Biochemical properties of eukaryotic and retroviral DNA polymerases.
\r\n\tThe purpose of the book is to bring together the latest knowledge about genetic diversity by presenting the studies of some of the scientists who are engaged in development of new tools and ideas used to reveal genetic diversity, often from very different perspectives. The book should prove useful to students, researchers and experts in the area of biology, medicine and agriculture.
",isbn:"978-1-80356-945-1",printIsbn:"978-1-80356-944-4",pdfIsbn:"978-1-80356-946-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"0b1e679fcacdec2448603a66df71ccc7",bookSignature:"Prof. Mahmut Çalışkan and Dr. Sevcan Aydin",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11643.jpg",keywords:"PCR Based Methods, Protein Based Methods, Sequencing, Conservation of Genetic Resources, Natural Variation, Molecular Markers, Genetic Manipulation in Animals, Resistance to Disease, Genetic Manipulation in Plants, Use of Microorganisms in Biotechnology, Genetic Differentiation, Gene Therapy and Gene Editing",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 7th 2022",dateEndSecondStepPublish:"June 16th 2022",dateEndThirdStepPublish:"August 15th 2022",dateEndFourthStepPublish:"November 3rd 2022",dateEndFifthStepPublish:"January 2nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"22 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Professor of genetics and molecular biology and Head of Biotechnology division at İstanbul University in Turkey whose main research areas include plant molecular genetics, microbial biotechnology and characterization and biotechnological use of halophilic archaeal strains.",coeditorOneBiosketch:"Associate Professor of Biotechnology Division in Department of Biology at Istanbul University in Turkey whose main research areas include genetics, environmental biotechnology and bioengineering.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"51528",title:"Prof.",name:"Mahmut",middleName:null,surname:"Çalışkan",slug:"mahmut-caliskan",fullName:"Mahmut Çalışkan",profilePictureURL:"https://mts.intechopen.com/storage/users/51528/images/system/51528.png",biography:"Mahmut Çalışkan is a Professor of Genetics and Molecular Biology in the Department of Biology, Biotechnology Division, Istanbul University, Turkey. He obtained a BSc from Middle East Technical University, Ankara, and a Ph.D. from the University of Leeds, England. His main research areas include the role of germin gene products during early plant development, analysis of genetic variation, polymorphisms, and the characterization and biotechnological use of halophilic archaea.",institutionString:"Istanbul University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"8",institution:{name:"Istanbul University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:{id:"462767",title:"Dr.",name:"Sevcan",middleName:null,surname:"Aydin",slug:"sevcan-aydin",fullName:"Sevcan Aydin",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003QRfRpQAL/Profile_Picture_2022-03-24T08:49:06.jpg",biography:"Sevcan Aydın is an Associate Professor of Biotechnology Division in Department of Biology at Istanbul University in Türkiye. She obtained her bachelor's degree from Biology Department of Ege University. She obtained her Ph.D. in Biotechnology Programme of Istanbul Technical University. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"51894",title:"Multimodality Echocardiographic Assessment of Patients Undergoing Atrial Fibrillation Ablation",doi:"10.5772/64723",slug:"multimodality-echocardiographic-assessment-of-patients-undergoing-atrial-fibrillation-ablation",body:'\nThe most common sustained cardiac arrhythmia, nonvalvular atrial fibrillation (AF), has an increasing prevalence and incidence in association with increased age and medical comorbidities. Nonvalvular AF is defined as AF in the absence of prosthetic mechanical heart valves, or haemodynamically significant mitral stenosis (moderate or severe) [1]. Evaluation of patients with AF requires an assessment of cardiac structure and function by echocardiography. Such an assessment complements the clinical evaluation and helps decision-making regarding rhythm strategy (rhythm control vs. rate control), stroke risk stratification, and prognosis. Currently approved AF therapies are only partially effective and are associated with substantial morbidity and mortality. The new treatment standard in this arrhythmia, AF catheter ablation, requires a multidisciplinary team approach involving interventional cardiologists and imaging specialists. For AF ablation, there is a need to identify individualized mechanism-based ablation targets (defined as mapping), located especially in left atrium (LA). Achieving durable pulmonary vein isolation as first step in AF ablation therapy remains technically challenging. AF substrate ablation (by targeting LA myocardium attaint by fibrosis due to the LA structural remodelling), in addition to pulmonary vein isolation, may prevent AF recurrence if pulmonary veins reconnect or nonpulmonary vein triggers emerge. Intrinsic cardiac autonomic nerve activity precedes the onset of AF. Autonomic activity is mediated by discrete ganglionated plexi localized on the LA posterior epicardium. It promotes LA electrical remodelling. Targeting these ganglionated plexi is another method for AF ablation. New approaches to mapping and ablation may target regions of oscillating action potential duration (especially in the LA myocardium) that can cause wave breaks leading to AF [2]. Recently, European Association of Cardiovascular Imaging and the European Heart Rhythm Association published evidences available on the role of imaging techniques (including echocardiography) and their applications in patients with AF, and provided recommendations for their use in clinical practice [3]. Echocardiography is critical in the assessment of candidates for AF ablation, providing both anatomic and haemodynamic information; it offers the potential for improved safety of AF ablation. Echocardiography is very useful at each step of the procedure: before AF ablation (by patient selection and pre-procedural LA appendage thrombus exclusion), intraprocedural guidance, and after AF ablation for detection and monitoring for early and late ablation-related complications, and also atrial reverse remodelling occurrence after obtaining stable sinus rhythm.
\nTransthoracic echocardiography (TTE) allows rapid and comprehensive assessment of cardiac anatomical structure and function. It plays a central role in each of identifying comorbidities and identification of suitable candidates for AF catheter ablation. Pulmonary vein flow monitoring using echocardiography has the potential to an increasing role in the evaluation of cardiac diastolic function directly related to LA remodelling. Transoesophageal echocardiography (TOE) also provides accurate information about the presence of a thrombus in the atria or LA appendage (which is an absolute contraindication for AF ablation) and thromboembolic risk. The novel technique of intracardiac echocardiography (ICE) has emerged as a popular and useful tool in AF ablation during the procedure.
\n\nBiplane left atrial volume measurement by disk summation method in apical 4-chamber (a) and apical 2-chamber (b) views of bidimensional transthoracic echocardiography. LA: left atrium, LV: left ventricle, RA: right atrium, RV: right ventricle.
LA dilatation (structural remodelling) can occur in a broad spectrum of cardiovascular diseases including hypertension, left ventricular dysfunction, mitral valve disease, and AF. In general, two major conditions are associated with LA dilatation: pressure overload and volume overload. TTE has an important role to diagnose all these diseases in patients with AF. The LA size has an incremental value of overconventional risk factors. However, LA size has also prognostic value for long-term outcome. The current guidelines on management of patients with AF recommend a standard two‐dimensional (2D) TTE and Doppler echocardiogram, with assessment of LA
LA size in addition to LA anatomy and function are the parameters mandatory to be assessed before deciding to include a patient for AF ablation procedure. The LA anterior-posterior diameter was one of the first standardized echocardiographic parameters for assessment of
Alternatively, LA volume can be calculated using the disk summation technique by adding the volume of a stack of cylinders and area calculated by orthogonal minor and major transverse axes assuming an oval shape.
\nLA volume enables accurate assessment of the asymmetric structural remodelling of the LA and is a more robust predictor of cardiovascular events than linear or area measurements. However, the cornerstone of LA volume assessment is geometric assumptions about LA shape (as an ellipsoid shape).
\nThe upper normal limit for 2D echocardiographic LA volume is 34 mL/m2 for both genders. Single-plane apical four-chamber indexed LA volumes are typically 1–2 mL/m2 smaller than apical two-chamber volumes. Apical four- and two-chamber linear measurements and nonindexed LA area and volume measurements are not recommended for routine clinical use [4].
\nIn conclusion, TTE is the recommended approach for assessing LA size [4]. LA size should be measured at end-ventricular systole, at maximal LA size, with precautions to not underestimate or overestimate LA dimensions [4]. TOE slightly underestimates LA size; it provides good correlation with TTE. Although TOE permits good views on the LA and the LA appendage, it should not be used to assess LA size [4].
\nRecently has been demonstrated the feasibility of three‐dimensional (3D) TTE for the assessment of LA volumes [5]. 3D echocardiography has the advantage that no geometrical assumption about LA shape has to be made and it seems to be more accurate when compared to 2D measurements. In addition, this echocardiographic method has a lower intraobserver and interobserver variability as compared to 2D echocardiography [5]. However, there still remain some technical limitations: The spatial and temporal resolution is low, depends on adequate image quality, and requires patient’s cooperation; in addition, there are limited data on normal values [4].
\nLA size and volumes throughout the cardiac cycle can be acquired more precise with magnetic resonance image or computer tomography. Because the longitudinal axes of the left ventricle and LA frequently lie in different planes, dedicated acquisitions of the LA from the apical approach should be obtained for optimal LA volume measurements. However, these imaging methods are more expensive, sometimes with limited accessibility and more invasive (X-ray irradiation for computer tomography and potential kidney complications for both image techniques).
\nICE is only used during AF catheter ablation procedure [6]. Therefore, no standardized measurements of LA size or volume are available. Although ICE is limited by the monoplane character and the lack of standardized measurements of LA size, it is a valuable tool for guidance ablation procedure.
\nThe assessment of
Tissue Doppler Imaging study (at the level of basal segment of septal interventricular wall) in apical four-chamber view of transmitral inflow in a patient with paroxysmal atrial fibrillation during sinus rhythm. Sa represents systolic myocardial velocity of left ventricle; Ea represents early diastolic filling myocardial velocity of left ventricle; Aa represents late diastolic filling myocardial velocity of left ventricle.
In patients in sinus rhythm LA has three important functions: the reservoir, the conduit, and the booster pump function. The change in the
Pulsed-wave Doppler permits the assessment of late diastolic filling wave (A) on transmitral inflow pattern as marker of LA mechanical function. Both peak velocity and time-velocity integral of the mitral A wave could be used. However, in AF patients A wave is absent, so cannot be used for LA mechanical function assessment [5].
\nNew echocardiographic techniques, such as Tissue Doppler Imaging (TDI) and speckle tracking (strain and strain rate) imaging, allow noninvasive measurement of regional function of the myocardium (including LA). TDI allows the quantification of the low-velocity, high-amplitude, long-axis intrinsic myocardial velocities in both systole and diastole, and provides a relatively load-independent measure of both left ventricle systolic and diastolic function (Figure 2).
\nThe similar parameter of peak A velocity measured by TDI (Aa) is a myocardial velocity (not flow velocity) and could be also used as an atrial function parameter. It correlates with other parameters of atrial function as atrial fraction and atrial ejection force. In addition, it seems that Aa velocity assessed by TDI correlates with LA fractional area and volume change [5].
