Summary of property changes resulting from heat treatment of two gold alloys for all-metal restorations. [http://www.jelenko.com/, accessed August 15, 2012]
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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All these issues require a clear understanding of the existing technologies, and it is crucial to identify the real opportunities that the current technological revolution may pose. As railway transportation planning processes change and pursue a multi-objective vision, diagnostic and maintenance issues are becoming even more crucial for overall system performances and alternative fuel solutions.",isbn:"978-1-83880-692-7",printIsbn:"978-1-83880-691-0",pdfIsbn:"978-1-83962-902-0",doi:null,price:119,priceEur:129,priceUsd:155,slug:"railway-transport-planning-and-management",numberOfPages:130,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"5cb54cc53caedad9ec78372563c82e2c",bookSignature:"Stefano de Luca, Roberta Di Pace and Chiara Fiori",publishedDate:"June 28th 2022",coverURL:"https://cdn.intechopen.com/books/images_new/10988.jpg",numberOfDownloads:483,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:null,numberOfDimensionsCitations:0,numberOfDimensionsCitationsByBook:null,hasAltmetrics:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 16th 2021",dateEndSecondStepPublish:"April 13th 2021",dateEndThirdStepPublish:"June 12th 2021",dateEndFourthStepPublish:"August 31st 2021",dateEndFifthStepPublish:"October 30th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"271061",title:"Prof.",name:"Stefano",middleName:null,surname:"de Luca",slug:"stefano-de-luca",fullName:"Stefano de Luca",profilePictureURL:"https://mts.intechopen.com/storage/users/271061/images/system/271061.jpeg",biography:"Stefano de Luca is a Full Professor of Transportation Planning and Transportation Systems Theory, at the University of Salerno, Italy, where he is also the director of the Transportation Systems Analysis Laboratory and rector’s delegate to Transport and Mobility. His research includes transportation planning techniques, choice modelling, signal settings design, traffic assignment models and algorithms, and freight/passenger terminal simulation and optimization. He serves on the editorial advisory board for the Journal of Advanced Transportation and Sustainability. He has authored more than 100 book chapters and journal articles, and is a consultant for the Italian Ministry of Transportation, the Transport Commission of Campania Region, and the Salerno and Avellino Transportation Departments. He is a member of IEEE Intelligent Transportation Systems Society, the Italian Association of Transport Academicians, and the Italian Transport Policy Society.",institutionString:"University of Salerno",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"University of Salerno",institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"271713",title:"Dr.",name:"Roberta",middleName:null,surname:"Di Pace",slug:"roberta-di-pace",fullName:"Roberta Di Pace",profilePictureURL:"https://mts.intechopen.com/storage/users/271713/images/system/271713.jpeg",biography:"Roberta Di Pace received an MSc and Ph.D. in Transportation Engineering from the University of Naples “Federico II,” Italy, in 2005 and 2009, respectively. She is a Professor of Transportation Engineering, Department of Civil Engineering, University of Salerno, Italy. She is also an aggregate professor of Technique and Transport Economics and Transportation Systems Design. Since 2010 she has been a member of the Transportation Planning and Modelling Laboratory. Her main research fields include the development of analytical tools for advanced traveler information systems, traffic flow modelling, network signal setting design, and advanced traffic management systems. 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Her research interests include testing, modeling, and simulation of electrified vehicles powertrains (for personal, public, and freight mobility) and their impact assessment on eco-routing and electric power grids; integration of microscopic traffic flow and energy consumption models and effects on traffic control systems; well-to-wheels analysis; modeling, simulation, and impact assessment of port operations in urban contexts; and Multi-Vehicle Dynamic Traffic Assignment.",institutionString:"University of Salerno",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Salerno",institutionURL:null,country:{name:"Italy"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"830",title:"Railway Engineering",slug:"railway-engineering"}],chapters:[{id:"78422",title:"An Integrated Approach of Strategic Planning and Multi-Criteria Analysis to Evaluate Transport Strategies in Railway Network",doi:"10.5772/intechopen.99609",slug:"an-integrated-approach-of-strategic-planning-and-multi-criteria-analysis-to-evaluate-transport-strat",totalDownloads:138,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter presents a methodology for selecting transport strategy for railway passenger transport development. The strategic planning, as Political, Economic, Social, Technological, Legal, and Environmental (PESTLE) analysis and Strengths - Weaknesses – Opportunities - Threats (SWOT) analysis integrated with Multiple-criteria decision-making (MCDM) have been applied as a tool to make decision. The proposed methodology consists five stages. The first stage formulates the alternatives of the policies for railway manager. The criteria in each PESTLE group have been defined in the second step. The total number of 24 criteria has been studied. In third stage, the SIMUS method based on linear programming has been applied to rank the alternatives and assess the criteria in PESTLE groups. The fourth stage represents the ranking by application the different multi0criteria approaches as distance based, utility based and outranking methods to make decision. The combination the PESTLE analysis with SWOT analysis for strategic planning is done in the fifth stage. The integration of the PESTLE with technical, economic, technological and environmental (TETE) analysis in presented. The application of methodology has been demonstrated with an example for Bulgarian railway network. Three strategies of railway transport development have been evaluated and compared. It was found that the most important are the political (0.29), social (0.25) and technological (0.25) groups in PESTLE analysis.",signatures:"Svetla Stoilova",downloadPdfUrl:"/chapter/pdf-download/78422",previewPdfUrl:"/chapter/pdf-preview/78422",authors:[{id:"414706",title:"Associate Prof.",name:"Svetla",surname:"Stoilova",slug:"svetla-stoilova",fullName:"Svetla Stoilova"}],corrections:null},{id:"81390",title:"From Nobel Prizes to Safety Risk Management: How to Identify Latent Failure Conditions in Risk Management Practices",doi:"10.5772/intechopen.98960",slug:"from-nobel-prizes-to-safety-risk-management-how-to-identify-latent-failure-conditions-in-risk-manage",totalDownloads:42,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The aim of the Chapter is to introduce readers to the Cognitive Biases found in Railway Transport Planning and Management domain. Cognitive biases in planning of railway projects lead to cost overruns, fail to achieve performance and fulfil safety objectives as well is noted in the economics, business management and risk management literature as well. Unbiased decision making is a core goal of systems engineering, encouraging careful consideration of stakeholder needs, design alternatives, and programmatic constraints and risks. However, Systems engineering practices dealing with Railway Transport Planning and Management fields do not pay attention to the human factors and organisational factors at initial stages of planning where driveability of European Railway Traffic Management System (ERTMS) Trains emerges as a concern in real time operations is noted in the Railway Transport Planning and Management domain. Therefore, there is a case for studying the Cognitive Biases in this domain. The System for Investigation of Railways (SIRI) Cybernetic Risk Model (2006), (2017) is a Systems engineering response to the internal research brief by RSSB, a GB Railways Safety Body. The SIRI Cybernetic Risk Model (2017) incorporating the “Heuristics and Biases” approach was published by the UK Transport Select Commission as a Written Evidence in 2016 on the occasion of the Inquiry theme of Railway Safety. The validity of the SIRI Risk Model (Swiss Cheese Model) is further illustrated through the 2019 historical survey of railway accidents and the two recent RAIB investigations of track worker fatal accident and signalling related near miss event in the form of Swiss Cheese Model. The data and information in the RAIB Reports (17/2019) and (11/2020) is supplemented by further research and the author’s own past studies of accident analyses. The results of the study show that the Guide to Railway Investment Process (GRIP) (2019) (now deleted by Network Rail) has no provision for incorporating measures to address to deficiencies raised by the accident reports or safety analysis reports as the RSSB (2014) Taking Safe Decisions Framework does not include all Hueristics and the biases they lead in the information used for taking decisions. Thus, the Duty Holder Investment process fails to meet the requirements of the mandatory regulatory requirements of the Common Safety Method-Risk Assessment (CSM-RA) Process. The results of the Case Studies in the Chapter remain the same despite the proposed changes in the Shapps-Williams Reform Plan (2021) as the safety related matters are not yet addressed by the plan. The author hopes when the lessons that are learnt from the Case Studies are embedded in railway organisations then we may see improvements in the railway planning and management practices by considering the risk factors at the conceptual stage of the projects and meet the requirements of ISO Standard 27500 (2016) for Human Centred Organisation. National Investigations Bodies (NIB) also may be benefitted.",signatures:"Sanjeev Kumar