an awareness about new \n technological advancements\n \n° Providing professional training for students and post. Graduates in the area of Orbital and\n Attitude Dynamic and Control\n\nB. INDUSTRIAL\n\nSept. 1998 – Feb. 1999 – Olympia Engineering Ltd. (Toronto)\n\nResearch and Development Engineer\n\n•\tDevelopment of measuring instrument for measuring remote measuring of micro- deformations of machinery (milling machine) equipment\n•\tResearch and testing of differential GPS survey equipment and antennas in environment of industrial facility for developing a new remote method for the measuring of machinery micro-deformations\n\n\n\n\nFeb.1999 – Jun.2002 – Saskatoon Engineering Division of Calian Company, \n Radarsat-1 Operation Team (CSA, Montreal)\n\nAttitude Control System Analyst\n\n•\tWorking as RADARSAT-1 Attitude Control System Analyst performing day-to-day operation TLM data analysis; reporting, monitoring and solving ACS flight anomaly problems, maintaining ACS software and performance \n•\tAuthor of many reports (see attached list of publications), devoted to solving of Radarsat-1 non-benign Safe Hold Mode problem, Momentum Wheel failure problems and improvement of the performance of attitude determination method with Magnetometer and Sun Sensor (back up, ADM3 mode for the case of potential failure of Horizon Scanner).\n•\tPreparation and implementation of the solution for RADARSAT-1 operation without failed Momentum Wheels, that saved the satellite mission after the wheel failures\n(This work was prolonged after in CSA and awarded by the Canadian Government Award for the invention used by the Government)\n•\tDesign and implementation of new dynamic simulators (based on Simulink\ntoolbox) for Radarsat-1 ACS for operation support\n•\tPreparation for operation of new Canadian satellites Scisat and RADARSAT-2 \n\n\n\nJan. 1994 – Sep. 1997 – Israel Aviation Industry (IAI factories: TASHAN, LAHAV)\n\nAvionics system engineer\n\n•\tResearch and preliminary design of the Special Data Fusion System for a fighter-interceptor\n•\tIntegration of Inertial Navigation System with Global Position System into Upgraded Avionics Suit and installation in aircraft cockpit for A/C – trainer T-38\n\nNov. 1977 – Apr. 1993 – Moscow Research and Design Institute of Electromechanic and Automatic (formerly P/B: M5537, presently “Aviapribor” Corporation)\n\n \nHead of Division (R&D in Pilot-Navigation Systems)\n\n•\tLeadership of the Division, performing planning, financial and methodological duties, related to this position, reporting to the R&D deputy director of the Institute\n•\tResponsibility for Pilot-Navigation System integration, interaction, tests and transferring for serial production and operational support\n•\tInitiation and methodical leadership of innovative research and development projects\n•\tReviewing, commenting and implementation of Technical standards and Navigation norms\nas well as sharing progressive methods and results within Aerospace organizations within former USSR\n \n Head of Department (INS and Flight Management System SW Development)\n\n•\tLeadership and performing of duties of Head of Department \n•\tResponsibility for the prospective research and preliminary design of the Inertial Navigation Systems (INS) and Flight Management Systems (FMS)\n•\tDesign of the INS and FMS algorithms and simulation of expected performance\n•\tDevelopment of INS/FMS flight code\n•\tDevelopment of test procedures and simulators for FMS, and pilot nav.complexis for aircrafts \n•\tResponsibility for system performance analysis in the ground and flight tests\n\n Head of Sector (System Flight Test data analysis) \n\n•\tLeadership of the Sector\n•\tDevelopment of ground and flight test simulation procedures and requirements for test equipment and simulators, for flight test aircraft measuring equipment, installation and recorded data processing\n•\tDesign of Estimation and Identification algorithms for ground and flight data processing\n•\tTest data analysis, preparation of test results analysis reports and conclusions\n\n Senior Scientific Fellow\n\n•\tResearch, development and principal design of the special Suboptimal Kalman Filter for the fusion of data of various navigation sensors for aviation and space platforms\n•\tDevelopment of new Guidance and Navigation methods for aviation and space platforms\n•\tAnalysis of INS and FMS performance in ground and flight tests\n\nC. ACADEMIC \n\n1977–1993 – Moscow Aviation Institute, Moscow Institute of Instrument -\n Making, Aviation Industry Ministry Upgrade Qualification Institute\n(Part Time) Professor, Associate professor, Chairmen of State Diploma Commission,\n Member of Scientific Council\n•\tLecturer of the disciplines: Applied Oscillation, Theory (MIIM), Design of Instruments (MIIM), Integrated Navigation Systems (MUQI)\n•\tChairman of the State Diploma Commission -Gyro Instruments and Systems (MAI)\n•\tLeadership of postgraduates, participation in sessions of Scientific Council (MAI)\n•\tMethodical management of cathedra of Orientation and Navigation in MAI \n\n2009 McGill University, Montreal\n\nPart time lecturer for course (in English): Aircraft Performance, Stability and Control\n\n1970–1977 – Moscow Aviation Institute \n(Full Time) Associate Professor, Senior Researcher, Assistant Lecturer \n•\tLecturer of the courses: Spacecraft orbital mechanics and attitude determination and control, Inertial Navigation Systems, Gyro Instruments and Systems\n•\tResearch and development of suboptimal robust estimation methods for navigation data processing\n•\tResponsibility for the navigation systems laboratory\n•\tDeputy head of cathedra of Orientation and Navigation\n\nFIELDS OF THEORETICAL AND METHODOLOGIC EXPERTISE:\n \n•\tSpace vehicle Orbit and Attitude determination and control\n•\tGyro instruments and systems\n•\tRadio navigation systems\n•\tInertial Navigation systems\n•\tAirplane Navigation and Control\n•\tAnalytical mechanics \n•\tApplied oscillation theory\n•\tAutomatic control theory\n•\tStochastic estimation theory\n\nENGINEERING EXPERIENCE:\n\n•\tFlight and laboratory tests of Aerospace Avionics Equipment\n•\tDistribution of mission requirements between Aerospace vehicle subsystems, definition of functions and ICD \n•\tSpacecraft operation and performance maintenance\n•\tAvionics system (hardware and software) development and testing (autonomously and integration)\n•\tInertial navigation systems\n•\t Development of Avionics for Soviet Military aircrafts: Tu-142, Tu-95MC, An-124, An-70, A-40, Soviet Space shuttle “Buran” (responsibility for preliminary design of radio-navigation automatic landing system), \n•\tIsrael (IAI) upgrade of Avionics system for T-38 (USA Air force trainer) \n•\tOperation and modification in space Canadian Satellite RADARSAT-1 Attitude Control system\n•\tParticipation in commissioning of ACS of Canadian Satellite Scisat\n•\tDevelopment of a generic mathematical simulator for satellite AODCS analysis and simulation of expected performance for a family of Canadian new generation small satellites\n\nSCIENTIFIC EXPERIENCE:\n\n•\tTheoretical and experimental investigation in the fields of S/C Orbital and Attitude Control\n•\tKalman Filter suboptimization and robust guarantee estimation theory development: authorship of new Suboptimal Kalman Filter modification, methods of INS correction and calibration, Geomagnetic Inertial Navigation System\n•\tResearch in areas of ACS and INS sensors development, their performance improvement\n•\tVarious Avionics Systems Mathematical models development and mathematical and semi-natural simulation\n•\tCoordination of research and development projects related to Aerospace equipment performed by Universities and Industries\n•\tScientific reports and articles reviewing and editorship \n•\tMembership in Scientific Counsels and Commissions\n•\tTutorship of under-graduate, graduated and post -graduate students \n\n•\tScientific reports and inventions in the field of GN&C for aircraft and spacecraft methods development \n•\tSeveral articles dedicated to the development of new methods in estimation theory: new suboptimal Kalman Filter with limited growth of the memory, observability and factor of state vector components estimation, guaranteed ellipsoidal estimation and stochastic estimation comparison \n\nLANGUAGES:\n \n•\tEnglish, Russian, Ukrainian, Hebrew, French (beginning level)\n•\tProgramming languages: Matlab/Simulinc/С",institutionString:"Canadian Space Agency",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Canadian Space Agency",institutionURL:null,country:{name:"Canada"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"15",title:"Mathematics",slug:"mathematics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453623",firstName:"Silvia",lastName:"Sabo",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/453623/images/20396_n.jpg",email:"silvia@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and 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In many steps during tumor progression, tumor cells’ interaction with each other and with their microenvironment is an essential element in their survival, growth and progression. This dependence on cell-cell interactions provides an opportunity for therapeutic interventions. In addition to long range interactions through growth factors, cytokines and other released molecules, the cells use various structures to interact directly, including gap junctions (GJ), tight junctions, adherens junctions and desmosomes.
