Summary of the mechanisms of mitochondrial dysfunction promoted by anticancer agents (GI, gastrointestinal tract; MPT, mitochondrial permeability transition; mtDNA, mitochondrial DNA; SERMs, selective estrogen receptors modulators).
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6286",leadTitle:null,fullTitle:"Photon Counting - Fundamentals and Applications",title:"Photon Counting",subtitle:"Fundamentals and Applications",reviewType:"peer-reviewed",abstract:"Photon counting is a unified name for the techniques using single-photon detection for accumulative measurements of the light flux, normally occurring under extremely low-light conditions. Nowadays, this approach can be applied to the wide variety of the radiation wavelengths, starting from X-ray and deep ultraviolet transitions and ending with far-infrared part of the spectrum. As a special tribute to the photon counting, the studies of cosmic microwave background radiation in astronomy, the experiments with muon detection, and the large-scale fundamental experiments on the nature of matter should be noted. The book provides readers with an overview on the fundamentals and state-of-the-art applications of photon counting technique in the applied science and everyday life.",isbn:"978-953-51-3908-9",printIsbn:"978-953-51-3907-2",pdfIsbn:"978-953-51-4081-8",doi:"10.5772/intechopen.69183",price:119,priceEur:129,priceUsd:155,slug:"photon-counting-fundamentals-and-applications",numberOfPages:296,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"cb9826a544c5714e517d67fa8ea29150",bookSignature:"Nikolay Britun and Anton Nikiforov",publishedDate:"March 21st 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6286.jpg",numberOfDownloads:18279,numberOfWosCitations:18,numberOfCrossrefCitations:13,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:22,numberOfDimensionsCitationsByBook:2,hasAltmetrics:1,numberOfTotalCitations:53,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 22nd 2017",dateEndSecondStepPublish:"June 12th 2017",dateEndThirdStepPublish:"November 25th 2017",dateEndFourthStepPublish:"December 25th 2017",dateEndFifthStepPublish:"February 25th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"176901",title:"Dr.",name:"Nikolay",middleName:null,surname:"Britun",slug:"nikolay-britun",fullName:"Nikolay Britun",profilePictureURL:"https://mts.intechopen.com/storage/users/176901/images/system/176901.jpeg",biography:"Nikolay Britun graduated from Kiev National University, Ukraine, in 2002 and received a PhD degree from Sungkyunkwan Univeristy, South Korea, in 2008. He is currently working in the laboratory “Chimie des Interactions Plasma-Surface” at the University of Mons, Belgium. His research interests are related to plasma spectroscopy, plasma chemistry, and in particular to diagnostics of the processes related to CO2 decomposition in non-equilibrium discharges.",institutionString:"University of Mons",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"176861",title:"Dr.",name:"Anton",middleName:null,surname:"Nikiforov",slug:"anton-nikiforov",fullName:"Anton Nikiforov",profilePictureURL:"https://mts.intechopen.com/storage/users/176861/images/system/176861.png",biography:"Dr. Anton Nikiforov received the PhD degree in 2004 in the field of Physical Chemistry from the Russian Academy of Sciences. From year 2009 he works in Ghent University, the Department of Applied Physics, Research Unit of Plasma Technology (RUPT). Main research activity of Dr. A. Nikiforov is essentially experimental work that focuses on the physics, engineering and applications of non-equilibrium (“cold”) atmospheric pressure plasmas. On-going physical studies bear on plasma-surface interactions, on plasmas in liquids and on the advanced diagnostics in non-equilibrium discharges. His current research interests include plasma diagnostics and laser spectroscopy; plasma engineering of biomaterials and plasma-surface interactions.",institutionString:"University of Gent",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Ghent University",institutionURL:null,country:{name:"Belgium"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1230",title:"Quantum Optics",slug:"quantum-optics"}],chapters:[{id:"58029",title:"Principles and Early Historical Development of Silicon Avalanche and Geiger-Mode Photodiodes",doi:"10.5772/intechopen.72148",slug:"principles-and-early-historical-development-of-silicon-avalanche-and-geiger-mode-photodiodes",totalDownloads:1929,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"The historical development of technology can inform future innovation, and while theses and review articles attempt to set technologies and methods in context, few can discuss the historical background of a scientific paradigm. In this chapter, the nature of the photon is discussed along with what physical mechanisms allow detection of single-photons using solid-state semiconductor-based technologies. By restricting the scope of this chapter to near-infrared, visible and near-ultraviolet detection we can focus upon the internal photoelectric effect. Likewise, by concentrating on single-photon semiconductor detectors, we can focus upon the carrier-multiplication gain that has allowed sensitivity to approach the single-photon level. This chapter and the references herein aim to provide a historical account and full literature review of key, early developments in the history of photodiodes (PDs), avalanche photodiodes (APDs), single-photon avalanche diodes (SPADs), other Geiger-mode avalanche photodiodes (GM-APDs) and silicon photo-multipliers (Si-PMs). As there are overlaps with the historical development of the transistor (1940s), we find that development of the p-n junction and the observation of noise from distinct crystal lattice or doping imperfections – called “microplasmas” – were catalysts for innovation. The study of microplasmas, and later dedicated structures acting as known-area, uniform-breakdown artificial microplasmas, allowed the avalanche gain mechanism to be observed, studied and utilised.",signatures:"Edward M.D. Fisher",downloadPdfUrl:"/chapter/pdf-download/58029",previewPdfUrl:"/chapter/pdf-preview/58029",authors:[{id:"199505",title:"Dr.",name:"Edward",surname:"Fisher",slug:"edward-fisher",fullName:"Edward Fisher"}],corrections:null},{id:"58205",title:"High Sensitivity Photodetector for Photon-Counting Applications",doi:"10.5772/intechopen.71940",slug:"high-sensitivity-photodetector-for-photon-counting-applications",totalDownloads:2207,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"In the last years, there has been a large development of low-light applications, and many of them are based on photon counting using single-photon detectors (SPDs). These are very sensitive detectors typically with an internal gain. The first candidate SPD was the photomultiplier tube (PMT), reaching a very high gain (~106), but there have been a large development of many other solutions, like solid-state solutions. Among them, single-photon avalanche diodes (SPADs) have been used in spectroscopy, florescence imaging, etc., particularly for their good detection efficiency and time resolution (tens of picoseconds). SPADs have been developed in silicon and III–V materials, for the NIR wavelength range. SPADs can be used as single high-performance pixels, or in arrays. SPAD arrays have imaging capabilities, with high sensitivity. Another kind of array is the silicon photomultiplier (SiPM), where all the pixels are connected to a common anode and a common cathode. SiPMs are used in nuclear medicine, physics experiments, quantum-physics experiments, light detection and ranging (LIDAR), etc., due to their high detection efficiency combined with large sensitive areas, and high dynamic range. SiPMs with many small cells present several advantages and nowadays the SPAD pitch can be reduced down to 5 μm.",signatures:"Fabio Acerbi and Matteo Perenzoni",downloadPdfUrl:"/chapter/pdf-download/58205",previewPdfUrl:"/chapter/pdf-preview/58205",authors:[{id:"99506",title:"Mr.",name:"Matteo",surname:"Perenzoni",slug:"matteo-perenzoni",fullName:"Matteo Perenzoni"},{id:"213861",title:"Dr.",name:"Fabio",surname:"Acerbi",slug:"fabio-acerbi",fullName:"Fabio Acerbi"}],corrections:null},{id:"58843",title:"Quantum Non-Demolition Measurement of Photons",doi:"10.5772/intechopen.72871",slug:"quantum-non-demolition-measurement-of-photons",totalDownloads:1557,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"According to Heisenberg’s uncertainty principle, measurement of a quantum observable introduces noise to this observable and thus limits the available precision of measurement. Quantum non-demolition measurements are designed to circumvent this limitation and have been demonstrated in detecting the photon flux of classical light beam. Quantum non-demolition measurement of a single photon is the ultimate goal because it is of great interest in fundamental physics and also a powerful tool for applications in quantum information processing. This chapter presents a brief introduction of the history and a review of the progress in quantum non-demolition measurement of light. In particular, a detailed description is presented for two works toward cavity-free schemes of quantum non-demolition measurement of single photons. Afterward, an outlook of the future in this direction is given.",signatures:"Keyu Xia",downloadPdfUrl:"/chapter/pdf-download/58843",previewPdfUrl:"/chapter/pdf-preview/58843",authors:[{id:"210723",title:"Prof.",name:"Keyu",surname:"Xia",slug:"keyu-xia",fullName:"Keyu Xia"}],corrections:null},{id:"57572",title:"Photon Counting for Studying Faint Astronomical Variable Signals in Optical Band",doi:"10.5772/intechopen.71072",slug:"photon-counting-for-studying-faint-astronomical-variable-signals-in-optical-band",totalDownloads:1435,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Although physics of neutron stars as pulsars together with their emission mechanisms leave discussions open, such objects represent the best targets to be deeply investigated by photon counting through the high-speed photometry technique. In this scenario, the capability of devices based on the silicon photomultiplier technology allows detecting single photons with remarkable time resolutions (few tens of nanoseconds). Whenever performing (optical) ground-based observations of variable sources, time of arrivals of incoming photons must be corrected because Earth’s reference frame system is not inertial. Time corrections provide time of arrivals to be moved to the Solar System Barycentre inertial reference frame. If the pulsar belongs to a binary system, further corrective terms, due to the orbital motion of the companion star, have to be taken into account. In this chapter, we report experimental results obtained from observations performed on two different variable sources, the isolated Crab pulsar and Hz Her/Her X-1 binary system, with a very fast custom astronomical photometer.",signatures:"Filippo Ambrosino and Franco Meddi",downloadPdfUrl:"/chapter/pdf-download/57572",previewPdfUrl:"/chapter/pdf-preview/57572",authors:[{id:"210583",title:"Dr.",name:"Filippo",surname:"Ambrosino",slug:"filippo-ambrosino",fullName:"Filippo Ambrosino"},{id:"210939",title:"Prof.",name:"Franco",surname:"Meddi",slug:"franco-meddi",fullName:"Franco Meddi"}],corrections:null},{id:"58015",title:"Computational Methods for Photon-Counting and Photon- Processing Detectors",doi:"10.5772/intechopen.72151",slug:"computational-methods-for-photon-counting-and-photon-processing-detectors",totalDownloads:1361,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"We present computational methods for attribute estimation of photon-counting and photon-processing detectors. We define a photon-processing detector as any imaging device that uses maximum-likelihood methods to estimate photon attributes, such as position, direction of propagation and energy. Estimated attributes are then stored at full precision in the memory of a computer. Accurate estimation of a large number of attributes for each collected photon does require considerable computational power. We show how mass-produced graphics processing units (GPUs) are viable parallel computing solutions capable of meeting the required computing needs of photon-counting and photon-processing detectors, while keeping overall costs affordable.",signatures:"Luca Caucci, Yijun Ding and Harrison H. Barrett",downloadPdfUrl:"/chapter/pdf-download/58015",previewPdfUrl:"/chapter/pdf-preview/58015",authors:[{id:"211916",title:"Ph.D.",name:"Luca",surname:"Caucci",slug:"luca-caucci",fullName:"Luca Caucci"},{id:"213953",title:"Dr.",name:"Yijun",surname:"Ding",slug:"yijun-ding",fullName:"Yijun Ding"},{id:"213954",title:"Dr.",name:"Harrison",surname:"Barrett",slug:"harrison-barrett",fullName:"Harrison Barrett"}],corrections:null},{id:"58499",title:"Laser-Induced Fluorescence of Hydroxyl (OH) Radical in