\n\nHowever, regional LA function is not routinely assessed, and therefore, no standardized parameters for regional LA functions are yet available [5]. A strong limitation for current using of this parameter is LA walls, which are thin and therefore difficult to be measured during wall moving. Improvement of LA regional function as marker of atrial electromechanical remodelling is an important outcome in patients that underwent AF catheter ablation.
\nTotal electromechanical activity of the atria could be calculated by the interval between the onsets of the P‐wave on the electrocardiogram to the end of the Aa wave on the TDI. However, TDI evaluation of regional LA function is the angle dependent. Therefore, careful adjustment of the beam and gain settings should be made to avoid aliasing and to allow reliable measurement of tissue velocities of the LA.
\nAnother brand new technique, namely speckle tracking, is based on myocardial deformation assessment. Strain and strain rate are the two parameters that measure myocardial tissue velocity gradient by speckle tracking. This technique has some major advantages comparing with TDI: It is independent of wall movements and could differentiate between active and passive motion [5].
\nAll TDI‐derived parameters of the LA, including tissue velocities, strain and strain rate, were significantly reduced in patients with AF. Using TDI and/or strain imaging techniques, the decreased compliance of LA walls, the impairment of the reservoir and conduit function of LA, and the loss of the booster pump function in patients with AF were found.
\nAfter catheter ablation of AF, decreasing of these parameters means a possible criterion of do not interrupt the antiarrhythmic and anticoagulation treatment even in sinus rhythm due to the AF recurrences [5].
\nAll changes in left ventricle diastolic function reflect on pulmonary venous flow morphology assessed by pulsed-wave Doppler [5]. In patients with AF due to LA pressure and functions (mainly the reservoir function), the following changes are possible: The wave of atrial reverse flow is absent due to the active LA mechanical function disappearance; peak velocity of systolic flow decreases and is related to the LA appendage dysfunction and thromboembolic risk; peak diastolic velocity higher than peak systolic velocity; an early systolic reverse flow is present [5]. In patients with AF catheter ablation pulmonary venous flow monitoring is important to assess LA mechanical function recovering. Preserved reservoir function of LA during AF is predictive of satisfactory recovery of mechanical function after pulmonary vein isolation [4, 5].
\nPulmonary venous diastolic deceleration time is very useful to predict diastolic left ventricle filling pressure, as estimated by pulmonary capillary wedged pressure in AF [9]. This parameter is easy to be assessed after pulmonary venous flow registration by pulsed-wave Doppler. It is defined as duration between peak diastolic velocity and the upper deceleration slope extrapolated to the baseline.
\nAccording to the current guidelines, all these measurements should be taken on 5–10 cardiac cycles during a heart rate of 60–80 beats/min.
\nIt seems that pulmonary venous deceleration time correlates better with pulmonary capillary wedged pressure than transmitral deceleration time in patients with AF [10]. Pulmonary venous deceleration time ≤150 ms could predict pulmonary capillary wedged pressure ≥18 mm Hg with 100% sensitivity and 96% specificity in patients with AF [10].
\nPatients with larger LA size, reduced LA function, and increased LA fibrosis (as marker of advanced electrical and structural remodelling) content are more likely to experience AF recurrences after ablation. The new echocardiography techniques have an emerging role in assessment of atrial fibrosis in patients with AF [7]. The appropriate selection of patients is mandatory for better outcomes in AF ablation; less fibrosis (that means less structural remodelling) seems to translate in better outcomes. Until now, there are not known imaging techniques able to predict AF ablation rate success tailored to each patient undergoing this treatment. However, there are some useful clinical tools (risk scores such as CHADS2, CHA2DS2-VASc, or APPLE scores) to identify patients with low, intermediate, or high risk of AF recurrence after AF ablation. However, echocardiography is very useful to detect and monitor LA reverse remodelling and improvement in atrial or ventricular function after AF ablation.
\nAtrial cardiomyopathies may provide the basis for the development of atrial fibrillation. The molecular alterations may also contribute to the occurrence of atrial thrombi. Thus, the concept of thrombogenic endocardial remodelling was introduced. In the future, echocardiography might be useful in this new type of atrial remodelling assessment.
\nThe presence of LA appendage or LA thrombi is an absolute contraindication for AF ablation. Therefore, echocardiography assessment of thrombi presence is mandatory before AF ablation procedure. 2D TTE has a low sensitivity for detection of thrombi in LA and especially LA appendage. 2D or 3D TOE provides excellent visualization of posterior cardiac structures because of the anatomic relationship of these structures to the oesophagus. TOE is one of the modality of choice for detecting LA or LAA thrombi (Figure 3a).
\nTwo-dimensional transesophageal echocardiogram, midoesophageal view, allowing the identification of a left atrial appendage thrombus (a); zoom of the left atrial appendage illustrating the presence of a dense spontaneous echo contrast with swirling movements in the left atrial appendage (b).
(a) Two-dimensional transesophageal echocardiogram, midoesophageal view, shows left atrial appendage with muscular ridge, namely coumadin ridge and pectinate muscles which could be misinterpreted as clots. (b) Pulsed-wave Doppler of the left atrial appendage demonstrates the decreased emptying and filling velocities in patients with atrial fibrillation.
It can detect thrombi with a high degree of sensitivity and specificity varying from 93% to 100% [5]. LA appendage has a very complex anatomy with variable shape, size, and orientation, with the possibility of several lobes and branches; therefore, thrombi assessment can be challenging. The muscular ridges and pectinate muscles (Figure 4a) must be carefully observed, because they can be misinterpreted as clots. Also ICE is very useful during AF ablation procedure to make the difference between muscular ridges and pectinate muscles (Figure 5). However, 3D TOE could make a better distinction between the pectinate muscles and thrombi, comparing with 2D TOE [11]. In addition, TOE is helpful in assessment of LA appendage velocities by pulsed-wave Doppler (Figure 4b). Usually, in patients in sinus rhythm without history of AF the average LA appendage filling velocity is 40–50 cm/s and correlates well with the LA appendage contraction velocity; the average LA appendage contraction velocity is 50–60 cm/s. Low LA appendage emptying flow velocities (defined as <20 cm/s) in AF correlate strongly with the presence of spontaneous echo contrast and thrombus formation. For patients with AF, TOE risk factors for thromboembolism associated with high risk of stroke include at least one of the following factors: LA appendage thrombus, severe spontaneous echo contrast, low flow velocities at LA appendage ostium, and complex aortic plaques [3].
Intracardiac echocardiography shows very clearly anatomic structures during ablation procedure. This image was offered by courtesy of the editor. RVOT: right ventricle outflow tract; LSPV: left superior pulmonary vein.
Thrombus identification is also challenging even if the appendage is visualized adequately. In the absence of formed thrombi, a dense spontaneous echo contrast (Figure 3b) has been demonstrated to be strong a predictor of thromboembolism. Spontaneous echo contrast can be classified into four groups (1 to 4+), depending on the intensity, location, and presence of the swirling movement [12]. It seems that patients under anticoagulation and with thromboembolic risk scores (CHADS2 and CHA2DS2-VASc) <2 have a negative predictive value approaches to 100%; therefore, TOE before catheter ablation of AF might be avoided [13].
\nSometimes it is difficult to distinguish small thrombi from artefacts, including prominent trabecular structures, duplication artefacts, and adipose tissue within the transverse sinus. It is necessary to attempt to differentiate any suspicious abnormalities from thrombus in multiple views. The mechanical function of LA appendage is best assessed with TOE utilizing pulsed-wave Doppler measurement of LA appendage emptying and filling velocities.
\nIn addition to LA appendage Doppler assessment, measuring LA appendage area and ejection fraction (evaluated through vector velocity imaging), TDI, and 3D TOE are less validated and less frequently performed parameters associated with cerebrovascular events and the formation of LA appendage thrombus [11]. Pre-procedural multislice computed tomography may also identify the presence of thrombi in the LA appendage, but the gold standard is TOE [11]; in addition to the anatomy of the LA and pulmonary veins, it also provides detailed information on surrounding structures, such as the oesophagus and coronary arteries.
\nAccording to the new theories of AF physiopathology, some ablation strategies were elaborated; however, none is known as golden standard of this therapy. Depending on ablation technique, LA anatomy and pulmonary vein morphology are of essential importance to be well known during the ablation procedure. The veno-atrial junctions and anatomical structures of the LA, such as Coumadin ridge or the ridge between the left superior pulmonary vein and LA appendage, are critical for a safe and successful procedure.
Two-dimensional transesophageal echocardiogram, midoesophageal view, shows (a) interatrial septum with left-right shunt in colour Doppler through patent foramen oval and (b) lipomatous interatrial septum. Ao: aorta; IAS: interatrial septum; LA: left atrium; RA: right atrium.
For pulmonary vein isolation or LA substrate ablation, it is mandatory to puncture the interatrial septum to gain left atrial posterior wall and pulmonary veins. If the patient has a patent foramen oval (Figure 6a), some operators say that transseptal puncture could be avoided. However, this is arguable, because accessibility to LA to gain pulmonary veins is difficult through a patent foramen oval. During TOE, a microbubble test under Valsalva manoeuvre could unmask a patent foramen oval. Rarely, TTE in subxiphoid view could identify the presence of a patent foramen oval. However, TOE has better sensibility to diagnose patent foramen oval before AF ablation. In patients with the lipomatous hypertrophy of the interatrial septum (Figure 6b), transseptal puncture could be difficult, without echocardiographic guidance.
\n\nTransseptal puncture guided by bidimensional TOE shows direct visualization of the transseptal catheter and its relationship to the fossa ovalis and the ascending aorta. Ao: aorta; IAS: interatrial septum; LA: left atrium; RA: right atrium.
Uses of ICE for transseptal puncture guidance. LA: left atrium; RA: right atrium. This image was offered by courtesy of the editor.
Transseptal puncture allows procedural access to the LA. Anatomic structures are not directly visualized during transseptal puncture by fluoroscopic guidance. TTE and especially TOE may be helpful in performing this procedure by allowing direct visualization of the transseptal catheter and its relationship to the fossa ovalis. Anatomic variability in the position and orientation of the fossa ovalis and its surrounding structures may be challenging to even those interventional cardiologists with significant transseptal experience. However, echocardiography imaging offers increased safety to the operator, by avoiding the puncture of the intrapericardial aorta, a serious complication of transseptal puncture. In addition, radiation minimizes the fluoroscopy time required for the procedure, being very important during the learning curve. It was shown that TOE is of great value in performing transseptal punctures in AF ablation procedures. TTE can delineate the aorta and interatrial septum, and the characteristic bulging (or tenting) of the fossa ovalis and saline contrast echocardiography with TTE may help confirm needle position in the right atrium before puncture and in the LA after puncture (Figure 7). Anatomical variations in interatrial septum such as aneurismal septum, double-membrane septum, patent foramen oval, and others make this process complicated. Because TTE does not always offer sufficient imaging resolution, TOE and more recently ICE are preferably (Figure 8).