\n\t\t\tGap junction intercellular communication (GJIC), is a process involved in the transfer of second messengers such as cAMP, cGMP, glutamate, NAD+, IP3, glutathione, and Ca++ ions, between cells, through channel structures called gap junctions (GJ). It is involved in various biological functions including regulation of cell growth, cell differentiation, and maintenance of tissue homeostasis (Wei et al. 2004). Structurally, gap junctions are formed by two head-to-head opposing hexameric transmembrane channels called connexons or hemichannels contributed by two interacting cells (Yeager and Harris 2007). The building units of connexons are the connexin proteins (Cxs), which are tetraspan integral membrane proteins (Nakagawa et al. 2010).
\n\t\t\tExpression and functional analysis of connexins and GJIC revealed that, in general, they are lost in cancer (Kandouz and Batist 2010) and their restoration has tumor inhibitory effects, which led to the concept that this type of intercellular communication plays a tumor suppressor role. Consequently, it early became clear that restoring GJIC and connexin expression, using different chemical treatments or by gene transfer, can be used to inhibit tumor cell growth (Fernstrom et al. 2002).
\n\t\t\tGJIC and Cxs have also been suggested to be involved during metastasis, although this role is still largely unclear. For example, on one hand connexin43 (Cx43) affects angiogenesis
However, although connexins and gap junctions are tightly associated, connexins are capable of functions of their own. The exact role of GJIC-dependent versus –independent functions of connexins is still ill-understood and sometimes even paradoxical (Mesnil et al. 2005) (Dbouk et al. 2009). For example, connexins seem to act as tumor suppressors as well as tumor facilitators in the breast (McLachlan et al. 2007). The above-mentioned role of Cx43 in angiogenesis seems GJIC-independent (McLachlan et al. 2006).
\n\t\t\tVisibly, more studies are needed to understand the complex role of GJIC and Cxs in cancer. This lack of information is a major obstacle to the full use of the therapeutic potential of Cxs and GJIC in cancer. Nevertheless, this obstacle didn’t prevent from a attempting many creative and promising therapeutic strategies.
\n\t\tA major limitation to cancer gene therapy is the often limited transfection efficiency of target cells. This is the specific aspect where the field of gap junctions has been particularly helpful, using a mechanism to amplify the cytotoxic signal originating from a limited population of target cells.
\n\t\t\tFor the GJIC researchers, it quickly became clear that the ability of cells to transmit signaling moieties to their neighbors would offer an interesting opportunity. This strategy, based on a process called “bystander effect” (BE) (Figure 1), doesn’t require the therapeutic agent to reach all tumor cells (van, I et al. 2002). Thanks to the BE, triggering the death process in a single cell could be amplified by transfer of the cytotoxic signaling molecules via the GJICs, resulting in similar changes and fate in interacting cells. A major mechanism of the BE involves direct gap junctional intercellular communication (GJIC) and changes in connexins’ levels translate into changes in the BE potential (Asklund et al. 2003; Elshami et al. 1996; Yamasaki and Katoh 1988). Therefore, the BE is an important factor in the efficiency of cancer therapy (Mothersill and Seymour 2004), but its function requires direct intracellular contacts to undergo cytotoxicity. So far, a major application for the BE has been gene therapy. Many authors have shown a decade ago that the BE promotes the so-called “suicide gene therapy”.
\n\t\t\t\tThe first explorations of the BE therapeutic potential involved the use of enzyme/prodrug gene therapy approaches. In this therapy, target cells are made to express an enzyme that converts a prodrug inside the cell into the cytotoxic active drug that is transmitted to and kills the interacting cells. Two combinations of enzymes and prodrugs have been particularly tested: the bacterial cytosine deaminase (CD) with the antifungal drug 5-fluorocytosine (CD/5-FC) and, most widely, the herpes simplex virus thymidine kinase (HSVtk) with the antiherpetic ganciclovir (HSVtk/GCV) (Mesnil et al. 1996; Trinh et al. 1995). In the CD/5-FC system, CD converts 5-FC into the active cytotoxic form 5-fluorouracil (5-FU) (Mullen et al. 1992). While ganciclovir (GCV), a nucleoside analogue, is poorly metabolized by mammalian thymidine kinases, it is phosphorylated by the HSVtk and cellular kinases and thus converted into the nucleotide GCV triphosphate, a cytotoxic drug (Chen et al. 1994). The later works by incorporating into and blocking replication of DNA in dividing cells, resulting in induction of cell death (Thompson 1999). The phosphorylated form of GCV will be transmitted to neighboring cells via GJIC. For example, transfection of tumor cells expressing Cx43 with HSVtk will allow GCV to kill target as well as by-standing cells (Mesnil et al. 1996). GJIC and connexins have been shown to be involved during the BE-based HSV-tk/GCV therapy (Dilber et al. 1997; Vrionis et al. 1997; Elshami et al. 1996; Fick et al. 1995; Mesnil et al. 1996). BE using the UPRT/5-FU system (uracil phosphoribosyltransferase (UPRT) of E. coli origin and 5-fluorouracil (5-FU)) was found to be correlated to the level of Cx43 and GJIC (Kawamura et al. 2001). The extent of the role of GJIC and Cxs in BE-mediated cytotoxicity is most certainly underestimated. Many experimental therapeutic strategies make use of the BE but the role of GJICs or Cxs in their mechanism of action has not been investigated yet.
\n\t\t\t\tBystander Effect. A death signal, such as the one from the enzyme/prodrug system, triggered in a single cell is transmitted, through GJIC-dependent or –independent mechanisms, to neighboring cells. These bystanding cells are, in turn, destined to die without being directly targeted by the cytotoxic stimuli.
The efficacy of the enzyme/prodrug approach in vitro and in animal xenograft models has been demonstrated (Xu and McLeod 2001). However, there are many factors which immediately affect the efficacy of the approach. Although the % of cells expressing either HSVtk or CD has been shown to have some importance, the extent of contacts between cells was found to be the most crucial condition, as it requires contact between cells as well as their ability to transfer small cytotoxic molecules from one to another (Bi et al. 1993; Fick et al. 1995; Trinh et al. 1995). Using a murine breast cancer model transgenic for the activated rat neu oncogene under the control of the mouse mammary tumor virus long terminal repeat (MMTV-LTR), the efficacy of the HSVtk/GCV system has been shown in vivo. However, this approach showed an incomplete antitumor potential, the limiting factors being low viral transduction efficiency and functionality of the BE and GJIC in mammary tumor cells (Sacco et al. 1996; Sacco et al. 1995).
\n\t\t\t\tAs previously stressed, there is need for further deciphering of the respective roles played by GJIC, Cxs and the BE in these enzyme/prodrug systems in different cellular and cancer contexts. Characterizing the interdependence of the BE and GJIC in gene therapy systems could allow their more effective use. It has been reported that the BE resulting from the thymidine kinase/ganciclovir (tk/GCV) system requires functional GJIC while in the thymidine phosphorylase/5′-deoxy-5-fluorouridine (tp/DFUR) system, whereas thymidine phosphorylase (TP) converts 5′-deoxy-5-fluorouridine (5′-DFUR, doxifluridine) to 5-FU and its anabolite 5-fluoro-2′-deoxyuridine (5-FdUrd), the BE occurs via the cell culture medium and is independent of GJIC and apoptosis. Nevertheless, combining these two systems showed more BE than each system separately (Denning and Pitts 1997). It has also been reported that, in comparison to the HSVtk/GCV system, bystander killing resulting from the CD/5-FC system is GJIC-independent, and both communication-competent and -incompetent CD-transduced cells were killed dramatically more than bystander cells (Lawrence et al. 1998). Shared culture medium rather than direct cell-cell contacts were incriminated in the BE-mediated cell killing (Bai et al. 1999). Taken together, these findings particularly support the need for a better understanding of GJIC-independent BE to better rationalize the therapeutic use of this approach. This is particularly true when combining enzyme/prodrug targeting with connexin overexpression.
\n\t\t\tThe cytotoxic effects of these enzyme/prodrug systems via the BE are due to the induction of apoptosis (Hamel et al. 1996). GJIC can either mediate apoptotic cell death or potentiate the efficacy of pro-apoptotic agents. The BE allows these drugs or their signaling intermediates to reach by diffusion more cells than they would do alone (Peixoto et al. 2009) (Jensen and Glazer 2004; Udawatte and Ripps 2005). In fact, it has been shown that gap junctions remain open during the apoptotic process (Cusato et al. 2006). However, there are additional, less understood mechanisms for the role of gap junctions in BE cytotoxicity. In other respect, the BE can be instrumental in drug resistance. For instance, Src activation induces Cx43 tyrosine phosphorylation and GJIC decrease, resulting in resistance to Cisplatin (Peterson-Roth et al. 2009).