Cold Atmospheric Discharges",doi:"10.5772/intechopen.72274",slug:"laser-induced-fluorescence-of-hydroxyl-oh-radical-in-cold-atmospheric-discharges",totalDownloads:1547,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The application of laser-induced fluorescence (LIF) to measurement of absolute concentration of hydroxyl radicals in cold atmospheric discharges is described. Though only the case of OH is presented, the method can be directly applied to other molecules as well. Starting from the rate equations for the LIF process, the main formulas for two- and multi-level excitation scheme are derived. It is also shown how to use partially saturated LIF in practice, enhancing the signal-to-noise ratio. Practical tips for automating the data evaluation are given, allowing processing large data sets, particularly suitable for planar measurements. Gas temperature estimation from fluorescence on different rotational absorption lines is shown as an attractive method for obtaining temperature maps with high spatial resolution. The important aspects of calibration are discussed, particularly the overlap of the laser line with the selected absorption line and the measurement of the Rayleigh scattering for sensitivity calibration, together with the common sources of errors. The application of OH(A, v′ = 0 ← X, v″ = 0) excitation scheme to the effluent of atmospheric pressure plasma jet ignited in argon and of OH(A, v′ = 1 ← X, v″ = 0) to the plasma of coplanar surface barrier discharge in air and in water vapor is shown.",signatures:"Jan Voráč, Pavel Dvořák and Martina Mrkvičková",downloadPdfUrl:"/chapter/pdf-download/58499",previewPdfUrl:"/chapter/pdf-preview/58499",authors:[{id:"212518",title:"Dr.",name:"Jan",surname:"Voráč",slug:"jan-vorac",fullName:"Jan Voráč"},{id:"212522",title:"Dr.",name:"Pavel",surname:"Dvořák",slug:"pavel-dvorak",fullName:"Pavel Dvořák"},{id:"212530",title:"MSc.",name:"Martina",surname:"Mrkvičková",slug:"martina-mrkvickova",fullName:"Martina Mrkvičková"}],corrections:null},{id:"58165",title:"Study of Formation and Decay of Rare-Gas Excimers by Laser- Induced Fluorescence",doi:"10.5772/intechopen.71942",slug:"study-of-formation-and-decay-of-rare-gas-excimers-by-laser-induced-fluorescence",totalDownloads:1207,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The aim of this chapter is to review the experimental and numerical techniques for the estimation of the laser-induced fluorescence (LIF) decay in rare gases using time-correlated single-photon counting. The advantages of single-photon counting technique are discussed by means of measurement uncertainty analysis. In addition, this chapter provides information concerning the application of this technique to filamentary dielectric barrier discharges (DBD) and radiation trapping of the resonant transitions.",signatures:"Frédéric Marchal, Neermalsing Sewraj, Jean-Pierre Gardou, Nofel\nMerbahi and Mohammed Yousfi",downloadPdfUrl:"/chapter/pdf-download/58165",previewPdfUrl:"/chapter/pdf-preview/58165",authors:[{id:"129101",title:"Prof.",name:"N.",surname:"Merbahi",slug:"n.-merbahi",fullName:"N. Merbahi"},{id:"213960",title:"Associate Prof.",name:"Frédéric",surname:"Marchal",slug:"frederic-marchal",fullName:"Frédéric Marchal"},{id:"213963",title:"Dr.",name:"Jean-Pierre",surname:"Gardou",slug:"jean-pierre-gardou",fullName:"Jean-Pierre Gardou"},{id:"213964",title:"Prof.",name:"Mohammed",surname:"Yousfi",slug:"mohammed-yousfi",fullName:"Mohammed Yousfi"},{id:"221392",title:"Dr.",name:"Neermalsing",surname:"Sewraj",slug:"neermalsing-sewraj",fullName:"Neermalsing Sewraj"}],corrections:null},{id:"58782",title:"Silicon Photomultiplier for the Plug & Imaging PET system: Physics, Technological Challenges and Application to Modern Nuclear Medicine",doi:"10.5772/intechopen.73007",slug:"silicon-photomultiplier-for-the-plug-imaging-pet-system-physics-technological-challenges-and-applica",totalDownloads:1255,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"We propose the design of a Silicon Photomultiplier at the 180 nm GLOBALFOUNDRIES BCDLITE CMOS technology node. We perform a characterization of the device, in comparison with other results obtained a CMOS technology node and we investigate the limits and strengths of this approach. Finally we show possible future applications of the SiPM in Nuclear Medicine, in particular to digital positron emission tomography systems.",signatures:"Nicola D’Ascenzo and Qingguo Xie",downloadPdfUrl:"/chapter/pdf-download/58782",previewPdfUrl:"/chapter/pdf-preview/58782",authors:[{id:"173909",title:"Dr.",name:"Qingguo",surname:"Xie",slug:"qingguo-xie",fullName:"Qingguo Xie"},{id:"213828",title:"Dr.",name:"Nicola",surname:"DAscenzo",slug:"nicola-dascenzo",fullName:"Nicola DAscenzo"}],corrections:null},{id:"58411",title:"Parallelized Integrated Time-Correlated Photon Counting System for High Photon Counting Rate Applications",doi:"10.5772/intechopen.72273",slug:"parallelized-integrated-time-correlated-photon-counting-system-for-high-photon-counting-rate-applica",totalDownloads:1218,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Time-correlated single-photon counting (TCSPC) applications usually deal with a high counting rate, which leads to a decrease in the system efficiency. This problem is further complicated due to the random nature of photon arrivals making it harder to avoid counting loss as the system is busy dealing with previous arrivals. In order to increase the rate of detected photons and improve the signal quality, many parallelized structures and imaging arrays have been reported, but this trend leads to an increased data bottleneck requiring complex readout circuitry and the use of very high output frequencies. In this paper, we present simple solutions that allow the improvement of signal-to-noise ratio (SNR) as well as the mitigation of counting loss through a parallelized TCSPC architecture and the use of an embedded memory block. These solutions are presented, and their impact is demonstrated by means of behavioral and mathematical modeling potentially allowing a maximum signal-to-noise ratio improvement of 20 dB and a system efficiency as high as 90% without the need for extremely high readout frequencies.",signatures:"Imane Malass, Wilfried Uhring, Jean-Pierre Le Normand, Norbert\nDumas and Foudil Dadouche",downloadPdfUrl:"/chapter/pdf-download/58411",previewPdfUrl:"/chapter/pdf-preview/58411",authors:[{id:"105785",title:"Prof.",name:"Wilfried",surname:"Uhring",slug:"wilfried-uhring",fullName:"Wilfried Uhring"},{id:"221406",title:"Dr.",name:"Imane",surname:"Malass",slug:"imane-malass",fullName:"Imane Malass"},{id:"221407",title:"Dr.",name:"Jean-Pierre",surname:"Le Normand",slug:"jean-pierre-le-normand",fullName:"Jean-Pierre Le Normand"},{id:"221408",title:"Dr.",name:"Norbert",surname:"Dumas",slug:"norbert-dumas",fullName:"Norbert Dumas"},{id:"221409",title:"Dr.",name:"Foudil",surname:"Dadouche",slug:"foudil-dadouche",fullName:"Foudil Dadouche"}],corrections:null},{id:"59541",title:"Application of Fluorescence Spectroscopy for Microbial Detection to Enhance Clinical Investigations",doi:"10.5772/intechopen.73616",slug:"application-of-fluorescence-spectroscopy-for-microbial-detection-to-enhance-clinical-investigations",totalDownloads:1882,totalCrossrefCites:4,totalDimensionsCites:7,hasAltmetrics:0,abstract:"Microbial biofilms are complex multi-layered communities of bacteria and fungi which cause a range of oral and other diseases. Efficient detection of biofilms is important for the clinical management of diseases they cause and for providing an endpoint to clinical treatments. For bacterial biofilms, bacterial metabolites such as porphyrins are important molecules for diagnostic purposes, since they fluoresce in the red and infrared regions of the spectrum. Fluorescence is a versatile and powerful diagnostic approach for detection of bacterial biofilms, particularly in dentistry. This chapter provides an overview of fluorescence spectroscopic methods for detection and analysis of biofilms and their derivatives such as deposits of dental calculus and how current technology can be extended using photon-counting detectors. Fluorescence can be used to help discriminate these from healthy tissues. The approaches described have broad applications to clinical and industrial situations where non-invasive detection of microbial biofilms is important.",signatures:"Fardad Shakibaie, Laurent Lamard, Halina Rubinsztein-Dunlop and\nLaurence J. Walsh",downloadPdfUrl:"/chapter/pdf-download/59541",previewPdfUrl:"/chapter/pdf-preview/59541",authors:[{id:"179467",title:"Prof.",name:"Laurence",surname:"Walsh",slug:"laurence-walsh",fullName:"Laurence Walsh"},{id:"225292",title:"Dr.",name:"Fardad",surname:"Shakibaie",slug:"fardad-shakibaie",fullName:"Fardad Shakibaie"},{id:"235998",title:"Prof.",name:"Halina",surname:"Rubinsztein-Dunlop",slug:"halina-rubinsztein-dunlop",fullName:"Halina Rubinsztein-Dunlop"},{id:"235999",title:"Dr.",name:"Laurent",surname:"Lamard",slug:"laurent-lamard",fullName:"Laurent Lamard"}],corrections:null},{id:"59489",title:"High-Speed and High-Resolution Photon Counting for Near-Range Lidar",doi:"10.5772/intechopen.74350",slug:"high-speed-and-high-resolution-photon-counting-for-near-range-lidar",totalDownloads:1303,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The near-range lidars for hard target and atmosphere detection should follow to the quick motion/activity of the measurement target. The transmitting optical power will be lowered for safety in the human activity space. And the lidar should increase the pulse repetition frequency to get the enough signal-to-noise ratio. The high-speed, high-resolution and high-repetition photon counting is desired for the near-range lidar. It is not a single photon counting at a certain delay time, but a multi-channel scaler with a deep memory for a series of delay times, that is, ranging data acquisition for lidar application. In this chapter, the mini-lidar for near-range observation is discussed. The targets are dust, gas, and atmosphere (aerosols). The activity monitoring of the atmosphere within a few hundred meters is the purpose of this mini-lidar. To follow and visualize the rapid motion of the target, high-speed and high-resolution photon counters (multi-channel scalers) were developed. The observation range can be easily adjustable depending on the lidar setup. The system can visualize the rapid motion of target with the high-resolution of 0.15 m (BIN width of 1 ns) and the minimum summation time of 0.2 s.",signatures:"Tatsuo Shiina",downloadPdfUrl:"/chapter/pdf-download/59489",previewPdfUrl:"/chapter/pdf-preview/59489",authors:[{id:"4840",title:"Associate Professor",name:"Tatsuo",surname:"Shiina",slug:"tatsuo-shiina",fullName:"Tatsuo Shiina"}],corrections:null},{id:"58155",title:"Detectors for Super-Resolution & Single-Molecule Fluorescence Microscopies",doi:"10.5772/intechopen.71943",slug:"detectors-for-super-resolution-single-molecule-fluorescence-microscopies",totalDownloads:1384,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The resolution of light microscopy was thought to be limited to 250–300 nanometers based on the work of Ernest Abbe. This Abbe diffraction limit was believed to be insurmountable until the invention of Super-resolution microscopic techniques in the late 20th century. These techniques remove this limit and have provided unprecedented detail of cellular structures and dynamics down to several nanometers. An emerging goal in this field is to quantitatively measure individual molecules. Measurement of single-molecule dynamics, such as diffusion coefficients and complex stoichiometries, can be accomplished using fluorescence fluctuation techniques to reveal nanosecond-to-microsecond temporal reactions. These powerful complimentary experimental approaches are made possible by sensitive low-light photodetectors. In this chapter, an overview of the principles of super-resolution and single-molecule microscopies are provided. The different types of photodetectors employed in these techniques are explained. In addition, the advantages and disadvantages for these detectors are discussed, as well as the development of next generation detectors. Finally, example super-resolution and single-molecule cellular studies that take advantage of these detector technologies are presented.",signatures:"Robert T. 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It is estimated that the global cancer rate may increase by 75 %, with predicted 22.2 million new cases by 2030 compared with 12.7 million cases in 2008 [1]. The scientific community has made tremendous efforts to develop new therapies to deal effectively with this growing problem. As the recent advances in cancer therapy are improving the cancer patient survival, the toxic effects promoted by anticancer agents have a higher potential impact on long-term outcomes.