Appicharla",downloadPdfUrl:"/chapter/pdf-download/81390",previewPdfUrl:"/chapter/pdf-preview/81390",authors:[{id:"110711",title:"Mr.",name:"Sanjeev",surname:"Kumar Appicharla",slug:"sanjeev-kumar-appicharla",fullName:"Sanjeev Kumar Appicharla"}],corrections:null},{id:"79558",title:"Analysis of Methods Used to Diagnostics of Railway Lines",doi:"10.5772/intechopen.100835",slug:"analysis-of-methods-used-to-diagnostics-of-railway-lines",totalDownloads:66,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Complex diagnostics of railway lines involves techniques based on discrete and continual data acquisition. While discrete measurements belong to conventional methods, the modern continual ones use automated robotized instruments with continuous recording. Observations have become more time-efficient, but the processing epoch has become longer to evaluate a large number of data. Railway line diagnostics is realized by relative methods lead to determine relative track parameters as the track gauge, elevation, and track gradients and absolute, geodetic techniques determine directional and height ratios of the track, defined in a global coordinate and height system.",signatures:"Jana Izvoltova, Libor Izvolt and Janka Sestakova",downloadPdfUrl:"/chapter/pdf-download/79558",previewPdfUrl:"/chapter/pdf-preview/79558",authors:[{id:"414505",title:"Associate Prof.",name:"Jana",surname:"Izvoltova",slug:"jana-izvoltova",fullName:"Jana Izvoltova"},{id:"422743",title:"Prof.",name:"Libor",surname:"Izvolt",slug:"libor-izvolt",fullName:"Libor Izvolt"},{id:"422744",title:"Dr.",name:"Janka",surname:"Sestakova",slug:"janka-sestakova",fullName:"Janka Sestakova"}],corrections:null},{id:"78929",title:"New Approach Measuring the Wheel/Rail Interaction Loads",doi:"10.5772/intechopen.100031",slug:"new-approach-measuring-the-wheel-rail-interaction-loads",totalDownloads:122,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter suggested new methods for monitoring the dynamic processes of rolling stock/rail interaction. This study develops a new technical solution for measuring the wheel/rail interaction forces on a significant part of the sleeper. The theoretical part of this study, using FEM, confirm the ability of piecewise continuous recording of vertical and lateral forces from the wheel/rail interaction by measuring the stresses in two sections of the rail. Also, the optimum location of strain gauges and the effective length of the measuring zone have been determined. The experimental part of this study has been carried out on the stands and the railway track to confirm the effectiveness of the method to determine the vertical and lateral wheel/rail interaction forces, increase the reliable statistical data, improve the measurement accuracy, reducing the time and cost compared with current testing methods. The developed method is recommended to determine the wheel/rail interaction forces and identify defects on the wheels when diagnosing rolling stock on operational and travel regimes.",signatures:"Yuri P. Boronenko, Rustam V. Rahimov and Waail M. Lafta",downloadPdfUrl:"/chapter/pdf-download/78929",previewPdfUrl:"/chapter/pdf-preview/78929",authors:[{id:"357075",title:"Dr.",name:"Waail M.",surname:"Lafta",slug:"waail-m.-lafta",fullName:"Waail M. Lafta"},{id:"357078",title:"D.Sc.",name:"Rustam",surname:"V. Rahimov",slug:"rustam-v.-rahimov",fullName:"Rustam V. Rahimov"},{id:"416358",title:"Dr.",name:"Yuriy",surname:"P. Boronenko",slug:"yuriy-p.-boronenko",fullName:"Yuriy P. Boronenko"}],corrections:null},{id:"78167",title:"Hydrogen as a Rail Mass Transit Fuel",doi:"10.5772/intechopen.99553",slug:"hydrogen-as-a-rail-mass-transit-fuel",totalDownloads:115,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"There is a continually growing need for mass transport and along with customer desire for greater comfort and speed, its consumption of energy will grow faster still. The fiscal cost of energy plus global warming has spurred efficiency improvement and thoughts now concentrate on fuels. In the UK for major lines for trains, this is electricity generated in a benign fashion in large facilities nominally remote from the train and track. Electric trains tend to be lighter, hence more efficient and demand less maintenance than their diesel counterpart. Similar arguments, including pollution emissions apply to city mass transit systems. For medium density and lower density routes, whether fuel cells or the next generation of IC or GT engines are employed, hydrogen is a prime energy candidate and here we examine its feed, production, distribution, and application, including generator location. Hydrogen from steam hydrocarbon reformers have even been installed in ships. Other countries have similar desires to those of the UK, including Saudi Arabia, but their problems are different and outline examples from Australia and Saudi Arabia are included.",signatures:"Stephen A. Lloyd, Luke L.B.D. Lloyd and W.J. Atteridge",downloadPdfUrl:"/chapter/pdf-download/78167",previewPdfUrl:"/chapter/pdf-preview/78167",authors:[{id:"357039",title:"M.Sc.",name:"Stephen A.",surname:"Lloyd",slug:"stephen-a.-lloyd",fullName:"Stephen A. Lloyd"},{id:"414073",title:"Mr.",name:"Luke",surname:"L.B.D. Lloyd",slug:"luke-l.b.d.-lloyd",fullName:"Luke L.B.D. 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Major areas of usage are: (1) restorative dentistry and prosthodontics (dental amalgam and gold alloy restorations for single teeth, metallic restorations for multiple teeth, including metal-ceramic restorations, removable partial denture frameworks, and dental implants), (2) orthodontics (wires which provide the biomechanical force for tooth movement), and (3) endodontics (rotary and hand instruments for treatment of root canals). Heat treatment of the metal can be performed by the manufacturer, dental laboratory, or dentist to alter properties intentionally and improve clinical performance. Heat treatment of the metal also occurs during the normal sequence of preparing a metal-ceramic restoration, when dental porcelain is bonded to the underlying alloy substrate. Moreover, intraoral heat treatment of some metallic restorations occurs over long periods of time. There is an enormous scientific literature on the heat treatment of metals for dentistry. A search of the biomedical literature in May 2012, using PubMed [http://www.ncbi.nlm.nih.gov/pubmed/] revealed nearly 450 articles on heat treatment of dental alloys. The purpose of this chapter is to provide a review of the heat treatment of metallic dental materials in the foregoing important areas, describing the important property changes, with a focus on the underlying metallurgical principles.
Dental amalgams are prepared in the dental office by mixing particles of a silver-tin-copper alloy for dental amalgam that may contain other trace metals with liquid mercury. The initially mixed (termed triturated) material is in a moldable condition and is placed (termed condensed) directly by the dentist into the prepared tooth cavity, where it undergoes a setting process that produces multiple phases and can require up to one day for near completion. Extensive information about the several different types of dental amalgams are provided in textbooks on dental materials [1,2]. Particles of the alloy for dental amalgam are manufactured by either lathe-cutting a cast ingot or directing the molten alloy through a special nozzle. Both the machining of the lathe-cut particles and the rapid solidification of the spherical particles create residual stress. In addition, the microstructure of the solidified silver-tin-copper alloy has substantial microsegregation. Consequently, manufacturers of the alloy powder for dental amalgam perform a proprietary heat treatment to relieve residual stresses and obtain a more homogeneous microstructure. This heat treatment is of considerable practical importance since it affects the setting time of the dental amalgam after the powder is mixed with mercury. Subsequently, the dental amalgam restorations undergo intraoral aging, which can be regarded as heat treatment, and detailed information about the microstructural phase changes for prolonged intraoral time periods has been obtained from clinically retrieved dental amalgam restorations [3].
Gold alloys are principally used for all-metal restorations (inlays, crowns and onlays) in single posterior teeth. These alloys are cast by a precision investment process, and the restorations are cemented by the dentist into the prepared tooth cavity. The original gold casting alloys contained over approximately 70 wt.% gold, but the very high price of gold has led to the development of alloys that contain approximately 50 wt.% gold. These alloys also contain silver, copper, platinum, palladium, zinc, and other trace elements, including iridium for grain refinement. Information about the dental casting process and the gold alloys is available in dental materials textbooks [1,2]. Detailed compositions and mechanical properties of specific alloys are available on the website of the major manufacturers. Another valuable reference is the current ISO Standard on metallic materials for fixed and removable dental appliances [4], which stipulates mechanical property requirements. In the normal dental laboratory procedure, gold castings for all-metal restorations are water-quenched after solidification, following loss of the red heat appearance for the sprue. This results in formation of a disordered substitutional solid solution and leaves the alloy in the soft condition, which is preferable since adjustments are more easily made on the restoration by the dental laboratory or dentist. The gold alloy casting can also be placed in the soft condition by heating at 700°C for 15 minutes and water-quenching. The quenched gold casting may be placed in the hard condition by heat treatment at 350°C for 15 minutes and air-cooling. This heat treatment results in formation of ordered AuCu or AuCu3 regions in the disordered matrix of the high-gold or lower-gold alloys, respectively. Examples of changes in clinically important mechanical properties from heat treatment are shown in Table 1 for two gold alloys, where (S) and (H) represent the soft and hard conditions.
