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",isbn:"978-1-83968-760-0",printIsbn:"978-1-83968-759-4",pdfIsbn:"978-1-83968-761-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"cc49d6034d85f8f2e2890c6acc3cc629",bookSignature:"Dr. Abhijit Biswas",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10285.jpg",keywords:"Mott Insulators, Semi Metals, Polycrystals, Single Crystals, Electronic Properties, Magnetic Properties, PLD, MBE, Topological Insulators, Topological Hall Effect, Devices Applications, Catalysis",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 9th 2020",dateEndSecondStepPublish:"October 7th 2020",dateEndThirdStepPublish:"December 6th 2020",dateEndFourthStepPublish:"February 24th 2021",dateEndFifthStepPublish:"April 25th 2021",remainingDaysToSecondStep:"4 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in the field of tailoring metal oxide crystal surfaces and growth as well as engineering of thin films for various emergent phenomena and energy applications. Dr. Biswas received his Ph.D. from POSTECH, South Korea.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"194151",title:"Dr.",name:"Abhijit",middleName:null,surname:"Biswas",slug:"abhijit-biswas",fullName:"Abhijit Biswas",profilePictureURL:"https://mts.intechopen.com/storage/users/194151/images/system/194151.png",biography:"Dr. Abhijit Biswas is a research associate at the Indian Institute of Science Education and Research (IISER) Pune, in India. His research goal is to design and synthesize highest quality epitaxial heterostructures and superlattices, to play with their internal degrees of freedom to exploit the structure–property relationships, in order to find the next-generation multi-functional materials, in view of applications and of fundamental interest. His current research interest ranges from growth of novel perovskite oxides to non-oxides epitaxial films, down to its ultra-thin limit, to observe unforeseeable phenomena. He is also engaged in the growth of high quality epitaxial layered carbides and two-dimensional non-oxide thin films, to exploit the strain, dimension, and quantum confinement effect. His recent work also includes the metal-insulator transitions and magneto-transport phenomena in strong spin-orbit coupled epitaxial perovskite oxide thin films by reducing dimensionality as well as strain engineering. He is also extremely interested in the various energy related environment friendly future technological applications of thin films. In his early research career, he had also extensively worked on the tailoring of metal oxide crystal surfaces to obtain the atomic flatness with single terminating layer. Currently, he is also serving as a reviewer of several reputed peer-review journals.\nDr. Biswas received his B.Sc. in Physics from Kalyani University, followed by M.Sc in Physics (specialization in experimental condensed matter physics) from Indian Institute of Technology (IIT), Bombay. His Ph.D., also in experimental condensed matter physics, was awarded by POSTECH, South Korea for his work on the transport phenomena in perovskite oxide thin films. Before moving back to India as a national post-doctoral fellow, he was a post-doc at POSTECH working in the field of growth and characterizations of strong spin-orbit coupled metal oxide thin films.",institutionString:"Indian Institute of Science Education and Research Pune",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Indian Institute of Science Education and Research Pune",institutionURL:null,country:{name:"India"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"20",title:"Physics",slug:"physics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"205697",firstName:"Kristina",lastName:"Kardum Cvitan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/205697/images/5186_n.jpg",email:"kristina.k@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"8356",title:"Metastable, Spintronics Materials and Mechanics of Deformable Bodies",subtitle:"Recent Progress",isOpenForSubmission:!1,hash:"1550f1986ce9bcc0db87d407a8b47078",slug:"solid-state-physics-metastable-spintronics-materials-and-mechanics-of-deformable-bodies-recent-progress",bookSignature:"Subbarayan Sivasankaran, Pramoda Kumar Nayak and Ezgi Günay",coverURL:"https://cdn.intechopen.com/books/images_new/8356.jpg",editedByType:"Edited by",editors:[{id:"190989",title:"Dr.",name:"Subbarayan",surname:"Sivasankaran",slug:"subbarayan-sivasankaran",fullName:"Subbarayan Sivasankaran"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],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:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"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:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"55577",title:"Computational Approaches in the Development of Phosphodiesterase Inhibitors",doi:"10.5772/intechopen.68842",slug:"computational-approaches-in-the-development-of-phosphodiesterase-inhibitors",body:'The early application of computational methods as a means to identify and design phosphodiesterase (PDE) inhibitors goes back to the 1980s where the first reported study tried to explain the relation between specific physicochemical properties and potency of known inhibitors [1]. The result was the identification of pharmacophore for PDE inhibitors [2]. Computational methods of drug design and discovery have impacted the overall process of drug discovery in a big way over the last two decades [3, 4]. The cost as well as time of drug discovery has been reduced due to the inclusion of computational methods as well as high‐throughput synthesis and screening. Computational methods have undergone development at immense pace and newer and more accurate methods have come up. Traditionally, computational methods have been classified into structure‐based methods and ligands‐based methods [4]. Structure‐based methods like docking‐based virtual screening has been used for new lead identification for phosphodiesterase (PDE) inhibitors, while ligand‐based methods such as quantitative structure activity relationships (QSAR) have been mostly used for lead optimization [5–8]. However, ligand‐based methods, such as pharmacophore development, have played an important role in many lead discovery programs. Structure‐based methods like molecular dynamics (MD) simulations have been used to study the binding of PDE inhibitors with the enzyme. While the information derived from MD simulations has been used to optimize the structure of inhibitors [9–13]. As far as exploring the inhibitor structural features determining selectivity variations, the computational approach could rely on both structure‐based and ligand‐based strategies. However, due to high degree of similarity observed among all the PDE catalytic sites, the ligand‐based approach could represent a much more promising tool to deeply investigate the selectivity issues around PDE inhibitors as compared to structure‐based approach.
This chapter aims to provide an update of the recent advances in the field of rational design of PDE inhibitors. Attempt has been made to explore both scientific journals as well as patent literature.
The most prominently used ligand‐based drug design methods include QSAR and pharmacophore mapping. There are several reports where QSAR has been used for optimizing the PDE inhibition activity of ligands having specific structural scaffolds. Some studies have reported unique applications of ligand‐based methods, i.e., ligand‐based homology modeling and exploration of selectivity toward specific receptor subtypes.
Among the several PDE subtypes inhibitors, PDE10A inhibitors have attracted enormous interest recently for their potential in the treatment of schizophrenia and Huntington’s disease, whereby they can fill up the voids present in the current therapeutic approach. In one of the recent studies on PDE10A inhibitors, Mondal et al. reported the application of ligands‐based methods toward optimization of cinnolines as PDE10A inhibitors [14]. 2D‐QSAR, HQSAR (hologram quantitative structure activity relationship), pharmacophore mapping, and three‐dimensional (3D)–QSAR analyses in combination with structure‐based methods like molecular docking and MD simulations were used for the purpose.