\nICE could be useful only during the ablation procedure. It enables visualization of anatomical particularities of LA, being mostly important in transseptal puncture guidance and circular Lasso catheter positioning [14]. ICE enables to visualize the tenting of the interatrial septum due to the transseptal sheath tip during the puncture. It is important to be correctly placed in the posterior region of the fossa ovalis to avoid potential life-threatening complications such as aortic root perforation or LA lateral wall penetrating. For an appropriate mapping and ablation lesions, a good placement of Lasso catheter at the pulmonary vein antrum is mandatory. It could avoid important complications such as acute thrombus formation or early or late pulmonary vein stenosis by power, impedance, and temperature monitoring during energy delivery. Impedance increasing could be proceeding by microbubbles due to tissue superheating. ICE enables directly visualization of these microbubbles. In this case, immediate interruption of lesion creation is recommended to prevent severe complications such as cardiac tamponade by LA perforation, oesophageal injury or pulmonary vein stenosis. ICE is a useful tool also for the placement of mapping/ablation catheter according to anatomic landmarks and morphologic lesion changes monitoring for a safety and efficacy AF ablation procedure [7]. ICE has becoming a gold standard in complex AF ablation procedures by replacing fluoroscopy technique [14].
\nThere has been a revival in the use of transseptal catheterization due to the increased use of radiofrequency ablation in the LA. Utilization of ICE in conjunction with fluoroscopy allows the electrophysiologist to clearly identify the interatrial septum and adjacent structures. ICE provides excellent views of the fossa ovalis and of the transseptal apparatus [7]. Life-threatening complications following inadvertent puncture of anatomic structures can be avoided under direct visualization. For electrophysiologist is important a direct visualization of the Brockenbrough needle and the Mullins sheath during the transseptal puncture. Sheath position in the LA could be verified by saline microbubbles or intravenous contrast injection. The location of the Marshall vein, relevant in AF ablation, can also be identified from imaging of the “Q-tip” ridge, seen between the LA appendage and left pulmonary veins [7].
\nDuring AF ablation procedure, the mapping is followed by energy applications and lesion creation. Atrial myocardium suffers some alterations after energy application such as thickening, dimpling, and hyper-echogenicity. ICE enables identification of all myocardium sites transformed during ablation. The characteristics of lesions could be controlled by monitoring and titrating of energy parameters (temperature, impedance, and power). In addition, ICE allows identification of triggers sites such ligament of Marshall and to treat by applications under direct visualization. The applications on LA posterior wall could translate into fistula between anterior wall of the oesophagus and LA, a lethal complication of an extensive AF ablation procedure. Therefore, ICE is very useful during the procedure to titrate energy parameters to avoid this. In conclusion, ICE is used only during the ablation procedure; it allows better results of the procedure and lower risk of complications [15].
\nAll echocardiography methods, TTE, TOE, or ICE, have the ability to detect early and avoid potential lethal complications during AF ablation [15]. Appropriate anticoagulation could prevent spontaneously thrombus formation and embolization during the procedure. Immediate detecting of thrombus by ICE allows prompting removal of catheters to avoid embolic complications.
\nMicrobubbles visualization is most useful for prompting discontinuation of energy delivery when microbubbles are seen. Early detection of a pericardial effusion before cardiac tamponade (preferable before signs of haemodynamic compromise) and catheter-based treatment of the effusion are two facilitations allowed by TTE, TOE, or ICE. Pulmonary vein stenosis is a serious complication that can be detected early by visual tissue swelling and assessing severity with peak velocity measurements and colour flow parameters or pulsed-wave Doppler imaging, available with phased-array imaging [14].
\nDuring ablation procedure, ICE can accurately visualize LA anatomy and related structures and may guide transseptal catheterization and it is helpful in monitoring potential complications during catheter ablation procedures. In addition, it allows to establish a clear-cut relationship between the catheter tip and underlying tissue and to visualize the lesion formation; it can be performed with minimal additional patient risk and discomfort, without additional sedation or general anaesthesia; it does not need prolonged oesophageal intubation, accompanying patient discomfort, or the risk for aspiration. ICE offers imaging that is comparable with or superior to TOE and is an alternative to TOE in selected patients with absolute contraindications to TOE (oesophagectomy). This technique is quite safe with a negligible rate of complications and good patient tolerance. It allows improvement in success rate and decrease in complication when compared to fluoroscopic approach. ICE has been shown to improve patient comfort, shorten both procedure and fluoroscopy times, and offer comparable cost with TEE-guided interventions [5].
\nComparing with TOE, ICE has some advantages: clearer image, reduced irradiation, and shorter duration of the procedure [16]. It has also some disadvantages such as: the shaft is thick without the possibility to have ports for pressure, therapeutic devices, and guide wires; the phased-array catheters are cost-ineffective (single use, higher costs); ICE offers only monoplane image views being difficult to obtain some sections as for TOE [10].\nIn addition, there are not still standard views for ICE as for other echocardiographic imaging modality such as TTE or TOE. In addition, in the literature there are described some potential risks of vascular lesion, cardiac perforation, arrhythmias, thromboembolism, and cutaneous nerve palsy [5]. However, it is expected to be used widely in clinical practice and even to become the standard for the transseptal catheterization.
\nEchocardiography is very useful after AF ablation for detection and monitoring for early and late related complications, and also for LA reverse remodelling assessment in patients with stable sinus rhythm.
\nPulmonary veins flow monitoring is used to detect early pulmonary vein stenosis after AF ablation, which could occur in 1% to 3% of current series [17]. TOE allows the suspicion of a significant PV stenosis (Figure 9) by a combination of elevated peak pulmonary vein velocity (≥110 cm/s) with turbulence and little flow variation [17]. Although TOE has been used, it does not usually provide adequate assessment.
(a) Colour Doppler mode by transoesophageal echocardiography at the level of left superior pulmonary vein identify a significant pulmonary vein stenosis. (b) Pulsed-wave Doppler of left superior pulmonary vein inflow confirms haemodynamically significant stenosis. LA: left atrium, AO: aorta, LSPV: left superior pulmonary vein.
However, TTE or TOE are limited by its inability to image deeply into all four pulmonary veins and are less useful in establishing the extent and location of pulmonary vein stenosis. Diagnostic tests of value include magnetic resonance angiography and computed tomography. Progression of stenosis is unpredictable and may be rapid. Recurrent restenosis after angioplasty and stenting, as therapeutic solution of this complication, may occur in 30–50% of patients with pulmonary veins stenosis [17]. Follow-up of these patients typically involves computed tomography imaging to document restenosis.
\nPulmonary vein stenosis could occur late after AF ablation. TOE could raise the suspicion by detection of high pulmonary vein velocities. Follow-up of these patients typically involves computed tomography or magnetic resonance imaging to document stenosis.
\nTOE and ICE allow early identification of complications related with procedure including damage to intracardiac structures, thrombus formation, pulmonary vein stenosis, and pericardial effusion during catheter ablation of AF.
\nA TOE performed 3–6 months after AF ablation can also evaluate thromboembolic risk and need for long-term anticoagulation, as echocardiographic risk factors may be present even if restoration of sinus rhythm is successful.
\nCatheter ablation has been demonstrated to be successful in the restoration of sinus rhythm and is performed in an increasing number of patients with symptomatic drug‐refractory paroxysmal and persistent AF. It has been demonstrated that restoration and maintenance of sinus rhythm after catheter ablation is associated with a decrease in LA volumes (reverse structural LA remodelling), with subsequent improvement of LA function [5]. Using the new tissue Doppler‐derived parameters, it was shown that in parallel with the improvement in LA function, both left ventricle systolic and diastolic function improved in the patients who maintained sinus rhythm [5]. In addition to LA reverse remodelling, even the area of the pulmonary venous ostia may decrease after successful catheter ablation procedures [5]. Post-procedural imaging to evaluate the extent of reverse LA remodelling after catheter ablation is critical to appropriate decisions regarding ongoing anti-arrhythmic therapy and long-term anticoagulation.
\nConversion of AF and atrial flutter to sinus rhythm could result in a transient mechanical dysfunction of LA and LA appendage, termed atrial stunning [17]. Atrial stunning has been reported including after radiofrequency ablation. This phenomenon is well recognized with peak A velocity of transmitral inflow (by a very low value or absence) as well as TDI or strain imaging. Atrial stunning is at maximum immediately after procedure and improves progressively with a complete resolution within a few minutes to 4–6 weeks depending on the duration of the preceding AF, atrial size, and structural heart disease [18]. This suggests that a dissociation of electrical and mechanical recovery occurs after successful restoration of sinus rhythm, with a delay in gradual improvement of atrial mechanical function.
\nStiff LA syndrome, defined as pulmonary hypertension with LA diastolic dysfunction, has regained attention in patients who had undergone catheter ablation for AF, especially after multiple ablation procedures [19]. This syndrome is a rare but potentially significant complication of AF ablation. Severe LA scarring, LA ≤45 mm, diabetes mellitus, obstructive sleep apnoea, and high LA pressure are clinical variables that predict the development of this syndrome [19]. The main echocardiographic findings include pulmonary hypertension in the absence of pulmonary vein stenosis or LA pressure tracings in the absence of mitral regurgitation. Pulmonary vein diastolic flow velocity (assessed by TTE or TOE) and E/Ea (by TTE using pulse wave Doppler and TDI) can be used as a noninvasive parameter predicting high LA pressure peak (during sinus rhythm) in patients with AF [19]. Elevated LA pressure was closely associated with electroanatomical remodelling of the LA and was an independent predictor for recurrence after AF ablation [20, 21].
\nMultimodality echocardiography is needed at each step of AF ablation procedure. LA size, morphology, and function together with other cardiac parameters are mandatory for patient selection. 2D TTE allows rapid and comprehensive assessment of cardiac anatomical structure and function. 2D or 3D TOE provides accurate information about preprocedural LA appendage thrombus in the atria and thromboembolic risk and is very useful for intraprocedural guidance. The novel technique of ICE has emerged also as a popular and useful tool in the guidance of AF ablation procedure. TTE or TOE is need for early and late ablation-related complications detection and monitoring. In the future, echocardiography might be useful in thrombogenic endocardial remodelling assessment, a novel concept in atrial cardiomyopathies such as atrial fibrillation.
\nHumans are persistently exposed to various chemical and physical agents that have the potential to damage genomic DNA, such as, irradiation (IR), ultraviolet (UV) light, reactive oxygen species (ROS), et cetera [1]. The integrity and survival of a cell is critically dependent on genome stability and mammalian cells have established multiple pathways to repair different types of target DNA lesions to safeguard the genome from deleterious consequences of various kinds of stresses [2]. The significance of the DNA repair in the protection of genomic stability is highlighted by the fact that many proteins/factors involved have been preserved through evolution [3].