\n\t\t\t\tTherefore, one expected limitation to the enzyme/prodrug gene therapy approach would come from the fact that in cancer cells, many apoptosis-related signaling pathways are often aberrant. It has been shown for example that HSV-tk/GCV-induced BE is influenced by mutations in p53 (van, I et al. 2005), a tumor suppressor gene frequently mutated in cancer and which regulates apoptotic cell death. A study by Garcia-Rodríguez et al. showed a strong correlation of E-cadherin expression and the TK/GCV bystander effect and that increasing the expression of E-cadherin improved TK/GCV cytotoxicity and triggered a potent antitumoral effect in vivo, through reduction of the anti-apoptotic protein Bcl-2 (Garcia-Rodriguez et al. 2011a). Similarly, the efficacy of this gene therapy strategy could be undermined by certain treatment combinations. Treatment with dexamethasone significantly reduced their apoptotic response in glioma cells, as a result of diminished GJIC-dependent BE and efficacy of HSVtk gene therapy (Robe et al. 2005). This finding warns against future usage of dexamethasone as a symptomatic treatment if HSVtk gene therapy were to be attempted. Luckily, the outcome of this gene therapy strategy can also be improved by a multitude of other treatments (Robe et al. 2004) as will be discussed below.
\n\t\t\tAttempts to use the BE in gene therapy studies are limited by the ability of target cells to communicate by gap junctions. Restoring GJIC to these cells in the enzyme/prodrug systems could not only bypass this limitation, it by itself has a gene therapy potential (Figure 2). Indeed, two different approaches have been used in the literature:
\n\t\t\tintratumoral delivery of Cx-encoding vectors that could either be used to enhance enzyme/prodrug gene therapy or potentiate the effect of pharmacological drugs, and
pharmacological induction of Cx expression and GJIC, which could be combined to enzyme/prodrug gene therapy.
Different GJIC, BE and/or Cx-based gene therapy approaches. Connexins (Cx) restoration could be performed either by direct gene delivery or by induction using pharmacological drugs. The Cx tumor suppressing effect is then either GJIC-dependent or independent (indep). Similarly, the BE-mediated cytotoxic effect of the enzyme/prodrug (E/P) approach could either be GJIC-dependent or independent. It could be improved by Cx restoration or by pharmacological intervention.
A major hurdle facing the enzyme/prodrug approach proved to be the loss of connexins and GJICs in the target cells, the malignant ones. Therefore, increasing the levels of Cxs and GJIC in cancer cells would result in a better response to BE-based gene therapy cytotoxicity. Transfecting cells with vectors encoding viral thymidine kinase and connexin genes has proven efficient in many studies (Cirenei et al. 1998; Ghoumari et al. 1998; Marconi et al. 2000; Tanaka et al. 2001a)(table 1).
\n\t\t\t\tEnzyme/Prodrug system | \n\t\t\t\t\t\t\tConnexin | \n\t\t\t\t\t\t\tTargeting Vector | \n\t\t\t\t\t\t\tCell type | \n\t\t\t\t\t\t\tReference | \n\t\t\t\t\t\t
HSVtk/GCV | \n\t\t\t\t\t\t\tCx43 | \n\t\t\t\t\t\t\tRetroviral | \n\t\t\t\t\t\t\tGlioblastoma (U-87) | \n\t\t\t\t\t\t\t(Cirenei et al. 1998) | \n\t\t\t\t\t\t
HSVtk/GCV | \n\t\t\t\t\t\t\tCx43 | \n\t\t\t\t\t\t\tPlasmid | \n\t\t\t\t\t\t\tHepatocellular carcinoma cells (Hepa1-6) | \n\t\t\t\t\t\t\t(Ghoumari et al. 1998) | \n\t\t\t\t\t\t
HSVtk/GCV | \n\t\t\t\t\t\t\tCx43 | \n\t\t\t\t\t\t\tA Herpes simplex viral vector (HSV) | \n\t\t\t\t\t\t\tGlioblastoma (U-87) and fibrosarcoma (L929) | \n\t\t\t\t\t\t\t(Marconi et al. 2000) | \n\t\t\t\t\t\t
HSVtk/GCV | \n\t\t\t\t\t\t\tCx26 | \n\t\t\t\t\t\t\tAdenoviral multigenic | \n\t\t\t\t\t\t\tBladder cancer (UM-UC-3 and UM-UC-14) | \n\t\t\t\t\t\t\t(Tanaka et al. 2001a) | \n\t\t\t\t\t\t
HSVtk/GCV | \n\t\t\t\t\t\t\tCx26 | \n\t\t\t\t\t\t\tRetroviral | \n\t\t\t\t\t\t\tPancreatic tumor cells (NP-9, NP-18, NP-31) | \n\t\t\t\t\t\t\t(Carrio et al. 2001) | \n\t\t\t\t\t\t
HSVtk/GCV | \n\t\t\t\t\t\t\tCx43 | \n\t\t\t\t\t\t\tPlasmid | \n\t\t\t\t\t\t\tCervical cancer (Hela) | \n\t\t\t\t\t\t\t(Tanaka et al. 2001c) | \n\t\t\t\t\t\t
HSVtk/GCV | \n\t\t\t\t\t\t\tCx43 | \n\t\t\t\t\t\t\tPlasmid | \n\t\t\t\t\t\t\tCervical cancer (Hela) | \n\t\t\t\t\t\t\t(Duflot-Dancer et al. 1998) | \n\t\t\t\t\t\t
HSVtk/GCV | \n\t\t\t\t\t\t\tCx43 | \n\t\t\t\t\t\t\tRetroviral | \n\t\t\t\t\t\t\tBreast cancer (MDA-MB-435) | \n\t\t\t\t\t\t\t(Grignet-Debrus et al. 2000) | \n\t\t\t\t\t\t
Examples of gene therapy studies combining the enzyme/prodrug and Cx restoration approaches.
Nevertheless, enforced expression of Cxs might not always be sufficient to alleviate the inefficiency of the enzyme/prodrug system. For example, in a study of the efficacy of the HSVtk/GCV system combined with overexpression of Cx26 in a panel of pancreatic tumor cells, not all cell lines showed improved CJIC or bystander cytotoxicity (Carrio et al. 2001). Inability of Cx43 to properly localize at the cell surface prevented human colon tumor cells from being targeted by the BE and cytotoxicity of HSVtk (McMasters et al. 1998). The localization of Cx43 and the level of gap junctions functionality were also found to influence the BE in glioblastoma cells (Cottin et al. 2008). Therefore, a better understanding of the mechanisms involved in the stability and trafficking of connexins as well as the process of gap junction formation is needed. In particular, connexins’ phosphorylation is an essential post-translational modification in their life cycle (Solan and Lampe 2009) and so are their stability and degradation by the lysosomal and proteasomal systems (Leithe and Rivedal 2007). For example, abnormal trafficking and lysosomal degradation can impede with the function of Cx43 (Qin et al. 2003a). Apigenin, a cancer chemopreventive flavonoid, was able to improve the effect of HSVtk only after concurrent transfection with the Cx43 gene, which suggests that, unlike other chemicals, it affects gap junction functionality rather than inducing connexin expression (Touraine et al. 1998). It has also been suggested that different connexins might have different abilities to modulate the BE. Cx32 and Cx26 were reported to be significantly more effective than Cx43 at mediating the BE in cocultures of connexin-expressing and HSVtk-expressing C6 glioma cells (Jimenez et al. 2006).
\n\t\t\t\tAnother issue that is not completely elucidated is the importance of targeting tumor cells to express both the suicide gene and the connexin at the same time. It has been suggested that separate introduction of the HSVtk and connexin genes in tumor cells might have higher killing efficiency than simultaneous expression, as illustrated by transfection of HeLa cells with Cx43 and HSVtk genes (Tanaka et al. 2001c). Interestingly, the Cx-expressing cells induce the Cx-devoid cells to contribute to GJIC through an unknown mechanism (Tanaka et al. 2001b). This is an encouraging observation in view of the known heterogeneity of tumors or in situations where Cx-negative malignant cells are scattered within Cx-positive normal tissues (i.e. gliomas), which means that gene therapy targeting of these tumors with the enzyme/prodrug system might still be efficient even when only a small subpopulation of tumor cells expresses connexins.