Eighty‐one cinnoline derivatives having PDE10A inhibitory activity were used as the data set. 2D‐QSAR models were developed by multiple linear regression and partial least square (PLS) analyses using both atom‐based and whole molecular descriptors. The best model, having considerable internal (q2 = 0.812) and external (R2 pred = 0.691) predictabilities, demonstrated importance of atom‐based topological and whole molecular E‐state as well as 3D topological indices.
Hologram QSAR, a relatively newly developed QSAR technique, relates biological activity to structural fragments [15]. HQSAR eliminates the need for generation of 3D structures, putative binding conformations, and molecular alignments. The process of generating HQSAR models involve the fragmentation of the data set structures and then hashing into array bins. Molecular hologram fingerprints are then generated. Holograms are constructed by cutting the fingerprint into strings at various hologram length parameters. After the generation of descriptors, partial least square (PLS) methodology is used to find the possible correlation between dependent variable (activity) and independent variable (descriptors generated by HQSAR structural features) [15]. The best HQSAR model for cinnolines as PDE10A inhibitors was found to be statistically significant (q2 = 0.664, R2 pred = 0.513), and it highlighted some important structural features.
Pharmacophore mapping was also employed in this case. The pharmacophore hypothesis showed the importance of hydrogen bond acceptors and ring aromatic and hydrophobic features for higher activity. The compounds were mapped to the pharmacophore as per their activity, and the pharmacophore provided an efficient means of aligning the compounds for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies.
Finally, three‐dimensional QSAR methods implemented as CoMFA and CoMSIA were applied on the data set. 3D‐QSAR models were generated using two different types of alignment procedures—(1) pharmacophore based and (2) docking based. Docking‐based alignment produced better results for both CoMFA (q2 = 0.578; R2 pred = 0.841) and CoMSIA (q2 = 0.610; R2 pred = 0.824) methods.
Molecular dynamics (MDs) simulations were also performed for two ligand–receptor complexes, and the findings of MD simulations were consistent with the interpretations obtained from ligand‐based analyses methods described above. The role of hydrogen bond acceptors and aromatic and hydrophobic features in determining PDE10A inhibition potential was unraveled. The study clearly puts forth guideline for the design and development of cinnolines as potent and selective PDE10A inhibitors and demonstrates the role of ligand‐based drug design methods combined with structure‐based drug design (SBDD) methods.
PDE4 has long been considered as target for design of antiinflammatory molecules, and numerous PDE4 inhibitors have been developed [16–21]. Quinolines as a third‐generation of PDE4 inhibitors show an increased antiinflammatory effect without being dose limited by side effects compared to the first‐ and second‐generation of PDE4 inhibitors such as rolipram and roflumilast. Recently, newer quinoline derivatives were developed as selective PDE4B inhibitors using ligand‐based pharmacophore and atom‐based 3D‐QSAR modeling along with structure‐based docking and ADME methods [21].
These studies, in combination, led to new understanding about the selection of target molecules from many candidates. In this case, computational methods were not the primary tools used for designing the ligands rather they were used for identifying and confirming the binding site of the ligands on PDE4B. The 3D‐QSAR model of PDE4B inhibitors developed for this study proved to be reliable with r2 value of 0.96 and q2 value of 0.91. The specific pharmacophore for PDE4B was then mapped and selected for virtual screening, and the potent PDE4B inhibitors were finally confirmed their selectivity ability for PDE4B by docking, ADME analysis, and MD, and then, molecules were developed as selective PDE4B inhibitors (Figure 1) [21].
In silico strategy to discover PDE4B specific inhibitors.
Like PDE4, PDE7, a cAMP‐specific phosphodiesterase, is also highly expressed in human immune system such as thymus, lymph nodes, spleen, and blood leukocytes, suggesting PDE7 as a possible target for treating CNS and airway diseases [22–25]. A recent study by Cichero et al. whereby they applied 3D‐QSAR methods for the development of selective PDE 7 inhibitors is worth noting. Herein, 72 derivatives of thieno[3,2‐d]pyrimidin‐4(3H)‐one were selected from literature and were used to develop new selective PDE7 inhibitors [26]. The uniqueness of the study was the application of 3D‐QSAR to identify the structural features required for the selectivity for a particular target.
Docking‐based 3D‐QSAR followed by redocking was performed to identify the most suitable bioactive conformations of derivatives and most comparable binding mode with that of X‐ray structure. The conformations of the compounds showed good agreement with the conformations in the known PDE7A‐ligand complex. The compounds were further submitted to a CoMFA and CoMSIA analysis. Since inhibitors which showed high selectivity for PDE7, rather than PDE4, are candidates for antiinflammatory molecules, two models (PDE7 selectivity (model A) and PDE4B selectivity (model B)) were established. Predictive models for both the activities were obtained, i.e., CoMFA(model A) (optimum number of components (ONC = 6, r2 = 0.946, and standard error of estimate, SEE, = 0.292), CoMSIA(model A) (r2 = 0.961, SEE = 0.249), CoMFA(model B) (ONC = 6, r2 = 0.968, and SEE = 0.353), and CoMSIA(model B) (r2 = 0.968 and SEE = 0.356; Figure 2). The role of steric, electrostatic, and hydrophobic features in the binding mechanism of ligands to both PDE7 and PDE4 was identified. The study unraveled structural information for the development of new PDE7 inhibitors with high selectivity.
CoMFA and CoMSIA models for (a) PDE7 selectivity and (b) PDE4B selectivity (CoMFA: green, favored for bulky groups; yellow, disfavored for bulky groups) (CoMSIA: blue, favorable for more positively charged groups; red, favorable for less positively charged groups). (Cichero et al. [26] – Published by The Royal Society of Chemistry).
Another unique application of ligand‐based methods was reported by Cichero et al. earlier in 2013. Since the X‐ray structure of PDE11 was not available, ligand‐based homology modeling technique was applied to explore the 3D structure of PDE11 [27]. Consistent with the sequence similarity of PDE11 and PDE5, several tadalafil analogs (PDE5 ligands) showed binding affinity to PDE11 too [28–30]. Thus, the 3D structure of PDE11 was built on the basis of PDE5‐tadalafil complex using homology modeling technique [31]. Besides the conventional homology modeling steps such as insertion and deletion of extra atoms during the energy minimization stages, evolution, including model building and refinement were performed in this specific case. Specifically, residues located in H‐loop and M‐loop were involved in obtaining PDE11 structure as they are important for substrate recognition [32]. The coordinates of PDE11 were derived from PDE5‐tadalafil complex, and the amino acid sequences were obtained from the SWISSPROT database. This was followed by the development of models using MOE software without significant main chain deviations. AMBER94 force field was applied to minimize the structure energy, and Ramachandran plots were applied to assess the final obtained model. Successively, reliability of the derived PDE11 model was further confirmed by molecular docking and MD simulations with selective PDE11 inhibitors and dual PDE5‐PDE11 inhibitors. This study provided new information of target structure of PDE11 to design selective PDE11 inhibitors for the treatment of cardiac pathologies [33]. The success of this approach is supposedly due to the synergic interaction between theory and experiment.