Anticancer agents are known to cause severe toxic effects that should be anticipated and carefully monitored. Therapeutic regimens targeting the cell cycle also affect the proliferation of normal cells, such as blood cells in the bone marrow, cells in the digestive tract and hair follicles, resulting in neutropenia, hair loss, and gut toxicity. The side effects observed are dependent on the type of therapy, but they are generally reversible and disappear after the end of the treatment. However, some anticancer agents may also affect, sometimes in a permanent manner, the function of vital organs, such as the heart, kidney, liver and the nervous system. Some of these effects may develop during or shortly after treatment, or may only become apparent a long period after completion of the treatment; if this delay is long enough, it may correspond to the time of progression free survival and affect the benefit-risk balance [2, 3].
Both the liver and kidneys are vulnerable to the toxic effects of cancer therapy and also to the direct impact of cancer itself. The liver has a great capacity to resist injury and to regenerate, but this capacity also makes it susceptible to anticancer drugs toxicity [2]. Indeed, the liver injury induced by anticancer drugs is a significant cause of morbidity and mortality. However, most of these reactions are idiosyncratic and are not typically dose-dependent [2, 4]. Diagnosing liver damage due to anticancer agents is particularly challenging because competing etiologies, such as hepatotoxicity due to the intake of other medications, opportunistic infections, radiation therapy, and pre-existing liver disease, are frequent and greatly affect the host’s susceptibility to liver injury [2, 4]. The major mechanisms underlying chemotherapy-related hepatotoxicity are based on the production of reactive metabolites, immunological injury, or mitochondrial dysfunction [4]. On the other hand, the spectrum of cancer-associated renal disease has changed in the last decades, mainly due to the introduction of new chemoradiotherapy regimens. Nevertheless, renal failure remains an important complication of cancer treatment [5, 6]. Considering that drugs are primarily metabolized in the liver and excreted by the kidneys, hepatic and renal impairment can have an unpredictable impact on the metabolism and clearance of drugs that may ultimately affect the treatment outcome and toxicity.
In addition, cardiotoxicity is a common complication not only related to conventional cancer therapy, such as anthracyclines, but also to new antitumoral targeted therapy, such as trastuzumab. Due to the increasing number of patients treated with these agents, the incidence of cardiotoxicity is continuously growing and strongly affecting the patients’ quality of life and overall survival, regardless of the oncologic prognosis [3]. Also, peripheral neuropathy is reported by 30-40 % of the patients and is one of the major reasons responsible for cessation of treatment [7]. Certain structural and functional features of peripheral nervous system make it more vulnerable to the action of anticancer drugs, namely the absence of a vascular barrier and of lymph drainage [7]. Furthermore, mammalian nerves are more susceptible to oxidative stress because of their high content of phospholipids, mitochondria rich axoplasm and weak cellular antioxidant defenses. Moreover, the enhanced free radical production promoted by anticancer drugs causes physical damage to neurons [7].
A thorough understanding of the mechanisms of injury is therefore a matter of great importance since it may contribute to detect toxic mechanisms at an early stage of drug development and, importantly, it can contribute to develop strategies aiming to minimize the toxicity. Mitochondrial dysfunction often underlies drug-induced toxicity and the works published over the last years point out that some of the severe adverse effects promoted by anticancer agents involve the targeting of mitochondria [8-11]. The heart, the kidneys, and the central nervous system, which have high energetic demands and are heavily dependent on oxidative phosphorylation, are more prone to the impact of mitochondrial damage. On the other hand, considering the exposure to high concentrations of drugs, the liver is another common organ showing mitochondrial dysfunction [12].
This chapter aims to provide an overview of the mechanisms of mitochondrial dysfunction induced by anticancer drugs and their involvement in several adverse effects, and particularly liver damage. Finally, possible combinations of therapeutic drugs to minimize the mitochondrial dysfunction promoted by these agents are discussed.
We searched literature published in English language included in PubMed for the period of 1970 to 2014. The main keywords searched were “mitochondrial dysfunction”, “anticancer drugs and toxicity” and “tissue failure”. The remaining papers were found in the reference list of the searched publications.
Mitochondria are dynamic and multifunctional cytoplasmic organelles, which possess a double membrane: an outer membrane (OMM) that is essentially permeable to ions and solutes up to 14 kDa, and an inner membrane (IMM), which is folded, forming the cristae, which is impermeable to ions and polar molecules. In the IMM are located several transporters, including the ATP/ADP and the aspartate/malate transporters, among others that regulate the movements of molecules across the IMM, and also the multisubunit complexes involved in the oxidative phosphorylation. Between the OMM and the IMM is located the intermembrane space (IMS), whereas the space enclosed by the IMM is the matrix (Fig.1). The IMS contains proteins such as the adenylate kinase and the creatine kinase (CK), as well as the cytochrome
The NADH and FADH2 generated in metabolic pathways, including glycolysis, fatty acid oxidation and Krebs cycle are oxidized by complexes I and II of the mitochondrial electron transport chain, respectively. The electrons liberated are then passed to ubiquinone (coenzyme Q) that shuttles electrons to complex III, where it is oxidized; the electrons are then passed to complex IV through cytochrome
Structure of mitochondria and main mechanisms by which anticancer agents affect mitochondrial functions. Drugs can compromise mitochondrial bioenergetic functions by interfering with the generation system of ΔµH+, by dissipating the transmembrane proton gradient and by directly affecting the complex V or the substrate transporters. Drugs can also trigger or inhibit the mitochondrial permeability transition (MPT) by interfering with the proteins that compose or regulate the MPT or by modulating the critical factors to its onset, which may ultimately lead to cell death. Other drugs induce changes in the redox regulation of mitochondrial functions, promoting several deleterious events, including the interference with oxidative phosphorylation, nutrient oxidation and MPT. Drugs can also damage the mtDNA and, indirectly, compromise the ATP synthesis and favor the production of ROS (ANT, adenine nucleotide translocase; CyPD, cyclophilin-D; Cytc, cytochrome
Xenobiotics can affect mitochondrial bioenergetic functions either by interfering with the generation system of ΔµH+or by causing the dissipation of the transmembrane proton gradient, as well as by affecting directly the F1Fo ATPase and the substrate transporters, including the adenine nucleotide translocase (ANT) and the phosphate–hydrogen co-transporter (phosphate carrier) (Fig.1) [14].
In fact, the inhibition of the electron transport chain by drugs may not only lead to ATP depletion, but also hinders the reoxidation of NADH and FADH2 into NAD+and FAD, respectively, which are required for the activity of several dehydrogenases of the Krebs cycle and the mitochondrial β-oxidation [15, 16]. In addition, the inhibition of the electron transport chain favors the accumulation of electrons in the electron transport system complexes that can escape and directly react with oxygen to form the superoxide anion radical [17]. The excessive reactive oxygen species (ROS) production can promote several deleterious events (described in more detail in section 3.3), but it is noteworthy that, in this context, both lipid accumulation and lipid peroxidation are favored [15, 16].
On the other hand, drugs can compromise the impermeability of the IMM to protons and dissipate the proton gradient impairing the production of ATP. The IMM impermeability can be surpassed by drugs that either disrupt the mitochondrial membranes or act as ionophores, uncouplers of the oxidative phosphorylation and inducers of the mitochondrial permeability transition (MPT) [12-14]. Moreover, drugs that interfere with the basic components of the phosphorylative system can also impair the production of ATP. These different effects on mitochondria induce changes in cellular bioenergetics, one of the key hallmarks in tissues.
Besides serving as the cells’ primary energy source, mitochondria are implicated in the maintenance of calcium homeostasis through calcium uptake and release pathways. The rise of mitochondrial matrix free calcium concentration in the presence of a variety of sensitizing factors can lead to the opening of the MPT pore that may serve either the purpose of providing a fast calcium release or can convey both apoptotic and necrotic death signals.
MPT can be defined as an increase in the IMM permeability to solutes with molecular masses up to 1 500 Da, due to the opening of a voltage and calcium-dependent, cyclosporine A (CyA)-sensitive channel [18].
The molecular identity of the MPT pore is still under debate [19] (Fig. 1). Cyclophilin-D is the binding site for CyA, the golden standard of MPT inhibitors, and among the several components that have been proposed to play a role on MPT, cyclophilin-D is probably the most consensual. The ANT and the voltage-dependent anion channel (VDAC) were also considered key components of the MPT pore complex for many years. Knockout mice devoid of cyclophilin-D are resistant to necrosis promoted by ROS and calcium overload and the mitochondria isolated from the liver, heart and brain of these animals are resistant to MPT
The phosphate carrier was also proposed to play a key role in MPT [25], but a later study demonstrated that the reduction of phosphate carrier protein expression does not affect the MPT [26]. A more recent work suggested that the MPT pore complex is composed of ATP synthase dimers and pointed out that cyclophilin-D binds the lateral stalk of the ATP synthase at the same site as benzodiazepine 423, increasing the sensitivity to calcium [27]. However, the composition of MPT still remains a contentious issue.
Besides the calcium concentration in the matrix, the level of oxidative stress is possibly the most critical factor regulating MPT pore opening. Indeed, both the ANT and cyclophilin D were shown to be modulated by S-oxidation reactions [28-29]. However, other factors may contribute as well: the depletion of adenine nucleotides and high concentrations of phosphate increase the sensitivity of MPT to calcium, while a low pH and a high (negative) ΔΨ inhibit MPT pore opening [30].
Drugs can trigger MPT either by interfering with the proteins that compose or regulate the MPT or by modulating the critical factors to its onset (Fig.1) [8]. As a consequence of MPT pore opening, the IMM loses its impermeability to protons, which allows the movement of solutes between the matrix and the cytosol, the dysregulation of cellular ionic homeostasis and the dissipation of ΔµH+. Moreover, since the protein concentration is higher in the matrix, a high osmotic pressure is generated and may lead to mitochondrial swelling, rupture of OMM, and loss of proapoptotic proteins that may trigger the apoptotic pathway in the cytoplasm [30, 31]. These events, together with the bioenergetic failure and the redox catastrophe, can culminate in cell death; if there are no sufficient levels of ATP, necrotic death may predominate over apoptosis [32]. Thus, depending on the cell type involved, different pathological conditions can occur as consequence of MPT induction.