\n\t\t\tModulating GJIC and Connexins has been used to sensitize to chemotherapy using a variety of pharmacological drugs (Figure 2). For example, Cx32 expression enhanced the sensitivity of human renal cell carcinoma (RCC) cells to vinblastine (VBL)
In addition to exogenous delivery of connexins, their expression can be increased using pharmacological treatments that affect different levels of gene regulation. The strategy of restoring Cx expression to favor BE-mediated cytotoxicity is mainly confronted to a flagrant misunderstanding of the mechanisms of loss of Cx expression in cancer. Many transcriptional and post-transcriptional aberrations have been described so far but, as expected, none provide a ubiquitous explanation (Carystinos et al. 2003; Gao et al. 2007; Villares et al. 2009; Leithe and Rivedal 2007; Solan and Lampe 2009). Nevertheless, the available knowledge has significantly been used in a therapeutic perspective. Transcriptional silencing of Cx expression has been shown to involve epigenetic events such as promoter methylation and chromatin acetylation. Restoration of Cx32 in human RCC cells by 5-aza-2\'-deoxycytidine (5-aza-CdR), a DNA demethylating agent, suppressed tumor growth in a xenograft model (Hagiwara et al. 2008). 4-phenylbutyrate (4-PB), a histone deacetylases inhibitor (HDACi), induced connexin expression and enhanced GJIC between pancreatic cancer cells in culture and potentiated HSVtk/GCV bystander killing effect in glioma cells (Ammerpohl et al. 2004; Ammerpohl et al. 2007). Other HDACi such as Trichostatin A (TSA) and sodium butyrate (NaBu), restored Cx43 expression and increased GJIC (Hernandez et al. 2006; Ammerpohl et al. 2007). It is not known if these HDACi would affect the outcome of the suicide gene therapy. Some of the compounds might also affect the BE independently of their gene expression-modulatory functions. N-butyrate, an inducer of histone hyperacetylation, was shown to enhance the GJIC and the BE in GJIC-deficient glioma cells independently from its HDACi function (Robe et al. 2004).
\n\t\t\t\tPost-transcriptional regulation of Cx expression via mRNA trafficking, stability, splicing and translation, are probably the least studied aspects of Cx life cycle and their impact in gene therapy improvement is still far-fetched. There is fortunately little more data on post-translational regulation, especially protein modification and degradation by proteasomal and lysosomal mechanisms (Kjenseth et al. 2010; Berthoud et al. 2004). Additional regulatory mechanisms include microRNA (Anderson et al. 2006) (Yang et al. 2007; Kedde et al. 2007). In addition, an active Cx43 pseudogene (PsiCx43) has been identified and found to be expressed in breast cancer cell lines but not in normal breast epithelial cells (Kandouz et al. 2004). Inhibition of this pseudogene using short interfering RNAs (siRNAs) can be used to restore Cx43 expression, thus improving chemosensitization of breast cancer cells (Bier et al. 2009). Although there are ways to specifically target these different pathways to restore Cx expression, it is not known whether this would succeed in enhancing the BE cytotoxicity.
\n\t\t\t\tIn principle at least, connexins could also be targeted via various interaction partners that affect their localization, turnover and function such as the interaction of Cx30 with cytoskeletal (microtubules, actin filaments) and tight/adherens junction proteins (Carette et al. 2009; Qu et al. 2009) or the interaction of Cx43 with the Rab GAP-like protein CIP85 (Lan et al. 2005).
\n\t\t\tAnother strategy is the use of chemical inducers of Cx expression to improve the efficiency of the enzyme/prodrug gene therapy (Figure 2). The inhibition of ATP-sensitive potassium (KATP) channels with tolbutamide resulted in increased Cx43 and GJIC, enhancing the bystander effect in HSVtk/GCV therapy in U373 human glioma cells (Paino et al. 2010). All-trans retinoic acid was shown to induce Cx43 expression and to increase GJIC in tumor cell lines, resulting in an increased efficiency of the HSVtk/GCV-induced cytotoxicity in vitro and in vivo (Park et al. 1997). A similar result was observed after 8-bromo-cyclic-AMP treatment, (Carystinos et al. 1999; Kunishige et al. 1998). This approach has particularly been viewed as a chemopreventive one (King and Bertram 2005). The green tea flavonoid compound (–)Epicatechin, prevents tumor promoting chemicals such as the 12-O-tetradecanoylphorbol-13-acetate (TPA) from inhibiting GJIC (le-Agha et al. 2002). Resveratrol (3,5,4\'-trihydroxy-stilbene), a natural polyphenol, provides a similar preventive effect against TPA and the insecticide DDT (Nielsen et al. 2000), and so do carotenoids (Zhang et al. 1991). It is yet to be examined whether these treatments could increase the cytotoxic potential of the HSVtk/GCV and other gene therapy systems, but we could already infer from the available data that pharmacologic upregulation of Cxs and gap junctions could be useful to combine with these gene therapy systems in clinical trials.
\n\t\t\tPart of the reasons why the original strong faith in the strategy to target connexins in the treatment of human tumors has been shaken is due to the focus on the BE and GJIC only. However, it is now obvious that in many contexts, the tumor suppressor effect of Cxs’ overexpression is GJIC-independent (Li et al. 2008b). Cx43 affect angiogenesis
Another advantage of BE-based gene therapy strategies is that treatment could be aimed not only to the tumor cells but also to cellular partners within the microenvironment such as stromal and endothelial cells. For instance, when HSVtk-transduced endothelial cells and non-HSVtk-transduced tumor cells were co-cultured, treatment with GCV resulted in the BE-dependent death of both endothelial and tumor cells in vitro and in vivo (Trepel et al. 2009). Targeting human umbilical vein endothelial cells (HUVECs) with a Cx37-encoding adenovirus induced their death by apoptosis (Seul et al. 2004).
\n\t\t\tAlthough largely hypothetical at this point, we can envision a strategy where GJIC between tumor and stromal cells would be enforced to render tumor cells susceptible to cell killing. In other words, targeting tumor-associated endothelial cells for example, with delivery of connexins and an enzyme/prodrug system, could result in the demise of both the tumor and its irrigating blood vessels. Using a tridimensional model of cell culture, Benalalam et al. showed that GJIC between endothelial and tumor cells are required for antigenic peptide transfer to endothelial cells resulting in the latter’s recognition and elimination by cytotoxic T cells (CTL) (Benlalam et al. 2009). Using the attraction of bone marrow-derived stem cells (BMSCs) for glioma cells, Huang et al. took advantage of GJIC between the two cell types to improve the efficiency of the HSVtk/GCV suicide gene therapy. Indeed, combining the expression of HSVtk by BMSCs and the expression of Cx43 by glioma cells enhanced the bystander effect and improved suicide gene therapy (Huang et al. 2009). Similarly, the formation of gap junctions between adipose-tissue derived human mesenchymal stem cells (AT-MSC) and human glioblastoma cells contributed to bystander cytotoxicity of HSVtk (Matuskova et al. 2009).
\n\t\t\tParadoxically, GJIC-enabled bystander cells have been shown to confer protection against GCV to the very HSVtk-transduced cells that are the source of the cytotoxic signal. The impact of this observation on the therapeutic efficacy is not known. Indeed, as suggested by the authors of this study, it can either increase the efficacy of the treatment, by decreasing the demise of the HSVtk cells, thus prolonging their cytotoxic effect, or have an opposite effect by increasing their survival (Wygoda et al. 1997). Nevertheless, this observation shows that the so-called “bystander cells” and their ability to communicate by GJIC are an important element to take into consideration in the BE-based therapy. This applies to tumor cells as well as the stromal cells with which they communicate.
\n\t\t\tThe therapeutic potential of the neural stem cells (NSCs) in the treatment of brain tumors have been demonstrated and, in many reports, have been shown to rely on bystander effect. NSCs are highly migrating cells able to cross the blood–brain barrier and which show tropism for tumor cells. Many studies showed that NSCs can be genetically modified to target tumor cells and the use of the cytosine deaminase (CD)/5-fluorocytosine (5-FC) system delivered particularly important results in medulloblastomas and gliomas (Aboody et al. 2000; Shimato et al. 2007; Kim et al. 2006) as well as breast or melanoma metastases to the brain (Joo et al. 2009; Aboody et al. 2006). Combined delivery of the CD/5-FC system with Interferon-β (IFN-β), known for its anti-tumor effects, showed a stronger bystander killing effect in glioma both in vitro and using an orthotopic xenograft in vivo model, where animals were intravenously infused with CD/IFN-β-expressing NSCs and administred with the prodrug 5-FC (Ito et al. 2010). Also, migratory HSVtk-transduced NSCs were able to kill untransduced glioma cells by a GJIC-mediated BE (Uhl et al. 2005).