DNA damage, induced by endogenous and exogenous agents, is a common event and must undergo a variety of DNA damage repair in order to ensure the faithful transfer of genetic information during cell division [3]. Four main DNA polymerases are involved with nuclear DNA replication: DNA polymerase α, β, δ and ε [1] (Figure 1). DNA repair pathways, which are also recognized as guardians of the genome, protect cells from numerous damages leading to DNA breaks [4]. Failure to restore DNA lesions or inappropriate repair of DNA damage give rise to genomic instability, which is a hallmark of cancer. Remarkably, mild and massive DNA damage are differentially integrated into the cellular signaling networks and, in consequence, provoke different cell fate decisions. After mild damage, the cellular response is cell cycle arrest, DNA repair, and cell survival, whereas severe damage, drives the cell death response. The inability of the DNA damage response (DDR) to repair following endogenous and exogenous insults can lead to (i) an accumulation of errors in genomic DNA, (ii) subsequent malignant transformation, (iii) cancer progression and (iv) further impairment of the DNA repair capacity. DNA repair mechanisms comprise the detection and deletion (excision) of the lesion, the rejoining of DNA ends and the restoration of the complementary sequence based on a DNA template.
Sub-cellular localization of eukaryotic and retroviral DNA polymerases.
Since cancer cells typically have many mutations compared to a non-cancer cell, it was proposed that one of the earliest changes in the development of a cancer cell is a mutation that increases the spontaneous mutation rate [5]. The presence of a “mutator phenotype” could increase the acquisition of alterations that could lead to enhanced drug resistance limiting the effectiveness of anti-cancer drug treatment.
Viral infection is characterized by the high genetic variability found in virus populations [6]. This phenomenon is attributed to the inaccuracy of the replication machinery that is unique to the viral life cycle. Virulence, pathogenesis and the ability to develop effective antiretroviral drugs and vaccines are largely dependent on genetic diversity in viruses [7]. Retroviruses are RNA viruses that replicate through a DNA intermediate in a process catalyzed by the viral reverse transcriptase (RT) in cytoplasm (Figure 1) [7]. Human immunodeficiency virus type 1 (HIV-1), the etiological agent of AIDS, exhibits exceptionally high mutation frequencies [8]. The accepted explanations for the inaccuracy of HIV-1 RT are the relatively low fidelity of the enzyme during DNA synthesis and the deficiency of intrinsic proofreading activity. A strong mutator phenotype is also observed for herpes viral DNA polymerase mutants with reduced intrinsic 3′ → 5′ exonuclease activity [9].
Mitochondrial DNA (mtDNA) alterations have been associated with various human diseases with impaired mitochondrial function [10]. Mitochondrial DNA polymerase γ (pol γ) is responsible for replication of mtDNA and is implicated in all repair processes (Figure 1) [11]. Mitochondrial DNA is prone to mutations, since it is localized near the inner mitochondrial membrane in which reactive oxygen species are generated. Additionally, mtDNA lacks histone protection and the highly efficient DNA repair mechanisms [12]. The mutation rate of mtDNA is estimated to be about 20–100-fold higher than that of nuclear DNA [13]. The mutagenic mechanisms were shown to be replication errors caused by mis insertion (as a result of a dNTP excess), or decreased proofreading efficiency [14, 15].
Thus, in various compartments of the cell, enhanced DNA replication fidelity is a vital activity for the preservation of genomic stability for many organisms.
Genomic integrity of the cell is crucial for the successful transmission of genetic information to the offspring and its survival [16]. DNA is constantly being damaged. Essentially, DNA lesions can occur in two major ways, affecting either a single-stranded break (SSB) or double-stranded (DSB) or mono-adducts and inter-strand crosslinks, respectively. To combat this, eukaryotes have developed complex DNA damage repair (DDR) pathways (Figure 2). The active pathways for DNA repair are base excision repair (BER), nucleotide excision repair (NER), and mismatch repair MMR for SSB repair, whereas homologous recombination (HR) and non-homologous end-joining (NHEJ) for DSB repair [16]. Nucleotide excision repair (NER) removes a variety of helix-distorting lesions such as typically induced by UV irradiation, whereas base excision repair (BER) targets oxidative base modifications. Mismatch repair (MMR) scans for nucleotides that have been erroneously inserted during replication. The most deleterious types of damage in DNA are DSBs that are typically induced by IR and resolved either by NHEJ or by HR, whereas RECQ helicases assume various roles in genome maintenance during recombination repair and replication.
DNA damage and repair mechanisms. Various DNA damaging agents cause a range of DNA lesions with different outcomes at both the genomic and cellular levels. Each are corrected by a specific DNA repair mechanism, namely, base-excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR)/non-homologous end-joining (NHEJ) or mismatch repair (MMR).
A low fidelity of DNA synthesis in various compartments of the cell by main replicative DNA polymerases leads to genomic instability (mutator phenotype) [17]. The errors produced during DNA synthesis could result from three fidelity determining processes: a) nucleotide misinsertion into the nascent DNA, b) lack of exonucleolytic proofreading activity, that is, the mechanism to identify and excise incorrect nucleotide incorporated during DNA synthesis, and c) extension of mismatched 3′-termini of DNA (Table 1) [18].
Biochemical properties of cellular DNA polymerases | |||
---|---|---|---|
Function | 3′ → 5′ exonuclease | Proofreading | |
Nuclear DNA polymerases | |||
α | primase | no | no |
β | repair | no | no |
δ | Lagging DNA synthesis, repair | yes | yes |
ε | Leading DNA synthesis, repair | yes | yes |
Mitochondrial DNA polymerase | |||
γ | DNA synthesis | yes | yes |
Retroviral DNA polymerase | |||
HIV-1 RT | DNA synthesis | no | no |
Biochemical properties of eukaryotic and retroviral DNA polymerases.
Incorrectly repaired DNA lesions can lead to mutations, genomic instability, changes in the regulation of cellular functions, progression of cancer and premature aging. Cells can repair the large variety of DNA lesions through a variety of sophisticated DNA-repair machineries, recognizing and activating battery of proteins/factors for the repair of damaged DNA. DNA replication is a complex process influenced by numerous proteins/factors. The most important part of the DNA damage response is the activation of tumor repressor p53 protein [18].
The p53 represents a major factor for the maintenance of genome stability and for the suppression of cancer [19, 20]. The p53 protein is commonly referred to as the “
Under normal conditions within the cell, p53 is maintained at low levels by the E3 Ubiquitin ligase MDM2, mediating p53 proteasomal degradation [23]. In response to exposure to various endogenous and exogenous stress signals (such as DNA damage, oncogene activation, hypoxia, and nutrient depletion), the protein is stabilized and functionally activated by a series of post-translational modifications (
In response to various endogenous and exogenous stress signals, the activated p53 arrests the cell cycle until the DNA damage is repaired thereby preventing the cancer. If the DNA damage cannot be repaired apoptosis occurs for eliminating cells that contained excessive and irreparable damaged DNA.
p53 exhibits the functional heterogeneity in its basal (non-induced) state and under various p53 inducible circumstances [20]. Increasing evidences suggest various “non-transcriptional functions” of p53, that can contribute to tumor suppressor activity [25]. p53 may modulate DNA repair through processes, which are independent of its transactivation function. p53 is actively transported between the nucleus and cytoplasm. Furthermore, p53 translocate to mitochondria [26]. p53 can directly interact with DNA repair related cellular factors [27]. The origin, duration, intensity of the stress signals, the interaction with other cellular or viral proteins, and stress-mediated subcellular localization of p53 determines the outcome of the p53 response, namely, its pro- or anti-survival functions [28]. p53 protein executes multi-compartmental functions in the cell by either numerous p53-regulated proteins or by its intrinsic biochemical activities [28].
The functioning of the eukaryotic genome relies on effective and accurate DNA replication and repair [2]. DNA replication in the nucleus of eukaryotic cells employs DNA polymerases (pols) α, β, δ, and ϵ, that are the key enzymes required to maintain the integrity of the genome under all these circumstances [1, 3]. However, the maintenance of genomic integrity is complicated by the fact that the genome is persistently challenged by a variety of endogenous and exogenous DNA-damaging factors [4]. DNA lesion can block DNA replication, which can lead to double-strand breaks (DSB) or alter base coding potential, leading to mutations. The accumulation of damage in DNA can affect gene expression leading to the malfunction of many cellular processes [4]. Various DNA repair systems operate in cells to remove DNA lesions, and several proteins are known to be the key components of these repair systems.
The presence of p53 was demonstrated in different nuclear compartments and suggested that the p53 population not engaged in transcriptional regulation could exert functions other than induction of growth arrest or apoptosis and directly participate in processes of repair [25]. p53 mediating various activities are correlated with the levels of the p53 protein in the cells [27, 29]. The non-genotoxic stress may include a long-lasting, moderate accumulation of p53 in nucleus. Conversely, acute genotoxic stress may induce rapid and transient accumulation of very high levels of p53 with preferential activation of target genes involved in apoptosis [29]. There is a possibility that both transcriptional and transcription-independent pathways act in synergy thereby amplifying the potency of involvement of p53 in DNA repair.
p53 localized in cell nuclei in response to replication stress actively participate in various processes of DNA repair and DNA recombination via its ability to interact with components of the repair and recombination machinery and by its various biochemical activities [30, 31]. Both
The C-terminal 30 amino acids of p53 were shown to recognize several DNA damage-related structures.
In addition, full range of various intrinsic biochemical features of the p53 protein support its possible roles in DNA repair. After DNA damage: (a) p53 is able to recognize and bind sites of DNA damage, such as ssDNA and dsDNA ends [33, 34], (b) p53 catalyzes DNA and RNA strand transfer and promotes the annealing of complementary DNA and RNA single-strands [35, 36], (c) p53 binds insertion/deletion mismatches and bulges [37], (d) p53 binds to three-stranded heteroduplex joints and four-stranded Holliday junction DNA structures with localization specifically at the junction, suggesting that p53 directly participates in recombination repair [38], (e) it can bind DNA in a non-sequence-specific manner [39], (f) p53 exhibits a Mg2+ dependent 3′ → 5′ exonuclease activity [40, 41, 42, 43].
Noticeably, the same central region within p53, where tumorigenic mutations are clustered, recognizes DNA sequence specifically, is required for junction-specific binding of heteroduplex joints and is necessary and sufficient for the 3′ → 5′ exonuclease activity on DNA [28]. In addition to p53’s biochemical activities, numerous reports on physical and functional protein interactions further strengthened the proposal of a direct role of p53 in BER, NER, and DSB repair.
