Selected molecular prognostic markers for glioblastoma.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"10080",leadTitle:null,fullTitle:"Vortex Dynamics Theories and Applications",title:"Vortex Dynamics Theories and Applications",subtitle:null,reviewType:"peer-reviewed",abstract:"The book comprises of different areas in which vortex dynamics is important, its generation, evolution, interactions with other motions, and finally the ways it can be controlled. Vortex characteristics are important in many aspects of our lives, from blood circulation in the arteries to the high-speed jet. Flow control and manipulation of vortices have been used to reduce drag for large tankers resulting in billions of dollars in savings. An effective smoke management system must be put in place for critical areas to ensure the safety of people, for example in a very large shopping complex or a large airport. Advanced computational and cloud-computing facilities have contributed significantly to large-scale simulation projects. Therefore, validations could be performed for larger windows of study so that it can now cover the entire e.g. central business district (CBD) for urban heat island (UHI) study or land-ocean interactions.",isbn:"978-1-83962-617-3",printIsbn:"978-1-83962-616-6",pdfIsbn:"978-1-83962-618-0",doi:"10.5772/intechopen.87912",price:119,priceEur:129,priceUsd:155,slug:"vortex-dynamics-theories-and-applications",numberOfPages:234,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"ea97962e99b3e0ebc9b46b48ba5bea14",bookSignature:"Zambri Harun",publishedDate:"December 9th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/10080.jpg",numberOfDownloads:5735,numberOfWosCitations:3,numberOfCrossrefCitations:4,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:6,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:13,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 9th 2019",dateEndSecondStepPublish:"March 2nd 2020",dateEndThirdStepPublish:"May 1st 2020",dateEndFourthStepPublish:"July 20th 2020",dateEndFifthStepPublish:"September 18th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"243152",title:"Dr.",name:"Zambri",middleName:null,surname:"Harun",slug:"zambri-harun",fullName:"Zambri Harun",profilePictureURL:"https://mts.intechopen.com/storage/users/243152/images/system/243152.jpg",biography:"Dr. Zambri Harun is a senior fellow at the Faculty of Engineering and Built Environment, National University Malaysia (UKM). He graduated with a BSc and MEng both from Rensselaer Polytechnic Institute, New York, US. His experience in the industry stretches over almost a decade; being an engineer at Motorola Malaysia and in a civil project. His PhD was on turbulence flow from the University of Melbourne, Australia. His research covers the wind tunnel and atmospheric turbulence as well as building and tunnel flow management.",institutionString:"The National University of Malaysia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"935",title:"Fluid Dynamics",slug:"materials-science-fluid-mechanics-fluid-dynamics"}],chapters:[{id:"73094",title:"The Role of Micro Vortex in the Environmental and Biological Processes",doi:"10.5772/intechopen.93531",slug:"the-role-of-micro-vortex-in-the-environmental-and-biological-processes",totalDownloads:515,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This work presents a short review of the theoretical developments in the application of vortex dynamics to the processing of environmental and biological systems. The mechanisms of complex fluid-particle interaction in vortex dominated and non-vortex dominated flows are briefly discussed from theoretical and practical perspectives. Micro vortex propagation, characteristics and their various applications in environmental process engineering are briefly discussed. Several existing and potential applications of vortex dynamics in turbulent flows are highlighted and as well as the knowledge gaps in the current understanding of turbulence phenomenon with respect to its applications in the processing of solid-liquid suspension and biological systems.",signatures:"Benjamin Oyegbile, Brian Oyegbile and Guven Akdogan",downloadPdfUrl:"/chapter/pdf-download/73094",previewPdfUrl:"/chapter/pdf-preview/73094",authors:[{id:"236404",title:"Dr.",name:"Benjamin",surname:"Oyegbile",slug:"benjamin-oyegbile",fullName:"Benjamin Oyegbile"},{id:"245434",title:"Prof.",name:"Guven",surname:"Akdogan",slug:"guven-akdogan",fullName:"Guven Akdogan"},{id:"326010",title:"Dr.",name:"Brian",surname:"Oyegbile",slug:"brian-oyegbile",fullName:"Brian Oyegbile"}],corrections:null},{id:"71906",title:"Vortices in Rotating and Gravitating Gas Disk and in a Protoplanetary Disk",doi:"10.5772/intechopen.92028",slug:"vortices-in-rotating-and-gravitating-gas-disk-and-in-a-protoplanetary-disk",totalDownloads:504,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Nonlinear equations describing dynamics of 2D vortices are very important in the physics of the ocean and the atmosphere and in plasma physics and Astrophysics. Here linear and nonlinear 2D vortex perturbations of gravitating and light gaseous disks are examined in the geostrophic and post-geostrophic approximations. In the frame of geostrophic approximation, it is shown that the vortex with positive velocity circulation is characterized by low pressure with negative excess mass density of substance. Vortex with negative circulation has higher pressure and is a relatively tight formation with the positive excess mass density. In the post-geostrophic approximation, structures of the isolated monopole and dipole vortex (modons) solutions of these equations are studied. Two types of mass distributions in dipole vortices are found. The first type of modon is characterized by an asymmetrically positioned single circular densification and one rarefaction. The second type is characterized by two asymmetrically positioned densifications and two rarefactions, where the second densification-rarefaction pair is crescent shaped. The constant density contours of a dipole vortex in a light gas disk coincide with the streamlines of the vortex; in a self-gravitating disk, the constant density contours in the vortex do not coincide with streamlines. Possible manifestations of monopole and dipole vortices in astrophysical objects are discussed. Vortices play decisive role in the process of planet formation. Gas in a protoplanetary disk practically moves on sub-Keplerian speeds. Rigid particles, under the action of a head wind drags, lose the angular momentum and energy. As a result, the ~10 cm to meter-sized particles drift to the central star for hundreds of years. Long-lived vortical structures in gas disk are a possible way to concentrate the ~10 cm to meter sized particles and to grow up them in planetesimal. Here the effect of anticyclonic Burgers vortex on formation of planetesimals in a protoplanetary dusty disc in local approach is also considered. It is shown that the Burgers vortex with homogeneously rotating kernel and a converging radial stream of substance can effectively accumulate in its nuclear area the meter-sized rigid particles of total mass ∼1028 g for characteristic time ∼106 year.",signatures:"Martin G. Abrahamyan",downloadPdfUrl:"/chapter/pdf-download/71906",previewPdfUrl:"/chapter/pdf-preview/71906",authors:[{id:"273621",title:"Dr.",name:"Martin",surname:"Abrahamyan",slug:"martin-abrahamyan",fullName:"Martin Abrahamyan"}],corrections:null},{id:"71136",title:"Vortices on Sound Generation and Dissipation in Musical Flue Instruments",doi:"10.5772/intechopen.91258",slug:"vortices-on-sound-generation-and-dissipation-in-musical-flue-instruments",totalDownloads:755,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Musical flue instruments such as the pipe organ and flute mainly consist of the acoustic pipe resonance and the jet impinging against the pipe edge. The edge tone is used to be considered as the energy source coupling to the pipe resonance. However, jet-drive models describing the complex jet/pipe interaction were proposed in the late 1960s. Such models were more developed and then improved to the discrete-vortex model and vortex-layer model by introducing fluid-dynamical viewpoint, particularly vortex sound theory on acoustic energy generation and dissipation. Generally, the discrete-vortex model is well applied to thick jets, while the jet-drive model and the vortex-layer model are valid to thin jets used in most flue instruments. The acoustically induced vortex (acoustic vortex) is observed near the amplitude saturation with the aid of flow visualization and is regarded as the final sound dissipation agent. On the other hand, vortex layers consisting of very small vortices along both sides of the jet are visualized by the phase-locked PIV and considered to generate the acceleration unbalance between both vortex layers that induces the jet wavy motion coupled with the pipe resonance. Vortices from the jet visualized by direct numerical simulations are briefly discussed.",signatures:"Shigeru Yoshikawa",downloadPdfUrl:"/chapter/pdf-download/71136",previewPdfUrl:"/chapter/pdf-preview/71136",authors:[{id:"186319",title:"Dr.",name:"Shigeru",surname:"Yoshikawa",slug:"shigeru-yoshikawa",fullName:"Shigeru Yoshikawa"}],corrections:null},{id:"73949",title:"A Fully Discrete SIPG Method for Solving Two Classes of Vortex Dominated Flows",doi:"10.5772/intechopen.94316",slug:"a-fully-discrete-sipg-method-for-solving-two-classes-of-vortex-dominated-flows",totalDownloads:371,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"To simulate incompressible Navier–Stokes equation, a temporal splitting scheme in time and high-order symmetric interior penalty Galerkin (SIPG) method in space discretization are employed, while the local Lax-Friedrichs flux is applied in the discretization of the nonlinear term. Under a constraint of the Courant–Friedrichs–Lewy (CFL) condition, two benchmark problems in 2D are simulated by the fully discrete SIPG method. One is a lid-driven cavity flow and the other is a circular cylinder flow. For the former, we compute velocity field, pressure contour and vorticity contour. In the latter, while the von Kármán vortex street appears with Reynolds number 50≤Re≤400, we simulate different dynamical behavior of circular cylinder flows, and numerically estimate the Strouhal numbers comparable to the existing experimental results. The calculations on vortex dominated flows are carried out to investigate the potential application of the SIPG method.",signatures:"Lunji Song",downloadPdfUrl:"/chapter/pdf-download/73949",previewPdfUrl:"/chapter/pdf-preview/73949",authors:[{id:"178658",title:"Dr.",name:"Lunji",surname:"Song",slug:"lunji-song",fullName:"Lunji Song"}],corrections:null},{id:"72918",title:"Discrete Vortex Cylinders Method for Calculating the Helicopter Rotor-Induced Velocity",doi:"10.5772/intechopen.93186",slug:"discrete-vortex-cylinders-method-for-calculating-the-helicopter-rotor-induced-velocity",totalDownloads:451,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"A new vortex model of a helicopter rotor with an infinite number of blades is proposed, based on Shaidakov’s linear disk theory for calculating inductive speeds at any point in space in the helicopter area. It is proposed to consider the helicopter rotor and the behind vortex column as a system of discrete vortex cylinders. This allows building a matrix of the influence of the vortex system under consideration on any set of points, for example, the calculated points on the rotor itself, on the tail rotor, etc. The model allows calculating inductive velocities at any point near the helicopter using matrix multiplication operation. It is shown that the classical results for the momentum theory remain constant even in the discrete simulation of the helicopter rotor vortex system. The structure of the air flow behind the rotor and the simulation results obtained by the proposed method is compared with the structure of the tip vortices and the results of the blade vortex theory. In addition, the experimental data were compared with the simulation results to verify the correctness of the model under real operating conditions by the helicopter trimming.",signatures:"Evgeny Nikolaev and Maria Nikolaeva",downloadPdfUrl:"/chapter/pdf-download/72918",previewPdfUrl:"/chapter/pdf-preview/72918",authors:[{id:"314415",title:"Dr.",name:"Evgeny",surname:"Nikolaev",slug:"evgeny-nikolaev",fullName:"Evgeny Nikolaev"},{id:"328042",title:"Dr.",name:"Maria",surname:"Nikolaeva",slug:"maria-nikolaeva",fullName:"Maria Nikolaeva"}],corrections:null},{id:"72525",title:"Wake-Body Interaction Noise Simulated by the Coupling Method Using CFD and BEM",doi:"10.5772/intechopen.92783",slug:"wake-body-interaction-noise-simulated-by-the-coupling-method-using-cfd-and-bem",totalDownloads:406,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In many engineering applications, obstacles often appear in the wake of obstacles. Vortices shed from an upstream obstacle interact with downstream obstacle and generate noise, for example blades in a turbomachinery, tubes in a heat exchanger, rotating blades like a helicopter and wind turbine and so on. This phenomenon is called wake-body interaction or body-vortex interaction (BVI). The rod-airfoil and airfoil-airfoil configurations are typical models for the wake-body interaction. A rod and an airfoil are immersed upstream of the airfoil. In this chapter, we review the noise mechanism generated by the wake-body interaction and show the numerical results obtained by the coupling method using commercial CFD and acoustic BEM codes. The results show that depending on the spacing between the rod or airfoil and the airfoil, the flow patterns and noise radiation vary. With small spacing, the vortex shedding from the upstream obstacle is suppressed and it results in the suppression of the sound generation. With large spacing, the shear layer or the vortices shed from the upstream obstacle impinge on the downstream obstacle and it results in the large sound generation. The dominant peak frequency of the generated sound varies with increase in the spacing between the two obstacles.",signatures:"Masaaki Mori",downloadPdfUrl:"/chapter/pdf-download/72525",previewPdfUrl:"/chapter/pdf-preview/72525",authors:[{id:"290435",title:"Ph.D.",name:"Masaaki",surname:"Mori",slug:"masaaki-mori",fullName:"Masaaki Mori"}],corrections:null},{id:"72530",title:"Application of Vortex Control Principle at Pump Intake",doi:"10.5772/intechopen.92853",slug:"application-of-vortex-control-principle-at-pump-intake",totalDownloads:1028,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Vortex flow in a pump intake could affect a pump operation significantly if not treated appropriately. Many researches have been conducted to determine the best control method for vortex flow in pump sumps so that the pump lifespan can be maximized. In this study, a vortex control principle designed to minimize the impact of submerged vortex flow in pump sump on major pump components is presented. This principle employs a device called the plate type floor splitter which serves the function of eliminating vortices formed on the sump floor and reduces the intensity of swirling motion in the intake flow. A pump sump model was built to carry out the study by installing a floor splitter plate sample under the pump suction inlet and the corresponding parameters used to quantify the swirl intensity known as the swirl angle was measured. Procedures for the measurement were conducted based on ANSI/HI 9.8-2018 standard. A numerical simulation was performed to study the flow in a full-scale pump sump. The results showed that the installation of floor splitter plate can eliminate vortices efficiently and reduce swirl angle significantly. However, optimization of floor splitter design is needed to achieve a reduction effect that can reduce swirl angles to an acceptable value of lower than 5° according to ANSI/HI 9.8-2018 standard.",signatures:"Zambri Harun, Tajul Ariffin Norizan and Wan Hanna Melini Wan Mohtar",downloadPdfUrl:"/chapter/pdf-download/72530",previewPdfUrl:"/chapter/pdf-preview/72530",authors:[{id:"243152",title:"Dr.",name:"Zambri",surname:"Harun",slug:"zambri-harun",fullName:"Zambri