In practice, dental laboratories do not perform heat treatments on the cast gold restorations because of the time involved. However, it appears to be fortunate that the gold alloys that contain sufficient copper to undergo ordering will undergo age hardening in the mouth. Figure 1 compares the intraoral aging behavior of a traditional high-gold dental alloy (Type lV) and a special gold alloy containing gallium (AuCu-3wt%Ga) [5].
Alloy | Vickers Hardness | 0.2% Offset Yield Strength | Percentage Elongation | |||
Firmilay (74.5% Au) | 121 (S) | 182 (H) | 207 MPa (S) | 276 MPa (H) | 39% (S) | 19% (H) |
Midas (46% Au) | 135 (S) | 230 (H) | 345 MPa (S) | 579 MPa (H) | 30% (S) | 13% (H) |
Summary of property changes resulting from heat treatment of two gold alloys for all-metal restorations. [http://www.jelenko.com/, accessed August 15, 2012]
Comparison of the two-week aging behavior at 37°C for a high-gold dental alloy and a dental gold alloy containing gallium that was designed to undergo intraoral aging. From [
Metal-ceramic restorations are in widespread clinical use for restorative and prosthetic dentistry, and are employed for single-tooth restorations and for restorations involving multiple adjacent teeth (fixed prostheses or crown-and-bridgework). An alloy is cast using the precision investment procedure in dental laboratories to fit accurately to the prepared tooth or teeth, and to form a substrate (termed the coping) for the porcelain. After an initial oxidation step that forms a native oxide on the metal surface, one or two layers of opaque porcelain are bonded to the metal, followed by the application of a layer of body porcelain and a surface glaze [1,2]. In order to have a strong bond between the porcelain and metal, which is essential for clinical longevity of the metal-ceramic restoration, the coefficients of thermal contraction for the metal and porcelain must be closely matched, and a difference not exceeding 0.5 ppm/°C is generally desired. Mechanical property requirements for the alloys are stipulated in ANSI/ADA Specification No. 38 (ISO 9693) [6], and the minimum value of 250 MPa for the 0.2% offset yield strength is important, since the thin coping must withstand intraoral forces without undergoing permanent deformation. The metal-ceramic bond strength (termed the bond compatibility index) is measured with a three-point bending test that uses thin cast alloy strip specimens having a centrally located area of sintered porcelain, and a minimum bond strength (shear stress) of 25 MPa is stipulated.
Both noble and base metal alloys are used for bonding to dental porcelain. The current American Dental Association classification has four alloy groups for fixed prosthodontics [7]: (1) high-noble (gold-platinum-palladium, gold-palladium-silver and gold-palladium); (2) noble (palladium-silver, palladium-copper-gallium, and palladium-gallium); (3) predominantly base metal (nickel-chromium and cobalt-chromium); (4) titanium and titanium alloys. Information about these alloys for metal-ceramic bonding is summarized in a textbook on fixed prosthodontics [8]. The principal mechanisms for metal-ceramic bonding are (a) mechanical interlocking from the initially viscous porcelain at the elevated sintering temperatures flowing into microirregularities on the air-abraded cast metal surface and (b) chemical bonding associated with an interfacial oxide layer between the metal and ceramic. These two mechanisms are evident from photomicrographs, found in numerous references [8], of the fracture surfaces for metal-ceramic specimens prepared from a wide variety of dental alloys. This native oxide forms on the cast alloy during the initial oxidation firing step in the dental porcelain furnace. Noble alloys for bonding to dental porcelain contain small amounts of secondary elements, such as tin, indium and iron, which form the native oxide and also increase the alloy strength. However, Mackert et al [9] found that during initial oxidation heat treatment, metallic Pd-Ag nodules formed on the surface of a palladium-silver alloy for metal-ceramic restorations and only internal oxidation occurred for the tin and indium present in the alloy composition. They concluded that porcelain bonding arose predominantly from mechanical interlocking with the nodules. Internal oxidation has also been reported for high-gold [10] and high-palladium [11] alloys for bonding to porcelain, but both alloy types also formed surface oxides [10,12].
The initial oxidation step and subsequent sintering (also termed baking or firing) of the dental porcelain layers causes the alloy to experience substantial heat-treatment effects. Under normal dental laboratory conditions, the porcelain firing sequence is performed rapidly. For example, in one study heating of high-palladium alloys in the dental porcelain furnace was performed at approximately 30°C/min over a temperature range from 650°C to above 900°C, and the total heating time for the several firing cycles at these elevated temperatures was about 45 minutes [11]. Studies [13-15] have shown that the as-cast microstructures of noble metal alloys for bonding to porcelain are highly inhomogeneous in the initial as-cast condition, presumably from substantial elemental microsegregation that occurs during the rapid solidification involved with casting into much cooler investment [1,2]. After simulation of the dental porcelain firing sequence, the noble metal alloy microstructures become substantially homogeneous, and there are accompanying changes in the mechanical properties, as shown in Table 2.
Peaks in Vickers hardness for heat treatments at temperatures that span the porcelain-firing temperature range indicate that influential precipitation processes can occur in some noble alloys for fixed prosthodontics [13,16]. For the gold-palladium-silver alloy in Table 1, heating an as-cast specimen to 980°C caused a pronounced decrease in Vickers hardness, and subsequent heat treatments at temperatures from 200° to 980°C revealed a pronounced peak in Vickers hardness at approximately 760°C. The absence of substantial changes in Vickers hardness for similar heat treatments of the gold-palladium alloy in Table 2 arises from differences in the precipitates that form in the two complex alloy compositions. Figure 2 presents the age hardening behavior of a palladium-silver alloy, where specimens were subjected to isothermal annealing for 30 minute time periods at temperatures from 400°C to 900°C that span the range for the porcelain firing cycles [16]. Bulk values of Vickers hardness were obtained with 1 kg loads, and 25 g loads were used to obtain hardness values for specific microstructural regions. In contrast, research suggests that microstructures of popular nickel-chromium base metal alloys used with dental porcelain are not changed substantially during dental laboratory processing [17].
Alloy Type | Vickers Hardness | 0.2% Offset Yield Strength | Percentage Elongation | |||
Au-Pd-Ag (Neydium) | 199 (C) | 218 (P) | 420 MPa (C) | 490 MPa (F) | 6% (C) | 8% (F) |
Au-Pd (Olympia) | 213 (C) | 225 (P) | 500 MPa (C) | 540 MPa (F) | 13% (C) | 20% (F) |
Mechanical properties for two noble metal alloy types used with dental porcelain, comparing the as-cast condition (C) and simulated porcelain firing heat treatment (F) [13].
Annealing behavior of a palladium-silver alloy for fixed prosthodontics, showing changes in Vickers hardness for a heat treatment temperature range that spans the porcelain firing cycles. Reproduced from [
Base metal casting alloys (nickel-chromium, cobalt-chromium and cobalt-chromium-nickel) are popular for fabricating the metallic frameworks for removable partial dentures because of their lower cost [1,2]. Once an active area of dental metallurgy research, studies have found that these alloys have dendritic microstructures in the as-cast condition, because of the absence of suitable grain-refining elements, and that heat treatment is ineffective for producing improved mechanical properties [18]. A more recent publication shows the dendritic microstructures of some current alloys and their mechanical properties [19].
Removable partial denture frameworks have clasps that engage the teeth. These clasps can be cast as part of the entire framework, or alternatively wire clasps can be joined to the cast framework in the dental laboratory [1,2]. Both noble metal and base metal wires for clasps are available [20]. Because of their superior strength compared to the cast base metal alloys, wire clasps with smaller cross-section dimensions can be used with the frameworks, but caution is required during joining in the dental laboratory to avoid overheating that will cause loss of the wrought microstructure. Wire clasps are used in the as-received condition; heat treatment is not recommended before joining to the framework.
Dental implants in current widespread clinical use are manufactured from CP (commercially pure) titanium or Ti-6Al-4V, and some implants have a thin bioceramic surface coating (typically hydroxyapatite, the principal inorganic constituent of bone and tooth structure). Proprietary heat treatments [21] are performed on Ti-6Al-4V by manufacturers to obtain optimum microstructures for the implants; minimal information is currently available about these microstructures in the dental scientific literature.