\n\t\t\tAn additional level of complexity is the formation of different types of GJICs between different cell types. Homotypic gap junction channels formed of identical connexons and heterotypic channels made of connexons containing different connexins (Vaney and Weiler 2000; Kapoor et al. 2004) can show different permeabilities (Weber et al. 2004; Bevans et al. 1998b). This implies that Cx-mediated gene therapy will necessitate an elaborate “customization” effort to target specific interactions and avoid non specific effects. For instance, transformed cells form GJICs between them that are independent of the GJICs formed within adjacent nontransformed cells, with apparently no heterologous communication (Yamasaki and Katoh 1988). Therefore, it is in principle possible to target cancer-specific GJIC compartments without affecting normal cells.
\n\t\tMany clinical trials have been performed to validate the enzyme/prodrug gene therapy approach and test its effects. These include the trial of adenovirus mediated delivery of HSVtk combined with GCV treatment in operable primary or recurrent high-grade gliomas, which resulted in a clinically and statistically significant increase in mean patient survival (Immonen et al. 2004). A phase I dose escalation clinical trial was conducted in 11 men with localized recurrent and metastatic hormone-refractory prostate cancer. In this trial, an adenovirus vector carrying osteocalcin promoter-driven HSVtk was used to target both prostate cancer cells and their neighboring stromal cells and valacyclovir, another anti-herpetic prodrug converted to aciclovir, was given orally. The results showed a good tolerance with no serious adverse events but with local cell death in treated lesions in 63.6% of patients (Kubo et al. 2003). In another clinical phase I/II study, 36 prostate cancer patients with local recurrence after radiotherapy which received single or repeated cycles of adenoviral vector-mediated HSVtk/GCV intraprostatic gene therapy (Miles et al. 2001) showed no significant side effects and a significant increase in biological responses such as the mean serum PSA-doubling time (PSADT), prostate-specific antigen recurrence (PSAR), return to initial PSA (TR-PSA), and activated CD8(+) T cells present in the peripheral blood. In another phase I trial, nine courses of intraprostatic injections of adenoviral HSVtk followed by intravenous injection of GCV in 8 patients with local recurrence of prostate cancer after definitive hormonal therapy, showed no adverse events and a significant prolongation of the median serum PSADT. In five patients, decrease of PSA values was also observed (Nasu et al. 2007). Also, intraperitoneal administration of an HSVtk-encoding adenovirus and intravenous GCV showed significant efficacy in women with recurrent ovarian cancer (Alvarez et al. 2000). Finally, an adenoviral vector encoding the HSVtk gene was also used in a phase I trial where it has been introduced into the pleural cavity of patients with malignant mesothelioma in combination with systemic GCV treatments and showed good tolerance and detectable gene delivery (Sterman et al. 1998).
\n\t\t\tMost of these clinical trials focused on issues of tolerance of the therapy and efficacy of delivery. Although it is understood that these gene therapy attempts rely mainly on the BE, it is frustrating that no data is available that correlates these clinical results with the formation of gap junctions and Cx expression in the targeted tumors.
\n\t\tBystander effect is a big step forward in attempts to use gene therapy in cancer treatment. The idea that one can kill more cells than initially targeted has been a revolutionary concept. However, the biggest challenge to the translation of this concept into an effective therapy has been the lack of information in many aspects surrounding the BE and the role of GJIC and connexins. As further basic science studies are performed, we will be able to comprehend the mechanisms of loss of Cx expression in cancer and how they could be alleviated. Whether and how these mechanisms could be used to improve gene therapy is, again, wide open to exploration. An immediate impact of these studies would be the analysis of tumors for GJIC or Cx expression to identify a subset of patients most likely to benefit from gene therapy using enzyme/prodrug systems such as HSVtk/GCV.
\n\t\t\tOther potential strategies could make use of the ability of gap junctions to transmit different types of cytotoxic signals. Radiotherapy for instance could benefit from this knowledge, based on the finding that death signals could be transmitted through BE from irradiated to nonirradiated cells (Azzam et al. 2001; Prise and O\'Sullivan 2009). Radiation therapy could be combined with gene therapy interventions aimed at increasing GJIC which would amplify the cellular responsiveness to radiation therapy
\n\t\t\tThe function of gap junction channels involves conductance and electrical and chemical gating that can be affected by many factors, including the nature and stoichiometry of the contributing connexins, ensuring selective permeability to various molecules (Saez et al. 2010; Nakagawa et al. 2010; Bevans et al. 1998a). In theory, BE-based gene therapy combined with Cx expression restoration would benefit from identifying Cxs with the best conductance in specific cancer settings. Furthermore, it would be possible to introduce specific mutations that would improve the conductance of BE cytotoxic molecules. Another possibility is to regulate opening and closure of gap junctional channels. The search for chemical inhibitors has delivered a series of drugs that result in either opening or closure of gap junctions (Salameh and Dhein 2005). Another approach involved the use of mimetic peptides that bind to connexin hemichannels, and modify their conductance (Evans and Leybaert 2007). Although it is yet to be assessed, targeting GJ opening and conductance properties could optimize the effect of the BE gene therapy. However, again, the relevance to cancer of channel gating functions of connexins versus GJIC-independent functions is a major unknown. Although this pharmacological approach is most likely to be successful in diseases such as arrhythmia or seizure, where hyperpolarization is a major issue, its possible impact in cancer therapy, especially in combination with gene therapy, should not be excluded.
\n\t\t\tAnother issue of potential importance in improving the efficiency of the BE-based gene therapy is the nature of metabolites that could or could not be transmitted by BE as illustrated by the differential ability of pyrimidine nucleoside analogues such as GCV to pass the gap junctions and trigger cytotoxicity (Degreve et al. 1999). Enzyme/prodrug combinations involving pyrimidine analogues (BVDU, BVaraU) presented smaller bystander killing than the combination involving the purine analogue (GCV) (Grignet-Debrus et al. 2000).
\n\t\t\tIn addition to connexins, another family of proteins called pannexins is increasingly being scrutinized for their ability to form gap junctions (D\'hondt et al. 2009). Unless and until their role in cancer and GJIC has been clearly established, the only GJIC-based therapeutic strategies will likely keep focusing on connexins.
\n\t\t\tFinally, so far only clinical trials on localized malignancies have been conducted, such as direct intra-tumoral injection of the vector in glioma therapy. Future studies are necessary to develop intravenous delivery of viral vectors in the enzyme/prodrug gene therapy approach, to allow targeting of other cancers. In addition, these Phase I trials have mainly addressed safety, toxicity and gene delivery issues. Further assessment of the anti-tumor effects and the correlation with GJIC and connexin expression should absolutely be on the list of future clinical trials. Combinations of these gene therapy approaches with other cancer therapeutic modalities should also be considered.
\n\t\t\tIn summary, the promises of the Bystander effect, GJIC and Connexin-based gene therapies are still alive. It is possible that the great enthusiasm for their potential was so high that it blinded us to the urgency of further examination of their mechanisms and regulations which, once performed, would much significantly improve the rationalization of the clinical application and outcome.
\n\t\tCardiovascular diseases are the leading cause of mortality worldwide. Their constant increasing rate is attributed to many factors as the adoption of poor dietary habits and sedentary lifestyle accompanied in some cases with hereditary background. The so-called Western way of living has led also to the rise of other diseases such as dyslipidemia, hypertension, obesity, diabetes mellitus and chronic kidney disease, which are the main risk factors of CVD. Those conditions are mainly responsible for the rapid progression of vessel’s atherosclerosis and plaque formation. Intimal calcification of large vessels is the main effect of those disorders responsible for plaque’s progression. However, atherosclerosis is not the only factor. Vascular calcification is another major and independent risk factor strongly related with the development of vessel plaque leading to CVD [1]. It is a chronic and multi-factorial procedure related mainly with disorders such as chronic kidney disease and diabetes mellitus [2]. The metabolic pathways which are responsible for the progression of vascular calcification is not well-established and consequently treatment remains a challenge. Media arterial layer is the target area of calcification and can involve all vessel sizes regardless of the concurrence of atheromatic plaque [3]. The negative effect of this procedure can gradually lead to the development of valvural heart disease and coronary artery disease (CAD).
Matrix degradation and modification is the main reason of medial arterial calcification. Matrix Gla protein (MGP), Gla rich protein (GRP) and growth arrest specific gene-6 (Gas-6) are a group of vitamin-k dependent proteins that is considered to effectively inhibit the progression of vascular calcification. For example, in cases of vitamin-k deficiency, glutamic acid residues do not convert to the amino acid γ-carboxyglutamic acid residuals (Gla) which is a vital part for the normal function of MGP. Consequently, inactive forms of MGP (dp-ucMGP) accumulate in calcified tissues such as the blood vessels. Past studies have proposed ucMGP as a potential marker of vitamin-K deficiency, vascular calcification and cardiovascular disease [4]. Other trials have showed that patients under treatment with vitamin-k antagonists (VKAs) had higher scores of vascular calcification compared to a group of controls. Animal trial connected the administration of VKAs with an accelerated progression of medial calcification. On the other hand, when high doses of vitamin-K were administered, calcification lesions started slowly to improve [5]. Perspectives about the benefit of vitamin-K administration in specific population remain controversial, and therefore further research is required in this domain.