Harun"},{id:"313310",title:"Mr.",name:"Tajul Ariffin",surname:"Norizan",slug:"tajul-ariffin-norizan",fullName:"Tajul Ariffin Norizan"},{id:"317421",title:"Dr.",name:"Wan Hanna Melini",surname:"Wan Mohtar",slug:"wan-hanna-melini-wan-mohtar",fullName:"Wan Hanna Melini Wan Mohtar"}],corrections:null},{id:"72116",title:"The Effects of Curved Blade Turbine on the Hydrodynamic Structure of a Stirred Tank",doi:"10.5772/intechopen.92394",slug:"the-effects-of-curved-blade-turbine-on-the-hydrodynamic-structure-of-a-stirred-tank",totalDownloads:349,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This work is aimed at studying the hydrodynamic structure in a cylindrical stirred vessel equipped with an eight-curved blade turbine. Flow fields were measured by two-dimensional particle image velocimetry (PIV) to evaluate the effect of the curved blade turbine. Velocity field, axial and radial velocity distribution, root mean square (rms) of the velocity fluctuations, vorticity, and turbulent kinetic energy were presented. Therefore, two recirculation loops were formed close to the free surface and in the bottom of the tank. Moreover, the highest value area of the vorticity is localized in the upper region of the tank which follows the same direction of the first circulation loop. The turbulent kinetic energy is maximum at the blade tip following the trailing vortices.",signatures:"Bilel Ben Amira, Mariem Ammar, Ahmad Kaffel, Zied Driss and Mohamed Salah Abid",downloadPdfUrl:"/chapter/pdf-download/72116",previewPdfUrl:"/chapter/pdf-preview/72116",authors:[{id:"119394",title:"Prof.",name:"Mohamed Salah",surname:"Abid",slug:"mohamed-salah-abid",fullName:"Mohamed Salah Abid"},{id:"291713",title:"Ms.",name:"Ammar",surname:"Meriem",slug:"ammar-meriem",fullName:"Ammar Meriem"},{id:"317510",title:"Dr.",name:"Bilel",surname:"Ben Amira",slug:"bilel-ben-amira",fullName:"Bilel Ben Amira"},{id:"317511",title:"Dr.",name:"Ahmed",surname:"Kaffel",slug:"ahmed-kaffel",fullName:"Ahmed Kaffel"},{id:"317512",title:"Prof.",name:"Zied",surname:"Driss",slug:"zied-driss",fullName:"Zied Driss"}],corrections:null},{id:"71293",title:"Urban Heat Island Effects in Tropical Climate",doi:"10.5772/intechopen.91253",slug:"urban-heat-island-effects-in-tropical-climate",totalDownloads:756,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"This paper reviews some of the characteristics of urban climates and the causes and effects of urban heat island (UHI) issues in the tropical climate. UHI effect is a kind of heat accumulation phenomenon within the urban areas due to urban construction and human activities. It is recognized as the most evident characteristic of urban climate. The increase of land surface temperature in San Juan, Puerto Rico, caused by the UHI effect was influenced by the change of land use and material types in construction. The impacts of daily temperature, surface albedo, evapotranspiration (ET), and anthropogenic heating on the near-surface climate are discussed. Analyzed data and field measurements indicate that increasing albedo and vegetation cover can be effective in reducing the surface and air temperatures near the ground. Some mitigation and prevention measures are proposed for the effects of UHI, such as a flash flood warning system.",signatures:"Luz E. Torres Molina, Sara Morales and Luis F. Carrión",downloadPdfUrl:"/chapter/pdf-download/71293",previewPdfUrl:"/chapter/pdf-preview/71293",authors:[{id:"204434",title:"Ph.D.",name:"Luz Estella",surname:"Torres Molina",slug:"luz-estella-torres-molina",fullName:"Luz Estella Torres Molina"},{id:"313858",title:"Mr.",name:"Luis F.",surname:"Carrion",slug:"luis-f.-carrion",fullName:"Luis F. Carrion"},{id:"313859",title:"Mrs.",name:"Sara",surname:"Morales",slug:"sara-morales",fullName:"Sara Morales"}],corrections:null},{id:"72486",title:"The Effect of Liquid Viscosity on the Rise Velocity of Taylor Bubbles in Small Diameter Bubble Column",doi:"10.5772/intechopen.92754",slug:"the-effect-of-liquid-viscosity-on-the-rise-velocity-of-taylor-bubbles-in-small-diameter-bubble-colum",totalDownloads:601,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The rise velocity of Taylor bubbles in small diameter bubble column was measured via cross-correlation between two planes of time-averaged void fraction data obtained from the electrical capacitance tomography (ECT). This was subsequently compared with the rise velocity obtained from the high-speed camera, manual time series analysis and likewise empirical models. The inertia, viscous and gravitational forces were identified as forces, which could influence the rise velocity. Fluid flow analysis was carried out using slug Reynolds number, Froude number and inverse dimensionless viscosity, which are important dimensionless parameters influencing the rise velocity of Taylor bubbles in different liquid viscosities, with the parameters being functions of the fluid properties and column diameter. It was found that the Froude number decreases with an increase in viscosity with a variation in flow as superficial gas velocity increases with reduction in rise velocity. A dominant effect of viscous and gravitational forces over inertia forces was obtained, which showed an agreement with Stokes law, where drag force is directly proportional to viscosity. Hence, the drag force increases as viscosity increases (5 < 100 < 1000 < 5000 mPa s), leading to a decrease in the rise velocity of Taylor bubbles. It was concluded that the rise velocity of Taylor bubbles decreases with an increase in liquid viscosity and, on the other hand, increases with an increase in superficial gas velocity.",signatures:"Olumayowa T. 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In the United States, there are ~10,000 new cases diagnosed annually, and >50,000 patients living with the disease [2, 3]. The clinical responses of patients are particularly poor and vary greatly among individuals [4], and ~32% of all diagnosed cases survive less than a year [3]. This highly aggressive tumor develops either Schematic representation of the differentiation process of neural stem cells into different cell lineages of the CNS and putative cells of origin of gliomas. Protein markers for neural stem cells, progenitors cells, and differentiated cells are indicated in boxes. The normal differentiation process (green arrows) originates three main types of cells in the mature CNS, including neurons and glial cells (particularly oligodendrocytes and astrocytes; ependymal cells are not represented). The most classical hypothesis on the origin of glioma cells is represented by orange arrows (differentiated glial cells are malignantly transformed through a dedifferentiation process). The most recent hypothesis postulating that gliomas originate from the direct transformation of neural stem cells or glial progenitor cells is represented by grey arrows.Figure 1.
The true cellular origin of gliomas, including GBM, is still a debatable question. It is generally accepted that identifying such tumor-initiating cells may allow a better understanding of tumor biology, and ultimately help in designing improved therapies for GBM. All human tumors arise from a series of molecular alterations that occur in a small number, or even single, founder cells. These tumor cells present a clonal nature due to the sequential accumulation of multiple rare genetic and epigenetic events. The critical importance of the tumor microenvironment in influencing tumor cells behavior and evolution has been recently recognized [7]. Indeed, the tumor microenvironment has been associated with the generation and maintenance of tumor heterogeneity; thus, understanding not only the surrounding microenvironment but also tumor heterogeneity, as well as their relationships, may be crucial in understanding the biology of these tumors. In the case of the brain tissue, a highly complex microenvironment with extreme phenotypic and functional diversity, the multiplicity of putative brain tumor cells of origin, and the variety of niches in which the malignant cells may evolve, is even more challenging. Thus, understanding this complexity is crucial to provide firm evidence for the cellular origin of gliomas [8-10]. Two different hypotheses for the origin of glioma cells, or tumor cells in general, have been proposed (Figure 1), as detailed below.
\nOne classical hypothesis postulates that cancer cells arise from the accumulation of alterations that occur in differentiated mature cells (glial cells in the case of glioma tumors, including GBM), which would result in a dedifferentiation of these cells along the carcinogenic process. This concept is supported, for instance, by the histological similarities between functional and differentiated glial cells and tumor cells from gliomas. In addition, before the experimental identification of the adult neural stem cells (NSCs), glial cells were the only known replication-competent population of cells in the adult brain, which further supported the idea that highly-proliferative glioma cells could derive from accumulated alterations in differentiated and proliferative glial cells. A landmark study supporting this theory showed that differentiated cells could be transformed into a pluripotent embryonic stem cell phenotype by using a cocktail of transcription factors [11]. However, this hypothesis has never been adequately tested, as there have been experimental limitations that preclude its validation, including: (i) the absence of good mature “astrocyte” markers in i
The second and most recent hypothesis assumes that cancer cells arise from the accumulation of alterations that occur directly in stem cells, or progenitor (multipotent) undifferentiated cells, that are present in different tissues throughout the entire lifetime (neural stem cells or glial progenitor cells in the case of brain gliomas). According to this rationale, the tumorigenic process would not be accompanied by a dedifferentiation mechanism, as the molecular alterations would accumulate directly in undifferentiated cells [7-9, 14]. In support of this hypothesis is the concept of cancer stem cells (CSCs), which is a subpopulation of cells in the tumor that displays self-renewal capacity, and which can give rise to heterogeneous cancer cells that constitute the tumor. However, it should be noted that the concepts of CSCs and tumor-initiating cells have been frequently confused. The term ‘‘tumor-initiating cells’’ refers to the cells of origin of the tumor, whose alterations support tumor establishment and progression; in contrast, CSCs would more accurately be referred to as tumor-propagating cells, with stem cell-like properties, which are not necessarily the cells of origin [8, 14, 15]. A study by Chen and colleagues (2010) may help to distinguish these different cell populations and their role on tumor development, particularly in GBM [16]. They demonstrated a hierarchical organization of brain tumor-initiating cells by identifying subpopulations of clonal and long-term proliferating cells in GBM specimens. These subpopulations were shown to be hierarchically organized and to give rise to tumors with different molecular and histopathological features [16]. There are specific and very well delimited regions in the brain where neural stem cells and progenitor cells exist, particularly the subventricular zone (SVZ) of the fore brain lateral ventricles, and the subgranular zone (SGZ) in the dentate gyrus of the hippocampus [8-10]. It has been hypothesized that these are favorable regions where the process of gliomagenesis may originate, as these regions present an attractive microenvironment that has been described as propitious for the growth of stem cells, namely in the SVZ [8-10]. There is increasing experimental evidence that the SVZ is one of the most important regions of origin for malignant gliomas [10] as it may present ideal conditions for gliomagenesis, like the exposure to a transcription factor cocktail ideal for their growth. When compared to any other brain regions, stem cell-containing compartments have been shown to be more susceptible to tumor transformation [10], which additionally may argue in favor of this hypothesis of tumors arising from changes in stem/progenitor cells. Additionally, while it may be coincidence, there is a great similarity between the SVZ stem/progenitor cells and glioma cells. For instance, malignant astrocytic tumors in the brain typically appear close to the lateral ventricles [9, 10].
\nIn the recent years, the notable therapy resistance of gliomas, namely GBM, has been associated with the presence of glioma stem cells (GSCs). These cells present characteristics of stem cells, including: (i) self-renewal; (ii) multipotency, i.e., the capacity to differentiate into other cell lineages; and (iii) high replicative potential. GSCs are predicted to be difficult to target by anti-cancer therapeutics because they have a slow cell cycle, present high levels of proteins involved in drug efflux, and do not express or are dependent on particular oncoproteins for which targeted therapies are currently available [17]. GSCs were one of the first types of cancer stem cells isolated from solid tumors [18]. It was shown that as few as 100 GSCs could give rise to tumors that recapitulated the parental tumor when implanted in xenografted immunodeficient mice, whereas as many as 1,000,000 non-GSCs could not [18]. This suggests that neoplastic clones are maintained exclusively by a little fraction of cells with stem cell properties [18]. Of note, studies involving the use of GSCs face many difficulties, particularly in isolating such cells directly from biopsies, partly because of the high cellular heterogeneity composition of the specimen. On the other hand, currently there are no standardized methods available for cell sorting and assessment of “stemness” [8]. Indeed, there is a relevant discussion regarding the best methodology for culturing GSCs isolated from human GBM specimens. It has been argued by several authors that adherent monolayer cultures of glioma cells allow a more homogeneous exposure to the culture conditions (e.g., nutrients and oxygen levels) than nonadherent cultures, thus increasing the homogeneity of the cell population, reviewed in [8]. In contrast, the sphere-forming assay has been widely used for this purpose. The fidelity and benefits of these assays are still under debate. Thus, there is an exigency to standardize methods for identifying and isolating GSCs with unequivocal markers. It is believed that the use of NSCs markers is a good principle for identifying GSCs, as NSCs are now known to exist in very restricted areas of the brain, and can be unambiguously identified with specific markers [8]. Indeed, in the last decade, putative markers of GSCs have been identified, including Nestin, CD133, L1CAM, CD15, CD44, Id1, and integrin-α6 [8, 10, 14, 19-21]. Nonetheless, none of these markers is sufficient to, independently, identify specifically GSCs, implicating that a functional identification of GSCs (including their ability to (i) be tumorigenic in
GBM, like other cancers, is a disease that presents several alterations, including DNA mutations, copy number aberrations, and chromosomal rearrangements, but also DNA and histones epigenetic modifications, ultimately resulting in alterations in the gene expression profiles [22]. Molecular studies from the last decades have identified critical genetic alterations that affect many key pathways involved in the regulation of typical cancer hallmarks, such as alterations in cell cycle, migration, proliferation, survival, angiogenesis, invasion and apoptosis [22]. While several alterations in signaling pathways occur in GBM, such as Wnt, Notch and Shh pathways (particularly relevant due to their associations with cancer stem-cells and resistance to radiochemotherapy) [23, 24], the most frequent aberrations in GBM occur in three critical signaling pathways: (i) retinoblastoma (RB), (ii) p53, and (iii) RTK/RAS/PI3K pathways [22, 25, 26], as detailed in Figure 2 and below.