Structure‐based drug design (SBDD), as one of the in silico methods, is almost an integral part of any drug discovery and development project. These methods, in addition to the binding affinity between a specific protein target and a ligand, also provide insight into the interaction between the two. This helps in devising substituent modifications around the ligand scaffold leading to improved binding [34]. Based on the existing knowledge of 3D structures of PDEs, the great potential and success of structure‐based computational methods have been visible in the development of newer PDE inhibitors. In addition to the routine screening and interaction studies, many unique applications of structure‐based methods have been reported for the development of PDE inhibitors.
In one of the recent reports by Jing Li and team, virtual screening of natural product database was carried out to discover novel selective PDE4B inhibitors from natural products database [35]. Structure‐based approaches like docking and molecular dynamics simulation were used for the purpose, although pharmacophore‐based screening was also employed as initial filter. The screening led to the identification of four potential PDE4B‐selective inhibitors (ZINC67912770, ZINC67912780, ZINC72320169, and ZINC28882432; Figure 3). Compared to the reference drug (roflumilast), they scored better during the virtual screening process. DOCK and Vina were used for docking, and results were agreeable. Binding free energy was −317.51, −239.44, −215.52, and −165.77 kJ/mol, which is better than −129.05 kJ/mol of roflumilast. The MD studies also showed that ZINC28882432‐PDE4B complex reached stable RMSD faster than roflumilast‐PDE4B complex. This study demonstrates the successful application of MD in a virtual screening workflow.
Structure of ZINC28882432 a PDE4B inhibitor from natural sources identified by virtual screening.
The cross‐reactivity of PDE 5 inhibitors like sildenafil, vardenafil, and tadalafil with hERG1 is well documented. However, hERG1 is proven to be involved in the regulation of human ventricular myocyte action potential, thus blocking this hERG channel results in the function loss of the PDE5 inhibitors and further leads to serious life‐threatening disorders and cardiovascular problems [36, 37]. One of the recent studies explored this cross‐reactivity using docking. Open and open‐inactivated states of hERG1 potassium channel were used as protein structures and binding interaction patterns and affinity between the proteins and PDE5 inhibitors were studied [38]. Three different structure‐based docking tools including GOLD, MOE, and AUTODOCK were applied to identify the binding interactions between Sildenafil and hERG1 channel. In open‐state conformation of hERG1, both GOLD and MOE showed common interactions and further AUTODOCK and GOLD scoring analysis gave a 2.16 kcal/mol lower energy compared to open‐inactivated state. In open‐inactivated conformation of hERG1, three docking tools showed similar interaction patterns but MOE docking results were more specific in terms of H‐bonding, distance, and key residues. To further confirm the key residues which are responsible for binding affinity to the hERG1 channel, in silico alanine mutagenesis study was performed, and new promising molecules were designed based on the interaction patterns and alanine mutagenesis studies. MD simulations were finally used to confirm that the complex of the new compounds with hERG1 channel is much less stable than that with PDE5. This study showed new approach toward the design of PDE5 inhibitors with lower affinity for hERG1 channels.
In another study dealing with cross‐reactivity of PDE5 inhibitors, Kayık and team explored cross‐reactivity of PDE5 inhibitors with PDE6 and PDE11 [39]. The major challenge of their study was designing novel PDE5 inhibitors with decreased cross‐reactivity with PDE6 and PDE11. For this aim, the similarity‐based virtual screening protocol was applied for the “clean drug‐like subset of ZINC database that contained more than 20 million small compounds. Moreover, molecular dynamics (MD) simulations of selected hits complexed with PDE5 and off‐targets were performed to get insights for structural and dynamical behaviors of the selected molecules as selective PDE5 inhibitors. Since tadalafil blocks hERG1 K channels in concentration‐dependent manner, the cardiotoxicity prediction of the hit molecules was also tested. The study revealed important structural information for the design of novel, safe, and selective PDE5 inhibitors by applying SBDD.
Dual inhibitors of PDE1 and PDE 5 are known to produce vasodilation and have thus been explored as therapeutic agents for the treatment of different cardiovascular diseases, i.e., hypertension, angina, heart failure, and arteriosclerosis [40, 41]. Yamazaki et al. employed a ligand‐based virtual screening for the identification of novel lead candidates with potent dual inhibition of PDE1 and 5 [42]. These compounds have application in the treatment of different cardiovascular diseases, i.e., hypertension, angina, heart failure, and arteriosclerosis [42, 43].
They applied virtual screening that consists of classification and regression tree (CART) analysis with the utilization of 168 2‐center pharmacophore descriptors and 12 macroscopic descriptors which can result in finding of new lead compounds and drug candidates efficiently. The method applied started with the learning step of CART analysis where a prediction model is configured, and the explanatory variables are selected as per the discrimination index of training set. These variables should be independent from each other.
In the following step, they checked the potential energy term and solvation energy, which are the main constituents of the binding energy used in molecular modeling and simulation, to select the most suitable set of explanatory variables. The potential and solvation energy was obtained by summing up electrostatic potential term, van der Waals potential term, solvation free energy term, and hydrogen bond energy term. This situation is represented qualitatively by pharmacophore where it provides the binding features with the position of these features. In chemo‐informatic analysis, the pharmacophore descriptor is either a part or all of pharmacophore. The n‐center pharmacophore descriptor is the number of features that participate in binding and the distance between them, for example, 2‐center, 3‐center, etc. In this research, they adapted 2 for n to reduce the number of explanatory variables. Six binding features were used with eight classes of distance between them, this gives 168 two‐center pharmacophore descriptor.
In next stage, the virtual screening has been performed to screen the library of commercially available chemical compounds that was supplied by SPECS Inc. for PDE5 inhibitor activity. Based on Lipinski’s rule of five, the compounds with undesirable physicochemical and pharmacokinetic properties were filtered out, followed by selection of compounds with desirable inhibition activities for PDE5 by CART model. The next step involved the selection of structurally diverse 100 compounds. Finally, 19 drug‐like compounds out of 100 were selected and obtained from SPECS Inc. and assayed in vitro to test their inhibitory activity against PDE1 and PDE5 [42]. The results showed that the virtual screening along with the CART analysis have a high prediction capability for biological activity of new chemical compounds.
One of the least explored PDEs as a drug target singly has been PDE1, although it has been a combined target with PDE5 for vasodilator drugs [11, 44]. However, some of the studies have shown that it is a promising target for the treatment of cognitive impairments [45]. One such report by Li et al. recently presented novel PDE1 inhibitors for the treatment of cognitive impairments. They applied both ligand‐ and structure‐based drug design methods to discover these novel PDE1 inhibitors. Achieving high selectivity among PDE enzymes is challenging, since all PDE enzymes share a high degree of sequence homology in the catalytic domains [46–50]. They started by analyzing the published PDE inhibitors with various scaffolds and found out that pyrazolo[3,4‐d]pyrimidinones, which was reported by Xia and coworkers, could be the first step for designing a new, potent, and selective PDE1 inhibitors [51]. At the beginning, these compounds were developed as dual inhibitors for both PDE1 and PDE5 [46–49].