The correlation between low vitamin-K levels and rapid progression of vascular mineralization is supported by researchers in the past [6]. The pathophysiological pathways that justify such claims involve a group of vitamin-K dependent protein and calciprotein particles. Those proteins are the matrix Gla protein (MGP), gamma-carboxylated Gla-rich protein (GRP) which are both considered as strong inhibitors of vascular calcification and the growth specific arrest gene-6. Matrix Gla protein (MGP) is a vitamin-k2 dependent protein which is secreted by many cells, including the vascular smooth muscle cells (VSMC) and has high affinity to calcium crystals. Its effect on atherosclerotic plaque may probably derive from the blocking of calcium accumulation. It’s present in bones and cartilage, in kidneys but also in blood vessels, endothelium and coronary artery. Matrix Gla protein prevents from the calcification development in soft tissues such as the blood vessels. Additionally, its preventive effect is exerted by inhibiting the bone morphogenetic protein-2 and 4 (BMP-2, BMP-4). This effect is of outmost importance because it prevents the VSMC from the transdifferentiation into osteoblasts like-cells which lead into progressive calcification of atherosclerotic plaques. In order to exert its effect, MGP has to be synthesized locally in the VSMCs. Vitamin-k2 is used as co-factor to its formation through the post-translational γ-carboxylation and phosphorylation of inactive MGP [7]. Carboxylated MGP (cMGP) is the active protein form responsible for the prevention of the calcification of the arterial wall [8]. MGP’s expression from the VSMCs and the endothelium may give us the opportunity to measure its circulating levels. As it was mentioned before, cMGP has high affinity to calcium crystals and binds strongly to them preventing from their accumulation into the arterial wall. Considering that cMGP could evolve into a very promising biomarker for the prognosis and the progression of calcification as well as a prognostic factor to severe cardiovascular outcomes [9]. On the other hand, it should be mentioned that inactive forms of MGP have been associated with accelerated rate of vascular calcification but also with increased mortality [10]. Whereas the active form of MGP is both carboxylated and phosphorylated, the inactive forms have not undergone one of those two metabolic steps or both of them (uncarboxylated, dephosporylated MGP, dp-ucMGP). cMGP is the only factor that under specific conditions may promote the reversal of vascular calcification [11]. It is worth mentioning that calcified arteries have high concentrations of MGP and the severity of such lesions was related to MGP serum levels [12]. Gla rich proteins is another vitamin K dependent protein which is present in both bone and cartilage and also has high affinity to calcium. High concentrations of γ-carboxylated GRP have been observed in individuals with increased vascular calcification. However, suggested data derive mainly from animal studies and its functionality in humans is not well established. Calciprotein particles are particles that prevent from vascular calcification by blocking the formation of the calcium/phosphate crystals. These particles also contain high levels of MGP and GRP, so in cases of vitamin-k deficiency, their effect may be impaired. Vascular smooth muscle cells excrete also the growth arrest specific gene 6 protein (Gas-6) which is one of the stimulating factors of their growth. It exerts its preventive effect through several pathways. Initially it stimulates the bcl-2 anti-apoptotic protein which is responsible for the inhibition of caspase-3. Caspase-3 is a crucial protein for the pro-apoptotic cell procedure, so through that way Gas-6 protects VSMCs from transdifferentation into cells with osteoblast-like effects. Apoptotic cells could be used as substrate for the development of constant inflammation and excessive calcification. Thus, Gas-6 through this way Gas-6 prevents the arterial from this process. However, in order to exert its effects Gas-6 needs γ-carboxylation a process in which vitamin-k is a necessary co-factor [13]. Taking all that into consideration, Gas-6 is vitamin-K dependent and very important factor, against the VMSCs apoptosis and the progression of calcified plague. In cases of vitamin-k deficiency the lack of Gla proteins affect negatively the growth of VSMC [14] (Figure 1).
Summary of the effect of vitamin K deficiency on vascular calcification. Abbreviations: BMP-2, bone morphogenetic protein-2; VSMCs, vascular smooth muscle cell.
In past studies it was also observed that post-menopausal women with osteoporosis had increased rates of arterial calcification [15]. Based on that, researchers have investigated the potential correlation of vitamin-k status, bone formation rate and vascular calcification of post-menopausal women. Initially, lower bone formation rate in parallel correlation with low levels of serum vitamin-k. The same also applies for the increased frequency of vascular calcification observed in post-menopausal women [16]. Concerning, the lower bone mass of post-menopausal women, it seems that vitamin-k levels and osteocalcin induced remodeling bone process are closely related. Though not with the same metabolic way to vascular calcification but in both situations vitamin-k is necessary [17]. It is important to mention that few trials, evaluated the potential benefit of vitamin k2 supplementation in post-menopausal women with aortic calcification and osteoporotic lesions. According to the authors, calcified lesions were at least sustained or in some cases decreased. However, these beneficial effects were observed in individuals that received vitamin-k2 supplementation but not vitamin-k1 [18]. Finally, results from the study of Gast et al. in this group of patients, have showed that vitmamin-k2 had the greatest preventive effect in CAD [19]. There are data that suggest that osteoporotic women are on higher risk of cardiovascular disease compared to match-aged non-osteoporotic individuals. These evidence imply that this difference occurs due to increased vascular calcification of both large vessels and coronary artery in those patients. Vitamin-k2 may have an essential role both to bone formation via its effect on osteocalcin as well as to the reduction of vascular mineralization. Further and larger studies are needed in order to assess the potential benefit of vitamin-k2 supplementation in both bone mass loss, atherosclerotic progression and prevention of cardiovascular disease in this specific population [20].
Vitamin-k antagonists are oral anticoagualants that reduce the levels of vitamin-k by interfering in vitamin’s recycle. They essentially inhibit vitamin-k reductase complex-1 and consequently reducing active vitamin-k reserves. Thus, they prevent from the formation of blood clots. Nevertheless, vitamin-k depletion in serum has some detrimental effect on many sequences of steps in metabolic pathways like those mentioned before. Taking that in mind, previous studies have demonstrated the negative effect of VKAs on the progress of vascular calcification [5]. Win et al. examined the potential benefit of apixaban administration in patients with atrial fibrillation in terms of the atherosclerotic plaque progression. Study results showed that apixaban administration was associated with slower plaque progression as well as lower calcium scores compared to warfarin treated group. Taking into consideration the usual co-existence of atrial fibrillation and coronary artery disease, apixaban could be a preferable choice in patients with atrial fibrilation not only for the prevention of thromboembolic events but also to slow down coronary plague progression and prevent from fatal cardiovascular events [21]. Accordingly, outcomes from a trial that compared the use rivaroxaban against warfarin have also indicated the beneficial effect of NOAGs into the slower plaque progression arterial calcification [22]. Therefore, in cases of individuals with established CAD or high level of vascular atherosclerosis in need for anticoagulation, the physician should choose wisely the appropriate treatment. These data suggest the preferable choice of NOACs instead of VKAs though further studies are needed for more robust results. However, what about patients that are in need for VKAs coagulation, or the use of NOACs is contraindicated? Such dilemmas are common in clinical practice and therefore the presence of clearly defined guidelines is essential.