Oxidative DNA damage is largely repaired by the BER pathway. p53 might directly facilitate BER mainly via association with BER components. Wtp53 directly enhanced BER activity measured both
The cellular response depends on the dose of genotoxic agent introduced to the cells. Increasing doses of genotoxic agents cause the accumulation of activated p53 that determines the onset of BER or apoptosis. Low doses of DNA damaging agent resulted in the enhancement of p53-dependent BER activity whereas high levels induced different p53 post-translational modifications that down regulate BER pathway and instead provoked an apoptotic response [29]. The quantitative changes in p53 protein level were associated with qualitative changes in p53 phosphorylation status. In all, this may indicate that increasing doses of genotoxic agents cause the accumulation of activated p53 that determines the onset of BER or apoptosis.
NER is an important DNA repair process that detects and eliminates lesions including both chemical alteration and structural distortion of the DNA helix (
Pathogenic mutations in the GG components XPC and DDB2 (XPE) result in xeroderma pigmentosum (XP) a disease characterized by increased UV-sensitivity and skin cancer incidence [46]. Conversely, mutation in TC genes result in Cockayne’s syndrome that is characterized by neurological abnormalities but no increase in skin cancer incidence. Some NER proteins, particularly the GG damage recognition proteins, can decide a cell’s fate by triggering the initiation of the repair pathway or by signaling apoptosis [46]. Therefore, if the GG pathway is defective, neither DNA repair nor apoptosis occurs, resulting in a cancer cell containing high levels of UV-induced mutations that does not undergo apoptosis. How this non-transcriptional function of p53 contributes to tumor suppression is unclear.
DNA mismatch repair (MMR) is an important DNA repair pathway, which facilitates removal of incorrect nucleotides incorporated during replication. p53 facilitates excision of incorrect nucleotides produced from the error prone nature of DNA polymerases and misincorporation of the incorrect base [25]. Mismatched bases can be either a G/T or A/C pair. To initiate MMR a nick in the DNA either 5′ or 3′ to the mismatch must occur. Proteins that bind the mismatch in humans are
Mutator phenotypes (with the potential for cancer progression) have been reported for cells that lack a proofreading 3′ → 5′ exonuclease activity associated with the DNA polymerase [54]. Excision of incorrectly polymerized nucleotides by exonucleases is an imperious mechanism diminishing the errors during DNA polymerization [55]. Certain organisms with a deficiency of exonucleolytic proofreading, have an increased susceptibility to cancer, especially under conditions of stress. Because the misincorporation of non-complementary dNTPs during DNA replication represents a chief mechanism of gene mutation [56], the removal of the wrong nucleotides from DNA is critical for genomic stability. The intrinsic limited accuracy of DNA polymerases and the imbalance of intracellular dNTP pools are the two most important factors responsible for DNA replication errors [57, 58]. The proofreading for such replication errors by the 3′ → 5′ exonuclease activity associated with the DNA replication machinery is extremely important in reduction of the occurrence of mutations. Interestingly, the mammalian DNA pol α, an enzyme considered to be responsible for the lagging strand replication [59], lacks the 3′ → 5′ exonuclease proof-reading activity and is prone to making replication errors [60].
Three steps, base selection, exonucleolytic proofreading, and DNA elongation, ensure the high fidelity of DNA replication. wtp53 exhibits an intrinsic 3′ → 5′ exonuclease activity. wtp53, co-located with the DNA replication machinery [61], specifically interacts with pol α and has been shown to preferentially eliminate mismatched nucleotides from DNA with its 3′ → 5′ exonuclease activity, thereby enhancing the DNA replication fidelity of pol α
Hydroxyurea (HU), an inhibitor of ribonucleotide reductase involved in the
The functional interaction of DNA polymerase and exonuclease activity was observed with p53/pol-prim complex. p53-containing DNA pol-prim complex excised preferentially a 3′-mispaired primer end over a paired one and replaced it with a correctly paired nucleotide [63]. In contrast, a pol-prim complex containing the hot spot mutant p53R248H did not display exonuclease activity and did not elongate a mispaired 3′-end, representing that the p53 exonuclease from the p53/pol-prim complex was indispensable for the subsequent elongation of the primer by DNA polymerase. These findings support the view that p53 might fulfill a proofreading function for pol-prim and suggest that the defect in proofreading function of p53 may contribute to genetic instability associated with cancer development and progression [63].
DSBs are the most severe type of DNA damage, and these DSBs generated at the replication fork are repaired by two principal repair pathways: homology-based repair (HR) and non-homologous end-joining (NHEJ) [25, 31]. Furthermore, replication blocking lesions such as bulky adducts are subject to HR repair, thereby rescuing the replication fork. HR is considered the most error-free pathway, because sister chromatids are the preferred template, however, it can also produce genetic instability upon up- or down-regulation [25].
Depending on the type and quality of the DSB repair pathway involved, the repair process may end up with deletions, loss of heterozygosity, and chromosomal translocations which may accelerate the multistep process of tumorigenesis. p53 can control HR
p53 prevents the accumulation of DSBs at stalled-replication forks induced by UV or hydroxyurea (HU) treatment. When DNA replication is blocked, p53 becomes phosphorylated on serine 15 and associates with key enzymes of HR such as, Rad51, and Rad54 [68, 69]. Notably, during replication arrest p53 remains inactive in transcriptional transactivation, further supporting the direct involvement in HR regulatory functions unrelated to transcriptional transactivation activities.
p53 preferentially represses HR between certain mispaired DNA sequences. p53 specifically recognizes preformed heteroduplex joints structurally resembling early recombination intermediates, when comprising these mispairings [68]. p53 is able to attack DNA by 3′–5′ exonuclease activity principally during Rad51-mediated strand transfer and to display a DNA substrate preference for heteroduplex recombination intermediates with a further enhancement of the exonucleolytic activity for mispaired as compared to correctly paired heteroduplex DNA [38].
Highlighting the significance of p53 DNA interactions in the regulation of strand exchange events, p53 inhibits branch migration of Holliday junctions (HJs) [25, 31]. p53 recognizes this HJs -like structure and controls the generation and branch migration of the replication fork as well as its resolution, to prevent error-prone DSB repair and to cause replication pausing until the DNA lesion is repaired.
Mammalian cells repair the majority of double-strand breaks by NHEJ [69, 70] which is regarded as principally inaccurate process. The role of p53 in NHEJ remains unclear. p53 has an inhibitory effect on error-prone NHEJ but not error-free NHEJ [71], thereby suppressing genomic instability arising from low-fidelity repair. Remarkably, after the exposure to IR, DSB rejoining increases with loss of wtp53function. Inhibition of in vitro end-joining was observed with the oncogenic mutant p53(175H), whereas the phosphorylation-mimicking mutant p53(15D) failed to inhibit, thereby providing evidence for possible role of phosphorylated p53 in the regulation of NHEJ [72].
Various
Under normal conditions a basal pool of p53 is retained intra-cellular, with the distribution of p53 between the different subcellular compartments dependent on the cellular stress milieu [28]. Indeed, wtp53 occurs in cytoplasm in a subset of human tumor cells such as breast cancers, colon cancers and neuroblastoma [73, 74, 75]. Shuttling between nucleus and cytoplasm not only regulates protein localization, but also often impacts on protein function.
p53, localized in the cytoplasmic lysates of non-stressed p53-proficient cell lines [e.g. LCC2, HCT116 (p53+/+)] exerts an inherent 3′ → 5′ exonuclease activity displaying identical biochemical functions characteristic for recombinant wtp53 [76, 77]: 1) it removes 3′-terminal nucleotides from various nucleic acid substrates: ssDNA, dsDNA, and RNA/DNA template-primers, 2) it hydrolyzes ssDNA in preference to dsDNA substrate, 3) it shows a marked preference for excision of a mismatched vs. correctly paired 3′ terminus with RNA/DNA and DNA/DNA substrates, 4) it excises nucleotides from nucleic acid substrates independently from DNA polymerase, 6) it fulfills the requirements for proofreading function; acts coordinately with the exonuclease-deficient viral DNA polymerases.
Viruses exploits their cellular host for their successful replication, they utilize cell proteins for multiple purposes during their intracellular replication [78]. Since viral infection evokes cellular stress, the infected cells harbor stabilized activated p53 and manipulate p53’s guardian role. Interestingly, increased p53 levels have been noted following infection of cells with various viruses including retrovirus-human immunodeficiency virus [79], which exhibits exceptionally high genetic variability [6], due to the low fidelity of the replication apparatus that is exclusive to the retroviral life cycle.
Reverse transcriptase (RT) of HIV-1 is responsible for the conversion of the viral genomic ssRNA into the proviral DNA in the cytoplasm [7]. The lack of intrinsic 3′ → 5′ exonuclease activity, the formation of 3′-mispaired DNA and the subsequent extension of this DNA were shown to be determinants for the low fidelity of HIV-1 RT [80]. p53 can proofread for HIV-1 RT, increasing the fidelity of DNA synthesis by excising incorrectly polymerized nucleotides from RNA/DNA and DNA/DNA temple-primers in the direct exonuclease assay, when first binding to a 3′-terminus and during ongoing DNA synthesis
DNA polymerase (pol) γ is the sole DNA polymerase that is responsible for replication and repair of mtDNA [81]. It is well established that defects in mtDNA replication lead to mitochondrial dysfunction and disease [56, 60]. Mutations in mtDNA can arise from exogenous sources, from endogenous oxidative stress, or as spontaneous errors of replication during either DNA synthesis or repair events [82]. Mitochondrial DNA is replicated by DNA polymerase γ in concert with replisome accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, the multifunctional mitochondrial transcription factor A (TFAM) with important roles in mtDNA replication and initiating factors.
A high frequency of mutations within mtDNA, resulting in mitochondrial dysfunctions, is an important source of various diseases including cancer and human aging [81, 82]. To verify mtDNA integrity, cells hold various DNA damage response pathway(s) comprising mtDNA replication/repair preservation programs that either preclude or repair damage [83]. The mutagenic mechanisms were shown to be replication errors formed by either pol γ during DNA synthesis by incorporation of incorrect nucleotide or produced due to the presence of unbalanced dNTP concentrations, or by diminished proofreading efficiency. MtDNA is not protected by histones and mtDNA repair is ineffective [81]. Furthermore, a potentially important source of replication infidelity is damage due to ROS. pol γ, was demonstrated to stably misincorporate highly mutagenic 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) opposite template adenine in a complete DNA synthesis reaction
Because of the susceptibility of mtDNA to oxidative damage and replication errors, it is vital to protect mtDNA genomic stability to preserve health. Mitochondrial localization of p53 was observed in non-stressed and stressed cells [26]. Mitochondrial p53 (mit-p53) levels are proportional to total p53 levels, and the majority of p53 was present inside the intra-mitochondrial compartment-matrix, in which mtDNA is located [85]. The mit-p53 physically and functionally interacts with both, mtDNA and pol γ [86].