According to the available X‐ray crystal structures of human PDE enzymes, a hydrogen bond is formed between the N‐7 nitrogen of purine ring in guanine and adjacent amino acid residue in catalytic site. In pyrazolo[3,4‐d]pyrimidinone compounds, the hydrogen bond network is disrupted due to the shift of nitrogen in pyrozole ring from position 3 to position 2. Li et al. designed polycyclic 3‐aminopyrazolo[3,4‐d]pyrimidinone scaffold 2 to reestablish the hydrogen bond through the substitution of amino group at carbon 3 of pyrazole ring [50]. By applying a combination of ligand‐based and structure‐based drug design methods, they designed numerous novel scaffolds as PDE1 inhibitors. Their work resulted in the discovery of a clinical candidate (ITI‐214) which has excellent selectivity toward PDE1 (Figure 4). ITI‐214 is now in clinical trial phase I and is being tested for its ability in the treatment of cognitive deficits associated with neurodegenerative and neuropsychiatric disorders and other CNS and non‐CNS diseases [45, 50].
Structure of ITI‐214, a PDE1 inhibitor in clinical trials.
Another PDE which has emerged as a promising drug target recently is PDE9A [52]. PDE9A is now considered as an important therapeutic target for the treatment of diabetes and Alzheimer’s disease (AD) [53]. Most of the inhibitors of PDE9A until recently were based on the pyrazolopyrimidinone scaffold, thus there was need to identify novel scaffolds possessing this activity [54]. Zhe Li and team used a combinatorial method including pharmacophores, molecular docking, molecular dynamics simulations, binding free energy calculations, and bioassay to discover novel PDE9A inhibitors with new scaffolds (Figure 3) [55]. SPECS database containing about 200,000 compounds was screened using their combinatorial approach. The combination of ligand‐ and structure‐based methods in combinatorial fashion was done with the aim to reduce computational cost as structure‐based methods alone are computationally too expensive for virtual screening. The results were encouraging as has been the case whenever such combinatorial approach has been employed. Fifteen hits out of 29 molecules (a hit rate of 52%) with five novel scaffolds were identified to be PDE9A inhibitors with inhibitory affinities no more than 50 mM to enrich the structural diversity, different from the pyrazolopyrimidinone‐derived family. The high hit ratio of 52% for this virtual screening method indicated that the combinatorial method is a good compromise between computational cost and accuracy. Binding pattern analyses indicate that those hits with nonpyrazolopyrimidinone scaffolds can bind the same active site pocket of PDE9A as classical PDE9A inhibitors. The five novel scaffolds discovered in this study can be used for the rational design of PDE9A inhibitors with higher affinities (Figure 5).
Virtual screening strategy to discover novel PDE9 inhibitor scaffolds.
PDE2 is a key enzyme that hydrolyzes both cAMP and cGMP. It has been suggested that selective PDE2 inhibitors could be a promising therapy for some of the CNS disorders, such as Alzheimer’s disease, memory deficit, and depression since PDE2 modulates neuronal signaling involved in concentration, learning and memory, and emotion [56]. Bo Yang and coworkers examined the binding structures and free energies for PDE2 and benzo[1,4]diazepin‐2‐one derivatives (PDE2 inhibitors) by combining the molecular docking, molecular dynamics (MD), calculations of binding free energy, and binding energy decompositions [57, 58]. Molecular docking was performed followed by energy minimization. The docked structures were analyzed followed by the selection of the best pose for each ligand. The next step was MD stimulation. The binding free energy (ΔGbind) of PDE2A‐ligand complex was determined based on the MD trajectory for each complex [59]. The binding energy decomposition was estimated by using molecular mechanism/generalized Born surface area (MM/GBSA) method.
The results put forth important information regarding the PDE2A‐ligand binding patterns including the intermolecular interactions, hydrophobic interactions, and hydrogen bonding. The estimated PDE2A‐inhibitor binding patterns and the agreement between theoretical and experimental outcomes provided a firm base for further design of new, selective, and more potent PDE2A inhibitors [57].
In recent years, several potent inhibitors for PDE2 were developed but none reached the market due to either lack of selectivity or poor pharmacokinetic properties. This led work to focus on the optimization of pharmacokinetic properties of PDE2 inhibitors. Zhang et al. tried to discover selective potent PDE2A inhibitors with improved pharmacokinetic properties [60–67]. In their study, they described the identification of novel PDE2A inhibitors by structure‐based virtual screening. They combined pharmacophore model‐based screening and molecular docking along with MD simulations and bioassay to find new selective compounds with significant improvement in inhibition activity (Figure 6).
Discovery of LHB‐8, a potent PDE2 inhibitor. (Reprinted with permission from Zhang et al. [67] Copyright © 2017 American Chemical Society).
Beginning with the selection of small‐molecule database SPECS (comprising almost 200,000 small molecules) for virtual screening, this database was filtered by Lipinski’s rule of five to constitute databaset0 which is the initial data set. The crystal structures of PDE2A in a bound state were used to generate the 3D pharmacophore model. This model was applied for minimizing the size of database through efficient screening of dataset0 to obtain dataset1. Pan‐assay interfering compound substructures (PAINS) screening was used to obtain dataset2 by eliminating the false positive compounds that might interfere with other detecting methods and result in false positives.
In the next step, the dataset2 compounds were submitted for molecular docking to predict the preliminary optimal binding modes and binding energies between PDE2A and ligand. Those compounds with better scores than the reference and proper binding modes constituted dataset3. In the last step, MD stimulations and molecular mechanism/Poison‐Boltzman surface area (MM‐PBSA) method were applied for more accurate prediction of the binding modes and binding energies. AMBER 10.0 was utilized to stimulate the binding of PDE2A with the compounds in dataset3, whereas MM‐PBSA was used for the calculation of binding free energy. At the end, 30 molecules with optimal binding patterns and top binding energies were selected to make up the final dataset. Nine hits out of 30 molecules (a hit rate of 30%) were identified with less than 50 μM affinity for PDE2A.
The result of this study was the discovery of new compound LHB‐8 with IC50 = 570 nM (Figure 4). This compound poses novel scaffold benzo[cd]indol‐2(1H)‐one among PDE2A inhibitors, which can be used as the novel scaffold for designing of potent inhibitors of PDE2A [67].