Recently, there has been considerable research interest in the development of new titanium implant alloys for orthopedic applications that have improved biocompatibility compared to the Ti-6Al-4V alloy in widespread current use. There is particular interest in the beta-titanium alloys which have lower elastic modulus than Ti-6Al-4V to minimize stress shielding and subsequent loss of the surrounding bone which has a much lower elastic modulus. Stress shielding does not seem to be of concern for dental implants, presumably because of the threaded designs. Biocompatible titanium-niobium-zirconium beta alloys have been investigated, and oxide nanotubes can be grown on the alloy surface by an anodization technique, and subsequent heat treatment can be employed to modify the structure of the nanotubes [22]. In another exciting research area, titanium oxide nanowires have been recently grown on both CP titanium and Ti-6Al-4V using special elevated-temperature oxidation heat treatments in an argon atmosphere with low oxygen concentrations [23]. Both of these special types of surface oxide layers may prove to be useful for dental and orthopedic implants, but future testing in animals will be needed to examine their efficacy.
Orthodontic wires engaged in brackets that are bonded to teeth, after being deformed elastically during initial placement, provide the biomechanical force for tooth movement during unloading. There are four wire types in current clinical practice: stainless steel, cobalt-chromium, beta-titanium and nickel-titanium [24]. The clinically important mechanical properties are (a) elastic modulus, which is proportional to the biomechanical force when wires of similar dimensions are compared; (b) springback, which is generally expressed as the quotient of yield strength and elastic modulus (YS/E), and represents the approximate strain at the end of the clinically important elastic range; and (c) modulus of resilience, expressed as YS2/2E and representing the spring energy available for tooth movement. (The permanent deformation portion of orthodontic wire activation is ineffective for tooth movement.) Round orthodontic wires are manufactured by a proprietary drawing sequence that involves several stages with intermediate annealing heat treatments. Rectangular orthodontic wires are manufactured by a rolling process utilizing a Turk’s head apparatus. The wire drawing process with the heat treatments greatly affects mechanical properties.
A recent study that investigated stainless steel wires used in orthodontic practice found that most products were AISI Type 304 and that AISI Type 316L (low carbon) and nickel-free ASTM Type F2229 were also available [25]. While standard physical metallurgy textbooks consider the elastic modulus to be a structure-insensitive property, research has shown that the permanent deformation and heat treatments involved with the wire drawing process can substantially affect the elastic modulus of stainless steel orthodontic wires [26,27]. X-ray diffraction has revealed that conventional orthodontic wires manufactured from AISI Types 302 and 304, while predominantly austenitic structure, can contain the α′ martensitic phase, depending upon the carbon content and temperatures involved with the processing [28]. The presence of this martensitic phase accounts for the reduction in elastic modulus for some conventional stainless steel orthodontic wires. In addition, when fabricating complex stainless steel appliances, it is recommended that orthodontists perform a stress-relief heat treatment to prevent fracture during manipulation; a heating time up to 15 minutes and a temperature range of 300° to 500°C appears to be acceptable [29-31]. Heating austenitic stainless steel to temperatures between 400° and 900°C can result in chromium carbide precipitation at grain boundaries and cause the alloy to become susceptible to intergranular corrosion, and heating of austenitic stainless steel wires above 650°C should not be done because loss of the wrought microstructure causes degradation of mechanical properties.
The cobalt-chromium orthodontic wire (Elgiloy) marketed by Rocky Mountain Orthodontics (Denver, CO, USA) contains 40% Co, 20% Cr, 15.81% Fe, 15% Ni, 7% Mo, 2% Mn, 0.15% C carbon and 0.04% Be beryllium (https://www.rmortho.com/, accessed August 15, 2012). Four different tempers (spring quality) are available, and the soft Blue temper is favored by many orthodontists because the wire is easily manipulated in the as-received condition, and then heat treated to increase the yield strength and modulus of resilience. Heat treatment (not recommended for the most resilient temper) is conveniently performed with the electrical resistance welding apparatus commonly used in orthodontic practice, and the manufacturer provides a special paste that indicates when the heat treatment is complete. Alternatively, furnace heat treatment performed at 480°C for 5 minutes has been found to give satisfactory results [32]. An extensive study employing furnace heat treatment (480°C for 10 minutes) for three tempers and numerous sizes of the Elgiloy wires observed increases of 10% – 20% in elastic modulus and 10% – 20% in 0.1% offset yield strength, which resulted in substantial improvement of the modulus of resilience [27]. These changes in mechanical properties arise from complex precipitation processes during heat treatment that are not understood. Many other companies now market cobalt-chromium orthodontic wires, but studies of their mechanical properties and the results of heat treatment have not been reported.
Beta-titanium orthodontic wires have the advantages of: (a) known biocompatibility from the absence of nickel in the alloy composition; (b) lower elastic modulus than stainless steel and cobalt-chromium wires, which provides more desirable lower orthodontic force for tooth movement; (c) higher springback than stainless steel and cobalt-chromium wires, which is desirable for the archwire to have greater elastic range; and (d) high formability and weldability, which are needed for fabrication of certain appliances [24]. A recent study [25] of commercially available titanium-based orthodontic wires revealed that most products are Beta III alloys [21] containing approximately 11.5 Mo, 6 Zr, and 4.5 Sn, similar to the original beta-titanium wire introduced to orthodontics [33,34]. Beta C [21] and Ti-45Nb beta-titanium and Ti-6Al-4V (alpha-beta) wire products are also available [25]. Heat treatment is not performed by the orthodontist on these wires, but care with the wire drawing and intermediate heat treatments by the manufacturer are essential for obtaining the desired mechanical properties. These processes must be conducted under well-controlled conditions because of the highly reactive nature of titanium.
Following the pioneering work of Andreasen and his colleagues [35,36], near-equiatomic nickel-titanium (NiTi) wire was introduced to orthodontics by the Unitek Corporation (now 3M Unitek) [37]. This wire had the advantages of a much lower elastic modulus than the stainless steel and cobalt-chromium wires available at the time and a very large elastic range. The clinical disadvantage is that substantial permanent deformation of this wire is not possible to obtain certain orthodontic appliances that can be fabricated with the three preceding, highly formable, alloys. The original nickel-titanium wire had a work-hardened martensitic structure and did not exhibit the superelastic behavior (termed pseudoelasticity in engineering materials science) or the true shape memory characteristics displayed by subsequently introduced NiTi wires [1,38-41]. These nickel-titanium wires have been a very active area of research.
The mechanical properties of the nickel-titanium orthodontic wires are determined by the proportions and character of three microstructural phases: (a) austenite, which occurs under conditions of high temperature and low stress; (b) martensite, which occurs under conditions of low temperature and high stress; and (c) R-phase, which forms as an intermediate phase during the transformation between martensite and austenite. Very careful control of the wire processing and associated heat treatments, along with precise compositional control, by the manufacturer are needed to produce nickel-titanium wires with the desired superelastic, nonsuperelastic, or shape memory character [42,43].
Heat treatments have been exploited by manufacturers to control the orthodontic force ranges produced by nickel-titanium archwires [39]. Heat treatment temperatures have ranged from 400° to 600°C with times from 5 minutes to 2 hours [39,40]. Effects of heat treatment on cantilever bending plots for two sizes of a round superelastic nickel-titanium wire are presented in Figure 3 [40].
Effects of heat treatments on cantilever bending plots for 6 mm test spans of a superelastic nickel-titanium orthodontic wire. Reproduced from [
Loss of superelastic behavior occurs for the 2 hour heat treatment at 600°C, evidenced by the large decrease in springback (difference between the original deflection of 80 degrees and the final angular position on unloading). Heat treatment at 500°C for 10 minutes had minimal effect, while heat treatment for 2 hours caused a decrease in the average superelastic bending moment during the unloading region of clinical importance. Bending properties for nonsuperelastic wires were only slightly affected by these heat treatments. In addition to the use of furnace heat treatment, electrical resistance heat treatment [44] has also been exploited by one manufacturer to produce archwires where the level of biomechanical force varies with position along the wire [24].
Microstructural phases at varying temperatures in nickel-titanium orthodontic wires and their transformations are conveniently studied by differential scanning calorimetry (DSC) [45]. Temperature-modulated DSC provides greater insight into the transformations than conventional DSC [46]. Figures 4 and 5 present temperature-modulated DSC heating curves for shape memory and superelastic nickel-titanium orthodontic wires, respectively. The transformations involving austenite (A), martensite (M) and R-phase (R) are labeled. The austenite-finish (Af) temperature for completion of the transformation from martensite to austenite on heating is determined by the intersection with the adjacent baseline of a tangent line to the peak for the final transformation to austenite [47].