During the transfer of electrons along the electron transport chain to oxygen, and particularly at complexes I and III, some of these electrons escape and directly react with oxygen. The univalent reduction of oxygen generates the superoxide anion radical, which is then dismutated by the mitochondrial manganese superoxide dismutase into hydrogen peroxide, a key ROS signaling molecule due to its longer half-life and capacity to diffuse through membranes. The hydrogen peroxide is detoxified into water by the mitochondrial glutathione peroxidase and hence, in normal circumstances, most of the ROS generated by the electron transport chain are neutralized by the mitochondrial antioxidant defenses (Fig.1) [17]. The accumulation of hydrogen peroxide can promote the oxidation of thiolic groups, irreversibly deactivating the protein; likewise, the superoxide anion disassembles Fe–S clusters in several Krebs cycle enzymes and in respiratory complexes, and can combine with nitric oxide to form the highly toxic peroxynitrite. In addition, high levels of ROS can lead to the production of hydroxyl radical, which indiscriminately oxidizes biological macromolecules [33]. Other sources that can contribute to the total mitochondrial ROS include 2-oxoglutarate dehydrogenase, pyruvate dehydrogenase, dihydroorotate dehydrogenase, sn-glycerol-3-phosphate dehydrogenase, electron transfer flavoprotein:ubiquinol oxidoreductase, p66shc/Cytochrome C, Mia40p/Erv1p, and complex II [33]. When maintained within a certain concentration range, ROS act as important signaling molecules, contributing to the redox balance, which regulates the functions that assist the normal cellular physiology [33]. However, the excessive formation of ROS can promote a series of deleterious events that deregulate key mitochondrial functions, including oxidative phosphorylation, nutrient oxidation and MPT, which may ultimately lead to cell death, tissue failure and have also a key role in disease pathogenesis [33].
The mtDNA, maternally inherited, encodes 13 polypeptides that are subunits of the complexes I, III, IV and V, which are synthesized in mitochondrial ribosomes. The majority of the other mitochondrial proteins, including the subunits of complex II, are encoded by nuclear DNA, and imported into mitochondria after synthesis on cytosolic ribosomes [8-10].
The mtDNA is particularly vulnerable to the action of drugs, as it lacks histones, similarly to the bacterial DNA. Furthermore, the DNA repair mechanisms are less efficient that those of nuclear DNA. Therefore, and considering the proximity to the sites where ROS are routinely generated, the frequency of mtDNA mutation is much higher than that of nuclear DNA [13]. Mutations of mtDNA can seriously damage the respiratory chain as most of the polypeptides that form the respiratory chain complexes are encoded by mtDNA. As discussed in section 3.1., the impairment of the respiratory chain decreases the ATP synthesis capacity and enhances the production of ROS, which in turn will promote oxidative damage on several biomolecules, including the mtDNA itself, creating a vicious cycle that further enhances the insult [34].
In the last decades a large number of anticancer drugs have been reported to induce tissue failure by promoting changes in essential functions of mitochondria. The extent and type of mechanisms underlying the anticancer drug-induced mitochondrial dysfunctions are tissue-dependent and responsible for most of the idiosyncratic adverse drug responses.
In this section, we discuss some examples of the prominent members of different groups of anticancer drugs with evidences for the involvement of mitochondrial dysfunction in tissue impairment induced by these compounds.
Tamoxifen has been the endocrine therapy of choice for women with estrogen-receptor positive breast carcinoma over the last decades. Fatty liver is observed in more than 30 % of patients taking tamoxifen, which may persist after the discontinuation of the treatment [35, 36]. Nonalcoholic steatohepatitis, hepatic fibrosis, cirrhosis and hepatic necrosis were also reported [37-39].
Tamoxifen depresses the phosphorylation efficiency and the levels of ATP in a concentration-dependent manner in isolated rat liver mitochondria; these effects were attributed to a decrease in the active ANT content and a partial inhibition of the phosphate carrier [40, 41]. On the other hand, tamoxifen uncouples liver mitochondria respiration [40, 42] and, at higher concentrations, tamoxifen disrupts membrane integrity [43-44], enhancing the proton leak [40]. Tamoxifen also inhibits the electron transfer along the electron transport chain [40, 42] and the flavin mononucleotide site of complex I was identified as the target of tamoxifen [45]. The interaction of tamoxifen with complex III and IV was also shown [42]. The fact that tamoxifen interferes with membrane dynamics [46] may also decrease the diffusional mobility of membrane proteins and the electron transfer along the electron transport chain [40]. Furthermore, an
Interestingly, tamoxifen active metabolites, 4-hydroxytamoxifen and endoxifen, which are responsible for the antitumor actions of tamoxifen [48], do not significantly compromise mitochondrial bioenergetics at the concentrations reached in tissues [49, 50]. These results may indicate that the clinical use of tamoxifen metabolites instead of the prodrug may minimize liver damage. As the outcome of tamoxifen treatment seems to rely on its metabolic activation and endoxifen is a promising drug for cancer treatment, the future utilization of tamoxifen metabolites, and especially endoxifen, deserves further investigation. On the other hand, tamoxifen prevents and reverses the MPT induced by several agents [51-55]. Likewise, tamoxifen metabolites 4-hydroxytamoxifen and endoxifen also prevent and reverse the MPT induced by calcium and phosphate [50, 56]. Although the mechanisms underlying the inhibition of MPT by the antiestrogens are still under debate [57], this protective effect of TAM and its active metabolites regarding MPT might be of interest when considering combined anticancer drug therapies since it can decrease the toxicity of the associated drugs, as discussed in section 5.
Flutamide is a nonsteroidal anti-androgen used in the treatment of advanced prostate cancer, which has been associated with idiosyncratic drug-induced liver injury [58] and, although the mechanisms underlying liver damage are still unknown, mitochondria are a potential target of flutamide.
Indeed, high-doses of flutamide promote hepatocytes death in heterozygous Sod2(+/-) mice, but not in wild-type animals, suggesting that flutamide may exacerbate underlying mitochondrial abnormality [59]. Flutamide leads to the covalent binding of reactive electrophilic metabolites to proteins and diminishes the reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio, as well as the total protein thiols in isolated rat hepatocytes; these effects are associated with the release of lactate dehydrogenase (LDH) [60]. Similar findings were reported by others, which also demonstrated that flutamide increases the hepatic GSSG/GSH ratio, the protein carbonyl levels, and serum lactate levels, supporting the view that the liver damage promoted by flutamide involves oxidative stress and mitochondrondrial dysfunction [59]. Accordingly, the addition of cysteine increased hepatocellular GSH and decreased LDH release in male hepatocytes [60].
Additionally, flutamide markedly impairs rat liver mitochondrial respiration (mainly at the level of complex I) and decreases the levels of ATP in rat hepatocytes [60]. Moreover, flutamide-treated Sod2(+/-) mice present a decrease in the expression of complexes I and III subunits [59]. Therefore, it seems possible that the increased oxidative stress promoted by flutamide may damage mitochondrial proteins and mtDNA, particularly when the antioxidant system is compromised [59], contributing to liver damage (Fig.1).
Cisplatin, which crosslinks DNA, is widely used in the treatment of head, neck, bladder ovarian and testicular cancers, but it has also been used in the management of other malignancies. Unfortunately, cisplatin promotes severe side effects, and particularly nephrotoxicity [61] and neurotoxicity [62].
Peripheral neuropathy is the dose limiting side effect of cisplatin and occurs in 30 % of patients. Dorsal root ganglion neurons treated with cisplatin exhibit mitochondrial vacuolization and degradation both
About a quarter to one third of patients undergoing cisplatin treatment experience nephrotoxicity, which is manifested clinically as lower glomerular filtration rate and reduced serum magnesium and potassium levels [61]. Although the mechanism underlying cisplatin nephrotoxicity is not yet clear, the available evidence suggests that mitochondrial dysfunction plays a key role in renal tubular cell injury and death. Ultrastructural analysis of cisplatin-treated renal tubular cells of mouse kidney demonstrates the decrease in mitochondrial mass, disruption of cristae, and extensive mitochondrial swelling [66], supporting the involvement of mitochondria in cisplatin-induced nephrotoxicity. Cisplatin decreases manganese superoxide dismutase and complex II activity in rodents’ kidney [67]. The GSH-reductase activity and the levels of GSH are markedly diminished in porcine proximal tubular cells [68]. These observations suggest that cisplatin strongly reduces the antioxidant defenses and favors ROS formation. However, agents that are able to prevent ROS formation, do not prevent cell death, suggesting that ROS formation is not the direct cause of cell death [68]. Furthermore, cisplatin significantly impairs kidney mitochondrial bioenergetic functions. In porcine proximal tubular cells, cisplatin inhibits complexes I to IV and decreases intracellular ATP [68]. In fact, the kidney of animals treated with cisplatin presents decreased mtDNA content and reduced complex I, III and IV protein expression [67].
Cisplatin is a rare cause of hepatotoxicity (steatosis and cholestasis) at standard doses, but high doses may lead to liver damage, revealed by abnormal liver tests, especially aspartate aminotransferase (AST) and alanine aminotransferase (ALT) [69]. Light microscopic observations confirmed that high doses of cisplatin cause massive hepatotoxicity; alterations at the ultrastructural level, including atrophied mitochondria, were also found [70]. Cisplatin induces MPT in rat liver mitochondria [71]. Moreover, cisplatin stimulates state 4 respiration, but does not affect FCCP-uncoupled respiration, suggesting that cisplatin affects mitochondrial bioenergetics by increasing the IMM permeability to protons and not by interfering with respiratory chain complexes activity [71]. Both the induction of MPT and the effects on liver mitochondrial bioenergetics are prevented by thiol group protecting agents, suggesting that changes on the redox-status of thiol groups affect membrane permeability to cations and underlie liver mitochondrial dysfunction [71]. Accordingly, it was proposed that the mechanism of cisplatin-induced hepatotoxicity involves membrane rigidification, lipid peroxidation, oxidative damage of cardiolipin and protein sulfhydryl groups, as well as decreased GSH/GSSG ratio, ATP, GSH and NADPH [72].
Cyclophosphamide is an alkylating agent used in the treatment of lymphomas, multiple myeloma, and certain types of leukemia, retinoblastoma, neuroblastoma, ovarian cancer, and breast cancer. Generally, cyclophosphamide does not cause relevant cardiotoxicity, but when it occurs, it appears to be related to a single dose, unlike the anthracyclines [3]. Patients who were previously medicated with anthracyclines or that underwent chest irradiation are more prone to suffer from cyclophosphamide-induced cardiotoxicity [3]. Liver damage was also reported [73, 74].
Cyclophosphamide compromises calcium accumulation by heart or liver mitochondria, which can almost be restored by CyA [75]. As the increases in the levels of serum AST, serum ALT, glucose-6-phosphate dehydrogenase and creatine phosphokinase induced by cyclophosphamide can also be attenuated by the simultaneous administration of CyA, the induction of MPT is closely related to the hepatotoxicity and cardiotoxicity promoted by cyclophosphamide (Fig.1) [75].
Ifosfamide, another nitrogen mustard, is one of the most commonly implicated drugs in kidney injury [76]. Using mitochondria isolated from the kidney of rats treated with ifosfamide, it was shown that this alkylating agent significantly inhibits complex I, resulting in NADH elevation and NAD+depletion, and Krebs cycle impairment (Fig.1) [77]. Among the ifosfamide metabolites, only chloroacetaldehyde, which reaches high concentrations in the renal cortex, inhibits complex I, suggesting that this metabolite is responsible for the ifosfamide-induced nephrotoxicity [77].
Busulfan is an alkylating drug, which forms DNA intrastrand crosslinks, used in the clinical management of chronic myelogenous leukemia. Although in standard doses busulfan rarely causes liver dysfunction, some cases of hepatotoxicity during busulfan treatment were reported [78-80].
The toxicity of busulfan is thought to involve oxidative stress mechanisms as it promotes decreases in GSH in hepatocytes both
Doxorubicin is used in the clinical management of a wide range of cancers, and particularly in breast cancer treatment. The anticancer activity of doxorubicin involves its intercalation into DNA and disruption of topoisomerase-II-mediated DNA repair, as well as the generation of ROS that lead to lipid peroxidation, as well as membrane and DNA damage [82]. However, its therapeutic use is limited by its side-effects, mainly the dose-dependent myelosuppression and the cumulative and irreversible cardiotoxicity, which in the most severe forms may lead to patient death [83].