One of the early studies reporting the application of structure‐based drug design on PDE3 inhibitors was done by Fossa et al. [2]. They combined homology modeling techniques with docking to gain knowledge about the molecular requirements of selective inhibition of PDE3 and identified the important amino acids residues for substrate and inhibitor binding. They built a homology model of PDE3A catalytic site based on coupling of PDE4B2B crystal structure and PDE3A mutagenesis data. The amino acids sequences of PDEs were obtained and multiple sequence alignments of PDE isozymes were performed [68–70]. Then, phylogenetic relationship was used to calculate the amino acid conservation based on the obtained alignments followed by prediction of secondary structure [71, 72]. Fold recognition and sequence to structure alignment was also done during the course [2, 73]. 3D models were generated by the application of restraint‐based homology modeling methods [74]. At the end, the Amber force field was applied for energy minimization, and the generalized Born solvation model as implemented in AMBER was used for the calculation of molecular mechanic. The structural evaluation of the model proved that it is suitable for docking studies [75].
Another study was proposed by Kim et al. where they used a virtual screening approach to discover novel PDE3 inhibitors for obesity treatment. They started with the analysis of the structural features of the known PDE3 inhibitors and screening of virtual library with 30,000 diverse compounds, followed by docking study based on the 3D structure of PDE3B. In this work, Kim et al. built 3D structures of PDE3B‐ligand complex by utilizing a cocrystal structure. Docking was carried out, and 80 compounds with low energy conformation were identified by docking. These compounds were examined for their adipocyte lipolysis activity and finally four structurally unrelated compounds were identified. Among these leads, the most potent compound has IC50 = 14.8 nM for PDE3A activity and 88.4 nM for PDE3B activity [76].
Apart from those discussed in the previous section, there are many more examples of successful application of in silico methods in the discovery and design of PDE inhibitors. The applications are very diverse ranging from lead discovery to optimization. However, the major problem with various PDE subtype inhibitors, designed or discovered, is the lack of selectivity. Although with the application of computational methods inhibitors with significant selectivity for PDE subtypes have been designed lately, still none of them have been able to make it to the market. The advancement in computational hardware and MD simulation methods will be the major boost for solving the selectivity problem in future. These advancements will allow more deeper studies on a tinier time scale allowing the computational chemist to capture interactions and structural features required for high degree of selectivity. These developments bring hope that the unfulfilled potential of various PDE inhibitors will be realized in near future.
Surgical resection for early stage non-small cell lung cancer (NSCLC) (Stage I and II) is associated with the lowest risk for local and distant recurrence and the best 5-year survival compared to other available treatment options [1]. The preferred approach for the surgical management of resectable, early-stage NSCLC has shifted in recent years from open thoracotomy to minimally-invasive surgery (MIS). Although thoracotomy has evolved over several decades to utilize muscle sparing incisions and improved postoperative pain control using epidural and paravertebral catheter systems, this technique is associated with more significant muscle dissection, rib spreading, and increased risk for morbidity and mortality after surgery. This includes a protracted period of recovery following hospital discharge, a slower return to baseline quality of life, and the potential for chronic pain associated with a larger thoracotomy incision.
With fewer perioperative complications and quicker recovery, minimally invasive surgery offers expanded opportunities for surgical resection in patients who otherwise would not tolerate the morbidity of thoracotomy. There are additional benefits to minimally invasive resection, including significantly improved postoperative pain control, shorter hospital length of stay, quicker return to baseline quality of life, and earlier return to work that enhance and support the utilization of this platform for NSCLC [2, 3, 4]. These advantages have resulted in a significant shift in the surgical management of NSCLC patients, where formerly open resection and up to a week-long hospitalization were standard even without significant postoperative complications, current expectations for VATS lung resection include discharge to home in the majority of cases within 4–5 days or less [5]. Additionally, in cases where there may be a recommendation for adjuvant therapy, MIS patients are more likely to have recovered and be ready to receive such therapy earlier in their treatment course. Therefore, minimally invasive resection has significant advantages, especially when considering some percentage of thoracotomy patients might not receive adjuvant therapy given a challenging recovery from their index lung resection.
Video-assisted thoracoscopic surgery (VATS) for lung resection has been a part of the thoracic surgeon’s toolbox for the past three decades. Lewis et al. first described the use of VATS in 1992 [6]. The technique was quickly adapted to lobectomy in elderly patients with early-stage NSCLC, where some of the first cases were completed with similar or better results to historical controls [7]. Since these initial reports, VATS surgery has become increasingly common, with expanded use in complex lung resections, pneumonectomy, bronchovascular sleeve resections, and tumors that include the chest wall [8, 9, 10]. While only 8% of lobectomies in the United States were performed thoracoscopically in 2003, this figure has increased significantly over time, up to 54% as reported in 2014, especially among high-volume surgeons [11, 12, 13]. Trends that favor VATS adoption include being a dedicated thoracic surgeon in a high-volume center, performance of lung resection in a larger hospital, and lung resections performed in the Northeast. In one multi-variate analysis, there was a significant association between VATS adoption and surgeon volume (>15 lobectomies performed per year), which is not unexpected given the technical challenges associated with becoming proficient with this technique [11]. Although VATS adoption has significantly improved, there remains a large number of both general, dedicated thoracic, and cardiothoracic surgeons who continue to perform a thoracotomy for NSCLC, limited by both volume challenges and the learning curve associated with VATS lobectomy. Although the percentage of open lung resection has declined over time, this technique still represents a large proportion of early stage NSCLC surgery performed in the United States. As a result, there is an opportunity to expand on the availability of minimally invasive lung resection to patients, and to do so using technology that favors a natural transition for otherwise traditional open surgeons.
This need has led to another major technical innovation in thoracic surgery over the last two decades with the adoption of the Da Vinci robotic system (Intuitive Surgical Inc., Sunnyvale, CA, USA), a platform that is at the forefront of minimally-invasive lung, esophageal, and mediastinal tumor resection. In robotic-assisted thorascopic surgery (RATS), the surgeon is seated at a console adjacent to the sterile field which operates a bedside patient cart with several robotic arms (Figure 1). Attached to these arms are robotic instruments that enter the pleural space via keyhole incisions and robotic ports. At the console, the surgeon manipulates the robotic arms with three-dimensional controls which translate the surgeon’s hand movements to the wristed instruments on each of the robotic arms. A RATS platform aids the surgeon by enhancing visualization with a three-dimensional high-definition view, minimizing hand tremors, and improving dexterity of the instruments by functioning with multiple degrees of freedom. Wristed instruments mimic the surgeon’s actual hand movements, simulating open surgery, allowing for the precise dissection of vascular structures and a thorough lymphadenectomy, key steps to success when performing minimally invasive lung resection. While this technique is a dramatic change from either open or VATS procedures as the surgeon is not at the patient’s bedside, repetition and the frequency of performing robotic cases helps one’s personal comfort as they transition to RATS.
Da Vinci XI patient cart with four robotic arms. Image courtesy of © [2020] Intuitive Surgical, Inc.