\nMutations in genes implicated in cell cycle regulation that allow cells to proliferate uncontrollably have been frequently identified in GBM, as in other human tumors [26-28]. The RB pathway, which is important in the G1/S transition, is aberrantly inactivated in GBM through the alteration of several genes and proteins [28].
\nIn a normal condition, the RB protein (encoded by
In GBM, the
The
\n
GBM cells also commonly present a constitutive activation of cell growth signaling pathways by the overexpression of several mitogens and their specific membrane receptors [22, 24, 26, 33]. Glioma cells can also acquire mutations in the membrane receptors becoming independent of exogenous growth stimulation, increasing survival and motility [22, 24, 26, 33, 34]. In GBM, the deregulation of growth factor signaling occurs frequently by the amplification and/or activating mutations of RTKs [22, 26]. These play critical roles in several cellular processes, including cell growth, motility, survival and proliferation, and are tightly controlled by various physiological mechanisms (e.g., autocrine loops in which RTK ligands are produced in result of receptor activation) [26]. One of the most described RTK alteration in GBM is the deletion of exons 2-7 of epidermal growth factor receptor (
The development of new platforms of genome-scale screenings has allowed a more robust identification of the accumulation of genetic and epigenetic alterations. The Cancer Genome Atlas (TCGA) project, for example, was established with the aim of using genome-wide analysis technologies, which include DNA copy number, gene expression, DNA methylation, and nucleotide sequencing, to understand the molecular basis of cancer [26]. With this multiplatform profiling and using an integrative analysis, they identified a highly interconnected network of aberrations in GBM that include the pathways described above (RB, p53, RTKs and PI3K pathways) [26]. Interestingly, this integrative analysis showed a statistical tendency to mutual exclusivity for the specific alterations of components within each pathway. Nonetheless a great percentage of samples harbored aberrations in all signaling pathways [26], which is in agreement with the hypothesis that these pathways are a core prerequisite for GBM disease.
\nIn addition to the most common genetic alterations found in GBM, several other aberrations have been described. For example, mutations in
Using an unsupervised hierarchical clustering analysis, Verhaak
The identity of the classical subtype was defined by displaying the most common genomic aberrations of GBM, with 93% of samples presenting amplifications in chromosome 7 paired with loss of chromosome 10, 95% showing high levels of
The mesenchymal subtype presents a focal hemizygous deletions of 17q11.2 region that contains the
The most relevant features of the proneural subtype were high levels of
In what concerns the neural subtype, few characteristics were reported, and it was almost merely classified based on neuron markers expression, including neurofilament light chain polypeptide (NEFL), gamma-aminobutyric acid A receptor (GABRA1), synaptotagmin I (
It is widely recognized that the molecular stratification of GBM patients may prove crucial in rationalizing treatment decisions, for which a set of molecular markers predictive of tumor response to specific therapies and/or patient outcome are required. The most well established prognostic factors in GBM patients include age, general performance status, tumor histological features and the extent of tumor resection [48]. Recently, several studies have identified biological and molecular features of GBMs that present prognostic value [37, 46, 49-58] and may help in therapeutic decisions. The work performed so far presents reasons for both optimism and caution regarding the improvements in the diagnosis and treatment of patients, but also demand validation in prospectively followed and in uniformly treated patients. Therefore, the focus remains in the identification of biomarkers that truly foster patient distinction in ways that may improve therapeutic decisions. The current most relevant prognostic biomarkers for GBM are summarized in Table 1, of which the most promising are briefly discussed below.
\n\n | \n \n | \n
\n | \n [52] | \n
\n | \n [57] | \n
Loss of chromosome 10 | \n[56] | \n
Activation of the PI3K/AKT pathway | \n[50, 58] | \n
\n | \n [36, 37] | \n
\n | \n [35, 36] | \n
\n | \n [53, 56] | \n
miRNA expression signatures | \n[59] | \n
\n | \n [37] | \n
\n | \n [51, 55] | \n
\n | \n [55] | \n
Molecular signatures | \n[40, 46] | \n
High expression of angiogenic genes | \n[46] | \n
Stem-cell like gene expression signatures | \n[37, 49, 54] | \n
Activation of MAPK members | \n[58] | \n
\n | \n [46] | \n
Selected molecular prognostic markers for glioblastoma.
Many studies have shown that the methylation status of
Other important prognostic factors for GBM have been revealed by recent genomic studies and concern the presence of mutations in isocitrate dehydrogenase 1 and 2 genes (
Strikingly, as stated above, mutations in
Recent evidences have been revealing a remarkable resemblance between tumorigenic and developmental processes, indicating the relevance of molecular regulatory mechanisms crucial on normal development and on the tumorigenic process. Homeobox (
The aberrant expression of
The molecular prognostic biomarkers currently available require the evaluation of tumor tissue in order to assess gene expression and promoter methylation levels. Moreover, tumor progression and treatment responses are monitored using imaging techniques, which do not distinguish the effects of treatment and tumor regrowth. In fact, patients who are submitted to magnetic resonance imaging (MRI) shortly after radiotherapy show increased volume of the tumor, which in up to 50% of the cases, is a consequence of the increased blood vessel permeability due to radiotherapy, an effect called pseudoprogession [87]. As it is difficult to distinguish between the therapeutic effects and real growth of the tumor [88], in addition to the impossibility of multiple tumor sampling during the course of the malignancy [89, 90], demand the establishment of less invasive prognostic and predictive markers. Serum markers that correlate with tumor biological properties might prove crucial in providing prognostic information and response to treatment, therefore allowing the proper adjustment of therapeutics, and improve care of patients with GBM. A study conducted by Tanwar [91] analyzed gene expression microarray data of tumor tissue from glioma patients, and showed that chitinase 3-like 1 (
In conclusion, the identification of molecular biomarkers that truly aid in the distinction of patients and therapeutic decisions still requires much effort. The integration of clinical and molecular data is becoming more frequent, and easier to perform and analyze, which will probably lead to more targeted and effective treatments. Moreover, it seems probable that sets of molecular biomarkers for GBM will be established in the next few years, and will become part of the clinical routine, leading to tailored therapies for subgroups of GBM patients. Importantly, the timely identification of patients who are not likely to respond to a certain therapy would allow their integration in clinical trials with novel therapies, but also to avoid the possible adverse side effects of a therapy that may not prove beneficial. Equally interesting, the establishment of molecular biomarkers of tumor therapy resistance may lead to a more guided and rational design of novel therapeutic agents and clinical trials for GBM patients. In the search for GBM patient individualized therapy, the discovery of particular tumor molecular features, as the status of
As described throughout this chapter, the molecular and cellular heterogeneity of GBM represents a major therapeutic challenge, but also offers a large number of opportunities to specific targeting of tumor cells’ alterations. Furthermore, the unsatisfactory prognosis of GBM patients, independently of the used treatment approaches, and the absence of a cure or significant advances in the treatment of GBM, are the major drivers of GBM therapeutics research.
\nThe current standard therapy for the treatment of GBM includes maximal surgical resection, followed by radiotherapy (RT) with concomitant and adjuvant administration of alkylating agents [98]. Administration of RT is usually given after the surgical removal of the tumor in order to eliminate residual tumor cells [99]. Alkylating agents act by introducing methyl groups in different positions in the DNA, resulting in DNA damage and specific cytotoxicity, that ultimately leads to apoptosis and cell death [100]. Before 1999, only nitrosourea-based chemotherapeutics were approved for the treatment of GBM, which includes oral lomustine (CCNU) and intravenous carmustine (BCNU) [101]. In 1999, FDA approved Gliadel® that consists in a polymeric biodegradable wafer that is able to release carmustine during 2-3 weeks after implantation in the gap where the tumor was removed during surgery [101-103]. Furthermore, in this same year, FDA granted accelerated approval to the imidazole derivative of the second-generation class of alkylating agents, TMZ, mainly because of its efficient absorption after oral administration and its ability to easily cross the blood-brain barrier [101, 104].
\nTMZ was regularly approved by the FDA in 2005, and became the standard chemotherapeutic agent for the treatment of GBM [5]. The approval of TMZ was mainly due to the improvement in the OS of patients observed in a landmark study by Stupp
Besides TMZ, bevacizumab (BVZ, also known as Avastin®) was also conceded accelerated approval by the FDA in 2009 as monotherapy for patients with progressive GBM that did not respond to standard care (TMZ + RT) [101, 107]. This drug is a monoclonal antibody that targets VEGF, which is involved in the formation of new blood vessels [99]. Since GBM are highly vascularized tumors, this drug presented an attractive way to target tumor-associated increased angiogenesis [108]. When BVZ was combined with TMZ + RT for the treatment of newly diagnosed GBM patients in a phase II clinical trial, an improvement in OS (19.6 vs. 14.6 months) and progression-free survival (PFS, 13.6 vs. 6.9 months) was reported, when compared to the control cohort of the European Organization for Research and Treatment of Cancer-National Cancer Institute of Canada (EORTC/NCIC), in which patients were treated only with RT and TMZ [109]. BVZ also showed good radiographic responses in patients with recurrent GBM (71% and 35%, according to Levin and Macdonald criteria, respectively) when used first as a single agent, and later combined with irinotecan (topoisomerase I inhibitor) in a phase II clinical trial [110]. Although some exciting clinical results were described, several
Conceptually, the development of targeted therapies for the treatment of GBM represents a significant advance in the search for a cure for this devastating disease. First, the specificity of these therapies has the potential to reduce toxic side effects. Second, the direct blockade of altered oncogenic signaling cascades may allow the reduction of tumor cell proliferation [113]. This next part will review some of the most promising therapeutic molecular and targeting strategies, including membrane proteins and growth factor receptors (e.g. RTK), and intracellular signaling pathways.
\nRTKs represent attractive targets for this therapeutic approach, since they are associated with GBM oncogenesis, and the binding of growth factors to these receptors activate signaling pathways that drive GBM cells survival and proliferation [113, 114] (see section 2.3 for information). There are two kinds of inhibitors for RTKs: (i) inhibitors targeting the intracellular tyrosine kinase domain (TKD), and (ii) monoclonal antibodies that can block RTK activation or target the RTK-expressing cells [115].
\nEGFR
As stated above
Most of the
PDGFR
As referred previously,
VEGFR
The therapeutic targeting of GBM-associated angiogenesis is already an approved strategy through VEGF inhibition with BVZ, but can also be achieved through inhibition of VEGF receptors using specific inhibitors, like cediranib, sorafenib, sunitinib, pazopanib, vandetanib, CT-332 (all VEGFR), XL-184 (VEGFR2, Met, RET, c-KIT, Flt3, Tie-2), semaxanib or AEE 788 [98, 116, 133]. For instance, cediranib (AZD2171) inhibits all VEGFR subtypes and was explored in phase I, II and III clinical trials [116]. The outcomes of cediranib (AZD2171) treatment in GBM patients are described as similar to the ones observed for BVZ, although only one of the completed trials has published results (Table 2) [116]. As reported for BVZ, also cediranib was associated with infiltrative cells not visible with contrast-enhanced MRI [112, 134]. In orthotopic mouse models of GBM, this VEGFR inhibitor induced alterations in the permeability and diameter of blood vessels, alleviating edema and increasing the survival of the mice [135].
\nMet
Met is an RTK for hepatocyte growth factor (HGF) that activates a series of signaling pathways, as referred above in section 2.3, similar to what is observed for EGFR or PDGFR activation, which ultimately leads to proliferative and invasive behaviors of cancer cells [106, 136]. In a series of 62 GBM patient samples, Met was found to be overexpressed and associated with poor prognosis, and with an invasive phenotype, supported by invasive multifoci lesions and expression of metalloproteinases 2 and 9 [137]. Inhibitors targeting Met include tivantinib, and cabozantinib (XL184) a potent inhibitor of several kinases, cabozantinib (XL184), which hase shown significant inhibitory effect on GBM tumor growth [138]. Furthermore, three phase I and II clinical trials for the evaluation of cabozantinib on the treatment of newly diagnosed GBM (monotherapy or combined with RT + TMZ) and recurrent GBM (monotherapy) (NCT00960492, NCT00704288 and NCT01068782) are now ongoing [118]. Another therapeutic approach to target HGF/Met axis is the use of the monoclonal antibody against HGF, rilotumumab (AMG-102), which was already tested during a phase II [116] clinical trial for recurrent GBM (Table 2); a second phase II trial to test the combination of rilotumumab with Avastin in patients with recurrent MG is now recruiting patients (NCT01113398) [118].