Acute cardiotoxicity occurs in less than 1 % of the patients immediately after infusion and is usually reversible; the early-onset chronic progressive form affects 1.6–2.1 % of patients, during therapy or within the first year after treatment; the late-onset chronic progressive form occurs after one year of completion of therapy in 1.6–5 % of patients, supporting the need of long-term follow-up [3]. Doxorubicin causes myocardial damage as shown by the increase in serum levels of AST, ALT, LDH isoenzyme and creatine phosphokinase isoenzyme [84]. Doxorubicin-induced cardiotoxicity etiology seems complex, and several effects may be involved, triggering a domino effect [83]. Among the several mechanisms postulated, the induction of oxidative stress is the most widely accepted. The univalent reduction of the tetracyclic ring of anthracycline by complex I generates a semiquinone free radical; the unpaired electron of this semiquinone is transferred to oxygen, forming the superoxide radical, while the tetracyclic ring returns to the parent quinone [85]. The free radicals generated are thought to be related to the interference with calcium homeostasis and bioenergetic functions, lipid peroxidation, and mtDNA damage, which play a key role in the pathogenesis of doxorubicin cardiotoxicity (Fig.1).
Heart mitochondria isolated from rats treated with doxorubicin present decreased state 3 respiration and respiratory control ratio (RCR), whereas the state 4 respiration is not affected [86-88]; complex I activity is also inhibited [87]. Besides affecting nuclear DNA, doxorubicin damages mtDNA [89-91] and decreases its content in human hearts [90]. Accordingly, doxorubicin-exposed human hearts show low activity of complex I and IV (encoded by mtDNA) but not of complex II (exclusively encoded by nuclear DNA) [90]. The higher levels of superoxide in doxorubicin-exposed hearts correlate negatively with mtDNA content and with the activities of respiratory chain complexes encoded by mtDNA [90]. The damage leading to mtDNA adducts, as well as the higher rate of ROS formation and depression of GSH in heart tissue, persist for several weeks after cessation of doxorubicin treatment [92, 93].
Furthermore, mitochondria isolated from the heart of rats treated with doxorubicin present diminished ability to accumulate calcium [84, 86, 87, 94]. Similar effects were reported in mitochondria isolated from doxorubicin-treated human atrial trabeculae, and were shown to be reversed by CyA [95]. Considering that the decrease in left ventricular fractional survival promoted by doxorubicin is improved by the simultaneous administration of CyA, it seems that doxorubicin-induced heart damage is closely related to the induction of MPT pore opening [84, 96]. As discussed in section 3.3, oxidative stress is a major factor regulating MPT and doxorubicin leads to the oxidation of mitochondrial glutathione and to the accumulation of membrane disulfides, which may contribute to MPT induction. On the other hand, it has been proposed that the ANT is a key target for doxorubicin, as following doxorubicin treatment the amount of ANT protein and its active content are reduced in rats [94, 97]. The effects of doxorubicin on the ANT explain both the MPT induction and the effects on mitochondrial respiration [97]. Indeed, the decrease in state 3 respiration observed in heart mitochondria isolated from doxorubicin-treated rats is partially reversed by CyA or dithiothreitol, but not by trolox, suggesting that the toxic effects of doxorubicin on mitochondrial bioenergetics are at least in part a consequence of MPT induction and involve changes in the redox state of thiol groups [88]. Noteworthy, among several agents, including antioxidants, CyA was the only agent that was able to reverse the doxorubicin-induced alterations in the calcium accumulation capacity when added
Altogether, the results obtained so far suggest that the persistent nature of doxorubicin cardiotoxicity reflects a self-perpetuating mechanism, where mtDNA alterations accumulate, leading to a damaged respiratory chain and decreased calcium loading ability; the defective respiratory chain further enhances ROS generation and mtDNA insult (Fig.1) [83, 98].
The heart is the main target of doxorubicin toxicity, due to the abundance of mitochondria in heart tissue, the elevated rate of oxygen consumption and the lower antioxidant defenses [83]. However, mitochondrial dysfunction has also been observed in other tissues. Indeed, in isolated mitochondrial fractions from the brain of rats treated with doxorubicin, the thiobarbituric acid-reactive substances and the vitamin E levels are increased, whereas the reduced glutathione content is diminished [102]. In addition, doxorubicin increases the sensibility of brain mitochondria to MTP pore opening [102]. The use of doxorubicin was also associated with a higher risk for developing hepatotoxicity among breast cancer patients [103]. Liver mitochondria isolated from doxorubicin-treated rats present decreased RCR and the activity of complex IV is inhibited [107]. In addition, light microscopic observations confirmed that doxorubicin at high doses caused massive liver injury; alterations at the ultrastructural level, such as atrophied mitochondria, were shown [70].
Etoposide is a podophyllotoxin derivative used in the treatment of several cancers that acts as a topoisomerase II inhibitor. Cases of hepatic injury were reported using either standard doses [104] or high-dose regimens [105]. Etoposide induces calcium-dependent MPT in rat liver mitochondria [106]. Since the etoposide-induced MPT is prevented by several antioxidants, it was proposed that etoposide triggers MPT pore opening through the generation of oxidant species, which is further corroborated by the ability of antioxidants to prevent the apoptosis promoted by etoposide (Fig.1) [107]. Therefore, the generation of oxidant species that are able to induce mitochondrial dysfunction may contribute to hepatic injury.
Paclitaxel is a taxane-derived drug used in monotherapy or in combination with other agents, for the treatment of ovarian, breast and advanced non-small cell lung cancers, and AIDS-related Kaposi\'s sarcoma.
Painful peripheral neuropathy is the major dose-limiting side-effect of paclitaxel therapy, with the major drawback that the pain and sensory abnormalities can persist for months or years. Moreover, it may turn the patients unable to complete optimal chemotherapy schedules thus potentially compromising the treatment efficacy [108].
The involvement of mitochondrial dysfunction in paclitaxel-induced pain is suggested by the presence of swollen and vacuolated neuronal mitochondria [109]. Earlier investigations demonstrated that paclitaxel promotes a CyA-sensitive swelling in liver, kidney, heart, and brain mitochondria; the highest degree and slope of the swelling are observed in liver mitochondria, whereas the lowest are detected in brain mitochondria [110].
Using a rat model of paclitaxel-induced pain, it was shown that the non-specific ROS scavenger N-tert-butyl-α-phenylnitrone significantly decreases paclitaxel-induced mechanical hypersensitivity, whereas the superoxide selective scavenger 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-1-oxyl (TEMPOL) does not present significant effects [108]. Therefore, the authors suggest that ROS are involved in the development and maintenance of paclitaxel-induced pain, although such effects cannot be attributed to superoxide radicals alone [108]. Moreover, rat sciatic nerve samples taken after induction of painful peripheral neuropathy with paclitaxel exhibit significant impairment of both complex I- and complex II-mediated respiration and deficits in ATP synthesis; the mitochondrial dysfunction promoted by paclitaxel is abrogated by acetyl-l-carnitine, again supporting that paclitaxel promotes oxidative damage [65].
Paclitaxel is extensively excreted by the liver, and therefore its administration to patients with liver impairment should be handled with care [69]. Alterations of liver functions are seen in 4-17 % of patients treated with doses up to 190 mg/m2, but they can occur in 16-37 % of patients taking higher doses [69].
In isolated liver mitochondria, paclitaxel induces large amplitude swelling, the dissipation of mitochondrial membrane potential and the release of cytochrome c; these effects are inhibited by CyA, suggesting that paclitaxel induces MPT pore opening [110]. Paclitaxel also significantly increases complex IV-mediated ROS production (Fig.1) [110]. Paclitaxel does not inhibit mitochondrial respiration, but ROS formation is abolished by complex IV inhibitors, suggesting that paclitaxel promotes ROS production not by inhibiting the respiratory complexes, but through an effect on complex IV [110]. The abrogation of ROS formation does not prevent paclitaxel-induced MPT, suggesting that the induction of MPT is not secondary to enhanced ROS generation [110]. The combination with doxorubicin enhances the induction of oxidative stress [111].
The cardiotoxicity promoted by paclitaxel is usually represented by subclinical sinus bradycardia (approximately 30 % of patients), but more severe conditions were also reported [3]. A recent study suggests that microtubule disorganization in cardiac myocytes promoted by paclitaxel leads to MTP pore opening [112]. However, when isolated mitochondria are exposed to paclitaxel, no significant effects are detected; the authors suggested that paclitaxel does not promote MPT due to a direct effect on mitochondria [112]. However, it must be noted that lower concentrations were used in the latter study in comparison with previous work using liver mitochondria [110, 112].
Therefore, both the induction of MPT and mitochondrial ROS production can contribute to paclitaxel side effects in the nerve, liver, kidney and heart.
Methotrexate is a folic acid antagonist widely used in the treatment of leukemia and other malignancies. Gastrointestinal toxicity and liver function abnormalities are common in patients taking methotrexate and the use of methotrexate in patients with history of liver disease is not advisable [113].
In liver mitochondria, methotrexate promotes a significant rise in superoxide radical formation, as well as in lipid peroxidation, whereas the GSH levels are decreased [114]. Likewise, methotrexate significantly impairs the function of isolated heart mitochondria by promoting lipid peroxidation, mitochondrial swelling and by inhibiting complex I, II and IV activities [115].
Methotrexate administration also leads to small intestinal injury and damages in enterocyte mitochondria, as shown by the decrease in the RCR, an indicator of mitochondrial function [116]. Moreover, the activities of complexes II and IV are markedly decreased in enterocyte mitochondria, suggesting that the deleterious effects promoted by methotrexate on enterocyte mitochondria can compromise ATP synthesis (Fig.1) [116], thereby leading to the gastrointestinal toxicity seen in patients.
6-Mercaptopurine is an orally administered immunosuppressive drug used to treat acute lymphocytic leukemia. 6-Mercaptopurine is converted to its active metabolites, the 6-thioguinine nucleotides, or inactivated by xanthine oxidase or by thiopurine methyltransferase to 6-thiouric acid or 6-methylmercaptopurine, respectively [117]. Liver injury is an important adverse effect of 6-mercaptopurine, with an estimated frequency of liver test abnormalities within 1-9 % range [118]. Clinically relevant concentrations of 6-mercaptopurine are toxic to rat hepatocyte cultures by a mechanism that involves oxidative stress and ATP depletion (Fig.1) [119]. The decreased rat hepatocytes viability promoted by 6-mercaptopurine is nearly prevented by allopurinol (xanthine oxidase inhibitor) together with trolox (vitamin E analog), implying xanthine oxidase-mediated metabolism of the thiopurines and oxidative stress in the hepatotoxicity promoted by 6-mercaptopurine [119].
All-
All-
Trastuzumab is a recombinant humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), which is overexpressed by many adenocarcinomas. Trastuzumab improves cancer patient survival, but it also causes cardiotoxicity in a significant number of patients, ranging from 2-7 % when used as monotherapy, 2-13 % when used combined with paclitaxel, and up to 27 % when trastuzumab is used with both anthracyclines and cyclophosphamide [3]. In contrast to the cardiomyopathy promoted by doxorubicin, the cardiac dysfunction induced by trastuzumab does not appear to be dose dependent and is often reversible [123]. Neonatal rat cardiomyocytes treated with an inhibitory HER2 antibody exhibit an increased ROS production and cell death, which are reversed by N-acetylcysteine and by CyA, suggesting that the toxic effects of trastuzumab on the heart involve mitochondrial damage and enhanced ROS production (Fig.1) [129].