Although the technical advantages of RATS make the platform desirable, the adoption of minimally-invasive robotic surgery is associated with some challenges. While benefits such as reduced postoperative pain, decreased peri-operative morbidity, reduce risk for postoperative air leak, and shorter hospital length of stay have been described, concern over upfront investment and increased cost per operation may be considered a barrier to access. Additional training for operating room staff is required, capital investment into larger operating rooms and to modernize traditional open surgery rooms that might like technological infrastructure, as well as increased operating times impact the opportunity cost of performing other operations and can contribute to some level of adoption apprehension for hospitals that have no robotic experience. Despite any misgivings, there is clear evidence that the adoption of robotic surgery for lung resection is on the rise. In just two years, from 2010 to 2012, robotic surgery increased in popularity by 3-fold, accounting for 9.1% of lung resections annually in 2012 [14]. More recently, an estimated 17.5% of lobectomies were performed robotically in 2017 [15]. Trends in robotic adoption seem to suggest that the technical advantages associated with robotic lung resection outweigh the capital and educational investment needed to make such a program successful. What specific metrics drive robotic adoption and improve outcomes in thoracic surgery are defined in the literature. This chapter will address the advantages and disadvantages of MIS for NSCLC, including the role of robotic surgery, and discuss its future directions in this field.
Minimally-invasive thorascopic surgery, and in turn RATS, have several advantages over traditional open surgery. Compared to thoracotomy, VATS and RATS utilize small incisions to access the chest cavity, reducing peri-operative morbidity and enhancing recovery. This allows the surgeon to select a larger range of patients who may otherwise be unable to tolerate open resection. Avoiding the muscle dissection/division and rib spreading associated with thoracotomy, while not compromising on the oncologic efficacy of the procedure, are the key advantages to both VATS and RATS procedures. For the facile VATS surgeon, lung resection and complete lymphadenectomy can be accomplished with a high rate of success, low risk of complication, and an expedited pathway to recovery. There are specific subsets of patients at higher risk for conversion during VATS procedures, particularly in cases where dissection is difficult due to fibrocalcified nodes, large tumor >3 cm, or prior induction therapy [16, 17]. In these cases, the advantages of robotics can be significant. The fundamental benefit of the robotic platform is that it simulates open techniques but with the advantages of smaller incision surgery. RATS procedures utilize insufflation to help maximize exposure, 3-dimensional optics to help define important structures and their relationship to adjacent structures, 10× magnification rather to improve visualization, and the ability to reach farther into the chest with longer instruments while still performing fine dissection work, all without losing out on the ergonomics associated with open surgery. This includes the ability to use robotic stapling devices which are similar to open and VATS variants, bipolar energy devices that articulate, vessel sealing devices that articulate, and fluorescence imaging in cases where tumor localization or performance of segmental resection is preferred. Not only does this provide open-only surgeons with an easier opportunity to incorporate MIS into their technical portfolio but affords a larger number of patients with the opportunity to undergo minimally invasive lung resection when appropriate.
An additional advantage is the ease in which segmental resection can be performed. RATS visualization and the precision in which segmental anatomy can be dissected has helped improve the adoption of segmentectomy in the United States [18]. As new data becomes available regarding the advantage of segmental resection over wedge, and potentially the equivalence of segmentectomy to lobectomy for subsets of early stage NSCLC either <2 cm or in patients with non-solid nodules, the utilization of techniques to improve rates of segmentectomy will become more important. While VATS segmentectomy is both well described and widely performed, it remains a technical challenge for many surgeons to adopt with proficiency required that can be significantly more complex than superior segmentectomy. RATS segmentectomy may be an opportunity for lobectomy only surgeons to increase their success with segmentectomy given these advantages. Previously data has demonstrates that surgical outcomes are comparable between RATS and VATS segmentectomy, both in terms of oncologic outcome and the adequacy of lymph node evaluation [19]. This principle is important to keep in mind as there is no scenario in which the size of an incision is more important than achieving an appropriate and adequate lung cancer resection.
MIS allows surgeons to select patients who would otherwise be unable to tolerate open pulmonary resection. The morbidity of a thoracotomy precludes many patients from benefitting from surgery with otherwise resectable cancers, leading to suboptimal treatments and decreased survival. In these cases, some institutions may turn to a more liberal use of radiation therapy as a means of local control. However, many studies have demonstrated the increased risk of local recurrence and inferior 5-year survival that makes radiation a less desirable choice for subsets of NSCLC patients, even in early stage cancers [1, 20, 21]. The decision to pursue surgery and in what format requires clinical judgment and cannot be determined by looking a one particular clinical parameter (ex. FEV1/DLCO, performance status, specific comorbidities alone). For example, a patient with less than perfect but acceptable pulmonary reserve, a history of cardiac disease who is medically optimized with a negative stress test, and in a motivated patient with reasonable performance status, surgical resection is likely to be well tolerated and preferable to other local therapy options (ex. SBRT or ablation). In this subset, MIS has obvious benefits compared to open resection. For example, in patients who underwent minimally-invasive thorascopic surgery, preoperative FEV1 < 60% was noted to be significantly associated with a lower risk for postoperative compilations compared to thoracotomy patients [12]. Although this concept may have seemed novel at the time, there is clearly an association between postoperative pain control, patient ambulation and participation with pulmonary toilet, and risk for postoperative complications following lung resection. Therefore, in patients who might be viewed as medically more marginal, MIS provides these patients with an opportunity for a curative resection and the benefits of lung cancer survival identified in the lung cancer study group with a lower complication profile [22].
Elderly patients are also at risk of receiving suboptimal treatment due to a perception of high-risk associated with surgery. When evaluating the surgical candidacy of this group, it is critical to determine both: 1) preoperative cardiac fitness and performance status as well as 2) competing causes of death. In the current era, it is reasonable to consider MIS as a curative procedure for early stage NSCLC in patients in their 80’s or even in their 90’s. Without a competing cause of death, it is reasonable to consider surgical resection for early-stage NSCLC in this age group. However, thoracotomy is a physiologically demanding procedure, and in elderly patients, MIS should be strongly considered when possible. Previous reports have demonstrated that post-operative outcomes remain superior in RATS and VATS compared to open thoracotomy for elderly patients. One propensity score-adjusted analysis examining 2,766 patients over the age of 65 with stage I to IIIa NSCLC in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database found lower overall surgical complication rates in RATS versus thoracotomy, as well as lower rates of blood transfusion, shorter ICU stay, and a significant decrease in overall length of stay [23]. In the same study, both VATS and RATS were found to have lower complication rates, adequate lymph node evaluation, and equivalent lung cancer specific survival [23].