\nIntegrins
Therapeutic targeting of the cell adhesion receptors integrins, which are transmembrane glycoproteins that attach cells to extracellular matrix proteins of the basement membrane or to ligands on other cells, have also proved to be a valuable therapeutic strategy for the treatment of GBM, with several recent clinical trials testing the success of the integrin inhibitor cilengetide (EMD 121974) as a monotherapy or in combination with RT + TMZ (Table 2) [139]. Cilengitide is an RGD (Asp-Gly-Asp) synthetic peptide that inhibits integrins αVβ3 and αVβ5 by receptor binding competition [139].
PI3K/AKT/mTOR pathway
As already mentioned the PI3K/Akt/mTOR pathway represents one of the most altered pathways in cancer, including GBM [113, 116]. Several inhibitors targeting different elements of this pathway are available and being tested both pre-clinically and at the clinical level. Enzastaurin is a specific inhibitor of protein kinase C (PKC) proteins, thus indirectly inhibiting Akt [104, 113, 142]. In preclinical studies, this inhibitor was able to suppress proliferation of GBM cells and tumor growth in GBM xenograft mice models [143]. In clinical studies, especially for recurrent GBM patients this drug failed to improve patient outcome, with PFS, OS and 6-PFS inferior to that of patients treated with lomustine in phase III clinical trials (Table 2) [144]. Inhibition of Akt can also be achieved using perifosine (KRX-0401), which affects the interaction of PIP3 with the PH domain of Akt [24]. When this drug was compared to mTOR inhibition in
Several inhibitors of PI3K are also available, but the clinical evaluation of their efficacy is still very preliminary [150]. The class of pan-PI3K inhibitors (inhibit the catalytic p110 subunit) include LY294002, ZSTK474, and wortmannin. Derivatives of LY294002 and wortmannin, include SF1126 (LY294002 conjugated with an RGD peptide), PWT-458 and PX-866 (the first is a PEGylated derivate of wortmannin and the second is a wortmannin analog) [150]. From this group of specific PI3K inhibitors, only evaluation of PX-866 is proposed in a phase II clinical trial for the treatment of recurrent GBM patients, and is currently recruiting patients (NCT01259869) (Table 2) [118]. XL147 and GDC-0941 are also class I PI3K inhibitors, and IC877114 (targets p110δ) and TG100-115 (targets p110δ and p110γ) are PI3K isoform-specific inhibitors [150]. In turn, LY294002 was able to potentiate the citotoxicity of TMZ in glioma cells [151, 152]. Besides these agents that only target PI3K there are several dual PI3K/mTOR inhibitors, as PI-103, PI-540, PI-620, XL765, BEZ235 and BGT226 [150]. XL765 and XL147 were already tested in a phase I clinical trial with recurrent GBM patients (Table 2). Some preclinical studies support the theory of targeting these pathways in GBM therapeutics. Combination of LY294002 with the mTOR inhibitor rapamycin (or sirolimus) was able to diminish the self-renewal capacity of GBM cells and induce differentiation of cancer stem cell like cells (CSC); the same effect was achieved using a dual PI3K/mTOR inhibitor, NVP-BEZ235, which additionally reduced the ability of GBM CSLC to form tumors
For specific targeting of mTOR, several inhibitors were developed and tested clinically, like sirolimus (rapamycin), everolimus (RAD001) and temsirolimus (CCI-779) [106, 133]. All of these agents were already evaluated for the treatment of GBM in phase I and II clinical trials, but no significant improvements were seen (Table 2). A preclinical study showed that the outcome of mTOR inhibitory treatments could be efficiently monitored by Positron Emission Tomography (PET) based only in glucose and thymidine metabolism, through the uptake of [18F]FDG and [18F]FLT [154]. Furthermore, combination with other kinase inhibitors like AEE788 (inhibits both EGFR and VEGFR2) also showed some preclinical promising results, since its combination with everolimus (RAD001) resulted in increased effect on cell cycle arrest, proliferation and apoptosis, and impact tumor growth and survival
RAS/RAF/MEK/ERK/MAPK pathway
Another important pathway contributing to the neoplastic process is the one mediated by RAS/RAF/MEK/MAPK [106]. Inhibitors targeting members of this pathway include the farnesil transferase inhibitors of RAS, such as tipifarnib (Zanestra or R115777) and lonafarnib (Sarasar or SCH 66336) or multiple kinases inhibitors that target this pathway, like sorafenib [98, 116]. Some of the more significant clinical results of tipifarnib are summarized in Table 2. A phase I clinical trial to test the effectiveness of combining tipifarnib with TMZ and RT for newly diagnosed GBM or gliosarcoma is now ongoing (NCT00049387) [118]. Sorafenib is described as an inhibitor of EGFR, PDGFR and RAF, that can block MEK activation and, in preclinical studies, was able to induce apoptosis, and decreased proliferation of GBM cells [98, 158]. At the clinical level, it has been extensively studied in 12 clinical trials with completed, ongoing or recruiting status [118]; however, the results have still been somewhat different, with good results for newly diagnosed GBM and recurrent GBM, but when combined with BVZ for the treatment of recurrent GBM, it failed to improve survival, showing a high percentage of patients with progressive disease (Table 2) [118].
\nHistone deacetylases (HDACs)
Epigenetic events are crucial during the carcinogenic process, in which the chromatin state and remodeling are important mediators. Histone deacetylases (HDAC) are responsible for chromatin condensation and repression of transcription [159, 160]. Mechanistically they catalyze the elimination of acetyl groups from lysine residues in N-terminal tails of histone proteins [161]. The use of specific HDAC inhibitors has been described as an attractive opportunity to alter cancer-related epigenetic modifications [159]. These inhibitors are also reported as being able to block angiogenesis and invasion, promote cell cycle arrest and apoptosis, and to act as immunomodulators [116, 159, 160]. Valproic acid (VPA) is a short chain fatty acid, class I and IIa HDAC inhibitor, used as an anticonvulsant drug and frequently administered to treat glioma-associated seizures [159, 162, 163]. So, when the results of the EORTC/NCIC TMZ trial were analyzed taking in consideration the anti-epileptic drugs used, an interesting result showing a benefit in OS of the patients treated with TMZ + RT that were under VPA treatment was observed, suggesting that this drug could enhance the effects of TMZ + RT treatment [162]. VPA in combination with TMZ
\n | \n \n | \n \n | \n
Erlotinib (Tarceva®); EGFR | \n Phase I, and II clinical trials Acceptable toxicity and tolerable treatment with daily administrations of 150-200 mg/day dose Newly diagnosed GBM: combined with TMZ showed a PFS of 7.2 months and OS of 15.3 months; worse outcome for patients older than 70 years old; combined with standard care (RT + TMZ), the OS was 19.3 months, and correlated with Recurrent GBM: erlotinib as a single agent was not able to improve PFS compared to standard treatment (TMZ or carmustine + RT); combined with mTOR inhibitor sirolimus, treatment was well tolerated and OS was 33.8 weeks; combination with carboplatin showed a 30 weeks OS; Recurrent MG: combination with BVZ resulted in partial or total radiographic response for 48% of GBM patients and association with PFS; GBM tumors showing high levels of HIF-2α and VEGFR2 expression presented a worst prognosis. Recruiting or ongoing clinical trials combining erlotinib with isotretinoin, sirolimus and vorinostat, and also single agent administration for patients harboring the EGFR-vIII mutation (NCT01110876, NCT01103375, NCT01257594, NCT00509431). Nonprogressive GBM: as single agent, 1-year PFS was only 9% and less than 53% of 2 months, and less than 57% of the patients were alive after 1 year. | \n [118, 167-175] | \n
Gefitinib (Iressa or ZD1839); EGFR | \n Phase I, and II clinical trials Recurrent GBM: as single agent, the treatment was well tolerated and resulted in OS of 39.4 weeks and PFS of 8.1 weeks. In a phase II study, OS did not overcome 8.8 months. Newly diagnosed GBM: 1-year OS (54.2%) and 1-year PFS (16.7%) were not significantly different from controls of other clinical trials. | \n [176-178] | \n
Rindopepimut (CDX-110, PEP-3); EGFR-vIII | \n Phase I, II, and III clinical trials EGFR-vIII-positive newly diagnosed GBM: given with GM-CSF, TTP of 14.2 months (vs. 6.3 months of historical controls) and OS of 26 months (vs. 15 months of historical controls); administration with TMZ also improved TTP (15.2 months vs. 6.4 months) and OS (23.2 months vs. 15.2 months); phase III trial (recruiting status) is projected to test the efficacy of rindopepimut with TMZ (NCT01480479). Newly diagnosed GBM: TTP was 10.2 months and OS was 22.8 months (vaccine given with DC); Phase II clinical trial is recruiting patients with relapsed GBM EGFR-vIII positive to test the efficacy of rindopepimut with BVZ (NCT01498328). | \n [118, 124] | \n
Imatinib mesylate; PDGFR, KIT, ABL | \n Phase I, II, and III clinical trials Newly diagnosed GBM: a phase II study with 20 patients showed a OS of 6.2 months. Recurrent GBM or MG: as single agent was well tolerated until doses of 800-1200 g/day, but very poor outcome with 6-PFS of 3%, only 2/34 patients with PR, and 6/34 with SD; when combined with HU, 6-PFS (27%) improved, but still very poor; combination with HU and vatalanib was well tolerated and resulted in OS of 48 weeks, PFS of 12 weeks and 6-PFS of 25%. In another phase II study the outcome of patients treated with imatinib as single agent was also (in newly diagnosed GBM) very poor (6-PFS: 16%); when combined with HU, imatinib also lacked efficacy. A phase III clinical trial showed no differences in TMZ resistant GBM patients treated with imatinbib + HU or HU alone (NCT00154375); phase II clinical trials combining imatinib with HU and Zactima were also performed but no results have been published (NCT00613054). | \n [118, 126, 129-132, 179, 180] | \n
Cediranib (AZD2171); VEGFR | \n Phase I, II, and III clinical trials Recurrent GBM: as a single agent showed a PFS was 117 days and OS was 227 days (phase II); phase I trials to test cediranib + lomustine to treat GBM is already completed but without published results (NCT00503204); a phase III trial with the same combinatory approach for the treatment of recurrent GBM in currently ongoing (NCT00777153); recruiting trials include combination with gefitinib (NCT01310855) and with cilengitide (NCT00979862). Newly diagnosed GBM: all clinical trials are currently ongoing or recruiting – phase I and phase I/II cediranib + RT + TMZ (NCT01062425 and NCT00662506); phase I combination with BVZ (NCT00458731); phase I combination with gamma secretase inhibitor RO4929097 (NCT0130855). | \n [118, 181, 182] | \n
Rilotumumab (AMG-102); HGF | \n Phase II clinical trial Recurrent GBM: when combined with prior BVZ treatment, did not affect PFS (4-4.1 weeks vs. 4.1-4.7 weeks), but OS was significantly different (3.4-3.6 months vs. 10.9-11.4 months). | \n [183] | \n
PX-866; PI3K | \n Phase I, and II clinical trials Completed a phase I clinical study in patients with solid tumors (NCT00726583); Recruiting recurrent GBM patients for a phase II clinical trial (NCT01259869). | \n [118] | \n
XL765; PI3K/mTOR | \n Phase I clinical trial Recurrent GBM: combination with a PI3K inhibitor XL147 already completed phase I trial (NCT0124460). Recruiting for a phase I trial for combination with TMZ to treat MG (NCT00704080). | \n [118] | \n
Enzastaurin; PKCβ (indirect inhibition of Akt) | \n Phase I, II, and III clinical trials Recurrent or progressive MG: in recurrent HGG, monotherapy had no significant impact in 6-PFS (7%); when compared with lomustine in a phase III clinical trial, no improvement in OS or PFS was achieved. | \n [118, 142, 144, 184, 185] | \n
Everolimus (RAD001); mTOR | \n Phase I, and II clinical trials Phase I clinical trials showed that everolimus was well tolerated even when combined with RT + TMZ, BVZ or erlotinib. Changes in metabolism detected with FDG positron emission tomography days after administration of everolimus. \n Newly diagnosed GBM: combination with TMZ + RT + BVZ followed by BVZ + everolimus in a phase II clinical trial resulted in 57% PR, 1 CR, 18-months OS of 44%, and 18-months PFS of 29%. | \n [186-188] | \n
Temsirolimus (CCI779); mTOR | \n Phase I, and II clinical trials Phase I trial showed that temsirolimus combined with TMZ and RT increased the risk of infectious diseases (3/25 fatal infections). Recurrent GBM: it was well tolerated as a single agent, and 36% radiographic responses were observed; 6-PFS was 7.8%, and OS was 4.4 months (phase II). | \n [189, 190] | \n
Sirolimus; mTOR | \n Phase I, and II clinical trials Recurrent GBM or MG: in tumors without PTEN, mTOR inhibition correlated with decreased proliferation of the tumors (phase I/II); combination with erlotinib (phase II) resulted in 47% SD, no CR or PR and 6-PFS of 3.1%; phase I/II trial combinatory treatment with erlotinib is currently ongoing (NCT00509431); phase I trial is recruiting patients to test combinatory treatment with vandetanib (NCT00821080). Recruiting patients with solid tumors to test combination with a vaccine (NCT01522820). | \n [118, 172, 191] | \n
Tipifarnib (Zarnestra, R115777); RAS | \n Phase I, and II clinical trials Newly diagnosed GBM: combined with RT and with or without TMZ, this treatment was well tolerated until doses of 300 mg (4-week cycle) (phase I). Administration with RT well tolerated until 200 mg/day, OS of 12 months and 1/9 PR, 4/9 SD, and 3/9 rapid progression. No significant improvement in survival with tipifarnib before RT (OS of 7.7 months). Recurrent GBM: treatment well tolerated, but 6-PFS (11.9%) and PFS (8 weeks) very poor, although one GBM patient remained progression-free for 36 months. | \n [192-195] | \n
Sorafenib; RAF, VEGFR, PDGFR | \n Phase I, and II clinical trials Newly diagnosed GBM: combination of TMZ and sorafenib after RT + TMZ showed 13% PR, 53% SD, and 28% PD. OS was 12 months, 1-year PFS was 16%, and PFS was 6 months (phase II); also tested in combination with erlotinib/tipifarnib/temsirolimus (NCT00335764). Recurrent GBM: combination with TMZ resulted in OS of 41.5 weeks, 1-year OS of 34.4%, PFS of 6.4 weeks (6-PFS: 9.4%); 3% of the patients had PR, 4.7% SD, and 50% PD (phase II); combination with BVZ was also tested (NCT00621686). Ongoing or recruiting clinical trials: NCT00734526 (phase I/II: sorafenib + RT + TMZ for the treatment of newly diagnosed GBM), NCT00884416 (phase I single agent HGG), NCT00329719 (phase I/II: combination with temsirolimus for recurrent GBM). | \n [118, 196, 197] | \n
Cilengitide (EMD 121974); Integrins | \n Phase I, II, and III clinical trials Well tolerated until doses of 2400 mg/m2\n Newly diagnosed GBM: when combined with RT + TMZ, the OS was 16.1 months and patients with Recurrent GBM: as a single agent no complete responses were observed, but median OS was at least 6.5-9.9 months. | \n [118, 198-200] | \n
Vorinostat; HDAC | \n Phase I, and II clinical trials Progressive or recurrent GBM/MG: combination with bortezomib in a phase II trial resulted in very poor results (6-PFS 0%, OS 3.2 months, TTP 1.5 months); phase II monotherapy showed a 6-PFS of 15.2%, TTP of 1.9 months, PFS of 11.2 months, and OS of 5.7 months; Ongoing trials: phase I/II combination with BVZ and TMZ for recurrent MG (NCT00939991), phase I combination with TMZ for MG (NCT00268385), phase I combination with BVZ and irinotecan for recurrent GBM (NCT00762255). | \n [118, 201, 202] | \n
Romidepsin; HDAC | \n Phase II clinical trial Recurrent MG: no radiographic responses, 72% PD and 28% SD; 6-PFS of 3%, PFS of 8 weeks, and OS of 34 weeks; 83% of the patients stopped treatment due to tumor progression, and 11% due to treatment toxicity. | \n [203] | \n
PFS (median Progression-Free Survival); OS (median Overall Survival); TTP (median Time-to-Progression); PR (Partial Response); SD (Stable Disease); PD (Progressive Disease); 6-PFS (6 month PFS); BVZ (Bevacizumab); RT (Radiotherapy); TMZ (Temozolomide); GM-GSF (granulocyte macrophage-colony stimulating factor); DC (Dendritic Cells); HU (Hydroxyurea); MG (Malignant Glioma); HGG (High Grade Glioma). | \n
Examples of clinical trials with molecularly targeted therapies directed to the most commonly altered signalling pathways in GBM.