Heating temperature-modulated DSC plot for a shape memory nickel-titanium orthodontic wire. Reproduced from [
Heating temperature-modulated DSC plot for a superelastic nickel-titanium orthodontic wire. Reproduced from [
The Af temperature is below body temperature (37°C) for nickel-titanium wires that exhibit shape memory in the oral environment. The superelastic nickel-titanium wires have Af temperatures that are greater than mouth temperature and have more widely separated peaks for the successive transformations from M →R and R → A. The nonsuperelastic wires have much weaker transformations (lower values of enthalpy [ΔH]) and Af temperatures that are also greater than mouth temperature [45]. Examination of x-ray diffraction patterns for nickel-titanium orthodontic wires revealed the effects of heat treatment on the Ms temperature for the start of the cooling transformation to martensite as well as the occurrence of stress relief and perhaps some recrystallization [24,48].
Transformation of a low temperature martensite phase (M′) to the higher temperature form of martensite (M), shown in Figures 5 and 6, is readily detected as a large exothermic peak on the nonreversing heat flow curves from temperature-modulated DSC. Transmission electron microscopy has revealed that this transformation arise from low-temperature twinning within the martensite structure [49].
Traditionally, endodontic treatment was performed with stainless steel hand files and reamers to remove the injured or diseased dental pulp from the root canals of teeth. While conventional elevated-temperature heat treatment is not recommended for these instruments, they are subjected to sterilization procedures before being using again with a different patient. One study found that dry heat sterilization (180°C for 2 hours) and autoclave sterilization (220 kPa pressure and 136°C for 10 minutes) slightly decreased the flexibility and resistance to torsional fracture of the instruments but they still satisfied the requirements for minimum angular deflection in the ISO standard [50]. Further research is needed to gain insight into the metallurgical origins of the property changes.
Following the pioneering work of Walia et al that introduced the nickel-titanium hand file to the endodontics profession [51], engine-driven rotary instruments were introduced that enable rapid instrumentation of root canals. These instruments are in widespread clinical use, and research on the nickel-titanium files has been a highly intensive area of research.
The major mechanical property of the equiatomic nickel-titanium alloy that led to replacement of the traditional austenitic stainless steel files was the much lower elastic modulus of NiTi, which enabled curved root canals to be negotiated with facility. An excellent review article [52] describes the manufacturing process for the nickel-titanium files, which are generally machined from starting wire blanks. The conventional nickel-titanium rotary instruments have been fabricated from superelastic nickel-titanium blanks.
Defects caused by the machining process and metallurgical flaws in the starting blanks, along with inadvertent overloading by the clinician, can result in fracture of the file within the root canal, which causes considerable patient anguish since the broken fragments often cannot be easily retrieved [53,54].
A recent study investigated the effect of heat treatment on conventional nickel-titanium rotary instruments, using temperature-modulated DSC and Micro-X-ray diffraction [55]. Results are shown in Figure 6 (a) – (d) for heat treatment at temperatures from 400° to 800°C in a flowing nitrogen atmosphere.
Temperature-modulated DSC reversing (R), nonreversing (NR) and total (T) heat flow curves for specimens from conventional rotary endodontic instruments after heat treatment in flowing nitrogen for 15 minutes at (a) 400°, (b) 500°, (c) 600° and (d) 850°C. From [
Heat treatment between 400° and 600°C increased the Af temperature for as-received conventional NiTi rotary instruments to approximately 45° – 50°C, and the transformations between martensite and austenite were changed to a more reversing character than nonreversing character [55]. Heat treatment in a nitrogen atmosphere might lead to a harder surface from the formation of nitrides [56], which is beneficial for cutting efficiency of the rotary instrument. This research suggested that heat treatment at temperatures near 500°C in a nitrogen atmosphere might yield the optimum microstructure and mechanical properties, with improved resistance to deformation and fracture for conventional NiTi rotary instruments. Heat treatment at temperatures exceeding 600°C should not be performed, since the superelastic behavior is lost along with potential degradation of the wrought microstructure [24]. Another study has reported that heat treatment at 430° and 440°C greatly improved the fatigue resistance of one conventional rotary instrument product [57].
New nickel-titanium rotary instruments have been marketed, for which the wire blanks were improved by special proprietary processing techniques, including heat treatment. The first notable example was M-Wire, named for its stable martensitic structure [58]. Previous conventional rotary instruments were fabricated from superelastic wire blanks with evident transformable austenite detected by conventional DSC [59]. However, when the conventional instruments were cooled far below room temperature to attain the fully martensite condition, the enthalpy changes for transformations from martensite to austenite were far below those for superelastic orthodontic wires [44,45], indicating that these instruments contain a substantial proportion of stable martensite in their microstructures.
Two different batches of M-Wire (termed Type 1 and Type 2), with unknown differences in proprietary processing, were obtained for characterization by temperature-modulated DSC and Micro-X-ray diffraction [58]. Figure 7 shows the differences in the temperature-modulated DSC plots for (a) conventional superelastic wire and (b) Type 1 M-Wire.
Comparison of temperature-modulated DSC total heat flow for (a) conventional superelastic wire and (b) Type 1 M-Wire. Lower curves are the plots for the heating cycles. Reproduced from [
The general appearances of the temperature-modulated DSC plots in Figure 7 (a) and (b) are similar. However, the approximate Af temperatures for the conventional superelastic wire and Type 1 M-Wire were approximately 15°C and 50°C, respectively. The approximate Af temperature for the Type 2 M-Wire was 45°C. The proportions of the different NiTi phases were quite different for Type 1 and Type 2 M-Wire, as shown in Figure 8.
The Micro-X-ray diffraction pattern indicated that Type 1 M-Wire had an austenitic structure, and the Micro-X-ray diffraction pattern from the conventional superelastic wire was similar. In contrast, the Micro-X-ray diffraction pattern from Type 2 M-Wire contained additional peaks for martensite and R-phase, along with peaks for austenite. However, when M-Wire was examined by transmission electron microscopy, a heavily deformed martensitic structure was found [58]. The explanation is that the DSC peaks only reveal NiTi phases that are capable of undergoing transformation and that (stable) heavily deformed martensitic NiTi only produces weak x-ray diffraction peaks. Rotary instruments fabricated from M-Wire have been found to have similar Af values, microstructures and Vickers hardness, so the machining process and other proprietary fabrication steps do not appear to markedly alter the inherent structure and properties of the starting blanks [60].
Micro-X-ray diffraction patterns for (a) Type 1 M-Wire and (b) Type 2 M-Wire. Peaks for austenite (A), martensite (M) and R-phase (R) are labeled. Reproduced from [
Recently, new nickel-titanium rotary instruments have been introduced, in which the wire blank is heated to an appropriate temperature for transformation to the R-phase and twisted, along with repeated heat treatment and other subsequent thermal processing; instruments have been characterized by conventional DSC and cantilever bending tests [61]. Another recent study has characterized several new nickel-titanium rotary instruments by DSC and conventional x-ray diffraction, along with optical and scanning electron microscopic examination of their microstructures, including use of energy-dispersive x-ray spectroscopic analyses (SEM/EDS), to investigate the martensitic microstructures and composition of precipitates [62]. Because of the potentially great commercial importance, development of new rotary instruments with improved clinical performance is expected to remain an area of intensive research, along with study of the role of heat treatment [63].
It is essential to appreciate the complexity of the physical metallurgy of the nickel-titanium alloys and the effects of the severe thermomechanical processing of the starting wire blanks, along with heat treatments and machining of the wire blanks, on the metallurgical structure. Transmission electron microscopy and electron diffraction remain the best techniques to gain insight into the instrument microstructures and elucidate the relationships with mechanical properties and clinical performance.
The malignant transformation results in a specific rearrangement of metabolic processes called metabolic reprogramming of tumor cell. The altered metabolism causes a selective advantage to a transformed cell by facilitating its survival in a harsh environment and promoting the spread of tumor cells within the body.
Malignant cells very effectively adapt to high proliferation rate, metastasis, and invasion. Several molecular mechanisms were pointed out to drive such metabolic adaptation of cancer cells. The critical aspects of metabolic reprogramming in tumor cells substantially contribute to the
In particular, the regulation of mitochondrial processes in cancer cells differs from normal counterparts, and it may be specific to the stage of tumor [4]. Therefore, cancer cells are sensitive to drugs that disrupt energy homeostasis, such as Metformin (1,1-dimethylbiguanide, Met) [5].