Notably, with the exception of NER, components of these nuclear DNA repair pathways are also shared in mtDNA maintenance. Several studies illustrated the participation of p53 in mtDNA repair:
53 enhances mitochondrial BER (mtBER) through direct interaction with the repair complex in mouse liver and cancer cells [87]. p53 modulates mtBER through the stimulation of the nucleotide incorporation step.
p53 interacts physically with human mtSSB (HmtSSB)
Intra-mitochondrial p53 provides an error-repair proofreading function for pol γ by excision of misincorporated nucleotides [89]. The p53 in mitochondria may affect the accuracy of DNA synthesis by acting as an external proofreader, thus reducing the production of polymerization errors.
In addition to having a critical role in preservation of genome integrity, alterations in the expression, and function of DNA repair proteins are a major facilitator of tumor responses to chemo- and radiotherapy, commonly functioning by inducing DNA damage in tumor cells. Nucleoside analogs, clinically active in cancer chemotherapy (
The cytotoxic activity of gemcitabine (2′2’-difluorodeoxycitidine, dFdC) was strongly correlated with the amount of dFdCMP incorporated into cellular DNA [92]. The p53 protein recognizes dFdCMP-DNA in whole cells, as evidenced by the fact that p53 protein rapidly accumulated in the nuclei of the gemcitabine treated ML-1 cells [93]. Although, the excision of the dFdCMP from the 3′-end of the DNA was slower than the excision of mismatched nucleotides in whole cells with wtp53 (ML-1) and not detectable in CEM cells harboring mutant p53. ML-1 cells were more sensitive to the cytotoxic effect of the drugs compared to the p53-null or mutant cells. The recognition of the incorporated NAs in DNA by wtp53 did not confer resistance to gemcitabine, but may have facilitated the apoptotic cell death process. It was reported that treatment with gemcitabine resulted in an increased production of DNA-dependent protein kinase (DNA-PK) and p53 complex in nucleus, that interacts with the gemcitabine-containing DNA [93, 94]. DNA-PK and p53 sensor complex may serve as a mechanism to activate the pro-apoptosis function of p53. Apparently, the prolonged existence of the NA-stalled DNA end induced the kinase activity, which subsequently phosphorylated p53 and activated the downstream pathways leading to apoptosis.
Remarkably, p53 present in complex with DNA-PK exhibited 3′ → 5′ exonuclease activity with mismatched DNA, however the active p53 was unable of excising efficiently the incorporated drug from NA-DNA construct containing gemcitabine at the 3′-end [94]. Notably, the specific effects of gemcitabine exposure appeared to vary depending on the duration of treatment and upon the cell line.
It should be pointed out, that wtp53 in ML-1 cells removed the purine nucleoside analog fludarabine (F-ara-A) more efficiently than gemcitabine [93]. Further studies are needed to assess the role of p53 in cellular response to various anti-cancer purine and pyrimidine NA-induced DNA damage.
HIV-1 RT readily utilizes many NAs and the incorporation of nucleoside RT inhibitors (NRTIs) into the 3′-end of viral DNA leads to chain termination of viral DNA synthesis in cytoplasm [88, 95]. p53 protein in the cytoplasm excises the incorporated NAs during both RNA-dependent and DNA-dependent DNA polymerization reactions, although less efficiently than the mismatched nucleotides; longer incubation times were required for excision of the terminally incorporated analogs [96]. The data suggest that p53 in cytoplasm may act as an external proofreader for NA incorporation and confer cellular resistance mechanism to the anti-viral compounds.
Pol γ is unique among the cellular replicative DNA polymerases as it is sensitive to inhibition by nucleoside analogue reverse transcriptase inhibitors (NRTIs) used in the treatment of HIV, which can cause an induced mitochondrial toxicity [97]. Acquired mitochondrial toxicity occurs as a consequence of incorporation of NA into mtDNA or inhibition of mtDNA replication or both. A terminally incorporated NA may be removed by p53 in mitochondria [97]. The removal of the incorporated NA by p53 exonuclease, indicates that the presence of the cellular component-p53 in mitochondria may be important in defining the cytotoxicity of NAs toward mitochondrial replication, thus affecting risk–benefit approach (NA toxicity versus viral inhibition) [98, 99]. Apparently, the presence of p53 in mitochondria may be important, as the excision of the mispair and NA by p53 is favorable event for mitochondrial function.
p53 is a multifunctional protein with positive and negative effects. In general, drug resistance that occurs in cancer chemotherapy and antiviral therapy is a negative event that will decrease the efficacy of the treatment. The recognition and removal of NA from drug-containing DNAs by p53 exonuclease activity in various compartments of the cell may play a role in decreasing drug activity, leading to various biological outcomes: 1)the excision of the incorporated NA from DNA in nucleus may confer resistance to the drugs (negative effect) [93]; 2)the removal of the NA by p53 from DNA incorporated by HIV-1 RT in cytoplasm may confer resistance to the drugs by non-viral mechanism (negative effect) [96] and 3)the excision of NAs from mitochondrial DNA may decrease the potential for chain termination and host toxicity (positive effect) [97].
The genome is constantly under attack from extrinsic and intrinsic damaging agents. Uracil (dU) mis-incorporation in DNA is an intrinsic factor resulting in genomic instability and DNA mutations. The excessive levels of genomic uracil in DNA can modify gene expression by interfering with promoter binding and transcription inhibition, can change transcriptional stalling, or induce DNA strand breaks leading to apoptosis. The factors that influence uracil levels in DNA are cytosine deamination, de novo thymidylate (dTMP) biosynthesis, salvage dTMP biosynthesis, and DNA repair. Furthermore, mis-incorporation occurs when DNA polymerases incorporate dUTP into DNA, in place of dTTP, and the rate of misincorporation is believed to be determined by the intracellular dUTP:dTTP ratio [100, 101]. The enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase), which facilitates the conversion of dUTP to dUMP further utilized by thymidylate synthase (TS) for synthesis of dTMP, avoids mis-incorporation of dU into DNA in nucleus by decreasing the dUTP/dTTP ratio [101]. The misincorporation of dU, as a result of accumulation of dUTP, plays a critical role in cytotoxicity mediated by TS inhibitors, such as the commonly used anticancer drug 5-fluorouracil (5-FU) [102]. DNA directed cytotoxicity of chemotherapeutic agents (e.g.5-FU) not only depends on accumulation of dUTP, but may also be determined by the efficiency of the DNA repair mechanisms (e.g. excision repair) which preclude the incidence of the mistake.
Pol γ in mitochondria is incapable to readily correct U:A mismatches [11]. HIV-1 RT in the cytoplasm of HIV-infected cells efficiently inserts the non-canonical dUTP into the proviral DNA and extends the dU-terminated DNA [103]. The misincorporation of dUTP leads to mutagenesis, and to down-regulation of viral gene expression [104].
Within the context of error-correction events, p53 as a DNA binding protein, contributes an external proofreading function; upon excision of the dU, the p53 dissociates, thus letting the transfer of the substrate with the correct 3′-terminus to DNA polymerase and renewal of DNA synthesis.
The biochemical data show that the procession of U:A and mismatched U:G lesions enhances in the presence of recombinant or endogenous cytoplasmic or mitochondrial p53 [105]. p53 in cytoplasm can participate through the intermolecular pathway in a dU-damage-associated repair mechanism by its ability to remove preformed 3′-terminal dUs, thus preventing further extension of 3’ dU-terminated primer during DNA synthesis by HIV-1 RT. Similarly, p53 in mitochondria can function as an exonuclease/proofreader for pol γ by either decreasing the incorporation of non-canonical dUTP into DNA or by promoting the excision of incorporated dU from nascent DNA, thus expanding the spectrum of DNA damage sites exploited for proofreading as a trans-acting protein [106].
During genomic DNA replication another form of replication errors arises during the incorporation of nucleotides carrying the correct base, but the wrong sugar at substantial rates [107]. DNA polymerases often incorporate ribonucleoside triphosphates (rNTPs) into DNA because of the much higher concentration of rNTPs than that of dNTPs in the cellular nucleotide pool. Indeed, more than 106 rNMPs are incorporated during one round of replication of a mammalian genome [107]. Newly incorporated rNMPs destabilize DNA and pose a major threat to genome integrity due to their reactive 2’OH group. The inserted rNs are the most abundant non-canonical nucleotides in the genome. Failure of rN removal is associated with genome instability in the form of mutagenesis, replication stress, DNA breaks, and chromosomal rearrangements. The aberrant accumulation of rNs in the genome leads to human diseases including Aicardi–Goutières syndrome (AGS), the severe autoimmune disease, and tumorigenesis [108]. Mammalian cells have developed strategies to prevent persistent rN accumulation. In eukaryotes, rNs embedded into DNA are primarily repaired by RNase H2-initiated repair pathway. Ribonucleotide excision repair (RER) may be directly coupled to replication and results in rapid post-replicative repair of rNMPs [108]. Remarkably, exonuclease-proficient yeast and human DNA polymerases can proofread incorporated rNs, albeit inefficiently [107].
Recent studies have demonstrated the importance of p53 in 3′-terminal RER pathway through a functional collaboration with HIV-1 RT, acting in a coordinated manner to attain higher fidelity. p53, functioning as a trans-acting proofreader in cytoplasm, can decrease the stable incorporation of rNs, into DNA by HIV-1 RT [109]. p53 can influence events needed for RER by possessing the compatible biochemical properties: p53 is pertinent in the correction of replication errors produced by HIV-1 RT during distinct steps of rN incorporation through intermolecular pathway: by removal pre-existing 3′-terminal rN; by reducing rN incorporation; by preventing extension of a 3′ rN-terminated primer, by attenuating stable incorporation of rNs. Thus, p53, functioning as a trans-acting proofreader in cytoplasm, can decrease the stable incorporation of rNs.
The fact that p53 in cytoplasm can edit an incorrect sugar irrespective of the nature of base, expands the role of p53 as a proofreader in the repair of replication errors by removing both a base mismatch and an incorrect sugar.
Mammalian cells have evolved multiple strategies to safeguard the genetic information to prevent the fixation of genetic damage induced by endogenous and exogenous mutagens [16]. p53 protein plays a crucial role in the regulation of cell fate determination in response to a variety of cellular stresses. p53 may exert the functional heterogeneity in its non-induced and in its activated state [16]. Remarkably, DNA repair transcription-independent functions of wtp53, contributing to tumor suppression, were found to protect cells from DNA damage independently of the transcription-mediated functions of p53 [25]. Thus, a more comprehensive understanding of how p53 transcription- independent functions are induced in response to a variety of cellular insults is vital. This report focuses on direct roles of p53 in DNA repair during DNA replication in various compartments of the cell. Apparently, p53 has more than one contributions to DNA replication fidelity, which could depend on sub-cellular localization of p53, on the type and incidence of replication obstacles, on the levels of p53 protein [28].
p53 is able to elicit a spectrum of different effective DNA repair pathways in nucleus, cytoplasm and mitochondria (Figure 4). Within the nucleus, p53 regulates different repair mechanisms, in response to endogenous and exogenous replicative stress
p53 functions in DNA repair. p53 under both normal and stress conditions, can help cellular and viral DNA polymerases to promote the repair of DNA in various cellular compartments. The result of p53 activation depends on many variables, including the extent of the stress or damage. In this model, basal p53 activity or that induced by stress signals elicits the protector responses that support the repair of genotoxic damage by various pathways.