As stated above, a small population of cells within the tumor, called cancer stem-cells, presents self-renewal capacity, ability to differentiate and initiate tumorigenesis, and express several markers of neural stem cells [24, 33, 116]. Furthermore, these cells are increasingly recognized as a niche of radiochemotherapy-resistant cells, making then attractive targets for new therapies [24, 49, 204]. There are several signaling pathways altered in cancer stem cells and that represent possible targets, such as PI3K, OLIG2, Shh, Wnt and Notch signaling pathways [24, 116].
\nAnother novel therapeutic strategy to treat cancer-related diseases is gene therapy (GT). GT was proposed for a long time as a molecular strategy that may help circumvent the non-specific cytotoxicity of the current pharmacological inhibitors, through specific delivery of suicide, pro-apoptotic,
The induction of an immune response against tumor cells, called immunotherapy, is also a novel approach for the treatment of cancer, including GBM [210]. Immunotherapy can be performed with two different approaches: increasing the immune response to the tumor (active immunotherapy) with long term immunization, or delivering immune effectors to an immediate immune response (passive immunotherapy) [106]. Potent anti-tumor immunity is achieved through antigen-presenting cells, of which dendritic cells (DC) are the most promising [210, 211]. In a phase I clinical trial with 12 GBM patients (7 newly diagnosed GBM and 5 recurrent GBM) the administration of autologous DC vaccines showed that this treatment was well tolerated and minimally toxic. Additionally, it revealed promising outcome results, such as 2 long term-survivors (≥4 years) and OS of 23.4 months; however, the benefit in clinical outcomes were mainly observed in patients with stable disease and low levels of TGF-β2, who also had a higher number of infiltrating cytotoxic T-cells in the tumor bulk, suggesting that this treatment may favor particularly these patients [212]. In another phase I/II clinical trial with patients with recurrent GBM, it was found more beneficial the treatment with mature DC vs. non-mature DC, as well as intradermal and intratumoral administration of the DC pulsed with autologous tumor lysate, compared to intradermal approach alone [213]. The transfer of
As illustrated by the vast panoply of drugs and therapeutic strategies under investigation for the treatment of GBM, there is a major effort to develop more effective therapies to treat this highly malignant and therapy-insensitive disease. Unfortunately, the success of these new therapies has mostly been somewhat disappointing. Nevertheless, the efficacy of some of these approaches has yet to be determined. Of note, in addition to the strategies reviewed here, therapies targeting apoptotic elements (like Bcl-2, and inhibitor of apoptosis proteins), the mechanisms of resistance to TMZ (such as PARP and MGMT), or gene therapy to
Brazil is a large country of 8.5 million km2 [1]. The International Amazonia is vast, covering parts of nine countries (Brazil, Bolivia, Colombia, Ecuador, Guyana, French Guiana, Suriname, Peru, and Venezuela), equivalent to 8 million square kilometers of South America (Figure 1), of which approximately 65% is located in Brazil [2, 3]. The Brazilian population in this region is approximately 20 million [1].
Distribution of the main biomes of the International Amazonia in South America [
Brazil has a wide climatic and geomorphological variety. This variety is responsible for the presence of several important biomes and ecosystems, which are home to approximately 20% of the living species known worldwide. It is estimated that there are approximately 2 million species of plants, animals, and microorganisms in Brazil [4]. The most important biomes of Brazil are the Amazon Forest and deciduous forests in the North, the rainforest of the Eastern Coast (known as the Atlantic Forest), the savanna areas (
Brazil is at the top of 18 megadiverse countries, home to 15–20% of the world’s biological diversity, with more than 120,000 invertebrate species, approximately 9000 vertebrates, and more than 4000 plant species [5]. The Brazilian flora comprises approximately 55,000 described species [6, 7], a number that represents approximately 22% of the world’s total species [8]. The Brazilian fauna is also very diverse, with approximately 524 species of mammals, 517 of amphibians, 1622 of birds, 468 of reptiles, more than 3000 species of freshwater fish, and 10–15 million species of insects [8].
The climate of the International Amazonia is classified as humid equatorial—Af, Am, and Aw [9], as shown in Figure 2a. The average temperature is between 24 and 26°C, and the annual range is between 1 and 2°C. The rainy season of most of the Amazon Basin is between November and May, and the dry season runs from June to September. In the rainiest months, the relative humidity varies between 80 and 90%, and during the dry season, it reaches at least 75% [10]. Figure 2b shows the average annual rainfall accumulation throughout the region. Maximum precipitation values above 2500 mm per year are observed in the Northwest sector of the Amazon Basin and on the North coast [11].
(a) South American climate classification [
The Amazon River Basin (ARB) hosts the largest tropical forest and natural drainage basin on the planet (formed by large rivers and those of smaller volume, locally known as
Amazon River basin (ARB) and its respective elevations [
Upland forests represent approximately 83% of the Amazon Basin and are located above the maximum levels of the seasonal flooding of rivers, lakes, and large streams. The floodplain forests are seasonally flooded by nutrient-rich white-water rivers for 6–8 months, and water level fluctuations can reach up to 15 m, covering approximately 7% of the Amazon Basin [18]. The floodplain areas have different altitudes in the interior of the basin, all lower than 30 m altitude, close to the “Meeting of the Waters.” Figure 4 shows a typical cross section of a river in the Amazon Basin [19].
Schematic representation of some local denominations of flooded and non-flooded areas in the Amazon Basin (adapted from Ref. [
In the Amazonia, approximately 75% of the topsoil (0–50 cm) of the region is formed predominantly by a fine fraction of silts and clays [17], in both the upland (
(a) Topsoil after natural drying. (b) Loss of resistance of soil with a dispersed structure (right) (photos: NS Campelo).
Vicinal roads were built on (a)
Much of the soil diversity in the Amazon originated from the considerable differences in geology and the history of geomorphology that have arisen throughout the ARB [21]. These authors classified soils according to the main factors that condition their morphological, chemical, and physical properties. Thus, to demonstrate the diversity of Amazonian soils, each of the 14 different reference soil groups surveyed was summarized by limited weathering age, humid tropical climate, topography, and drainage and source material.
The natural drainage network formed by the ARB makes the rivers the true “roads” that connect the various interior cities to the capitals. In the Legal Amazon (formed by nine Brazilian States), the few existing federal roads (Figure 7) were opened slightly more than 60 years ago as part of the physical integration project of the national territory [22], in a time of strong deforestation for agrarian colonization, opening of fronts for agriculture, and predatory logging, a time that was characterized by the lack of concern about the deforestation of the native forest.
The most important federal and state highways are located in the Brazilian Legal Amazon [
Deposits of commercial rocky materials are limited to regions outside the Amazon Sedimentary Basin. Therefore, the coarse aggregate (crushed stone or pebble) is an input that makes paving services more expensive, given the large distances it needs to cover [23, 24]. Figure 8 shows the locations of the pebble extraction and crushed stone exploration areas in the state of Amazonas.
Locations of natural coarse aggregate (crushed rock and pebble) extraction in the State of Amazonas, Brazil [
In the Brazilian Amazonia, roads increase access to the forest, which is followed by deforestation with its ecological impacts [25, 26, 27]. The main roads have opened forest areas for settlement and resource extraction [28] and agricultural and timber activities [4], and most of the deforestation occurs in the areas less than 100 km from the main highways under the federal development program, which concentrates almost 90% of the deforestation measured [29]. However, there are more serious cases, in which 94.9% of all deforestation analyzed occurred in a well-defined accessible zone within 5.5 km of some type of road or 1.0 km of a navigable river [28].
Brazil has approximately 1.7 million km of federal, state, and municipal highways, of which only 12.4% are paved [30]. In the Legal Amazon, there are approximately 274,000 km of highways (Figure 7), and if the same proportion applies as does at the national level, then only 34,000 km of them are paved.
The National Department of Transportation Infrastructure (DNIT) is the official regulator of Brazilian federal highways. According to the requirements of this organ, the granular layers of the pavement should have a minimum thickness of 15 cm, with minimum California Bearing Ratio (CBR) values and maximum expansions provided in Table 1, as a function of the pavement layer.
Layer | CBR | Compaction energy | Expansion | Standard |
---|---|---|---|---|
Base | ≥80%, for N > 5·106 | Modified | ≤0.5% | DNIT 141/2010—ES |
≥60%, for N ≤ 5·106 | ||||
Subbase | ISC ≥ 20% | Intermediate | ≤1% | DNIT 139/2010—ES |
Reinforcement of the Subgrade | CBR > than that of the Subgrade | Normal | ≤1% | DNIT 138/2010—ES |
Subgrade | CBR ≥ 2% | Normal | ≤2% | DNIT 108/2009—ES |
CBR and pavement layer expansion values.
Thus, as seen in the previous paragraphs, the construction of highways in Brazilian Amazonia is problematic. The obstacles can be grouped into:
Natural: high annual rainfall; large natural drainage basin (rivers, lakes, channels, and
Technical: natural foundation ground (subgrade) composed of soils with low bearing capacity and poor drainage;
Economic: inputs (aggregates and construction materials) are expensive due to the lack of occurrence of suitable materials and the long transport distance between the source and the construction site;
Environmental: deforestation and ecological impacts on fauna, flora, soil, and water quality.
The Amazon Sedimentary Basin (ASB) is an intracratonic sedimentary unit that borders two main areas of the Archean-Proterozoic basement—to the North, the Guianas Craton, and to the South, the Brazil-Central Craton [31]. The ASB is geologically characterized by an extensive Phanerozoic sedimentary cover distributed in the Acre, Solimões, Amazonas, and Alto Tapajós Basins, which were deposited on a Precambrian rocky substrate, where rocks of igneous, metamorphic, and sedimentary nature predominate [32]. Figure 9 shows the tectonic map of South America [33].
Simplified tectonic map of northern and southern South America [
With a drainage area of 6.106 km2, the Amazon River Basin (ARB) is the largest hydrographic basin in the world, covering approximately 5% of the planet’s land. The Amazon River has an average annual flow of approximately 210.103 m3/s, contributing approximately 20% of the annual global freshwater discharge to the ocean. Considering its enormous scale, it is not surprising that among the 10 largest rivers in terms of water discharge in the world, four mega-rivers (defined as those with a mean annual discharge >17·103 m3/s) flow into the ARB (i.e., the Amazon, Madeira, Negro, and Japurá rivers), and 24 of the 34 largest tropical rivers also flow through it [34].