A generic drug, Metformin, has been widely used for treatment of
To date, several molecular mechanisms were reported to play critical role in anticancer activity of Met. In particular, it was established that Met may affect energy metabolism of cancer cells by inhibition of complex I of mitochondrial electron transport chain (ETC) in mitochondria, which results in adenosine-5′-triphosphate (ATP) depletion and remodeling of the network of biosynthetic processes within the cell [9]. Met may act as an anticancer drug through the activation of the main energy regulator within the cell, adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) [7], and inhibition of mechanistic target of rapamycin complex-1 (mTORC1) [10] in tumor cells. Some of the pharmacological effects of Met seem to be independent of its action on glycemia homeostasis. Several reports demonstrated that treatment of tumor cells with Met results in cell cycle perturbations and apoptosis [11, 12]. The intracellular targets affected by Met were comprehensively reviewed by Ikhlas and Ahmad [9] and Pierotti et al. [13].
Along with the advent of human papillomavirus (HPV) vaccines, the primary prevention of cervical cancer has become more successful, but cervical malignancy still remains the significant cause of cancer mortality in women worldwide. Currently, chemotherapy using cytostatic drugs (mainly cisplatin, cis-dichlorodiammineplatinum (II)) is still the primal regimen, despite low specificity and substantial toxicity in patients [14].
Aerobic glycolysis has been recognized as the most common metabolic feature of malignant cells. The alterations in metabolism of cancer cells combined with the overexpression of oncogenes (c-Myc) and transcription factors (hypoxia-inducible factor 1a, HIF 1a) confer a great advantage to malignant cells to avoid apoptosis induced by reactive oxygen species (ROS). In this study we focused on the effects of Met on metabolism of metastatic cervical tumor cells. Based on recent data, we reported that Met inhibited glycolytic phenotype of aggressive cervical cancer cells by regulation of expression of oncogenes and their downstream proteins, which led to cellular death. Furthermore, Met regulated mitochondrial metabolism, especially via supplementation of tricarboxylic acid cycle (TCA cycle, Krebs cycle) with pyruvate and glutamine. Met, by targeting epithelial and mesenchymal markers of tumor cells, alleviated invasive properties of cervical cancer cells.
This review summarizes recent findings on Met and cervical cancer underscoring new implications of this drug in regulation of peculiar metabolism of tumor cells. We discuss new perspectives about targeting specific alterations in cervical tumor metabolic pathways using Met.
A growing evidence suggests that the screening for molecular targets for anticancer therapeutic treatments should take into account the existing differences in tumor cell phenotypes. Therefore, the metabolic effects exerted by Met were studied using SiHa cells (American Type Culture Collection, ATCC designation HTB-35) originating from aggressive cervical tumor, which acquired malignant characteristics [15]. The regulation of apoptosis pathways in HTB-35 (SiHa) cells highly reflects the specificity of cervical tumor in vivo [16]. HTB-35 cells, even unstimulated with cytokines, have mesenchymal-like characteristics, especially high vimentin expression, along with enhancement of cell scattering and ability to move [17]. Another cell line, C-4I cells (ATCC, designation CRL1594) with epithelial phenotype, was derived from primary in situ tumor [18]. HTB-34 cells (ATCC designation MS751) were isolated from metastatic site in lymph node [19]. HTB-35, C-4I and HTB-34 are human squamous cell cervical carcinoma lines and it is worth noting that squamous cell cancer is the most common cervical cancer and accounts for almost 80% of cervical carcinomas in patients [14]. HeLa human cervical cancer cells (ATCC designation CCL2), which have been extensively used in mechanistic studies, expressed epithelial traits and were derived from
The reliance on glucose supply is linked to the aggressiveness of malignant cells. Such reprogrammed metabolism makes migrating cancer cells more robust and independent of environmental conditions. The dysregulation of glucose metabolism is caused by alterations in functioning of several oncogenes. Malignant cells may gain metabolic plasticity by upregulation of only few oncogenes, such as c-Myc, p53, phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) [20]. Additionally, the activation of transcription factors, such as HIF-1α, makes malignant cells more resistant to hypoxia (decreased oxygen level in microenvironment), which is one of the main factors affecting tumor growth [20]. The activation of HIF-1α is one of the crucial processes that promote glycolysis to generate ATP along with the decrease of mitochondrial pathways’ activity in aggressive tumors. What is more, the migrating tumor cells may avoid oxidative stress by relying on glucose catabolism. As a result, tumor cells have higher chance to survive detachment from extracellular matrix (ECM), whereas normal cells undergo programmed death due to anoikis in the absence of attachment to ECM [21]. Following detachment from primary tumor bed and transportation to plasma and lymph, malignant cells may spread within the body and form secondary tumors. Therefore, the reprogrammed metabolism plays a crucial role in facilitating tumor metastasis.
We found that Met may regulate glycolysis in aggressive cervical cancer cells. The glycolytic phenotype of tumor cells is triggered mainly by a master regulator HIF-1α and its downstream proteins. Our study showed that Met alleviated the hypoxia-induced activation of HIF-1α, which was followed by decreased expression of HIF-1α downstream protein effectors in HTB-35 cells, as demonstrated in [22]. In particular, Met downregulated GLUT transporters (solute carrier family 2 member receptors, SLC2A), specifically GLUT1 and GLUT3. Additionally, Met inhibited the regulatory enzymes of the glycolytic pathway, hexokinase 2 (HK2), bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), pyruvate kinase (PKM), and lactate dehydrogenase (LDH) (Figure 1). Met exerted greater effect on regulatory proteins in HTB-35 cells exposed to decreased oxygen level in the air than normal conditions.
Metformin inhibits glycolytic phenotype of cervical carcinoma cells (↑—activation, Ⱶ—inhibition) [
Recent studies have reported that overexpression of c-Myc oncogene plays a significant role in the formation of cervical cancer. The enhanced expression of c-Myc is also of particular relevance to promoting invasive phenotype of cancer cells. What is more, the upregulated c-Myc may collaborate with HIF to effectively induce glucose and glutamine consumption in tumor cells. As a result, mitochondrial oxidative phosphorylation decreases. In particular, the upregulated c-Myc enhances glutamine catabolism in tumor cells, since the oncogene controls glutaminase (GLS) expression [23]. As measured using qPCR analysis, Met decreased
Met triggered another pro-apoptotic mechanism in cervical carcinoma cells via regulation of Bcl-2 (B-cell lymphoma 2) protein family members’ expression [22]. Bcl-2 proteins are key players in the regulation of mitochondrial-dependent programmed cell death. The activation of BAX protein leads to disruption of mitochondrial membrane potential and apoptosis, whereas Bcl-2 acts as an apoptotic suppressor. The counterbalancing pro- and anti-apoptotic effectors of Bcl-2 protein family play a crucial role in the regulation of the mitochondrial apoptotic cascade within the cell and constitute another important apoptotic checkpoint [25]. However, the disturbance of BAX/Bcl-2 pathway may result in the resistance to apoptosis by inducing compensatory mechanisms, thereby influencing the efficacy of some therapeutic regimens [26]. The exposition of cervical tumor cells to Met significantly upregulated
The study using cervical cancer cells with metastatic phenotype cells showed that the downregulation of oncogenes/downstream regulatory proteins, together with the upregulation of pro-apoptotic BAX/Bcl-2, elucidated mitochondrial-dependent apoptosis in tumor cells. The obtained data suggest that Met was highly effective in facilitating cell death in cervical tumor cells [22], since it exerted its effect targeting independent events controlling mitochondrial apoptosis including the induction of ROS [11], the regulation of Bcl-2 protein family expression, and downregulation of cyclin D1. It should be emphasized that Met induced cell death solely in tumor cells, without causing detrimental effects to normal cells [11].
The reprogrammed metabolism of tumor cells not only meets high energetic demands but also provides intermediates for intensive proliferation. Therefore, glycolysis and mitochondrial oxidative phosphorylation may operate simultaneously in cancer cells. Many tumors may even switch between these pathways accordingly to the current requirements. Recent studies showed that most cancer cells have metabolically efficient mitochondria to provide intermediates for biosynthesis, generate reductive power (nicotinamide adenine dinucleotide phosphate, NADPH), and restore cofactor pool (e.g., nicotinamide adenine dinucleotide, NADH). In highly proliferating cancer cells, mitochondrial TCA cycle is active enough to sustain the biochemical reactions. Currently, the precise regulation of anabolic pathways and keeping their activities at adequate level is thought to play a key role in determination of “flexible” metabolic phenotype of cancer cells that enables their rapid division. Moreover, oxidative phosphorylation (OXPHOS) may represent a significant contribution to energy generation within malignant cell. On the other hand, inevitable products of OXPHOS are ROS and oxidative stress due to ROS overproduction may kill tumor cells [27].