Chronic kidney disease is strongly associated with the presence of increased cardiovascular risk. The most frequent cause of death in this population is coronary artery disease as well as stroke events. Hypertension, dyslipidemia, diabetes mellitus, which are common comorbidities in patients with renal failure, are important factors that can lead to excessive atherosclerosis and the development of CVD. Moreover, vascular calcification is also excessive in patients with chronic kidney disease (CKD) and so it constitutes an independent risk factor for the development of CVD [23]. Age, time on hemodialysis, persistent hyperphospahetamia and hypercalciemia are some of the causes of accelerated vascular calcification. High calcium and phosphate levels are associated with the deposition of hydroxyapatite into the arterial wall [24]. Whereas the presence of intimal calcification, which is related mainly to large vessels, is almost the same between individuals with or without end-stage renal disease, this is not the case for median calcification of the arterial wall. For example, aorta calcification is worse in patients with renal disease compared to those without. Aorta calcification increases arterial stiffness, which consequently aggravates the present hypertension and finally contributes to the development or the deterioration of a pre-existing left ventricular hypertrophy and left ventricular insufficiency. Patients with end-stage renal disease have increased vascular calcification compared to non-CKD individuals, especially those that are under hemodialysis [25]. Coronary artery calcification is common among older patients with CKD. However past studies have also showed that younger individuals with end-stage renal disease have also a high percentage of vascular calcification as well as coronary artery calcification [26]. Using high resolution computed tomography; researchers have proved that coronary calcification was higher in young adults that were on dialysis compared to those that were not. At this moment, the main treatment approach against the vessel mineralization of CKD patients is the strict regulation of calcium and phosphate balance. Additionally, clinician focus their attention to better treatment management of concomitant disorders that affect atherosclerotic plaque, such as diabetes, dyslipidemia and smoking cessation. Even though there is no strong evidence that support the administration of agents that inhibit calcification, it is easy to understand that those interventions might play a crucial role to the prevention of CVD in CKD-individuals. In a microenvironment of constant inflammation, vascular smooth cells are gradually transformed in osteoblasts like-cells promoting then the development of medial artery calcification. This process is mediated by multiple proteins and is facilitated by the presence of systemic or local inflammation. The latter is of outmost importance for the reason that macrophages excrete among others, matrix-metalloproteinase which lead to the apoptosis of elastic fibers and thus promote vascular calcification. In addition, vitamin k-dependent matrix Gla protein and Gia-rich protein are both important for vascular calcification. As it was mentioned before, low levels of those proteins have been associated with increased rate of calcification and development of cardiovascular disease. Several studies in the past have proved the increased coronary artery calcification in CKD-individuals by calculating the number of vessel calcifications using high resolution computed tomography. According to the study of Holden et al. in patients with CKD and/or end-stage renal disease vitamin-K deficiency is very common. It is possible that this outcome has some extra effect on the progressive calcification of these patients [27]. At this point, treatment in order to delay the progression of vascular calcification in ESRD and CKD patients targets to the regulation of calcium and phosphate. However, dietary advice in order to prevent hyperkaliemia or hyperphospatemia leads to the avoidance of food rich in vitamin k, inducing the existing deficiency. A recent study with hemodialysis patients have studied the ffect of vitamin-k supplementation on the plasma levels of ucMGP, uncarboxylated osteocalcin and PIVKA-II. The results were very promising, because have showed a significant decrease of the inactive form of MGP and also proved the vitamin-k deficiency in this specific population. The outcomes of this study may be the beginning of future randomized controlled trials that will evaluate the effect of vitamin-k supplementation on vascular calcification of CKD patients [28]. Respectively, another study by Oikonomaki et al. in hemodialysis patients have demonstrated the reduction in uc-MGP levels after 1-year of vitamin-k2 supplementation but the progression of vascular calcification remained the same between studied groups [29]. It is possible that only vitamin-k supplementation is not enough in order to overt calcification. This process in such individuals is so multi-factorial that need a comprehensive treatment approach that will slow the progression. Further studies are needed in order to clarify the benefits of vitamin-k supplementation in ESRD or CKD patients.
Vascular calcification and especially coronary calcification is a strong predictor of coronary events and this is a process that is regulated actively by vitamin K dependent proteins which are called matrix Gla proteins. There are currently no pharmacological means to improve vascular stiffness and vascular calcification. There is growing evidence that vitamin K, a cheap and safe intervention that can have beneficial effects on cardiovascular health. Vitamin K straightforward administration can reduce the progression of vascular calcification. The biological rationale is that supplementation with vitamin K will carboxylate (activate) Gla proteins, whose role, among others, is to reduce the progression of vascular calcification [30]. Coronary artery calcification which is a significant marker of cardiovascular disease is affected by these dependent vitamin K proteins. As it was mentioned before vitamin-K deficiency promotes coronary artery calcification [6]. In animal studies, MGP removal showed severe progression of vessel calcification and this empowered the theory about vitamin K role in this process [31]. The most of the clinical trials showed that supplementation with Vitamin K2 (menaquinone) had beneficial effects in cardiovascular calcification. But a clinical trial from Shea et al. showed that also supplementation with vitamin K1 (phyloquinone) slowed the progression of coronary artery calcification. Though its effect was enhanced by the parallel administration of vitamin-D and calcium supplements [32]. On the other hand, Beulens et al., with a cross-sectional study among 564 post-menopausal women reached the conclusion that only high intake of menaquinone is associated with reduced coronary calcification, as it was measured via computed cardiac tomography [31]. Also Vossen et al. wanted to study a sample of patients with coronary artery disease and follow them up via Agatston calcium score about the progression of coronary calcification as long as the individuals were under vitamin-k supplementation [33]. The Roterdam Study, a prospective population-based study, showed in a sample of 7983 men and women aged 55 y and over in a follow up to 10 years, that dietary intake of menaquinone had a protective effect against coronary heart disease [18]. Also a meta analysis of 3 US Cohorts, among 3891 patients, who measured fasting circulating phyloquinone levels, showed that low phyloquinone levels was associated with increased all – cause mortality but not of CVD [32]. Many clinical trials as referred above showed a possible correlation between vitamin K and increased artery calcification mainly in high risk patients. A systematic review from Hartley et al. tried to show if there is primary prevention from CVD in healthy individuals who received supplementation with vitamin K. They only found a small clinical trial with only 60 patients that fulfilled their criteria and there was no significant impact in primary prevention of CVD and other CVD factors such as blood pressure and plasma lipids level (Hartley). However, this was a small clinical trial with short duration. Further studies are necessary about the benefit of vitamin-k supplementation in the primary prevention of CVD.
Valvular calcification is a common degenerative disease characterized by progressive valvurar calcification. Nowadays the incidence of valvural disease is higher probably due to increased life expectancy. The most commonly calcified valves is aortic valve followed by mitral valve. Based on the role of vitamin K as protective agent for cardiovascular health and especially as a protector against vascular calcification, some trials evaluated the potential effect of vitamin-k as a protective factor against the development of valvular calcification. Bradenburg et al. with a small prospective, open label clinical trial with 99 patients, selected individuals with asymptomatic or mild symptoms with aortic calcified valve and separated them in two study arms with vitamin-k1 supplementation and placebo. Then, they calculated the amount of calcification of the valve via cardiac computed tomography, at the beginning of the trial and after 12 months. Also they measured the dephosphorylated undecarboxylated MGP as a circulating marker for vitamin-k deficiency. Over the 12 month period, aortic valve calcification volume score progressed 10% in the arm with vitamin K supplementation compared with 22% in the placebo group. Also plasma dp-ucMGP were significantly reduced by 45% in the vitamin K group. On the other hand, this trial had many limitations such as the small sample, the short duration of follow up, the open-label design and the broad spectrum of severity of valvural disease at baseline [34]. Another clinical trial that is planned and want to study the effect of vitamin K in aortic calcification is from Peeters et al. concerning especially the calcification progress of bicuspid aortic valve. Bicuspid aortic valve, a common congenital abnormality, occurring in 13,7 per 1000 people in general population is associated with early development of calcific aortic valve stenosis. In this double-blind study they will supply vitamin K2 and follow up 44 people in a period over 18 months. The follow up of the sample will be every 6 months with PET/cardiac MRI, cardiac CT and echocardiography. This trial will provide us with more information for calcium activity on aortic valve and the potential effect of vitamin K. It will also open the way for large scale randomized clinical trials in order to develop potential treatment option against the progression of calcific aortic valve stenosis [35].
Vitamin-K deficiency is associated with low-levels of MGP and Gas-6 and the accumulation of GRP, ucMGP and dpMGP forms in soft tissues and vessels. As it was described before, vitamin-K is used as co-factor for the post-translational γ-carboxylation of MGP and Gas-6 in order to maintain preventive effect on vessels and VSMCs respectively. In addition, vitamin-k deficiency is associated with higher circulating levels of uncarboxylated or dephosphorylated forms of MGP. A three arm randomized controlled trial assessed the levels of deposhpo-carboxylated MGP levels after 12 weeks of menaquinone-7 supplementation. The dp-ucMGP levels were reduced significantly. It is important to mention that according to the authors the outcome was dose-dependent and increased in time [4]. In a systematic review meta-analysis of trials with different study-design by Lees et al., dp-ucMGP levels were significantly reduced with the administration of vitamin-k. However, that effect did not lead to the improvement of vascular calcification with the exception of a small number of studies. Concerning the use of dp-ucMGP as biomarker of CVD the results are controversial and so that is not suggested. It is important to mention that the greater efficacy was achieved with vitamin-k2 supplementation rather than k1 [30]. These data suggest that dp-ucMGP could be an important marker of vitamin-k status. It is worth mentioning that the co-administration of vitamin-k and vitamin-D have showed some promising results concerning the prevention of fatal CVD. However, larger randomized controlled trials are needed in order to delineate if vitamin-k supplementation alone or in combination with vitamin-D could benefit patients with progressive vascular calcification [36] (Table 1).