Sorafenib is effective against renal-cell carcinoma and hepatocellular carcinoma, whereas sunitinib is used in the management of advanced kidney cancer, gastrointestinal stromal tumor, and pancreatic neuroendocrine tumors. In phase I–II trials, 11 % of patients taking sunitinib experienced cardiovascular events and approximately half of the patients developed hypertension [130]. The incidence of sorafenib-associated heart toxicity is lower than that of sunitinib, and hypertension occurred in about 17 % of patients in clinical trials [131].
Sorafenib compromises mitochondrial function at clinically relevant concentrations in a myoblastic cell line grown under conditions where cells are either glycolytically or aerobically poised; the other tyrosine kinase inhibitors investigated (imatinib, dasatinib, sunitinib) do not affect the mitochondria [132]. Sorafenib uncouples heart mitochondria and inhibits complex V and complex II+III; at much higher concentrations the complex I and IV are also inhibited (Fig.1) [132].
Using neonatal rat cardiomyocyte cultures, it was shown that sunitinib decreases the mitochondrial membrane potential, and that both sunitinib and sorafenib reduce the intracellular ATP levels [133]. Echocardiographic abnormalities are apparent in sorafenib, but not in sunitinib or pazopanib treated animals; the analysis of ventricular cardiomyocytes revealed that sunitinib promotes mitochondrial swelling, dense deposits, and matrix cavitation, whereas sorafenib disrupted mitochondrial cristae [133].
Bortezomib is a proteasome-inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma and its use in other types of cancer is currently under investigation. However, bortezomib induces dose-limiting peripheral neuropathy and compromises complex I- and complex II-mediated respiration, as well as ATP production in peripheral nerve axons, suggesting that mitochondrial dysfunction plays a key role in bortezomib-induced peripheral neuropathy (Fig.1) [134].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
All- | \n\t\t\tMiscellaneous agents | \n\t\t\tHeart and liver | \n\t\t\t[125-127] | \n\t\t
Paclitaxel | \n\t\t\tAntimicrotubules | \n\t\t\tHeart, liver, kidney | \n\t\t\t[110] | \n\t\t
Doxorubicin | \n\t\t\tEnzyme inhibitors | \n\t\t\tHeart and brain | \n\t\t\t[84, 86, 87, 94, 95, 102] | \n\t\t
Etoposide | \n\t\t\tEnzyme inhibitors | \n\t\t\tLiver | \n\t\t\t[106] | \n\t\t
Cisplatin | \n\t\t\tAlkylating agents | \n\t\t\tLiver | \n\t\t\t[71] | \n\t\t
Cyclophosphamide | \n\t\t\tAlkylating agents | \n\t\t\tHeart and liver | \n\t\t\t[75] | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
Tamoxifen | \n\t\t\tSERMs | \n\t\t\tLiver | \n\t\t\t[51-55] | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
Tamoxifen | \n\t\t\tSERMs | \n\t\t\tLiver | \n\t\t\t[40, 41, 159] | \n\t\t
Flutamide | \n\t\t\tAntiandrogens | \n\t\t\tLiver | \n\t\t\t[59, 60] | \n\t\t
All- | \n\t\t\tMiscellaneous agents | \n\t\t\tLiver | \n\t\t\t[127] | \n\t\t
Cisplatin | \n\t\t\tAlkylating agents | \n\t\t\tLiver and kidney | \n\t\t\t[67, 68, 71] | \n\t\t
Oxaliplatin | \n\t\t\tAlkylating agents | \n\t\t\tNerve | \n\t\t\t[65] | \n\t\t
6-Mercaptopurine | \n\t\t\tAntimetabolite | \n\t\t\tLiver | \n\t\t\t[119] | \n\t\t
Ifosfamide | \n\t\t\tAlkylating agents | \n\t\t\tKidney | \n\t\t\t[77] | \n\t\t
Methotrexate | \n\t\t\tAntimetabolites | \n\t\t\tHeart and GI | \n\t\t\t[115, 116] | \n\t\t
Paclitaxel | \n\t\t\tAntimicrotubules | \n\t\t\tNerve | \n\t\t\t[65] | \n\t\t
Doxorubicin | \n\t\t\tEnzyme inhibitors | \n\t\t\tHeart and liver | \n\t\t\t[86-88] | \n\t\t
Sorafenib | \n\t\t\tTargeted Therapy | \n\t\t\tHeart | \n\t\t\t[132, 133] | \n\t\t
Sunitinib | \n\t\t\tTargeted Therapy | \n\t\t\tHeart | \n\t\t\t[133] | \n\t\t
Bortezomib | \n\t\t\tTargeted therapy | \n\t\t\tNerve | \n\t\t\t[134] | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
Tamoxifen | \n\t\t\tSERMs | \n\t\t\tLiver | \n\t\t\t[47] | \n\t\t
Cisplatin | \n\t\t\tAlkylating agents | \n\t\t\tNeurons and kidney | \n\t\t\t[63, 67] | \n\t\t
Doxorubicin | \n\t\t\tEnzyme inhibitors | \n\t\t\tHeart | \n\t\t\t[89-91] | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
Flutamide | \n\t\t\tAntiandrogens | \n\t\t\tLiver | \n\t\t\t[59, 60] | \n\t\t
Doxorubicin | \n\t\t\tEnzyme inhibitors | \n\t\t\tHeart and brain | \n\t\t\t[85, 102] | \n\t\t
Paclitaxel | \n\t\t\tAntimicrotubules | \n\t\t\tLiver and nerve | \n\t\t\t[108, 110] | \n\t\t
6-Mercaptopurine | \n\t\t\tAntimetabolites | \n\t\t\tLiver | \n\t\t\t[119] | \n\t\t
Busulfan | \n\t\t\tAlkylating agents | \n\t\t\tLiver | \n\t\t\t[81] | \n\t\t
Cisplatin | \n\t\t\tAlkylating agents | \n\t\t\tKidney and liver | \n\t\t\t[67, 68, 72] | \n\t\t
Methotrexate | \n\t\t\tAntimetabolites | \n\t\t\tHeart and liver | \n\t\t\t[114, 115] | \n\t\t
Trastuzumab | \n\t\t\tTargeted therapy | \n\t\t\tHeart | \n\t\t\t[129] | \n\t\t
Summary of the mechanisms of mitochondrial dysfunction promoted by anticancer agents (GI, gastrointestinal tract; MPT, mitochondrial permeability transition; mtDNA, mitochondrial DNA; SERMs, selective estrogen receptors modulators).
The severe toxicity promoted by anticancer agents represents a substantial health care burden that may seriously affect the treatment outcome. Based on the previous sections, mitochondria take center stage within the toxicity mechanisms, and are in the first line for protection by pharmacological strategies aiming to avoid alterations that may prove deleterious both in the short and in the long term. Considering that some of these effects are irreversible or cumulative, it is desirable to prevent these events when planning the therapy of cancer patients.
As discussed in the previous section, oxidative stress has been established as one of the primary cause of mitochondrial dysfunction and toxicity induced by anticancer agents and, therefore, several antioxidants have been tested
Alpha-lipoic acid affords protection against the neurotoxic effects promoted by cisplatin and paclitaxel through its antioxidant and mitochondrial regulatory functions [135]. The toxic effects promoted by cisplatin on rat liver mitochondria are also prevented by thiol group protecting agents [71]. Curcumin, which has anti-inflammatory and anticancerous properties, counteracts the mitochondrial lipid peroxidation and GSH levels alterations in mitochondria isolated from the brain and liver of rats treated with cisplatin, suggesting that it can abrogate the toxic effects of cisplatin on brain and liver [136]. Likewise, epicatechin prevents the renal damage and mitochondrial dysfunction promoted by cisplatin by decreasing oxidative stress; noteworthy, epicatechin does not compromise the antitumor actions of cisplatin in HeLa cells [67].
The etoposide-induced MPT is prevented by ascorbate, the primary reductant of the phenoxyl radicals generated by etoposide, and by thiol protecting agents [107].
An
Acetyl-L-carnitine completely blocks the effects of bortezomib on mitochondria and pain [134].
Strategies to prevent doxorubicin-induced cardiotoxicity are probably the best studied, given the significant number of patients affected and the impact on the overall success of the treatment. Many studies reported that antioxidants could afford cardioprotection against doxorubicin therapy. The broad antioxidant resveratrol markedly ameliorates the cardiac dysfunction promoted by doxorubicin, while the ROS generation is decreased, and glutathione, superoxide dismutase and catalase activities are improved [137]. Also, flavonoids, and particularly 7-monohydroxyethylrutoside, protect against the cardiac toxic effects promoted by doxorubicin both
Studies in animals demonstrated that the inhibition of mitochondrial respiration and the decrease in mitochondrial calcium accumulation capacity promoted by doxorubicin are prevented by the coadministration of the beta-adrenergic receptor antagonist carvedilol [87]. The prophylactic use of carvedilol in patients receiving doxorubicin contributes to maintain left ventricle diameters constant and to preserve diastolic function [141]. Interestingly, the toxic effects promoted by doxorubicin on heart mitochondria and cardiac cell apoptosis are prevented by carvedilol, but not by atenolol, another beta-adrenergic receptor antagonist with no antioxidant action, suggesting that the antioxidant properties and not the beta-adrenergic receptor antagonism are responsible for the cardioprotective effects of carvedilol [142]. Likewise, metoprolol, which also has no antioxidative properties, failes to afford cardioprotection in lymphoma patients treated with doxorubicin [143].
Dexrazoxane, a well-studied therapeutic adjuvant for doxorubicin chemotherapy, is a free radical scavenger that was found to have cardioprotective effects by preventing the functional damage of cardiac mitochondria initiated by ROS [83, 144]. Dexrazoxane prevents or reduces cardiac injury in doxorubicin-treated children with acute lymphoblastic leukemia without affecting the antitumor activity of doxorubicin [145]. In contrast, other iron chelators have failed to afford the same degree of cardioprotection, suggesting that iron does not play a crucial role in the oxidative stress-mediated toxicity of doxorubicin [138, 146, 147].
Promising results were obtained when the potent phosphodiesterase-5 inhibitor sildenafil is combined with doxorubicin. Prophylactic treatment with sildenafil prevents cardiomyocyte apoptosis and left ventricular dysfunction in a mouse chronic model of doxorubicin-induced cardiotoxicity [148]. On the other hand, in breast cancer cells, sildenafil enhances sensitivity to doxorubicin without enhancing its toxicity in bone marrow cells or macrophages [149]. Furthermore, cotreatment with sildenafil enhances doxorubicin-induced apoptosis in prostate cancer cells and inhibits tumor growth in mice bearing prostate tumor xenografts, while attenuating left ventricular dysfunction promoted by doxorubicin [150].
Interesting results were also observed when retinoids and antiestrogens are combined. Antiestrogenic compounds inhibit the MPT-induced by retinoids in isolated liver mitochondria [127, 151, 152]. Noteworthy, the prevention of MPT by antiestrogens does not compromise the antitumor efficacy of all-
Considering the key role played by mitochondria in cell survival and death, the pharmacological modulation of mitochondrial activity has been investigated in cancer therapy [13, 158]. It is thought that this strategy may overcome the resistance mechanisms related with conventional chemotherapy that do not target mitochondria directly, but interfere with signaling pathways which lie upstream of mitochondria and that are frequently deregulated in cancer [158]. However, the targeting of mitochondria as a therapeutic strategy is often compromised by the absence of significant pathophysiological differences between mitochondria in normal and malignant cells, leading to reduced selectivity of drugs targeting mitochondria. Therefore, the actions that are beneficial in cancer cells may, in contrast, underlie some of the severe toxic effects promoted by these agents.