In the cytoplasm, p53 may contribute effective proofreading for exonuclease-deficient DNA polymerases (
Within the mitochondria, various studies illustrated the participation of p53 in mtDNA repair in a variety of systems: a)p53 enhances BER through direct interaction with the repair complex in mouse liver and cancer cells [87]. b) Intra-mitochondrial p53 provides an error-repair proofreading function for pol γ by excision of misincorporated nucleotides [89]. c)p53 is proficient of hydrolyzing the 8-oxo-7,8-dihydro-2′-deoxy-guanosine (8-oxodG) present at the 3′-end of DNA, a well-known marker of oxidative stress [88]. d)p53 regulates mtDNA copy number, which may impact mitochondrial and cellular functions [112].
Therapeutic strategies based on p53 are particularly interesting because they exploit the cancer cell’s intrinsic genome instability and predisposition to cell death-apoptosis [90, 91]. The role of p53 is predominantly relevant with respect to the development of anticancer and antiviral therapies. Removal of drugs by 3′ → 5′ exonuclease activity may also facilitate resistance to anti-cancer or anti-viral treatments. Clinical drug resistance limits the efficacy of these compounds. Uncovering the mechanisms, which are responsible for DNA repair of NA-induced DNA damage will have therapeutic value. The p53 protein is able to remove incorporated NA. The stress induced activation of p53 that occurs during anti-cancer or anti-viral therapy has negative and positive effects. p53 may remove incorporated therapeutic NAs from DNA or trigger apoptosis. More studies regarding functions of p53 in genome integrity and cancer evolution may facilitate drug screening and better design of therapeutic approaches.
The functional interaction between p53 and DNA polymerase may have important consequences for the maintenance of genomic integrity and in the development of p53- targeted clinical therapies. Further assessments are required to establish the role of p53 in DNA replication and the significance of these functions in various cellular compartments and treatment responses. Studies on the biology of various mutant p53 isoforms and their interaction with the factors involved in DNA repair and apoptosis, will be relevant to establish whether the direct involvement of p53 in DNA repair is a tumor suppressor function of this important anti-oncogene. Characterization of exonuclease-deficient H115N mutant p53 revealed that although exonuclease-mutant H115N p53 can induce cell cycle arrest more efficiently than wild-type p53, its ability to produce apoptosis in DNA damaged cells is markedly impaired [113]. By utilizing various function-mutant p53 isoforms, more studies must be conducted on the biology of mutant p53 forms and their interaction with the factors involved in DNA repair and apoptosis, in order to recognize the molecular mechanisms that mediate p53-dependent control of DNA replication by cellular and viral DNA polymerases.
p53 has a dual role in response to therapy, as exonuclease that by excision of incorporated anti-cancer drugs may confer resistance to drugs or as mediator of cell death induced by chemotherapy [93]. p53, by removal of the incorporated NA, could confer a cellular resistance mechanism to the antiviral compounds. Finally, the excision of NAs from mitochondrial DNA may decrease the potential for chain termination and host toxicity. These features could serve as a template for the development of p53-targeting therapies.
The control of the viral mutation rate could be a practical anti-retroviral strategy. The mutagenic capacity of a low fidelity DNA polymerase will be decreased through increase in exonuclease concentration or exonuclease targeting (increase in local p53 concentration). It is important to further elucidate the molecular mechanisms involved in governing fidelity not only at a molecular level (
A major issue in the future would be to characterize the cellular and biological functions of p53 in mitochondria in response to various stresses. There are many missing links about the biological functions of mitochondrial p53 that are required to be investigated. Whether p53 defines the percent of mutated mtDNA (heteroplasmy in a cell)? Uncovering the mechanisms by which pol γ-mediated mtDNA mutations and depletion are manifested in cells in the absence and presence of p53 is significant step in understanding underlying causes for mtDNA–related diseases. Depletion and mutation of mtDNA may lead to cellular respiratory dysfunction and release of reactive oxidative species, resulting in cellular damage [99]. Future NAs should provide higher specificity for HIV-RT and lower incorporation by pol γ to diminish mitochondrial toxicity. Whether the effective targeting of p53 in mitochondria by error-correction functions, may result in decrease of mitochondrial toxicity in response to conventional anti-viral therapies? Understanding how p53 can be imported into mitochondria, will be important and could contribute toward the design of new therapies for various diseases.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. 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Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. 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These physiological events occur smoothly in normal healthy individual and/or under normal conditions. However, in certain cases, these molecular events are retarded resulting in hard-to-heal or chronic wounds arising from several factors such as poor venous return, underlying physiological or metabolic conditions such as diabetes as well as external factors such as poor nutrition. In most cases, such wounds are infected and infection also presents as another complicating phenomenon which triggers inflammatory reactions, therefore delaying wound healing. There has therefore been recent interests and significant efforts in preventing and actively treating wound infections by directly targeting infection causative agents through direct application of antimicrobial agents either alone or loaded into dressings (medicated). These have the advantage of overcoming challenges such as poor circulation in diabetic and leg ulcers when administered systemically and also require lower amounts to be applied compared to that required via oral or iv administration. This chapter will review and evaluate various antimicrobial agents used to target infected wounds, the means of delivery, and current state of the art, including commercially available dressings. Data sources will include mainly peer-reviewed literature, clinical trials and reports, patents as well as government reports where available.",book:{id:"5290",slug:"wound-healing-new-insights-into-ancient-challenges",title:"Wound Healing",fullTitle:"Wound Healing - New insights into Ancient Challenges"},signatures:"Omar Sarheed, Asif Ahmed, Douha Shouqair and Joshua Boateng",authors:[{id:"183108",title:"Dr.",name:"Joshua",middleName:null,surname:"Boateng",slug:"joshua-boateng",fullName:"Joshua Boateng"},{id:"183399",title:"Dr.",name:"Omar",middleName:null,surname:"Sarheed",slug:"omar-sarheed",fullName:"Omar Sarheed"},{id:"188082",title:"Mr.",name:"Asif",middleName:null,surname:"Ahmed",slug:"asif-ahmed",fullName:"Asif Ahmed"},{id:"188083",title:"Ms.",name:"Douha",middleName:null,surname:"Shouqair",slug:"douha-shouqair",fullName:"Douha Shouqair"}]},{id:"51825",doi:"10.5772/64611",title:"Roles of Matrix Metalloproteinases in Cutaneous Wound Healing",slug:"roles-of-matrix-metalloproteinases-in-cutaneous-wound-healing",totalDownloads:3568,totalCrossrefCites:16,totalDimensionsCites:34,abstract:"Wound healing is a complex process that consists of hemostasis and inflammation, angiogenesis, re-epithelialization, and tissue remodeling. Matrix metalloproteinases (MMPs) play important roles in wound healing, and their dysregulation leads to prolonged inflammation and delayed wound healing. There are 24 MMPs in humans, and each MMP exists in three forms, of which only the active MMPs play a role in the pathology or repair of wounds. The current methodology does not distinguish between the three forms of MMPs, making it challenging to investigate the roles of MMPs in pathology and wound repair. We used a novel MMP-inhibitor-tethered affinity resin that binds only the active form of MMPs, from which we identified and quantified active MMP-8 and active MMP-9 in a murine diabetic model with delayed wound healing. We showed that up-regulation of active MMP-9 plays a detrimental role whereas active MMP-8 is involved in repairing the wound in diabetic mice. These studies identified MMP-9 as a novel target for therapeutic intervention in the treatment of chronic wounds. A selective inhibitor of MMP-9 that leaves MMP-8 unaffected would provide the most effective therapy and represents a promising strategy for therapeutic intervention in the treatment of diabetic foot ulcers.",book:{id:"5290",slug:"wound-healing-new-insights-into-ancient-challenges",title:"Wound Healing",fullTitle:"Wound Healing - New insights into Ancient Challenges"},signatures:"Trung T. Nguyen, Shahriar Mobashery and Mayland Chang",authors:[{id:"183405",title:"Prof.",name:"Mayland",middleName:null,surname:"Chang",slug:"mayland-chang",fullName:"Mayland Chang"},{id:"191152",title:"Mr.",name:"Trung",middleName:null,surname:"Nguyen",slug:"trung-nguyen",fullName:"Trung Nguyen"},{id:"191153",title:"Prof.",name:"Shahriar",middleName:null,surname:"Mobashery",slug:"shahriar-mobashery",fullName:"Shahriar Mobashery"}]},{id:"63675",doi:"10.5772/intechopen.81208",title:"Wound Healing: Contributions from Plant Secondary Metabolite Antioxidants",slug:"wound-healing-contributions-from-plant-secondary-metabolite-antioxidants",totalDownloads:1282,totalCrossrefCites:7,totalDimensionsCites:19,abstract:"Plants by their genetic makeup possess an innate ability to synthesize a wide variety of phytochemicals that help them to perform their normal physiological functions and/or to protect themselves from microbial pathogens and animal herbivores. The synthesis of these phytochemicals presents the plants their natural tendency to respond to environmental stress conditions. These phytochemicals are classified either as primary or secondary metabolites. The secondary metabolites have been identified in plants as alkaloids, terpenoids, phenolics, anthraquinones, and triterpenes. These plant-based compounds are believed to have diverse medicinal properties including antioxidant properties. Plants have therefore been a potential source of antioxidants which have received a great deal of attention since increased oxidative stress has been identified as a major causative factor in the development and progression of several life-threatening diseases, including neurodegenerative and cardiovascular diseases and wound infection. Consequently, many medicinal plants have been cited and known to effect wound healing and antioxidant properties. This chapter briefly reviews antioxidant properties of medicinal plants to highlight the important roles medicinal plants play in wound healing.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Victor Y.A. Barku",authors:[{id:"261027",title:"Prof.",name:"Victor Y. A.",middleName:null,surname:"Barku",slug:"victor-y.-a.-barku",fullName:"Victor Y. A. Barku"}]},{id:"66793",doi:"10.5772/intechopen.85020",title:"The Impact of Biofilm Formation on Wound Healing",slug:"the-impact-of-biofilm-formation-on-wound-healing",totalDownloads:1385,totalCrossrefCites:7,totalDimensionsCites:15,abstract:"Chronic wounds represent an important challenge for wound care and are universally colonized by bacteria. These bacteria can form biofilm as a survival mechanism that confers the ability to resist environmental stressors and antimicrobials due to a variety of reasons, including low metabolic activity. Additionally, the exopolymeric substance (EPS) contained in biofilm acts as a mechanical barrier to immune system cells, leading to collateral damage in the surrounding tissue as well as chronic inflammation, which eventually will delay healing of the wound. This chapter will discuss current knowledge on biofilm formation, its presence in acute and chronic wounds, how biofilm affects antibiotic resistance and tolerance, as well as the wound healing process. We will also discuss proposed methods to eliminate biofilm and improve wound healing despite its presence, including basic science and clinical studies regarding these matters.