The Amazon River rises in the Eastern Cordillera of the Peruvian Andes, at an altitude of approximately 5300 m, and throughout its course, it has many tributaries, the most important of which are the Ucayali and Napo in Peru, and the Javari, Juruá, Purus, Madeira, Tapajós, Xingu, Içá, Japurá, Negro, Trombetas, and Jari in Brazil. In part of the interior of Brazil, the Amazon River is called the Solimões and has, as tributaries of the left bank, the Putumayo-Içá and Caqueta-Japurá Rivers that were born in the Andes of Colombia. On the right bank is the Javari River, which marks the border between Brazil and Peru; the Jutaí, located in Brazil; and the Juruá and Purus, with their sources in Peru. Near the city of Manaus, State of Amazon, the Solimões River, together with the Negro River, forms the Amazon River, in what was conventionally called the “Meeting of the Waters.” The Negro River rises in Colombia at an altitude of approximately 1660 m. The Madeira River, which drains the Eastern Andes of Bolivia and Peru downstream of Manaus, joins the Amazon River on its right bank [35, 36, 37]. Figures 7 and 8 show part of the tributaries of the ARB.
This region is characterized by a great diversity of aquatic environments gathered in the same watershed. The variety of environments is related to the size of the natural drainage area and their strong relationship with environmental factors, relief, pedology, soil, climate, and the different types of vegetation present around the rivers and streams, which are responsible for the notable difference in the composition physics and chemistry of waters [38, 39, 40, 41].
In the Shield region, the Amazonian soils are well drained, but in the ASB, in relation to their drainage capacity, they may appear poorly drained, imperfectly drained, or well drained [42, 43]. Figure 10 shows the main groups of soils found in the International Amazonia [21]. The main classes of soils found in the Brazilian Amazonia are latosols (oxisols) and argisols (ultisols), representing approximately 75% of the superficial soils of the region [44]. Schaefer et al. [45] stated that the distribution of Amazonian soils is marked by geomorphological control—upland and flattened residual geoforms of low plateaus are commonly associated with red–yellow latosols in areas of crystalline rocks or with yellow latosols in areas of Tertiary sediments. In the middle and lower thirds of the hills or flattened residuals, there are argisols, with or without plinthite or petroplinthite, as well as quartzarenic neosols and spodosols. In the floodplain of white-water rivers, gleysols and Fluvic neosols predominate. Plinthosol soils predominate in the lowlands of the Upper Amazon River and in the Madeira/Purus/Juruá and Solimões/Japurá interfluves.
Soil distribution map of the Amazon Basin, based on the SOTERLAC-ISRIC database [
The chemical and mineralogical characteristics of Amazonian soils are largely dictated by the nature of the source material. Extensive areas of rich and eutrophic soils only exist where there is a current (alluvial plain) or past influence (terraces and low plateaus of the Acre and Upper Amazon River Basins) of Andean sediments or where rocks of higher chemical richness emerge (limestones and marls in Monte Alegre-Ererê; basalts and diabases in Roraima, Pará, and Amapá States). In general, in the other areas, the current bioclimatic conditions, the characteristics of the source material, and the geoforms lead to the formation of deep and weathered soils [46].
The technical deficiencies in the highways of the Amazonia are the result—for the most part—of the use of local materials analyzed under the same experimental techniques based on research carried out in regions of low temperatures (temperate climate) and well-distributed rainfall throughout the year; this condition is totally different from the climate of the equatorial zone, which is characterized by intense climatic variations, high temperatures, and high rainfall incidence [47]. In addition, the traditional soil classification systems—TRB and USCS—disregard the essential evaluation of the mechanical and hydraulic attributes of geomaterials [48]. The use of those conventional methodologies for the classification of natural materials for application in road pavement results in the neglect of materials with potential properties for use in pavement layers when the object of study is tropical soils [49]. As an alternative, in the last three decades, several scientific studies have confirmed the importance of adopting the MCT system (nomenclature for Miniature, Compacted, Tropical)—created by Nogami and Villibor [50]—for the study of fine-grained tropical soils. The main purpose of the MCT methodology is to provide an understanding of the importance of rationalizing the use of tropical soils on highways, to reduce the costs of road work and its impacts on the environment, and establish the difference between lateritic soils (oxisols) and saprolitic (argisols) [51].
The MCT methodology has undergone several modifications over time to improve this classification system for practical road purposes, taking advantage of the lateritic tropical soils, which are abundant in many areas of Brazil [52, 53, 54]. It has a structured laboratory test program that is composed of the Mini-MCV and Mass Loss by Immersion with both tests carried out on compacted miniaturized samples. These tests yield the values of classification indexes c′ (determined from the deformability curve slope), d′ (angular coefficient of the dry side of the compaction curve, corresponding to 10 blows), e′ (laterization index), and Pi (mass loss by immersion, in %). These values are graphed and placed in a classification abacus (Figure 11), which performs a pedological separation of the materials.
Graph for soil classification by the MCT method (adapted from [
On the other hand, it is worth noting that tropical soils also have horizons of occurrences consisting of, in addition to the fine-material content, a portion of coarse granulation formed by a gravel fraction of lateritic concretions (known as
Test program for the G-MCT classification. (a) Flowchart; (b) classification (adapted from ref. [
Vertamatti [57] conducted the first study of the MCT methodology for Amazonian soils, evaluating the use of fine and coarse (lateritic concretions compatible with the gravel fraction size) texture of lateritic soils in airport projects in the Brazilian Amazonia. He found that the soils generally showed good stability against the water (rains) influence due to the fine plastics present, resulting in a cohesive structure responsible for the great durability of the base layer of airports runways without asphalt course, even under successive periods of heavy rains in the region.
Sant’Ana [58] studied 20 samples of lateritic soil in the State of Maranhão to compare the mini-MCV test and the “rapid disk” method, a test proposed by Nogami and Villibor [59] in which a fraction of soil passed through a #40 (0.42 mm) sieve is molded in a stainless steel ring, measured its contraction (after drying in an oven), and penetrated by a standard needle (after saturation in water), within the MCT methodology. The author found a better classification relationship of the lateritic soils with the results of the mini-MCV test.
Santos and Guimarães [60] evaluated the mechanical behavior of coarse lateritic concretion soils used in road paving in the city of Porto Velho, State of Rondônia, Brazil. These authors found high values of resilient modulus (between 350 and 600 MPa) and low values of permanent deformation of these soil types. In the study made by Barbosa [61], the MCT methodology was applied to soil samples collected in a deposit located in the city of Rio Branco, State of Acre, Brazil, for the production of a synthetic coarse aggregate of calcined clay (SCACC), and mixtures for base courses. Baia [47] and Baia et al. [51] performed a comparative analysis between the tests of the USCS and TRB and the MCT soil classification systems, with geomaterial samples collected from the rural zone (lateritic soil) and the margin of
Almeida [72] evaluated a tropical clayey soil collected from a deposit in the metropolitan region of the city of Manaus using the MCT methodology for the application of the material with a chemical additive (synthetic zeolite cement) as a solution for low traffic volume rural road.
Delgado [62] studied the application of an essentially clayey soil with a high plasticity index for use as a subballast layer in an expansive stretch of the Carajás Railway in the Western region of the State of Maranhão. This soil would be discarded for the proposed purpose, considering the conventional standards of subballast selection, imported mostly from temperate climate countries. However, due to its tropical soil nature, the results obtained indicated high resilience modulus and low total permanent deformation values, showing that it is a material that, despite not meeting the criteria of traditional soil classification systems, would be adequate for use in the real field situations.
Although normalized by highway agencies in Brazil, there is still a lack of details about the MCT methodology of Brazilian tropical soils. It is important to continue efforts that yield new field and research data to define the geotechnical classification of these types of soils [56].
Before, during, and after floods caused by river floods or intense rains, the quality of the road infrastructure is essential [63]. During these events, pavement layers consisting of nonconsolidated (flexible) materials are more susceptible to erosion, while consolidated (rigid) materials are prone to failure when the lower layers are subject to erosion. Thus, evaluating pavements consisting of the
The properties of cement-stabilized materials are strongly determined by the nature of the raw material used, which may be clay, silt, sand, or gravel. The type of soil influences the choice of stabilizer and controls the structural properties of the stabilized product. To a large extent, the variability of soil properties comes from the particle size distribution, arrangement of the particles, shape of the grains, and mineralogical composition [65].
Soil-cement structures are prone to hydraulic retraction, especially during the moisture loss caused by cement hydration or temperature changes. The accumulation of cracks caused by shrinkage can accelerate the damage to the pavement, the erosion processes, and the reduction of the strength and durability of the base layer. Conversely, the addition of synthetic zeolite (ZS) additive, together with cement, for
(a) Effect of synthetic zeolite on shrinkage reduction and (b) on SCS gain as a function of dosage (adapted from [
Figure 14a shows scanning electron microscopy (SEM) images of soil stabilized with 8.2% cement, without additive, and with 0.174% ZS additive (RoadCem®) (Figure 14b) for the submerged curing condition. The samples were cured for 28 days, and the products of cement hydration and pozzolanic reactions (cation exchange and flocculation) already took place, joining the flocculated clay particles. A denser and more complex structure was observed in the samples with additives, indicating a greater amount of cement hydration products. Ettringite crystals (calcium sulfate and hydrated aluminate, with a size of 1 μm) were formed in needle shape in samples with the ZS additive under both curing conditions.
Scanning electron microscopy (SEM) images of stabilized soil with 8.2% cement: (a) without; and (b) with RoadCem® additive, for submerged curing at 28 days [
The execution of the base, subbase, and asphalt courses consumes a large volume of coarse aggregate. As explained in Item 1, there is a shortage of natural stone material (crushed stone or pebble) in the ASB, so there is a high cost of road paving construction services in this area.
The process of producing light expanded clay aggregates in a rotary kiln began in 1908 [74]. Depending on the clay mineral constituent of the raw material there are some types of clay that, when burned at temperatures below 800°C, do not generate light aggregates but only a calcined, coarse synthetic aggregate that is not expanded [75]. This latter material is designated here as SCACC [76] or “burnt clay” and can be used both in pavement subbases and bases, and in asphalt coatings and surface treatments [77].
The Texas Highway Department established a classification system for synthetic clay aggregates [78]. Moore et al. [79] stated that the firing temperature to produce the calcined aggregate should in general lower than that of the expanded clay aggregate, only hot enough to completely dehydrate the clay, approximately 550–750°C, for approximately 15 min.
There are reports of the use of SCACC in Nigeria [80], English Guiana, Sudan, Australia [81], and Thailand [82]. Their results showed greater durability of the road pavings using SCACC, in addition to better skid resistance, than with the conventional aggregate.
In Brazil, research on light aggregates has been done since 1966 [83]. Fabrício [84] developed a mobile prototype plant for the manufacture of expanded clay aggregates or SCACC in road paving works in Amazonia. Campelo et al. [85] demonstrated—from laboratory tests—the technical, economic, and environmental feasibility of using SCACC in asphalt mixtures burning
Campelo et al. [23] studied SCACC because it is an alternative material that offers a competitive price in relation to the conventional aggregate (crushed stone or pebble), in addition to the fact that the raw material is a
Material | Brazilian standard | Title | Acceptance Parameters |
---|---|---|---|
SCAAC | DNER—ME 225/94 | Synthetic aggregate of calcined clay—Pressure slaking test | Less than 6% |
SCAAC | DNER@—ME 222/94 | Synthetic aggregate of calcined clay—Los Angeles abrasion test | Less than 35% |
SCAAC, Pebble | NBR NM 53/2009 | Coarse aggregate—Determination of the bulk specific gravity, apparent specific gravity, and water absorption | Greater than 0.88 and 2.00 g/cm3; less than 18%, respectively |
Pebble | NBR NM 51/2001 | Coarse aggregate—Test method for resistance to degradation by Los Angeles machine | Less than 50% |
SCAAC, Pebble, Sand, Filler | NBR NM 248/2003 | Aggregates—Sieve analysis of fine and coarse aggregates | Within granulometric range |
SCAAC, Pebble | NBR 12583/1992 | Coarse aggregate—Coating to bituminous binder | Qualitative test (visual analysis) |
Sand | NBR NM 52/2009 | Fine aggregate—Determination of the bulk specific gravity and apparent specific gravity | Greater than 1.60 and 2.60 g/cm3, respectively |
Filler | NBR NM 23/2001 | Portland cement and other powdered material—Determination of density | Greater than 3.00 g/cm3 |
Natural and synthetic aggregate characterization tests [23].
The execution of stabilization with asphalt emulsion consists of two stages, spreading and compaction [87]. According to a study by Klinsky [88], soil-emulsion stabilization can occur in the following combinations:
Sand-Asphalt: Generates cohesion effect in materials with a fraction passing through the #200 sieve (0.074 mm) of between 5 and 12% and a plasticity index (PI) < 10%;
Soil-Asphalt: Reduces capillarity and infiltrability in clay-silty and clay-sandy soils;
Gravel-Bitumen: Provides cohesive effect in materials with a fraction passing through the #200 sieve of <12% and PI <10%.