Indeed, the induction of mitochondrial damage is an important contributor for some of the most well-known toxic effects of anticancer agents, namely the liver injury promoted by tamoxifen [159], the cardiotoxicity of doxorubicin or the cisplatin-induced neuropathy and nephrotoxicity. Organ dysfunction has a significant impact on the treatment outcomes and, therefore, the better understanding of the mechanisms of toxicity may unveil strategies to limit, or preferably to prevent, the incidence of these events and thereby improve the overall clinical success.
The recognition that mitochondrial dysfunction plays a key role in drug-induced toxicity may contribute to identify the drugs that are more likely to lead to such effects at an early stage. In this context, the use of isolated mitochondria fractions is a valuable tool to predict drug safety, since it provides relevant information while allowing to reduce the number of laboratory animals and the costs of preclinical studies [8].
On the other hand, our current knowledge does not allow to predict the idiosyncratic injury related with drug-induced mitochondrial dysfunction. It seems that genetic, metabolic and environmental factors that impair mitochondrial function can add their effects to those of anticancer drugs, compromising mitochondrial function to an extent where manifestations start to occur [17]. Therefore, therapeutic drug monitoring is mandatory. Furthermore, as organ damage may become apparent months or even years after the completion of the treatment (e.g. late-onset doxorubicin toxicity) the need of long-term follow-up is reinforced.
Finally, future studies should aim to develop strategies which are able to afford protection against both the short-term and long-term effects of anticancer drugs and without compromising their antitumor activity. Although antioxidants showed promise in
In conclusion, studies in suitable animal models are vital for a better understanding of the mechanisms underlying drug toxicity and the benefits of strategies aiming to prevent mitochondrial damage. So far most studies have used animal models devoid of tumors, which add an extra physiological burden that may influence the effects of drugs [83]. Moreover, as described in the previous section, some of the toxic effects on mitochondria are observed in several organs, including the liver and kidneys, which may compromise both the pharmacokinetics and the efficacy of the anticancer drugs, but also the benefit of therapeutic adjuvants aiming to protect the mitochondria. These observations emphasize the importance of performing
Practically all fields of science are moving forward at an increasingly rapid rate thanks to the results obtained from laboratories.
\nA laboratory [1] is a place equipped with all of the resources needed to carry out scientific, technological, or technical research, experiments, practices, and works, with the appropriate level of rigor:
It ensures that foreign influences, other than those specifically set out, do not occur and alter the result of experiment or measurement.
It guarantees the repeatability of the experiment or measurement, i.e., any other laboratory could repeat the process and obtain the same result.
How can we ensure the confidence of the results of the tests carried out by the laboratory?
\nAccreditation is the internationally established tool to build trust on the performance of a very specific type of organizations, named, in such a way, Conformity Assessment Organizations (CAO) (Figure 1), including testing laboratories, calibration laboratories, inspection agencies, certification bodies, and environmental verifiers [2].
\nConformity assessment organizations.
The main objective of the Conformity Assessment Organizations (CAO) is to demonstrate the society (administration, companies, and consumers at large) that the products and services made available comply with certain requirements related to quality and security. These requirements can be set by law, and therefore have a regulatory nature, or can be specified by standards, specifications, or other voluntary documents.
\nAccreditation arouses both controversy and interest; multiple studies try to deepen in the subject from different perspectives [3, 4, 5, 6, 7].
\n\n
Builds organization recognition.
Competitive advantage: accreditation provides independent assurance that your staff is competent.
Market access: accreditation is recognized and accepted in over 90 countries worldwide.
Fosters a continuous improvement dynamic within the organization.
Facilitates access to government contracting: accreditation has increasingly become an important criterion in the public procurement procedures.
Accredited bodies, both public and private, are already being used by governments as an effective market-led tool for delivering policy more efficiently, resulting in a substantial reduction in costs as well as best practice.
\nBy selecting an accredited body, businesses:
Reduce downtime and control costs.
Minimize risks.
Increase its customer confidence.
Increase its product acceptance in other markets.
Open up opportunities for competent supplier selection.
Reduce the risk of failures.
Accreditation organizations of different countries (Figure 2) perform their task pursuant to the same international criteria, using equivalent and transparent assessment methods, providing the necessary confidence to allow the mutual acceptance of results.
\nAccreditation organizations of different countries.
The ISO/IEC 17025 Standard was designed to be used by testing and calibration laboratories in the development of their quality, administrative, and technical management systems.
\nWorking under the standards of ISO/IEC 17025, the technical competence of the laboratory and the validity of its results are recognized, responding to the requirements of the organizations or entities that contract it and offering credibility to its clients [8].
\nProduct or service quality is the consumer’s perception of it and should be defined within the context under review.
\nFrom a value-added perspective, quality means bring value to the customer, i.e., offer product or service conditions of use superior to those that the customer expects to receive and at an accessible price.
\nFor good product or service quality [9], there are three very important points which we need to bear in mind:
In 1957 and 1988, respectively, the European Organization for Quality (EOQ) and the European Foundation for Quality Management (EFQM) are founded in Europe to promote total quality management; among the most important European quality infrastructure organizations are testing laboratories.
\nWhen you commission a laboratory to test products, to determine its characteristics, as part of the quality control or to determine compliance with particular requirements of standards or specifications, it is necessary to be sure that they supply you with accurate and reliable results. In other words, this is a laboratory technically competent.
\nIn order to ensure the reliability of its products or services, minimize risks, and increase customer confidence and product acceptance in other markets, it is essential for the organizations to call on a laboratory with the highest degree of technical competence.
\nThe first version of Standard ISO/IEC 17025 dates from 1999. The ISO/IEC 17025:2017 Standard on General Requirements for the Competence of Testing and Calibration Laboratories is currently in force, but it has had a long way before it arrived here from that first version in 1999.
\nThe ISI/IEC 17025:1999 Standard replaced the ISO/IEC 25:1990 former guide (General Requirements for the Competence of Calibration and Testing Laboratories) and the European EN 45001:1989 Standard (General Criteria for the Operation of Testing Laboratories), introducing new requirements in relation to responsibilities and commitment of upper management and giving greater emphasis to continuous improvement according to Deming method or PDCA (plan-do-check-act) (Figure 3) and to dialog with the customer.
\nDeming cycle.
The ISO/IEC 17025 Standard emerged in 1999 as a reference generic guideline for Testing or Calibration Laboratories; the existence and evolution of the quality management regulation stipulated in ISO 9001 Standard led to a revision to determine their alignment with the ISO 9001:2000 Standard in 2005 (Figure 4).
\nChronological evolution ISO/IEC 17025.
In 2017, to adjust its form to the structure of the rest of 17,000 Series Standards and with the objective of adapting to the latest changes in the laboratories sphere and to the new information technologies applied to work practices, the ISO/IEC 17025 Standard was once again reviewed. The revised standard is in line with ISO terminology, with a set of terms and definitions common to all the standards related to conformity assessment (Figure 5).
\nChronological evolution ISO 9001.
The ISO/IEC 17025 [10] goes to show that laboratories that implement this standard:
Operate an effective quality management system based on ongoing improvement
The laboratory implements a quality management system to administer and use its documentation, both in management and in technical areas.
Are technically competent
The laboratory demonstrates technical competence of staff, appropriate facilities and environmental conditions, validity of test methods, reliable test equipment, and reference standard materials with traceability to the international system of units.
Are capable of producing testing or calibration reliable results
The laboratory implements quality assurance programs, which generate technically valid results.
\nThe ISO 17025 Standard introduces two types of requirements:
Management requirements
These requirements are related to the laboratory quality management. Requirements analogous to those set out in the ISO 9001 Standard.
Technical requirements
These requirements are related to aspects with direct influence over the testing result.
\nWe should bear in mind that conformity with the scope defined in the ISO/IEC 17025 Standard does not mean that the laboratory quality management system meets all the requirements of the ISO 9001 Standard. Likewise, conformity of the laboratory quality management system with standard ISO 9001 requirements alone is no guarantee of the laboratory competence to generate theoretically valid data and results (Figure 6).
\nISO/IEC 17025 versus ISO 9001.
The laboratory certification guarantees compliance with requirements of the ISO 9001 Standard; the laboratory accreditation guarantees the technical competence for testing activities (Figures 7 and 8).
\nTechnical competence beyond quality management.
Relationship between the standards ISO/IEC 17025 and ISO 9001.
According to data from the ENAC, in Spain in 2010, there were 1040 accredited testing laboratories, and their number has soared to over 1138 in 2013. In 2014, due to the financial crisis, the number of accredited laboratories decreased significantly to 1043: some temporarily suspended accreditation while others even go out of business. Since 2015, is noted a constant and moderate growth; at the end 2017, there were already 1081 laboratories accredited (Figure 9).
\nENAC accreditations of testing laboratories (2010–2017).
The small size of a laboratory is not an impediment to the implementation of the ISO/IEC 17025 Standard; but the size and the laboratory characteristics have to take it into account to design the proper quality management system, trying to simplify.
\nA Fuel’s laboratory (R + D + i) accreditation. The laboratory is a member of a research center at a Spanish university.
\nTo establish the procedure to be followed, the path to the system established by the ENAC (National Accreditation Entity—Spain) to accredit a testing laboratory, LABCOMB, under internationally established criteria.
\nThe accreditation is a declaration of the technical competence of the laboratory to perform the activities included in the scope of the accreditation. This competence is established through the evaluation of laboratory compliance with the requirements established to that effect in international standards.
\nThe accreditation system for testing laboratories establishes the accreditation requirements to be met by the laboratories, as well as the accreditation framework and procedure. The accreditation granted is valid and is fully accepted in Spain and internationally.
\nThe accreditation does not imply in any case the acceptance or validation by the ENAC of the results of each test, nor does it exempt the laboratory from its responsibility in case of erroneous results.
\nThe ISO/IEC 17025 Standard establishes the general requirements related to the technical competence of the testing laboratories that ENAC uses as criteria for accreditation.