Obese patients pose unique challenges for thoracic surgery. While studies show obese patients may have similar risk for complications and long-term outcomes compared to patients with normal body mass index (BMI), severely overweight patients (BMI greater than or equal to 40 kg/m2) face an increased risk of any major postoperative complication, including atelectasis requiring bronchoscopy, pneumonia, ARDS, extended ventilatory support, reintubation, and tracheostomy [24]. In addition to consideration for postoperative pain control, adequate pulmonary toilet, the ability to transfer patients from bed to chair, and the need for postoperative patients to ambulate aggressively, a question that arises is an obese patient’s tolerability of a longer surgical case. This may be even more important when for RATS lung resection, especially for surgeons early in their learning curve where operative times may be longer than VATS procedures When we look to literature and evaluate best available data to help develop a recommendation, the use of RATS in obese patients has not been shown to be associated with a significantly higher risk of postoperative complications, longer hospital length-of-stay (LOS), and is associated with similar 5-year survival compared to open lobectomy, suggesting that a robotic approach remains safe in this patient population [25]. While the outcomes of RATS lung resection in the obese population may be similar to VATS, the technical advantages of performing an anatomic lung resection in this population remain significant. To date, no large database or single institution data has defined an association between BMI and inferior outcomes in obese patients that require conversion due to vascular injury or technical challenges associated with lung resection.
Patients undergoing RATS experience a similar or lower rate of perioperative complications compared to those who undergo open thoracotomy or VATS. Post-operative complications after robotic lung resection were seen in 10–39% of patients in a review which included five case series and four comparative studies [26]. The most common postoperative complications included prolonged air leaks and atrial fibrillation [26, 27]. Pooled analysis of several studies did not show a prolonged air leak risk that was significantly higher following robotic surgery compared to thoracotomy [28].
Major complications including acute respiratory distress, reoperation for air leak, pulmonary embolism, or arrhythmia requiring pacemaker placement were rare, seen in approximately 2.4% of patients [27]. The rate of major complication in robotic surgery appears lower than thoracotomy, with fewer instances of respiratory failure, hemorrhage, or reoperation [29, 30]. Currently, perioperative mortality at high volume centers where most robotic surgeries are performed is lower in RATS compared to open resection [31]. Although this outcome metric is difficult to interpret as mortality is low for all lung resection regardless of surgical technique, it should be expected than as more centers adopt robotics for minimally invasive resection, the morbidity and mortality of RATS should remain at a comparable level to open and VATS resection.
Conversion from RATS to an open procedure is also low. Recent studies demonstrated a conversion rate of 6.5–9.2% [27, 29, 32]. The most common indications for conversion were technical limitations, inability to achieve an adequate oncologic resection, and bleeding [27]. The learning curve for RATS proficiency appears to be in the range of 20–25 cases, after which the risk for conversion can be expected to go down significantly. Unlike VATS conversions, where the surgeon is present at the bedside and can more easily perform a thoracotomy expeditiously, RATS conversions require a coordinated and well planned ‘fire drill’ to ensure patient safety. This includes a bedside assist that can hold pressure on a bleeding structure via a non-robot port, that the robot arms can be moved away to allow for better access to the chest, and that the staff in the room are prepared to open instruments that are needed to complete the case. Although these processes may be unfamiliar to the novice robotic surgeon, adequate preparation for case should include discussion of these scenarios with the operating and anesthesia staff. When compared to VATS, there were no differences in conversion rates in recent independent studies or meta-analyses. [28, 29]
Robotic surgery holds several key advantages with regards to post-operative outcomes when directly comparing VATS and RATS techniques. In one retrospective propensity score-matched study of 774 patients undergoing anatomical segmentectomy at a single academic institution, there were no significant differences in operative time, blood loss, risk for postoperative complication, or length of stay between RATS and VATS [33]. In another study examining 50 RATS and 80 VATS segmentectomies for patients with stage IA lung cancer at the Shanghai Chest Hospital, there was a shorter mean operative time and lower blood loss with RATS during anatomic resection and mediastinal lymphadenectomy [34]. For centrally located tumors which may be more difficult to access through VATS, robotic surgery was found to be associated with less bleeding, shorter operative times, and reduced volume of chest tube drainage and days with a chest tube, while having comparable oncologic outcomes including disease-free survival [35]. In a meta-analysis of ten studies by Emmert examining perioperative outcomes of minimally invasive thoracic surgery, tube drainage duration, length of hospitalization, and mortality were lower in patients undergoing RATS compared to VATS [36]. Therefore, it is reasonable to consider that the technical advantages associated with the robotic platform, including enhanced visualization and use of articulating instructions, are responsible for the low complication rates seen in RATS lung resection, and that with proficiency the outcomes of this technique can be equivalent to VATS.
One important area of scrutiny associated with the adoption of robotic surgery has been that VATS outcomes are already significantly better than open surgery, and that an expensive minimally invasive alternative with surgeon only advantages is a challenge to justify. As with any new technology, are the important outcomes the same or better? This is a fundamental necessity in cancer surgery. These concerns have been expressed since the introduction of the first robot in 2001, particularly with respect to adoption of both VATS and RATS approaches. When studied well, it is clear that both VATS and RATS are associated with excellent oncologic outcomes, equivalent to open surgery particularly with respect to lymph node evaluation and adequacy of resection, and that depending on the platform chosen, a proficient surgeon can be expected to have outcomes that meet or exceed their open surgery experience.
Several studies have examined and compared margin status, recurrence, disease-specific survival, and overall survival in open thoracotomy, VATS, and RATS. A study of the National Cancer Database found similar positive margin status (2%) after robotic surgery as compared to open resection, which is considerable given the lack of haptic feedback associated with RATS [37]. Other series also describe similar R0 resection rates of 97% [38]. Five-year disease recurrence has reported to be from 3% to 24.9% depending on cancer stage, which is also comparable to open surgery for appropriately matched patients [32, 39]. In this series and others, overall and disease-free survival at three and five years did not differ between RATS and either open surgery or VATS [32, 37, 38, 40, 41, 42, 43]. These results all suggest that robotic lung resection is a non-inferior alternative to prior surgical options.
The data on nodal evaluation during lung resection is heterogenous for robotic surgery. Some studies report no advantage in nodal stations examined or nodal harvest when compared to open surgery or VATS [28, 29, 44, 45]. One study found that fewer lymph nodes were examined with RATS compared to VATS [14]. Others report improved lymph node examination and retrieval [30, 33, 37, 46, 47]. In particular, one study found N1 (hilar) lymph nodes were better evaluated by robotic surgery as compared to VATS, both in terms of the number (4 vs. 3) and stations (3 vs. 2) examined [33].The experience of these authors and others are that the technical advantages of robotic surgery allow for an equivalent lymph node dissection to VATS, with some significant advantages including improved hemostasis and thoroughness of lymph node resection performed during mediastinal lymphadenectomy. The use of articulating bipolar instruments allows for complete lymph node packet resection, while improved visualization helps to define lymph node associations to adjacent structures. This is clearly an advantage over VATS, were ring clamps or non-articulating instruments can be used to grasp lymph nodes and non-articulating energy devices are used to free lymph nodes from surrounding structures. Whether these technical advantages translate into differences in short or long-term outcomes is unknown. However, no study to date has demonstrated that taking fewer lymph nodes or an incomplete lymph node evaluation is better than comprehensive lymphadenectomy. Additionally, as surgical outcomes become more heavily scrutinized, particularly with respect to the adequately of lymph node dissection, the use of this platform is likely to help facilitate a comprehensive hilar and mediastinal lymphadenectomy to meet these expectations.