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Rafael A. Mendoza, Ji-Cheng Hsieh and Robert D. Galiano",authors:[{id:"253607",title:"M.D.",name:"Rafael",middleName:null,surname:"Mendoza",slug:"rafael-mendoza",fullName:"Rafael Mendoza"},{id:"254018",title:"Dr.",name:"Robert",middleName:null,surname:"Galiano",slug:"robert-galiano",fullName:"Robert Galiano"},{id:"271116",title:"Mr.",name:"Ji-Cheng",middleName:null,surname:"Hsieh",slug:"ji-cheng-hsieh",fullName:"Ji-Cheng Hsieh"}]},{id:"63086",doi:"10.5772/intechopen.80215",title:"Medicinal Plants in Wound Healing",slug:"medicinal-plants-in-wound-healing",totalDownloads:2815,totalCrossrefCites:6,totalDimensionsCites:11,abstract:"Wound healing process is known as interdependent cellular and biochemical stages which are in trying to improve the wound. Wound healing can be defined as stages which is done by body and delayed in wound healing increases chance of microbial infection. Improved wound healing process can be performed by shortening the time needed for healing or lowering the inappropriate happens. The drugs were locally or systemically administrated in order to help wound healing. Antibiotics, antiseptics, desloughing agents, extracts, etc. have been used in order to wound healing. Some synthetic drugs are faced with limitations because of their side effects. Plants or combinations derived from plants are needed to investigate identify and formulate for treatment and management of wound healing. There is increasing interest to use the medicinal plants in wound healing because of lower side effects and management of wounds over the years. Studies have shown that medicinal plants improve wound healing in diabetic, infected and opened wounds. The different mechanisms have been reported to improve the wound healing by medicinal plants. In this chapter, some medicinal plants and the reported mechanisms will be discussed.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Mohammad Reza Farahpour",authors:[{id:"253340",title:"Prof.",name:"Mohammadreza",middleName:null,surname:"Farahpour",slug:"mohammadreza-farahpour",fullName:"Mohammadreza Farahpour"}]}],mostDownloadedChaptersLast30Days:[{id:"55736",title:"Haemodynamic Monitoring in the Intensive Care Unit",slug:"haemodynamic-monitoring-in-the-intensive-care-unit",totalDownloads:3284,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Monitoring is a cognitive aid that allows clinicians to detect the nature and extent of pathology and helps assessment of response to therapy. The cardiovascular system is the most commonly monitored organ system in the critical care setting. It helps identify the presence and nature of shock and guides response to resuscitation by detection of cardiac rate and rhythm, evaluation of volume state, cardiac contractility and systemic vascular resistance. Newer technologies allow greater assessment of oxygen delivery to vulnerable tissues. We discuss the nature, history, modalities and interpretation of the most commonly available haemodynamic monitoring methods in clinical use currently.",book:{id:"5756",slug:"intensive-care",title:"Intensive Care",fullTitle:"Intensive Care"},signatures:"Mainak Majumdar",authors:[{id:"86678",title:"Dr.",name:"Mainak",middleName:null,surname:"Majumdar",slug:"mainak-majumdar",fullName:"Mainak Majumdar"}]},{id:"51825",title:"Roles of Matrix Metalloproteinases in Cutaneous Wound Healing",slug:"roles-of-matrix-metalloproteinases-in-cutaneous-wound-healing",totalDownloads:3569,totalCrossrefCites:16,totalDimensionsCites:34,abstract:"Wound healing is a complex process that consists of hemostasis and inflammation, angiogenesis, re-epithelialization, and tissue remodeling. Matrix metalloproteinases (MMPs) play important roles in wound healing, and their dysregulation leads to prolonged inflammation and delayed wound healing. There are 24 MMPs in humans, and each MMP exists in three forms, of which only the active MMPs play a role in the pathology or repair of wounds. The current methodology does not distinguish between the three forms of MMPs, making it challenging to investigate the roles of MMPs in pathology and wound repair. We used a novel MMP-inhibitor-tethered affinity resin that binds only the active form of MMPs, from which we identified and quantified active MMP-8 and active MMP-9 in a murine diabetic model with delayed wound healing. We showed that up-regulation of active MMP-9 plays a detrimental role whereas active MMP-8 is involved in repairing the wound in diabetic mice. These studies identified MMP-9 as a novel target for therapeutic intervention in the treatment of chronic wounds. A selective inhibitor of MMP-9 that leaves MMP-8 unaffected would provide the most effective therapy and represents a promising strategy for therapeutic intervention in the treatment of diabetic foot ulcers.",book:{id:"5290",slug:"wound-healing-new-insights-into-ancient-challenges",title:"Wound Healing",fullTitle:"Wound Healing - New insights into Ancient Challenges"},signatures:"Trung T. Nguyen, Shahriar Mobashery and Mayland Chang",authors:[{id:"183405",title:"Prof.",name:"Mayland",middleName:null,surname:"Chang",slug:"mayland-chang",fullName:"Mayland Chang"},{id:"191152",title:"Mr.",name:"Trung",middleName:null,surname:"Nguyen",slug:"trung-nguyen",fullName:"Trung Nguyen"},{id:"191153",title:"Prof.",name:"Shahriar",middleName:null,surname:"Mobashery",slug:"shahriar-mobashery",fullName:"Shahriar Mobashery"}]},{id:"63086",title:"Medicinal Plants in Wound Healing",slug:"medicinal-plants-in-wound-healing",totalDownloads:2819,totalCrossrefCites:6,totalDimensionsCites:11,abstract:"Wound healing process is known as interdependent cellular and biochemical stages which are in trying to improve the wound. Wound healing can be defined as stages which is done by body and delayed in wound healing increases chance of microbial infection. Improved wound healing process can be performed by shortening the time needed for healing or lowering the inappropriate happens. The drugs were locally or systemically administrated in order to help wound healing. Antibiotics, antiseptics, desloughing agents, extracts, etc. have been used in order to wound healing. Some synthetic drugs are faced with limitations because of their side effects. Plants or combinations derived from plants are needed to investigate identify and formulate for treatment and management of wound healing. There is increasing interest to use the medicinal plants in wound healing because of lower side effects and management of wounds over the years. Studies have shown that medicinal plants improve wound healing in diabetic, infected and opened wounds. The different mechanisms have been reported to improve the wound healing by medicinal plants. In this chapter, some medicinal plants and the reported mechanisms will be discussed.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Mohammad Reza Farahpour",authors:[{id:"253340",title:"Prof.",name:"Mohammadreza",middleName:null,surname:"Farahpour",slug:"mohammadreza-farahpour",fullName:"Mohammadreza Farahpour"}]},{id:"67217",title:"Nursing Implications in the ECMO Patient",slug:"nursing-implications-in-the-ecmo-patient",totalDownloads:2468,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Effective care and positive outcomes of the extracorporeal membrane oxygenation (ECMO) patient necessitate optimal interdisciplinary management from the healthcare team, including expert care from specially trained registered nurses (RNs). It is incumbent upon the RN caring for the ECMO patient to excel in both time management and assessment skills, as this population often demands care delivery at the pinnacle of intensive care unit (ICU) acuity. Astute and nuanced monitoring of neurological status, bleeding risk with potential (often massive) transfusions, poor hemodynamics, and integrity of the ECMO pump itself are only the few specialized areas of focus that must share priority with traditional nursing considerations involving the critically ill, such as prevention of pressure injuries and bloodstream infections. These high-intensity medical foci must be balanced with ethical considerations, as the ultimate goal of returning the patient to their normal life is not always possible. These demands highlight the dynamic proficiency of the RN caring for the ECMO patient. The following chapter will highlight the importance of specialized nursing care in the critically ill patient supported with ECMO.",book:{id:"7878",slug:"advances-in-extracorporeal-membrane-oxygenation-volume-3",title:"Advances in Extracorporeal Membrane Oxygenation",fullTitle:"Advances in Extracorporeal Membrane Oxygenation - Volume 3"},signatures:"Alex Botsch, Elizabeth Protain, Amanda R. Smith and Ryan Szilagyi",authors:[{id:"298623",title:"Mr.",name:"Alexander",middleName:null,surname:"Botsch",slug:"alexander-botsch",fullName:"Alexander Botsch"}]},{id:"66239",title:"Echocardiography Evaluation in ECMO Patients",slug:"echocardiography-evaluation-in-ecmo-patients",totalDownloads:2105,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Extracorporeal membrane oxygenation (ECMO) is a special form of organ support for selected cases of cardiovascular and severe respiratory failure. Echocardiography is a diagnostic and monitoring tool widely used in all aspects of ECMO support. The pathophysiology of ECMO, and its distinct effects on cardiorespiratory physiology, requires an echocardiographer with high skills to understand the interaction between the ECMO and the patient. In this chapter, we present the main application of echocardiography in ECMO patients and some general concepts on the ECMO working. ECMO, such as the standard cardiopulmonary bypass employed in cardiac surgery, V-V (veno-venous), can support the insufficient respiratory system by oxygenating and removing carbon dioxide from the blood. VA-ECMO (venous-arterial) can support haemodynamics by providing mechanical circulatory assistance. Today, ECMO can be used as bridge to decision, waiting for the development of the clinical conditions to support with other devices the evolution of cardiorespiratory failure or stop the assistance. Echocardiography (transthoracic (TTE) or transoesophageal (TOE)) can be used primarily to take decisions regarding appropriateness of ECMO support, therefore to control cannula insertion and confirm final position, to modify number and position of the cannulae in case of malfunctioning of these, and, finally, to assess clinical progress and suitability for weaning from ECMO.",book:{id:"7878",slug:"advances-in-extracorporeal-membrane-oxygenation-volume-3",title:"Advances in Extracorporeal Membrane Oxygenation",fullTitle:"Advances in Extracorporeal Membrane Oxygenation - Volume 3"},signatures:"Luigi Tritapepe, Ernesto Greco and Carlo Gaudio",authors:[{id:"284893",title:"Prof.",name:"Luigi",middleName:null,surname:"Tritapepe",slug:"luigi-tritapepe",fullName:"Luigi Tritapepe"},{id:"294005",title:"Prof.",name:"Ernesto",middleName:null,surname:"Greco",slug:"ernesto-greco",fullName:"Ernesto Greco"},{id:"294006",title:"Prof.",name:"Carlo",middleName:null,surname:"Gaudio",slug:"carlo-gaudio",fullName:"Carlo Gaudio"}]}],onlineFirstChaptersFilter:{topicId:"173",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:288,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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