\nThe laboratory identifies in its Quality Manual: MC/LABCOMB, the legal personality that assumes its legal responsibilities, defines its quality policy, and records all the documentation prepared in order to meet the criteria established in the ISO/IEC 17025 Standard:
Management requirements
Technical requirements
The documentary structure of LABCOMB’s quality management system consists of:
The Quality Manual:
MC/LABCOMB, Quality Manual ISO 17025
General procedures:
P/LABCOMB/01 | \nStaff skills | \n
P/LABCOMB/02 | \nInternal staff training program | \n
P/LABCOMB/03 | \nDocument and record control | \n
P/LABCOMB/04 | \nProcurement management and subcontracting | \n
P/LABCOMB/05 | \nSupplier evaluation | \n
P/LABCOMB/06 | \nComplaint handling | \n
P/LABCOMB/07 | \nDevelopment of testing procedures | \n
P/LABCOMB/08 | \nValidation procedures | \n
P/LABCOMB/09 | \nUncertainty calculation | \n
P/LABCOMB/10 | \nTest process | \n
P/LABCOMB/11 | \nEquipment and reagent management | \n
P/LABCOMB/12 | \nRegulation and legislation review | \n
P/LABCOMB/13 | \nInternal audits | \n
P/LABCOMB/14 | \nNonconformity treatment | \n
P/LABCOMB/15 | \nCorrective and preventive action management | \n
P/LABCOMB/16 | \nRevision of the system by the general direction | \n
Technical procedures: test procedures (PE) and calibration procedures (PC)
PE/LABCOMB/01 | \nDetermination of flash point, Pensky-Martens method | \n
PE/LABCOMB/02 | \nDetermination of cold filter plugging point (CFPP) | \n
PE/LABCOMB/03 | \nDetermination of cloud point | \n
PE/LABCOMB/04 | \nDetermination of distillation characteristics at atmospheric pressure | \n
PE/LABCOMB/05 | \nDetermination of sulfur content for UVF method | \n
PE/LABCOMB/06 | \nCalculation of cetane index by the four-variable equation | \n
PE/LABCOMB/07 | \nDetermination of density by the hydrometer method | \n
PE/LABCOMB/08 | \nDetermination of sulfur content for UVF method (<3 ppm) | \n
PE/LABCOMB/09 | \nDetermination of water, Karl-Fischer method | \n
PE/LABCOMB/10 | \nDetermination of water, Karl-Fischer method (>1%) | \n
PE/LABCOMB/11 | \nDetermination of kinematic viscosity | \n
PE/LABCOMB/12 | \nDetermination of flash and fire points, Cleveland method | \n
PE/LABCOMB/13 | \nDetermination of combustion heat | \n
PE/LABCOMB/14 | \nDetermination of water by distillation | \n
PE/LABCOMB/15 | \nDetermination of sulfur content, XRF method | \n
PE/LABCOMB/16 | \nDetermination of nickel and vanadium content, RXF method | \n
PE/LABCOMB/17 | \nDetermination of ash | \n
PE/LABCOMB/18 | \nDetermination of sulfated ash | \n
PE/LABCOMB/19 | \nDetermination of free water and particulate contamination | \n
PE/LABCOMB/20 | \nDetermination of water and sediments by the centrifuge method | \n
PE/LABCOMB/21 | \nCorrosiveness to copper. Copper strip test | \n
PE/LABCOMB/22 | \nCommercial butane and propane. Analysis by GC | \n
PE/LABCOMB/23 | \nDetermination of ASTM color of petroleum products | \n
PE/LABCOMB/24 | \nEstimation of net and gross heat of combustion | \n
PE/LABCOMB/25 | \nDetermination of total sulfur content. Method of elemental analysis | \n
PE/LABCOMB/26 | \nDetermination of pour point | \n
PE/LABCOMB/27 | \nNatural Gas. Analysis by GC | \n
PC/LABCOMB/01 | \nCalibration of thermal equipment | \n
PC/LABCOMB/02 | \nCalibration of volumetric material | \n
PC/LABCOMB/03 | \nCalibration of thermometers | \n
PC/LABCOMB/04 | \nCalibration of stopwatches | \n
PC/LABCOMB/05 | \nCalibration of hydrometers | \n
PC/LABCOMB/06 | \nCalibration of viscometers | \n
PC/LABCOMB/07 | \nCalibration of thermostatic baths | \n
The laboratory is not accredited to perform all the tests included in its offer. Accredited tests are included in the Scope.
\nThe accreditation scope describes the technical competence declared by LABCOMB (Figure 10) in order to be assessed by the ENAC. It finally constitutes the Technical Annex to the “Accreditation Certification,” and it should, therefore,
\nLABCOMB present scope (sheet 1).
LABCOMB is responsible for establishing the accreditation scope, although ENAC establishes the type of information that should be included to ensure its proper definition.
\nLABCOMB accredited tests include:
\nPE/LABCOMB/01 | \nDetermination of flash point, Pensky-Martens method | \n
PE/LABCOMB/02 | \nDetermination of cold filter plugging point (CFPP) | \n
PE/LABCOMB/03 | \nDetermination of cloud point | \n
PE/LABCOMB/04 | \nDetermination of distillation characteristics at atmospheric pressure | \n
PE/LABCOMB/05 | \nDetermination of sulfur content for UVF method | \n
PE/LABCOMB/06 | \nCalculation of cetane index by the four-variable equation | \n
PE/LABCOMB/07 | \nDetermination of density by the hydrometer method | \n
PE/LABCOMB/11 | \nDetermination of kinematic viscosity | \n
PE/LABCOMB/14 | \nDetermination of water by distillation | \n
PE/LABCOMB/19 | \nDetermination of free water and particulate contamination | \n
PE/LABCOMB/20 | \nDetermination of water and sediments by the centrifuge method | \n
PE/LABCOMB/21 | \nCorrosiveness to copper. Copper strip test | \n
PE/LABCOMB/23 | \nDetermination of ASTM color of petroleum products | \n
The accreditation process begins with the opening of the file in March 2010. ENAC understands that when applying for accreditation, LABCOMB complies with all the legally established requirements to carry out the activity for which accreditation is requested.
\nIf at any time during the accreditation process it becomes clear that this is not the case, ENAC proceeds to stop the process until the laboratory provides evidence that the detected problem has been adequately resolved.
\nENAC can request evidence of compliance with these legal requirements before initiating the accreditation process.
\nThe information received by ENAC, both in the application and throughout the entire accreditation process, will be considered as CONFIDENTIAL for all purposes with the following limitations:\n
Those established, as the case may be, by law.
In activities that take place in the regulated field or in those in which the laboratory operates with an administrative authorization, ENAC may, at the request of the competent administration, inform the latter of the results of the evaluations.
If the laboratory is accredited by other accreditors, ENAC can exchange information with them, in accordance with what is established by the cross-border accreditation procedures established by international accrediting organizations.
ENAC acknowledges receipt of the application and reviews the documentation provided in order to verify that the activity is susceptible to be accredited. Inform LABCOMB of the ENAC technician responsible for the follow-up of your file. If there is any legal, statutory, or other reason that prevents accreditation, it is communicated to the laboratory.
\nENAC evaluates whether the activity corresponds to the accreditation scheme under which it is requested, if the scope is clearly defined and the documentation is complete and adequate. ENAC can request, at this time or in subsequent phases of the process, additional information to ensure the correct execution of the accreditation process.
\nWithin any of the phases of the accreditation process, if more than 1 year passes without a response from the laboratory to a request for information, ENAC will consider the annulment of the file.
\nENAC may consider the convenience of making a preliminary visit to the laboratory, in order to prepare the following stages of the accreditation process so that it can be carried out as efficiently as possible.
\nENAC appoints, from its auditors and qualified experts, the members of the audit team that will carry out the evaluation process.
\nThe number of members of the audit team is a function of the scope of accreditation requested but in any case, with a chief auditor, and as many technicians as necessary in the tests for which the laboratory requests accreditation.
\nThe laboratory is informed in advance of the names of the members of the audit team and, if appropriate, of the organization to which they belong. The laboratory could recuse them in writing, providing that the reasons that they understand could compromise their independence and impartiality. In this case ENAC will analyze the reasons given and will communicate its decision to the applicant.
\nThe accreditation process begins with the study of the documentation by the auditors appointed to evaluate the adequacy of the procedures within the scope of accreditation requested. If the result of that documentary study is satisfactory, the audit will proceed.
\nOn the date agreed with the laboratory, the designated audit team conducts an audit visit, the purpose of which is to verify compliance with the accreditation criteria. Prior to the visit, the chief auditor sends the audit plan to the laboratory.
\nThe audit takes place in three phases:
\n1. Initial meeting: it takes place between the representatives of LABCOMB and the audit team. During this initial meeting, the appropriate presentations are made, the audit plan and the scope of the audit are confirmed, and the system to be followed is indicated.
\n2. Development of the audit: the audit team proceeds to observe the operation of the laboratory and to assess compliance with the accreditation requirements.
\nThe realization of some tests, of those included in the scope to be evaluated, to verify the correct performance of them is requested.
\n3. Final meeting: its main purpose is to present to the laboratory managers a summary of the results of the investigation.
\nThe audit team, within a period of no more than 15 business days from the date of the audit, prepares a report with the results and information gathered during the audit, which is sent to the laboratory for its information.
\nThe report of this audit has a validity period of 6 months from its date of issue. After this period it may be necessary to carry out a new audit to decide on the accreditation of the laboratory.
\nOnce the audit report is received, LABCOMB acts as indicated in Operational Note NO-11 “Deviations, classification, and treatment,” responding to the possible “nonconformities” and “observations” raised in the report. The laboratory can claim those extremes of the report with which it is dissatisfied.
\nThe decision of accreditation must be made within the validity period of the audit report; to ensure that the decision can be made within that period, the laboratory sends the response before the prescribed period is met.
\nTo grant accreditation, the Accreditation Commission must rely on the technical competence of LABCOMB to carry out the activities for which it requests accreditation and must trust that the accreditation requirements are met and the deviations detected in its case have been adequately addressed.
\nThe Accreditation Commission analyzes the information generated during the evaluation process and based on this adopts the decision of “grant accreditation” in July 2010.
\nAfter a favorable decision and once LABCOMB pays the corresponding costs, ENAC issues a Certificate of Accreditation, which attests to the granting of accreditation in favor of the laboratory.
\nOnce accredited, the laboratory has the right to make use of the ENAC trademark or reference to its accredited status under the conditions established in document CEA-ENAC-01 “Criteria for the use of the ENAC trademark or reference to the status of accredited.”
\nLaboratory accreditation is considered valid as long as LABCOMB continues to meet the criteria established by ENAC and the obligations resulting from its accreditation.
\nThe laboratory may, at any time, request a voluntary temporary suspension of all or part of the scope of accreditation. The voluntary temporary suspension implies the temporary prohibition of the use of the ENAC trademark or reference to the status of accredited as established in document CEA-ENAC-01.
\nThe maintenance of the accreditation is structured in a first cycle of 4 years and subsequent cycles not exceeding 5 years in which LABCOMB was submitted by ENAC to the following activities:
Follow-up audits between reevaluation periods
Reassessment audits: 2014 and 2018
In order to maintain accreditation, the Accreditation Commission must trust that the laboratory maintains its technical competence for the activities included in its accreditation scope, the accreditation requirements continue to be met and the detected deviations, if any, have been adequately addressed.
\nIn 2010, LABCOMB included five tests in the requested scope. Currently, the number of accredited tests is 13: between 2010 and 2018. LABCOMB has not only maintained accreditation but has also increased the number of tests within its scope.
\nObtaining the ISO/IEC 17025 accreditation by LABCOMB has allowed the laboratory to recognize its technical competence both nationally and internationally, which allows it to:
Work regularly for various strata of Spanish public administration
Greater visibility and better positioning among laboratories that offer the same services, which has increased the number of customers and has achieved their loyalty
Work for the European Commission, Directorate General, Joint Research Centre, Directorate-D, Institute for Reference Materials and Measurements from the certification of the cold filter plugging point (CFPP) and the cloud point (CP) in gasoil and biodiesel
The implementation of the ISO 9001 and ISO/IEC 17025 Standards has improved the overall management of the laboratory in all its activities and has made it possible to demonstrate its technical competence; but also, since it is a university laboratory, the staff that works and is trained in it gets a curricular bonus that makes it valuable for different companies that look for personnel trained in high-quality standards.
\nIn the near future, LABCOMB plans to extend its commitment to quality and consider Integrated Quality Management. There are many similarities between the concepts of quality management, environmental management, and management of occupational risk prevention, since the principles of good management are the same, as well as their implementations and regulatory points.
\nIntegrated Quality Management is an increasingly recurrent option that is chosen by those organizations that maintain a strong commitment to excellence in their products, services, and processes.
\nIntechOpen will act in accordance with its published Refund Policy if requests for refunds are made.
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\\n\\n3. In those rare instances where IntechOpen declines to publish a book that had been previously accepted, full refunds will be made to the same account or credit card from which the Author made the original payment.
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\n\n3. In those rare instances where IntechOpen declines to publish a book that had been previously accepted, full refunds will be made to the same account or credit card from which the Author made the original payment.
\n\nPlease note that refunded amounts will not always be exactly the same as original payment amounts due to bank transaction fees and expenses. Any such costs will be split evenly between IntechOpen and the Author.
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Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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