Vitamin-K sufficiency | Vitamin-K deficiency (ex. Inadequate intake, VKAs administration) | |
---|---|---|
MGP (vitamin-K dependent carboxylation) | ↑ active cMGP prevents: The hydroxyapatite formation The accumulation of calcium crystals Transdifferentiation of VSMCs into osteoblast like-cells Decreased BMP-2 activity | Significantly lower levels of MGP-2 and accumulation of its inactive forms (dp-uc MGP) with devastating impact on VC |
Gas-6 protein (γ-carboxylation with vitamin-K as co-factor) | Activation of anti-apoptotic protein Bcl-2 Inhibition of pro-apoptotic protein Caspase-3.* | ↓Gas-6 levels, inhibition of VSMCs growth and increased apoptosis |
VSMCs | Inhibition of apoptosis and transdifferention into osteoblast like-cells | Increased apoptosis and transdifferention into osteoblast like-cells |
Vascular Calcification | Suspended and possibly reversed medial VC** | Increased medial VC |
Summary of changes in vitamin-k dependent proteins.
Apoptotic cells are used as substrate for accumulation of calcium crystals.
Observed in small trials with co-administration with vitamin D. Further studies are needed.
VSMCs status and progression of vascular calcification depending on vitamin-k serum levels. Abbreviations: MGP, matrix GIa protein; Gas-6 protein, growth arrest specific gene 6 protein; VSMCs, vascular smooth muscle cell; VC, vascular calcification.
Vitamin-k is a fat-soluble vitamin mostly known for its significant role in the coagulation sequence of steps. However, vitamin-k is also important to other also important metabolic pathways. Vascular calcification has proved to be a multi-factorial procedure that leads to the transdifferentation of VSMCs into osteoblast phenotype like-cells and a vicious circle of arterial wall calcification. Vitamin-K dependent proteins MGP, GRP and Gas-6 play an important role in the regulation of this constant progressive process. In cases of vitamin-k deficiency, the preventive effect of those Gla proteins on the arterial wall declines and consequently the process of vascular calcification is enhanced. The calculation of the uncarboxylated and dephosphorylated forms of those proteins are considered a marker of vitamin-k deficiency. However, existing data do not suggest the use of dp-ucMGP as predicting factors of cardiovascular disease. Vitamin-k supplementation have been associated with a significant reduction in the dp-uc MGP circulating levels, although this reduction was not related with a reduction in the process of vascular calcification. Due to the multi-factorial process for the formation of calcified plagues, it cannot be suggested at this point that vitamin-k supplementation alone will reverse those lesions. Emerging evidence support the co-administration of vitamin-D and vitamin-K has a greater effect against the progression of vascular calcification. Concerning the effect of vitamin-k deficiency and cardiovascular health, evidence remains controversial. It is a given that more studies are needed in this area in order to draw safe and robust conclusions. Vascular calcification and atherosclerotic plaques are strongly related with arterial stiffness, hypertension and impaired cardiac function. It is of outmost importance to find solution of this degenerative procedure in order to develop additional preventive and therapeutic strategies against the development of cardiovascular diseases.
Ove Odredbe i uvjeti ističu pravila i regulacije u svezi korištenja IntechOpenove stranice www.intechopen.com i svih poddomena u vlasništvu IntechOpena, tvrtke sa sjedištem u 5 Princes Gate Court, London, SW7 2QJ, Ujedinjeno Kraljevstvo.
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\\n\\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
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\\n\\nMi koristimo kolačiće. Korištenjem IntechOpenove stranice slažete se s korištenjem kolačića u skladu s IntechOpenovom Politikom privatnosti. Većina modernih, interaktivnih stranica koristi kolačiće kako bi omogućila ponovno pronalaženje korisničkih detalja kod svakog posjeta. Na našoj stranici kolačići se uglavnom koriste kako bi omogućili funkcionalnost i olakšali posjetiteljima korištenje stranice.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:"Pristupom na stranicu www.intechopen.com slažete se s ovim odredbama, sa svim primjenjivim zakonskim odredbama, te se slažete s poštovanjem svih lokalnih zakona. Korištenje i/ili pristup ovoj stranici temelji se na potpunom prihvaćanju ovih odredbi. Svi materijali na ovoj stranici zaštićeni su primjenjivim zakonima o autorskim pravima i žigu.
\n\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
\n\nKlijent, stranka, vi, vaš odnosi se na vas, osobu koja pristupa ovoj stranici i prihvaća IntechOpenove Odredbe i uvjete;
\n\nKompanija, tvrtka, mi, naše odnosi se na tvrtku IntechOpen;
\n\nStranke, strane odnosi se na klijenta i na nas, ili samo na klijenta ili nas.
\n\nSve odredbe koje se odnose na ponudu, prihvat ili razmatranje plaćanja, a za koja mi pružamo asistenciju klijentu, bilo na ugovoreni ili fiksni način, a s ciljem da se ostvare potrebe i želje klijenta u svezi s našim uslugama, su podložne zakonskim odredbama Ujedinjenog Kraljevstva.
\n\nOsim ako nije suprotno navedeno, IntechOpen i/ili svi davatelji licence vlasnici su intelektualnog vlasništva nad svim materijalima na www.intechopen.com. Sva prava intelektualnog vlasništva su pridržana. Stranice sa www.intechopen.com možete gledati, preuzimati, dijeliti, dijeliti poveznice i printati za osobnu uporabu, a temeljem pravila sadržanih u ovim Odredbama i uvjetima.
\n\nMi koristimo kolačiće. Korištenjem IntechOpenove stranice slažete se s korištenjem kolačića u skladu s IntechOpenovom Politikom privatnosti. Većina modernih, interaktivnih stranica koristi kolačiće kako bi omogućila ponovno pronalaženje korisničkih detalja kod svakog posjeta. Na našoj stranici kolačići se uglavnom koriste kako bi omogućili funkcionalnost i olakšali posjetiteljima korištenje stranice.
\n\nIntechOpen ili njegovi suradnici niti u jednom slučaju neće biti odgovorni za štete (štete uključuju gubitak podataka ili profita, druge poslovne prekide, te sve ostale štete) koje nastanu zbog korištenja materijala na IntechOpenovoj stranici ili nemogućnosti da se iste koriste, čak i ako je IntechOpen ili njegov predstavnik o takvoj šteti obaviješten pismenim ili usmenim putem. Neke jurisdikcije ne dozvoljavaju ograničenja garancija ili ograničenja obveza za posljedične ili slučajne štete pa se u tom slučaju ova ograničenja možda ne odnose na vas.
\n\nMaterijali koji se pojavljuju na IntechOpenovoj stranici mogu sadržavati manje greške, tipfelere ili fotografske greške. IntechOpen može napraviti promjene na bilo kojem materijalu koji se nalazi na stranici u bilo koje vrijeme.
\n\nIntechOpen nije formalno povezan niti s jednom vanjskom stranicom čije poveznice vode na www.intechopen.com, osim ako to nije izravno navedeno. Iz tog razloga IntechOpen nije odgovoran za sadržaj koji se pojavljuje na takvim stranicama. Poveznica na IntechOpenovu stranicu ne implicira povezanost sa IntechOpenom. Korištenje takvih poveznica isključiva je odgovornost korisnika.
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\n\nAko smatrate da je bilo koja poveznica na našoj stranici sumnjiva iz bilo kojeg razloga, molimo vas da nas kontaktirate. U tom slučaju razmotrit ćemo micanje poveznice s naše stranice, iako nismo obvezni to napraviti.
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\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. 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From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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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. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of 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:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{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:{name:"University of Silesia",country:{name:"Poland"}}},{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:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{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:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{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:"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:"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:"Igor Victorovich Lakhno 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.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in 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 been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), 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 a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). 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: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",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. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"243698",title:"Dr.",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:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"312999",title:"Dr.",name:"Bernard O.",middleName:null,surname:"Asimeng",slug:"bernard-o.-asimeng",fullName:"Bernard O. 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This will ensure that we discover ways to live in our world that allows us and other beings to flourish. We can no longer rely on medicalized approaches to health that wait for people to become ill before attempting to treat them. We need to live in harmony with nature and rediscover the beauty and balance in our everyday lives and surroundings, which contribute to our well-being and that of all other creatures on the planet. This topic will provide insights and knowledge into how to achieve this change in health care that is based on ecologically sustainable practices.
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