In the study by Rebelo [89] with a soil sample from the city of Coari, State of Amazonas, it was demonstrated that after 7 days of curing, the addition of asphalt emulsion in the geomaterial provided increased resistance to the mixture. Sant’Ana [58], when evaluating soil samples from the Northwest region of the State of Maranhão, suggested specific guidelines and conditions for the acceptance of materials and dosages for asphalt stabilization. This author recommended determining the “optimum” content through its correlation with the SCS tests or tensile strength by diametral compression (TSDC) tests under the conditions of dry curing (air) and immersion for 7 days. The author considered immersed curing because he observed that specimens with 7 days of air curing showed more resistance, even without emulsion, though the same did not occur when applying immersion in steps that preceded the SCS test, as shown in Figure 15.
SCS test results of lateritic soil without emulsion, and with 4% emulsion, with 7 days of curing, immersed and non-immersed [
Soils to be stabilized with high levels of emulsifier should be discarded because they make the stabilization services unfeasible economically [58]. In addition, according to Ingles and Metclaf [90], excess binder impairs the interaction between the grains caused by the lubrication of the particles, thus decreasing the resistance of the mixture.
Baia [47], when evaluating the microstructure of soil samples extracted in the rural area of the city of Manaus, with and without the addition of asphalt emulsion (optimum content of 4%), found a certain volume increase (Figure 16b) of the solid-phase soil caused by the inclusion of the emulsion in the intergranular spaces. Similar behavior had been observed in soils of the city of Rio de Janeiro by Miceli Jr. [91], who concluded that the higher the binder content in the soil, the greater the volumetric expansion.
Scanning electron microscopy (SEM) images—magnified 500× (100 μm). (a) Natural soil; (b) soil with 4% RL-1C asphalt emulsion [
It is common to have a loss in the production process of red ceramics due to several factors, including the failure in the process of mixing and homogenization of the raw material
Waste ceramics are stacked in inappropriate places (Figure 17) within the pottery industry yard limits and may be a refuge for venomous and disease-transmitting animals [85]. This material is reused in the pottery industry itself [93], as a reducer of the plasticity of the
Ceramic waste stacked in the pottery yards (photos: NS Campelo).
Dias [95] evaluated the mechanical behavior of the typical soil (a yellow lateritic sandy silty-clay) of the city of Manaus, stabilizing it with ceramic waste to apply it in base and subbase courses. This author stated that the loss of red ceramic products (nonstructural and structural bricks, and tiles) was approximately 135 t/day of ceramic waste in the potter pole of the cities of Iranduba and Manacapuru. The author analyzed several soil-ceramic waste mixtures with different proportions, concluding that the mixture with the best performance to be used in the base or subbase course was 30% natural clayey soil, 30% sand, and 40% ceramic waste.
According to the study of Dias [95], based on the proportion of use of ceramic waste determined in the laboratory, it is then possible to construct a base or subbase course 65 km long, with 7 m of platform width, and 10 cm of thickness compacted, considering the bulk density of the ceramic waste as 1.81 t/m3. Considering the small total length of the urban and rural roads of the interior cities typical of the Brazilian Amazonia (cities with fewer than 30,000 inhabitants in the urban area), this length of 65 km represents a considerable portion of the total of the existing roads in these cities; therefore, the reuse of this waste would bring environmental, economic, and human health gains.
Historically, wooden piles have been used in the Brazilian Amazon, especially since the peak of natural rubber exploitation (1870–1920), in which European companies—mostly of British origin—were responsible for the construction of the infrastructure (concessionaires of water, sewage, electricity, ports, urban transport by electric trams, in addition to the paving of urban and rural roads, buildings, bridges, etc.) in the cities of Manaus and Belém, the two largest capitals of the Brazilian Amazonia.
Until the end of the 1980s, it was possible to use wooden piles for not very high loads in the Brazilian Amazonia, but then, due to a series of restrictions imposed by environmental laws, it is now virtually impossible to use this type of material unless it comes from certified areas. However, it is possible to use other types of piles, such as precast concrete and on-site piles.
A reinforced piled embankment consists of a geogrid-reinforced landfill on a pile foundation; generally, one or more horizontal geosynthetic reinforcement layers are installed at the base of the landfill. This geotechnical solution can be used for the construction of a road or railroad, when a traditional construction method would require a long construction time or when the excavation of soil with low bearing capacity could affect buildings in the neighborhood or even result in a substantial residual settlement, making frequent maintenance of these works necessary [96]. This is an excellent option for sites with natural subgrade formed by thick layers of soils with low bearing capacity, in which it is uneconomical to purge this material, either due to the volume of excavation or the time to be spent in the service.
Unfortunately, although this type of solution had already been used in some road works in the Brazilian Amazonia, this was not documented, except in those found by Silva [97] (Figure 18) and Maccaferri [98]. Silva [97] showed the use of wooden piles in a road embankment on a natural subgrade consisting of a very soft clay layer, 35 m thickness, driving the piles with dimensions of 25 cm in diameter and 10 m in length in equal spacings of 1.60 m in the plan. This road embankment is adjacent to a trapezoidal earthen open channel, using a geotextile reinforcement layer above the pile cap of the piles.
Use of wooden piles for the construction of a road embankment near the trapezoidal open channel (adapted from Ref. [
According to Swanson [99], the term
Much of the Amazonia landscape developed in lateritic terrain [100, 101]. The mature laterites are strongly leached from SiO2 and alkalis but enriched in Al2O3 and Fe2O3 [102, 103, 104]. The laterites of the Amazon are masked by thick sandy-clayey to sandy-clayey latosols and/or by sedimentary cover [102, 105, 106]. Laterite profiles typical of the Amazon are illustrated in Figure 19, showing their main horizons [107, 105]. Tropical residual soils, especially lateritic deposits, which have been the subject of research in the Amazonia for use in road paving, can also be identified [47, 60, 108, 109] due to their peculiarities in comparison to sedimentary soils, as previously described. Keller et al. [110] stated that the materials commonly used in the Amazonia region for road paving include local laterite deposits but that despite being a hard and cemented material, they may still contain a high clay content. As a paving material, it is widely used for the structural layers of highways, but the first challenge is to locate the deposits with an adequate quantity and quality of the material. Figure 20 shows some unusual uses of wood for the drainage of small watercourses (
Typical profile of laterite from the Brazilian Amazonia and its main horizons: (a) adapted from Ref. [
Use of wood in the drainage of
Brazilian standard | Title | Acceptance parameters |
---|---|---|
DNER-ME 030/94 | Soils-determination of the silica-alumina and silica-sesquioxide relations of soils | ≤2 |
DNER-ME 172/2016 | Soils—determination of the California Bearing Ratio (CBR) using deformed and unhandled soil samples | Expansion ≤2% CBR ≥ 80% (N > 5·106) CBR ≥ 60% (N ≤ 5·106) |
NBR-NM 248/2003 | Aggregates—Sieve analysis of fine and coarse aggregates | P#200 ≤ 30% P#200 ≤ (2/3)·P#40 |
DNER-ME 082/94 | Soils—determination of the plastic limit | P#40: LL ≤ 40%; IP ≤ 15% |
NBR-NM 51/2001 | Coarse aggregate—test method for resistance to degradation by Los Angeles machine | ≤65% |
Technical specifications for granulometrically stabilized base services using lateritic soil [111].
Notes: P#200, P#40: percentage of particles passing through the #200 and #40 sieves, respectively; LL: liquid limit; PI: plasticity index.
Much of the tropical topsoil is subject to unsaturated conditions, that is, not all its voids are filled by the aqueous phase. This is true both in the
Many engineering problems involve unsaturated soils. The construction of earth dams, highways, and airport runways uses compacted soils that are not saturated. An element of unsaturated soil can, therefore, be viewed as a mixture with two phases that reach equilibrium under applied stress gradients (i.e., soil particles and contractile skin) and two phases that flow under applied stress gradients (i.e., air and water) [113].
In unsaturated soils, the pore-water pressures are negative in relation to atmospheric conditions; this negative pore pressure is called matric suction when referring to the air pressure [114, 115]. As the soil approaches saturation, the pore-water pressure approaches the pore-air pressure. Therefore, the matric suction tends to zero, and there is a smooth transition to the stress state of saturated soil [114].
Fredlund and Rahardjo [116] reported that in recent years there is a better understanding of the role of negative pore pressure (or matric suctions) in increasing the shear strength of the soil, and that it is appropriate to perform an analysis of slope stability including the matric suction contribution.
Regarding slope stability, Ching et al. [117] reported that soil suction profiles play a significant role in the long-term stability of many natural slopes and steep cutting slopes. However, during or after periods of intense and prolonged rainfall, slope failures often occur because rains cause infiltration in the ground and reduce soil resistance because of matric suction loss. This augments the safety factors by considering the actual matric suctions of the soil, and therefore, they contribute substantially to the increases in shear strength [118, 119] and slope stability in unsaturated conditions [117, 114, 120, 121].
In tropical and subtropical areas, slope failures induced by rain are closely related to soil properties, slope geometry, groundwater position, and certain environmental factors, vegetation, and weathering effects [122]. Thus, the slopes are stable, with a high safety factor during dry periods, and tend to fail only during rainy periods [119].
The construction of highways in the Brazilian Amazonia is problematic because it faces nature-related, technical, economic, and environmental issues, which are interrelated.
The natural questions come from a range of origins, the main ones being geological-geotechnical, pedological, relief-related, and climate-related, and obviously cannot be gotten around given their territorial scope. The technical issues concern the natural subgrade, especially in floodplains (
The authors would like to thank CAPES for the grant of a scholarship for an academic master’s degree to the Civil Engineer Daniel Jardim Almeida.
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This chapter is an updated overview of the signaling pathways going from external signals such as osmolarity and ionic concentration and their membrane reception to their transduction through the membrane and their final reception at the flagellar axoneme level. Additional factors such as energy management will be addressed as they constitute a limiting factor of the motility period of fish spermatozoa. Modern technologies used nowadays for quantitative description of fish sperm flagella in movement will be briefly described as they are more and more needed for prediction of the quality of sperm used for artificial propagation of many fish species used in aquaculture. The chapter will present some applications of these technologies and the information to which they allow access in some aquaculture species.",book:{id:"7912",slug:"biological-research-in-aquatic-science",title:"Biological Research in Aquatic Science",fullTitle:"Biological Research in Aquatic Science"},signatures:"Jacky Cosson",authors:[{id:"188281",title:"Dr.",name:"Jacky",middleName:null,surname:"Cosson",slug:"jacky-cosson",fullName:"Jacky Cosson"}]},{id:"20911",doi:"10.5772/19948",title:"The Significance of Suspended Sediment Transport Determination on the Amazonian Hydrological Scenario",slug:"the-significance-of-suspended-sediment-transport-determination-on-the-amazonian-hydrological-scenari",totalDownloads:4177,totalCrossrefCites:13,totalDimensionsCites:24,abstract:null,book:{id:"304",slug:"sediment-transport-in-aquatic-environments",title:"Sediment Transport in Aquatic Environments",fullTitle:"Sediment Transport in Aquatic Environments"},signatures:"Naziano Filizola, Jean-Loup Guyot, Hella Wittmann, Jean-Michel Martinez and Eurides de Oliveira",authors:[{id:"36890",title:"Dr.",name:"Naziano",middleName:null,surname:"Filizola",slug:"naziano-filizola",fullName:"Naziano Filizola"},{id:"60004",title:"Dr.",name:"Jean-Michel",middleName:null,surname:"Martinez",slug:"jean-michel-martinez",fullName:"Jean-Michel Martinez"},{id:"60005",title:"Dr.",name:"Jean-Loup",middleName:null,surname:"Guyot",slug:"jean-loup-guyot",fullName:"Jean-Loup Guyot"},{id:"102592",title:"Dr.",name:"Hella",middleName:null,surname:"Wittmann",slug:"hella-wittmann",fullName:"Hella Wittmann"},{id:"102593",title:"Mr.",name:"Eurides",middleName:null,surname:"De Oliveira",slug:"eurides-de-oliveira",fullName:"Eurides De Oliveira"}]},{id:"60698",doi:"10.5772/intechopen.74923",title:"Overview on Mediterranean Shark’s Fisheries: Impact on the Biodiversity",slug:"overview-on-mediterranean-shark-s-fisheries-impact-on-the-biodiversity",totalDownloads:1120,totalCrossrefCites:14,totalDimensionsCites:19,abstract:"Bibliographic analysis shows that the Mediterranean Sea is a hot spot for cartilaginous species biodiversity, including sharks, rays, and chimaeras; 49 sharks and 36 rays were recorded in this region. However, they are by far the most endangered group of marine fish in the Mediterranean Sea. The IUCN Red List shows clearly the vulnerability of elasmobranchs and the lack of data; 39 species (53% of 73 assessed species) are critically endangered, endangered, or vulnerable. The biological characteristics of elasmobranchs (low fecundity, late maturity, and slow growth) make them more vulnerable to fishing pressure than most teleost fish. Overfishing, the wide use of nonselective fishing practices, and habitat degradation are leading to dramatic declines of these species in the Mediterranean Sea. In general, elasmobranchs are not targeted but are caught incidentally. In many fisheries, they are, however, often landed and marketed. A decline in cartilaginous fish species landings has been observed while fishing effort has generally increased. Better understanding of the composition of incidental and