It was demonstrated that the process of detachment of migrating squamous cancer cells from extracellular matrix (ECM) results in reprogramed metabolism toward glycolysis, particularly by PDH complex inhibition and following suppression of glucose respiration in mitochondria. Such metabolic phenotype of tumor cell enables efficient production of energy without excessive ROS generation. On the other hand, the stimulation of PDH activity may lead to increased anoikis sensitivity and attenuation of metastatic potential of cancer cells [28].
We found that Met may precisely regulate PDH metabolic checkpoint in cervical tumor cells (Figure 2). Met had great potency to activate oxidative decarboxylation of pyruvate to acetyl-CoA in HTB-35 cells expressing invasive phenotype, and it occurred via activation of PDH complex [11]. PDH complex plays a determinant role in the overall glucose disposal within the cell, since it funnels mitochondrial TCA cycle instead of lactate formation in cytosol. PDH activity is precisely regulated via covalent modification by the action of specific enzyme pyruvate dehydrogenase kinase (PDK). Several PDK activators were found to expand potent antitumor effect, also in cervical tumor HeLa cells [29]. We showed in aggressive cervical cancer HTB-35 cells that Met suppressed both PDK activity and the expression of gene encoding tumor-specific isoenzyme PDK1 [22]. This finding may have practical implications, since the screening strategy for PDK inhibitors should recognize the specificity among the PDK isoenzymes in order to avoid side effects in vivo [30]. Under hypoxic conditions inside tumors, the activation of HIF-1α decreases mitochondrial metabolism, which prevents the cell from oxidative stress and helps cancer cells avoid apoptosis [20, 23]. Our study showed that in aggressive cervical cancer cells Met counteracted these metabolic alterations by inhibiting PDK1, which is at the same time HIF-1α prime downstream effector. Furthermore, Met downregulated PDK1 gene expression also in normoxia [22].
Metformin regulates mitochondrial metabolism of cervical carcinoma cells (↑—activation, Ⱶ—inhibition) [
In tumor cells that have functional mitochondria, the generation of oxidative stress may become an important therapeutic target [27, 30]. The imbalance of metabolic regulation and the resulting overproduction of ROS in mitochondrial ETC cause oxidative stress, which, at some point, becomes toxic to cancer cells, and that escalation of ROS elicits apoptosis-inducing factors and triggers death program through multiple mechanisms. In compliance, it has been newly reported that Met significantly increased ROS level, altered apoptosis-associated signaling, and induced cell death in human gastric adenocarcinoma cells [31] and human cervical cancer HeLa cells [32]. We found that in HTB-35 cervical cancer cells, Met caused excessive generation of mitochondrial ROS and elicited apoptosis [11, 22]. As shown in [22], the effect of Met was specific to tumor cells, and the formation of mitochondrial ROS was not affected in normal cells exposed to Met.
Met concomitantly targeted cytosolic glycolysis and mitochondrial pathways in HTB-35 cells, which increased apoptosis and suppressed survival of cervical tumor cells under normoxic and hypoxic conditions [22].
Glutamine may provide precursors to feed TCA cycle under limited flux of pyruvate from cytosolic glycolysis within tumor cells. The facilitated use of glutamine is a significant metabolic adaptation of cancer cell, besides enhanced glucose catabolism, and it provides intermediates sufficient for intensive biosynthesis and energy production [20]. Glutaminase (GLS) is a key regulator of glutamine entry to TCA [33], and the inhibition of the enzyme may suppress tumor cell growth [25].
As shown in [11], the exposition of cervical cancer cells with invasive phenotype to Met downregulated the expression of GLS, thereby protecting mitochondrial anabolism from additional carbon supply for synthesis of macromolecules. Additionally, the effect of Met on GLS expression was specific toward cervical cancer cells, and in normal cells drug did not change the expression of the enzyme [11].
Glutamine entry to tumor cell not only improves carbon supply for macromolecules buildup, but it also replenishes the pool of cellular NADPH, since the conversion of malate to pyruvate catalyzed by malic enzyme 1 (ME1) is accompanied by the reduction of NADP+ (Figure 2). NADPH is used for biosynthesis, but it also plays a significant role in the antioxidant protection of tumor cell by reducing glutathione molecule. Met downregulated expression of ME1 and alleviated generation of NADPH in cells, which, in conditions of limited supplementation of HTB-35 cells with glucose (suppressed expression of GLUTs), resulted in hampering of biosynthesis and alleviation of ROS detoxification [11, 22].
Furthermore, Met treatment caused acute drop in ATP concentration in HTB-35 cells. This is in compliance with data obtained by Parker et al. [34] who demonstrated that non-small cell lung cancer (NSCLC) cells may be uniquely sensitized to metabolic stresses by the action of other biguanide, phenformin (1-(diaminomethylidene)-2-(2-phenylethyl)guanidine). The inhibition of ATP generation may block biosynthesis in cervical tumor cells which results in restraining of cell proliferation.
The facilitated fatty acid (FA) de novo synthesis together with upregulated glycolysis was recognized as one of the prime metabolic alterations in such tumor cells [35]. The enhanced FA biosynthesis meets high demands of rapidly proliferating malignant cells (generating components for cell membranes and signaling molecules). We found that Met decreased unsaturated lipid content in aggressive cervical cancer cells (Figure 2). The mechanism of Met action included downregulation of regulatory enzyme elongase 6 (ELOVL6), which catalyzes elongation of fatty acid molecule. Met also suppressed stearoyl-CoA desaturase (SCD1), which controls desaturation of FA. It was shown by Fritz et al. [36] that pharmacologic inhibition of SCD1 activity impaired unsaturated FA synthesis, which resulted in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells. The treatment of cervical cancer cell lines [22, 37] with Met decreased cervical tumor cell proliferation, but Met did not affect the growth of normal cells [11].
Emerging data indicate that the enhanced activity of enzymes regulating lipid de novo synthesis may contribute to activation of EMT process in tumor cells [36]. The activation of EMT program in epithelial cancer cells facilitates tumor progression, invasion, and metastasis. It has been shown in independent studies that Met inhibits EMT in various cancer cell lines [8, 37]. Recently, it has been reported that Met reversed EMT phenotype induced with
In our study, EMT process was induced upon 48 h incubation of cervical cancer cells with 10 ng/mL of cytokine TGF-β1, as described in detail in [17]. HTB-35 cells, even unstimulated, expressed mesenchymal-like characteristics, and the incubation with TGF-β further enforced expression of mesenchymal marker, vimentin, along with enhancement of cell scattering and ability to move [17]. The study showed that Met was an effective suppressor of mesenchymal phenotype and, in particular, downregulated vimentin in HTB-35 cells (Figure 3). Recently, it was reported by Laskov et al. [39] that Met downregulated the expression of vimentin in endometrial cancers in vitro and in vivo in diabetic patients. The incubation of cervical cancer cell lines with Met reduced cells’ ability to move, as shown using functional scratch test in C4-I and HTB-35 cells stimulated with TGF-β1 [17]. Mechanistic study revealed that Met inhibited the expression of transcription factors Snail-1, ZEB-1, and Twist-1. These mesenchymal markers facilitate EMT progress in cervical cancer cells.
Metformin inhibits TGF-β1-induced EMT phenotype of cervical carcinoma cells (↑—activation, Ⱶ—inhibition) [
Cheng and Hao [8] proposed another mechanism of Met action in cervical carcinoma cells via inhibition of mTOR/p70s6k signaling pathway and downregulation of glycolytic regulatory protein pyruvate kinase, isozyme M2 (PKM2), in HeLa cell line.