The true advantage of robotic surgery appears to be the technical advantages conferred to the surgeon, specifically the enhanced visualization and improved dexterity of the instruments. While comparisons between robotic and open thoracotomy appear to have similar rates of complications, outcomes of VATS versus RATS are less uniform. Robotic surgery, in some series, is associated with less bleeding, shorter operative time, and shorter tube drainage duration [35]. These studies are largely retrospective and do not offer a definitive answer as to the causation for these improvements. However, one factor that likely contributes to these perceived results are the ergonomics of the robotic system. Robotic instruments moved with seven degrees of freedom, and as a result the surgeon in control at the console can mimic natural motions of the hand and wrist in the handling of tissue. This allows a surgeon to perform more complex functions in a safer fashion, reducing the risk of inadvertent injury while maintaining the oncologic standards. Important moves during anatomic lung resection, including thorough performance of lymphadenectomy and circumferential mobilization of critical vascular structures, can be performed with improved hemostasis, improved visualization, and reduced risk of injury.
Overall, the literature supports RATS as an alternative to open surgery and VATS. Fewer perioperative complications, improved quality of life, and similar oncologic outcomes have been established following RATS lung resection, bringing minimally invasive surgical options to a wider range of patients. While the advantages of RATS over VATS are certainly up for debate and are more informed by surgeon preference, the ability to improve minimally invasive lung resection availability to patients across the United States helps to drive interest in outcomes related to RATS procedures. The literature clearly demonstrates that surgeons facile with VATS lung resection provide patients with an oncologically sound operation and survival/recurrence expectations that rival results demonstrated in the LCSG. However, this skillset is challenging to learn and the highest standards for technical excellence are not as reproducible as open surgical techniques. In this space, RATS lung resection continues to evolve as adoption of minimally invasive lung resection grows.
While robotic surgery has key advantages compared to open and VATS techniques, it has not been uniformly adopted. As compared to VATS, this technology requires a significant capital investment, is associated with its own learning curve, and requires robotically trained support staff for a surgeon to have a successful robotic lung resection practice. All of these characteristics can be overcome but require stakeholders from surgery and the operating room to commit to the success of this platform.
The cost of robotic surgery is one of its main points of contention. There are two aspects of robotic surgery which contributes to this cost. The first is the initial investment in the robotic system. The second includes intra-operative costs, consisting of the use of consumables and longer operative times associated with RATS [28, 33, 45]. As the second is modifiable, it has garnered more attention in the literature. One study using patients from the SEER-Medicare database found the total cost of lung resection was similar between RATS and thoracotomy ($54,702 vs. $57,104, p = 0.08) [23]. Much of the variability in cost associated with robotic surgery likely stems from the difference in post-operative complications when compared to open resection. In particular, overall length of stay after RATS is significantly shorter than open surgery [29, 31, 38, 47, 48], and may be similar or better than VATS (4 days vs. 5 days) [40]. Therefore, although the cost of the operation may be higher in RATS, the direct associated cost may not be significantly different compared to open or VATS [49]. In time, as familiarity with the robotic platform increases and operating room efficacy is improved to rival VATS procedures, further cost savings can offset the increased initial investment and operative costs.
Another concern for surgeons unfamiliar with robotic surgery is training and familiarization with a new surgical platform. In fact, one of the early difficulties with the transition from VATS to open surgery was the steep learning curve. Laparoscopic instruments are relatively inflexible compared to the dexterity a surgeon is accustomed to during open surgery. Circumferential mobilization of important blood vessels requires dissection facilitated by subtle changes in how one engages the tissue, and these techniques are both important and challenging to learn for a novice VATS surgeon. Additionally, the VATS camera is limited to 3.5x magnification, images are shown in only 2 dimensions, and the camera needs to be held and constantly adjusted by the surgeon assistant. At 10× magnification, with 3D imaging, and a fixed camera that is not subject to fatigue or the concept of ‘guess what I am thinking and look where I want you to look’, getting used to robotic optics is fairly quick. The learning curve for a robotic lobectomy is approximately twenty cases [26, 50]. In this regard, mastery of robotic surgery appears to easier than VATS, owing to the more natural movements afforded by the robot.
Efficiency of RATS does rely more heavily on the familiarity of supporting operating room staff and the surgeon’s bedside assistant than VATS procedures. As the surgeon is seated at a console away from the sterile field, a bedside assistant must assist in exchanging instruments and repositioning robotic arms as needed. Thus, in addition to surgeon training, it is imperative that adequate training be provided to dedicated staff supporting the surgeon in order to maintain a safe working environment and maximum efficiency.
In our experience, a surgeon who gains robotic proficiency prefers the robot for a majority of their cases unless the platform is unavailable. Technically, VATS offers little advantage over RATS for the operating surgeon. Few instances exist where cost and time to set up outweighs the benefit. We utilize VATS for short cases such as decortications and pleurodesis, but favor RATS for most pulmonary resections. For technically challenging cases such as pneumonectomies, open surgery may be preferred, however, some case series describe successful RATS applications in pneumonectomy [51, 52].
In conclusion, robotic surgery represents the latest innovation for lung cancer surgery and an important opportunity for general and thoracic surgeons who still perform open lung resection. RATS procedures are associated with comparable or better outcomes than open surgery or VATS, and over the past two decades has been shown to be a safe platform with which lung cancer procedures can be performed. RATS procedures have significant technical advantages for the surgeon, namely the 3D vision, 10× magnification, and articulating instruments that mimics open surgery and allows for the performance of critical components of an operation safely. Although the advantages of RATS for patients are similar to VATS procedures, the adoption of RATS by open surgeons allows for a larger number of lung cancer patients in the United States to undergo minimally invasive procedures than ever before, which further realizes the patient specific advantages of minimally invasive techniques in this often medically complex population. A lower complication rate and better tolerability increases access to a definitive resection for NSCLC, optimizing 5-year survival. In time, as the volume of robotic surgery increases, the capital investment associated with adoption is likely to decrease. Additionally, with increased surgeon experience, operative times, risks for air leak, and overall hospital length of stay are also expected to decrease, allowing for improved utilization of hospital resources and efficiency.
Justin D. Blasberg, MD MPH is a proctor for Intuitive Surgical.
None.
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\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\\n\\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\\n\\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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