targeted catches of sharks by commercial fisheries are fundamentally important for the conservation of these populations. Moreover, problems encountered by elasmobranchs in the area are highlighted, and conservation measures are suggested.",book:{id:"6266",slug:"marine-ecology-biotic-and-abiotic-interactions",title:"Marine Ecology",fullTitle:"Marine Ecology - Biotic and Abiotic Interactions"},signatures:"Mohamed Nejmeddine Bradai, Bechir Saidi and Samira Enajjar",authors:null},{id:"56153",doi:"10.5772/intechopen.69686",title:"Deep Gorgonians and Corals of the Mediterranean Sea",slug:"deep-gorgonians-and-corals-of-the-mediterranean-sea",totalDownloads:1756,totalCrossrefCites:7,totalDimensionsCites:16,abstract:"Recent studies, carried out by means of innovative technological tools as remotely operated vehicles (ROVs), have highlighted the richness of the Mediterranean deep‐sea environments, characterized by great diversity and abundance of organisms. In particular, corals, gorgonians, and sponges play the important ecological role of ecosystem engineers in deep marine environments, creating complex three‐dimensional habitats enhancing high biodiversity and ecosystem functioning at every level. Coral forests and bathyal white coral communities, starting from depths of 50–70 m and below 300 m, respectively, represent the richest ecosystems known so far for the Mediterranean basin. The different assemblages show a strong heterogeneity, varying in terms of specific composition, abundance, size of colonies, and associated fauna, even on a small spatial scale. Unfortunately, the high commercial fishing effort of trawling and longline fleets mainly operating along this bathymetric range represents a major threat for these vulnerable marine ecosystems, particularly in consideration of their structuring organisms which are long‐lived species with slow growth rates and recovery ability. Further knowledge on deep coral assemblages is urgently needed to implement effective management and proper conservation measures. This approach is now an international priority that proceeds together with the inclusion of the structuring species in numerous directives.",book:{id:"5765",slug:"corals-in-a-changing-world",title:"Corals in a Changing World",fullTitle:"Corals in a Changing World"},signatures:"Michela Angiolillo and Simonepietro Canese",authors:[{id:"197032",title:"Ph.D.",name:"Michela",middleName:null,surname:"Angiolillo",slug:"michela-angiolillo",fullName:"Michela Angiolillo"},{id:"197763",title:"Dr.",name:"Simonepietro",middleName:null,surname:"Canese",slug:"simonepietro-canese",fullName:"Simonepietro Canese"}]}],mostDownloadedChaptersLast30Days:[{id:"60368",title:"Biological and Medicinal Importance of Sponge",slug:"biological-and-medicinal-importance-of-sponge",totalDownloads:2582,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Sponges are multicellular, heterotrophic parazoan organisms, characterized by the possession of unique feeding system among the animals. They are the most primitive types of animals in existence, featuring a cell-based organization where different cells have different tasks, but do not form tissues. Sponges (Porifera) are a predominantly marine phylum living from the intertidal to the abyssal (deepest ocean) zone. There are approximately 8500 described species of sponges worldwide with a prominent role in many reef coral communities. Several ecological studies reported have shown that secondary metabolites isolated from sponges often serve defensive purposes to protect them from threats such as predator attacks, biofouling, microbial infections, and overgrowth by other sessile organisms. In the recent years, interest in marine sponges has risen considerably due to presence of high number of interesting biologically active natural products. More than 5300 different natural products are known from sponges and their associated microorganisms, and every year hundreds of new substances are discovered. In addition to the unusual nucleosides, other classes of substances such as bioactive terpenes, sterols, fatty acids, alkaloids, cyclic peptides, peroxides, and amino acid derivatives (which are frequently halogenated) have been described from sponges or from their associated microorganisms. Many of these natural products from sponges have shown a wide range of pharmacological activities such as anticancer, antifungal, antiviral, anthelmintic, antiprotozoal, anti-inflammatory, immunosuppressive, neurosuppressive, and antifouling activities. This chapter covers extensive work published regarding new compounds isolated from marine sponges and biological activities associated with them.",book:{id:"6344",slug:"biological-resources-of-water",title:"Biological Resources of Water",fullTitle:"Biological Resources of Water"},signatures:"Musarat Amina and Nawal M. Al Musayeib",authors:[{id:"213049",title:"Dr.",name:"Musarat",middleName:null,surname:"Amina",slug:"musarat-amina",fullName:"Musarat Amina"},{id:"213050",title:"Dr.",name:"Nawal",middleName:null,surname:"M. Al Musayeib",slug:"nawal-m.-al-musayeib",fullName:"Nawal M. Al Musayeib"}]},{id:"59865",title:"Marine Fisheries in Nigeria: A Review",slug:"marine-fisheries-in-nigeria-a-review",totalDownloads:3935,totalCrossrefCites:9,totalDimensionsCites:11,abstract:"Fisheries production especially from marine is important for the socio-economic development of Nigerians and its contribution to the nation’s economic growth through the Gross Domestic Product (GDP). Nigeria is blessed with enough marine fisheries resources that could enhance increased fish production. Yet, fish supply from domestic production is far below the fish demand of her citizens. This chapter is therefore focused on marine fisheries in Nigeria. We adopted a desk review approach. This chapter is divided into different sections such as the Nigerian fisheries sector, marine fisheries resources in Nigeria, status of marine fisheries production in Nigeria, marine fisheries regulations, and constraints to optimal marine fisheries production in Nigeria. We concluded that the contribution of aquaculture to marine fisheries production has been low, compared to the marine capture fisheries production. Also, we noted that despite the availability of regulations, noncompliance by fisher folks has not helped to optimize marine fisheries production. We therefore recommended that the culture of marine fishes should be intensified. Marine waters should also be protected against destruction and pollution as a result of human activities. Available marine fisheries regulations should be enforced and violators of the regulations should be punished as stipulated in the regulations.",book:{id:"6266",slug:"marine-ecology-biotic-and-abiotic-interactions",title:"Marine Ecology",fullTitle:"Marine Ecology - Biotic and Abiotic Interactions"},signatures:"Olalekan Jacob Olaoye and Wahab Gbenga Ojebiyi",authors:null},{id:"57327",title:"Closed Aquaculture System: Zero Water Discharge for Shrimp and Prawn Farming in Indonesia",slug:"closed-aquaculture-system-zero-water-discharge-for-shrimp-and-prawn-farming-in-indonesia",totalDownloads:2527,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"This chapter focuses on the development and application of zero water discharge (ZWD) system, which has become an alternative solution to conventional methods of aquaculture production. With this system, it is expected to answer many issues in aquaculture cultivation, such as environmental damage, disease outbreak, and land-use change, and to create a sustainable aquaculture cultivation system. ZWD system is an improved batch system with an emphasis on microbial manipulation in rearing tank. The principle of microbial selection is based on the role of each microbial component in nutrient cycle in the rearing tank. This chapter contains in detail how methods and stages are performed in order to conduct this system, including design of construction system, cultivation of microbial components, initial conditioning of this system, and microbial manipulation. The performance of the system was tested in crustacean culture such as white shrimp and giant freshwater prawns, and it showed that the system can increase the average survival rate of 10–20%. In addition, the technical and economic feasibility of this system was evaluated to illustrate the production efficiency upon the application of this system in the industry.",book:{id:"6344",slug:"biological-resources-of-water",title:"Biological Resources of Water",fullTitle:"Biological Resources of Water"},signatures:"Gede Suantika, Magdalena Lenny Situmorang, Pingkan Aditiawati,\nDea Indriani Astuti, Fahma Fiqhiyyah Nur Azizah and Harish\nMuhammad",authors:[{id:"216920",title:"Dr.",name:"Gede",middleName:null,surname:"Suantika",slug:"gede-suantika",fullName:"Gede Suantika"},{id:"220079",title:"Dr.",name:"Magdalena Lenny",middleName:null,surname:"Situmorang",slug:"magdalena-lenny-situmorang",fullName:"Magdalena Lenny Situmorang"},{id:"220081",title:"Dr.",name:"Pingkan",middleName:null,surname:"Aditiawati",slug:"pingkan-aditiawati",fullName:"Pingkan Aditiawati"},{id:"220082",title:"Dr.",name:"Dea Indriani",middleName:null,surname:"Astuti",slug:"dea-indriani-astuti",fullName:"Dea Indriani Astuti"},{id:"220083",title:"MSc.",name:"Fahma Fiqhiyyah Nur",middleName:null,surname:"Azizah",slug:"fahma-fiqhiyyah-nur-azizah",fullName:"Fahma Fiqhiyyah Nur Azizah"}]},{id:"59973",title:"Genetic Applications in the Conservation of Neotropical Freshwater Fish",slug:"genetic-applications-in-the-conservation-of-neotropical-freshwater-fish",totalDownloads:1716,totalCrossrefCites:3,totalDimensionsCites:9,abstract:"Neotropical fish correspond to approximately 30% of all fish species worldwide. The diversity of fish species found in Neotropical basins reflects variations in life-history strategies and exhibition of particular morphological, physiological and ecological attributes. These attributes are mainly related to different forms of feeding, life maintenance and reproduction. Today, fish populations are being threatened by anthropogenic actions that are having a visible impact on the natural state of continental aquatic ecosystems. The main causes are overfishing, non-native species introduction, reservoir-dam systems, mining, pollution and deforestation. The biology and population dynamics of the species are still unclear due to lack of research. Genetic tools can be useful resources for the conservation of Neotropical fish species in several ways. Molecular genetic markers are considered powerful tools to identify cryptic and hybrid fish and also allow the evaluation of the genetic variability and structure of populations of Neotropical ichthyofauna. Several analyses of molecular markers have been performed on Neotropical fish, including allozyme analysis, restriction fragment length polymorphisms in regions of DNA (RFLP), randomly amplified polymorphic DNA (AFLP), randomly amplified polymorphic DNA (RAPD), microsatellites, single nucleotide polymorphisms (SNPs) and mitochondrial DNA (mtDNA) markers. In order to analyse a high number of markers, next generation sequencing has allowed researchers to generate a large amount of genomic information that can be applied to the conservation of Neotropical fish.",book:{id:"6344",slug:"biological-resources-of-water",title:"Biological Resources of Water",fullTitle:"Biological Resources of Water"},signatures:"Vito Antonio Mastrochirico Filho, Milena V. Freitas, Raquel B.\nAriede, Lieschen V.G. Lira, Natália J. Mendes and Diogo T.\nHashimoto",authors:[{id:"215385",title:"Dr.",name:"Diogo",middleName:null,surname:"Hashimoto",slug:"diogo-hashimoto",fullName:"Diogo Hashimoto"},{id:"226741",title:"MSc.",name:"Vito",middleName:null,surname:"Matrochirico-Filho",slug:"vito-matrochirico-filho",fullName:"Vito Matrochirico-Filho"},{id:"226743",title:"MSc.",name:"Milena",middleName:null,surname:"Freitas",slug:"milena-freitas",fullName:"Milena Freitas"},{id:"226744",title:"MSc.",name:"Raquel",middleName:null,surname:"Ariede",slug:"raquel-ariede",fullName:"Raquel Ariede"},{id:"226745",title:"MSc.",name:"Natália",middleName:null,surname:"Mendes",slug:"natalia-mendes",fullName:"Natália Mendes"},{id:"226746",title:"MSc.",name:"Lieschen",middleName:null,surname:"Lira",slug:"lieschen-lira",fullName:"Lieschen Lira"}]},{id:"62582",title:"Mangrove Species Distribution and Composition, Adaptive Strategies and Ecosystem Services in the Niger River Delta, Nigeria",slug:"mangrove-species-distribution-and-composition-adaptive-strategies-and-ecosystem-services-in-the-nige",totalDownloads:2197,totalCrossrefCites:5,totalDimensionsCites:14,abstract:"Mangroves of the Niger River Delta grade into several plant communities from land to sea. This mangrove is a biodiversity hot spot, and one of the richest in ecosystem services in the world, but due to lack of data it is often not mentioned in many global mangrove studies. Inland areas are sandy and mostly inhabited by button wood mangroves (Conocarpus erectus) and grass species while seaward areas are mostly inhabited by red (Rhizophora racemosa), black (Laguncularia racemosa) and white (Avicennia germinans) mangroves species. Anthropogenic activities such as oil and gas exploration, deforestation, dredging, urbanization and invasive nypa palms had changed the soil type from swampy to sandy mud soil. Muddy soil supports nypa palms while sandy soil supports different grass species, core mangrove soil supports red mangroves (R. racemosa), which are the most dominant of all species, with importance value (Iv) of 52.02. The red mangroves are adapted to the swampy soils. They possess long root system (i.e. 10 m) that originates from the tree stem to the ground, to provide extra support. The red mangrove trees are economically most viable as the main source of fire wood for cooking, medicinal herbs and dyes for clothes.",book:{id:"6411",slug:"mangrove-ecosystem-ecology-and-function",title:"Mangrove Ecosystem Ecology and Function",fullTitle:"Mangrove Ecosystem Ecology and Function"},signatures:"Aroloye O. Numbere",authors:[{id:"215285",title:"Dr.",name:"Aroloye O.",middleName:null,surname:"Numbere",slug:"aroloye-o.-numbere",fullName:"Aroloye O. Numbere"}]}],onlineFirstChaptersFilter:{topicId:"659",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"August 3rd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",isOpenForSubmission:!0,annualVolume:11403,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},{id:"8",title:"Bioinspired Technology and Biomechanics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",isOpenForSubmission:!0,annualVolume:11404,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. 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Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:250,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"243698",title:"Dr.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"312999",title:"Dr.",name:"Bernard O.",middleName:null,surname:"Asimeng",slug:"bernard-o.-asimeng",fullName:"Bernard O. Asimeng",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}}]}},subseries:{item:{id:"3",type:"subseries",title:"Bacterial Infectious Diseases",keywords:"Antibiotics, Biofilm, Antibiotic Resistance, Host-microbiota Relationship, Treatment, Diagnostic Tools",scope:"