In order to clarify the molecular action of Met in cervical tumor cells with aggressive characteristics, the effect of the drug was tested in the hypoxic conditions. In cervical cancers, hypoxia and concomitant enhanced lactate formation result in acidification of microenvironment, which may promote the ability of metastatic cells to rapidly spread in tissue [41]. In such conditions, the activation of HIF1α induces its downstream protein carbonic anhydrase IX (CAIX). By regulation of tumor milieu pH, CAIX acts as a survival factor protecting malignant cells against enhanced acidification of microenvironment. As a result, lactate damages adjacent normal cells and does not harm tumor cells [42]. Due to its relevant role in cell invasion, CAIX was proposed as a potential therapeutic target, also in cervical cancers [41, 42]. We showed that the exposition of HTB-35 cells to Met under hypoxia suppressed HIF-1α, which resulted in decreased transcription of
Recently, numerous beneficial activities of Met were reported. Met was shown to improve cardiovascular outcomes in humans [43], and the ability of Met to extend life-span in mammals has attracted great attention [44]. Emerging data indicate that Met may be applied as adjuvant in therapies aiming at combating diseases with high mortality rate, also in cervical cancer [45]. The clinical benefits of the use of Met in gynecologic oncology in humans were reviewed by Irie et al. [46] and Imai et al. [47]. Met also reduced the incidence of endometrial tumors and improved survival of patients with diagnosed local or advanced endometrial cancer [48]. Several clinical trials showed the potential of Met to elicit apoptosis in the uterus and prostate cancers in humans [49].
The potential pathological effects of Met have been well studied in long term in human population. One of the most undesirable effects in the context of peculiar metabolic alterations of cancer cell is the enhanced generation of lactic acid caused by biguanides. In fact, the application of phenformin (1-(diaminomethylidene)-2-(2-phenylethyl)guanidine) was associated with a much higher risk of lactic acidosis in patients, than Metformin. Therefore, the former drug was withdrawn from clinical use. Currently, the contraindication for the use of Met in patients is renal failure, since this group has greater risk of lactic acidosis. However, the concerns over lactic acidosis were shown to be largely unfounded, unless kidney disease was advanced. Yet, based on the recent data, Met can be safely used in patients with mild renal dysfunction, provided that patients are monitored appropriately [43, 50].
The exposition of aggressive cervical cancer cells to Met restrained the function of HIF-1α master regulator and downregulated HIF-1α downstream glycolytic genes. Met also downregulated glycolytic phenotype of HTB-35 cells through inhibition of oncogene
Met precisely regulated PDH and GLS metabolic checkpoints in cervical tumor cells. In particular, in tumor cells Met targeted supplementation of mitochondrial pathways in pyruvate by downregulation of PDK1 gene expression and decreasing PDK activity. As a result, Met effectively enhanced TCA cycle flux in normoxic and hypoxic conditions. The downregulation of GLS and ME1 resulted in decreased regeneration of NADPH, the factor essential both for biosynthesis and cell protection against oxidative stress. The metabolic alterations of mitochondrial pathways caused by Met caused excessive generation of ROS which led to apoptosis. In cervical cancer cells, Met additionally induced apoptosis via upregulation of pro-apoptotic BAX protein expression and by downregulation of cyclin D1, oncogene
It is also important to highlight another cellular mechanism of Met action, namely, the suppression of EMT process in cervical tumor cells. EMT seems implicated into invasiveness and metastasis of cancer, and Met was able to inhibit EMT pathways. In cervical tumor cells stimulated with TGF-β1 as well as in unstimulated ones, Met decreased the expression of the main mesenchymal marker vimentin and reduced motility of cells. In addition, Met downregulated adaptive enzyme
These findings provide a new insight into regulation of glycolysis and mitochondrial pathways in cervical tumor cells using nontoxic and well-studied drug, Metformin, indicating the future prospect about utilization of this molecule in clinical oncological routine. The identification and targeting of specific alterations in tumor metabolic pathways may constitute a sole basis to design new precise therapeutic strategies in cervical malignancy. To date, very few innovative therapies against cervical malignancy are being tested in clinical trials; thus more specific and effective intervention is highly required.
The artworks were prepared using elements from Servier Medical Art.
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Journals",metaDescription:"IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors",metaKeywords:null,canonicalURL:"/page/publication-agreement-journals",contentRaw:'[{"type":"htmlEditorComponent","content":"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 Journal Article:
\\n\\n1. DEFINITIONS
\\n\\nCorresponding Author: The Author of the Article who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author. Co-Author: All other Authors of the Article besides the Corresponding Author. IntechOpen: IntechOpen Ltd., the Publisher of the Journal.
\\n\\nJournal: The publication as a collection of Articles compiled by IntechOpen .
\\n\\nArticle: 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\\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to publish, communicate to the public, reproduce, republish, transmit, sell, distribute and otherwise use and make available the Article in whole, partial or adapted from and/or incorporated in or in conjunction with other works, in electronic and print editions of the Publication and in derivative works and on any platform owned and/or operated by IntechOpen, throughout the world, in all languages, and in all media and formats now known or later developed.
\\n\\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to create and store electronic archival copies of the Article, including the right to deposit the Article in open access digital repositories.
\\n\\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to license others to reproduce, translate, republish, transmit and distribute the Article in whole, partial or adapted from and/or incorporated in or in conjunction with other works under the condition that the Corresponding Author and each Co-Author is attributed (currently this is carried out by publishing the Article under a Creative Commons 4.0 International Licence).
\\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 Article 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 Article 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. The 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 Article 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 Article.
\\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 Article as a consequence of IntechOpen's changes to the Article 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 Article, the Corresponding Author agrees to credit the Journal in which the Article 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 Journal in which the Article has been published as the source of first publication, as well as IntechOpen, when they are distributing or re publishing the Article.
\\n\\n3.2 When submitting the Article, the Corresponding Author agrees to:
\\n\\n• Comply with all instructions and guidelines provided by IntechOpen;
\\n\\n• Produce the Article with all due skill, care and diligence, and in accordance with good scientific practice;
\\n\\n• Submit all the corrections in due time as defined during the publishing process schedule.
\\n\\nThe Corresponding Author will be held responsible for the payment of the Article Processing Charge.
\\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 Article 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 Article does not and will not breach any applicable law or the rights of any third party and, specifically, that the Article 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 Article 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 Article has not been formally published in any other peer-reviewed journal or in a Journal 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
\\n\\nAgreement; 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 Article 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 Article 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 Article 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 Article 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 Article and has the right to contact the Corresponding Author and any Co-Author until the Article 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 Article,
\\n\\nIntechOpen 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"}]'},components:[{type:"htmlEditorComponent",content:"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 Journal Article:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Article who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author. Co-Author: All other Authors of the Article besides the Corresponding Author. IntechOpen: IntechOpen Ltd., the Publisher of the Journal.
\n\nJournal: The publication as a collection of Articles compiled by IntechOpen .
\n\nArticle: 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\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to publish, communicate to the public, reproduce, republish, transmit, sell, distribute and otherwise use and make available the Article in whole, partial or adapted from and/or incorporated in or in conjunction with other works, in electronic and print editions of the Publication and in derivative works and on any platform owned and/or operated by IntechOpen, throughout the world, in all languages, and in all media and formats now known or later developed.
\n\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to create and store electronic archival copies of the Article, including the right to deposit the Article in open access digital repositories.
\n\n• An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to license others to reproduce, translate, republish, transmit and distribute the Article in whole, partial or adapted from and/or incorporated in or in conjunction with other works under the condition that the Corresponding Author and each Co-Author is attributed (currently this is carried out by publishing the Article under a Creative Commons 4.0 International Licence).
\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 Article 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 Article 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. The 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 Article 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 Article.
\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 Article as a consequence of IntechOpen's changes to the Article 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 Article, the Corresponding Author agrees to credit the Journal in which the Article 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 Journal in which the Article has been published as the source of first publication, as well as IntechOpen, when they are distributing or re publishing the Article.
\n\n3.2 When submitting the Article, the Corresponding Author agrees to:
\n\n• Comply with all instructions and guidelines provided by IntechOpen;
\n\n• Produce the Article with all due skill, care and diligence, and in accordance with good scientific practice;
\n\n• Submit all the corrections in due time as defined during the publishing process schedule.
\n\nThe Corresponding Author will be held responsible for the payment of the Article Processing Charge.
\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 Article 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 Article does not and will not breach any applicable law or the rights of any third party and, specifically, that the Article 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 Article 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 Article has not been formally published in any other peer-reviewed journal or in a Journal 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
\n\nAgreement; 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 Article 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 Article 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 Article 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 Article 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 Article and has the right to contact the Corresponding Author and any Co-Author until the Article 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 Article,
\n\nIntechOpen 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).
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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. from Integral University, Lucknow, India, with his work titled ‘Development and evaluation of silymarin nanoformulation for hepatic carcinoma’. Currently, he is an Assistant Professor of Pharmaceutics, at the Faculty of Pharmacy, Integral University. He has been teaching PharmD, BPharm, and MPharm students and conducting research in the novel drug delivery domain. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than twenty-four original journal articles, two edited books, four book chapters, and several scientific articles to his credit. He is a member of the American Association for Cancer Research, the International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. 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Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. 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