\r\n\tManagement of these disorders requires good clinical evaluation, diagnostic tests, appropriate therapy and huge healthcare cost. Sometimes multiple specialties (gastroenterologists, \r\n\tgastrointestinal motility specialists, otolaryngologists, surgeons, speech therapists, medical oncologists and radiation oncologists) are involved in the management of dysphonia and dysphagia. In the recent years, there have been many updates in the management of these disorders. This book will discuss systematically the different etiologies and management of dysphonia, maxillofacial, oropharyngeal and esophageal dysphagia. This book will be a good \r\n\tguide to the practicing physicians for the management of voice and swallowing disorders.
",isbn:"978-1-83880-366-7",printIsbn:"978-1-83880-365-0",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"9a81e27eb29c12553e9524f20a93b57d",bookSignature:"Associate Prof. Monjur Ahmed",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7844.jpg",keywords:"Dysphonia, dysphagia, endoscopy for dysphagia, motility studies for dysphagia, imaging studies for dysphagia, management of dysphonia and dysphagia, incidence of dysphagia, prevalence of dysphagia, oropharyngeal dysphagia, esophageal dysphagia, botulinum toxin injection, Esophageal stent placement",numberOfDownloads:217,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 26th 2019",dateEndSecondStepPublish:"September 16th 2019",dateEndThirdStepPublish:"November 15th 2019",dateEndFourthStepPublish:"February 3rd 2020",dateEndFifthStepPublish:"April 3rd 2020",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,editors:[{id:"206355",title:"Associate Prof.",name:"Monjur",middleName:null,surname:"Ahmed",slug:"monjur-ahmed",fullName:"Monjur Ahmed",profilePictureURL:"https://mts.intechopen.com/storage/users/206355/images/system/206355.jpeg",biography:"Working as an Associate Professor of Medicine at Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Practicing gastroenterologist for 20 years. Special interest in eosinophilic esophagitis, gastrointestinal motility and dysphagia. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Chan and Manoj Kumar Tiwari",coverURL:"https://cdn.intechopen.com/books/images_new/3794.jpg",editedByType:"Edited by",editors:[{id:"252210",title:"Dr.",name:"Felix",surname:"Chan",slug:"felix-chan",fullName:"Felix Chan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"53444",title:"Phenolic Wastewaters: Definition, Sources and Treatment Processes",doi:"10.5772/66366",slug:"phenolic-wastewaters-definition-sources-and-treatment-processes",body:'\n
\n
1. Introduction, definitions and concepts
\n
Water is an important renewable natural resource; however, it is also reusable. For humans, its employment becomes a problem due to demographic growth and its application in agricultural and industrial enterprises. Thus, the limited availability of water for an eventual reuse appears to be the unique solution. In the past few years, wastewater treatment is the adopted solution in the majority of countries. Traditionally, industrial effluents are frequently contaminated by hazardous organic substances, such as phenolic compounds and aromatic intermediates, as well as other halogenated or volatile organic substances, metals (mainly, Sb, Cu, Pb, Zn, Cd, Cr, Ni, Hg) and other chemical species, such as cyanide (CN−), benzene and chloroform [1]. The presence of these compounds in wastewater and drinking water, due to their toxicity, become a serious problem affecting the ecosystem and causing, for example, health problems [2].
\n
The phenolic compounds are harmful to human health, causing necrosis, digestive problems, and liver and kidney damages. The presence of phenols in drinking water may cause serious public health problems, and the death of fishes, even at concentrations in the range of 1 mg L−1. At concentrations of less than 1 mg L−1 (ppm), they are also toxic to other biological species and destroy the aquatic environment [3].
\n
Phenolic substances are widely employed as industrial chemicals for wood preservation; in petroleum refineries and petrochemical plants; coke gasifiers; in manufacturing of pulp and paper; pharmaceutical plants; food industry; minerals; plastics; metals and organic chemical plants, as well as in agricultural activities as pesticides. However, several research studies indicated that some of these phenolic organic substances are recalcitrant and persistent in treated water as they are refractory to conventional treatment [4, 5]. The most detected organic pollutants in those wastewater are presented in \nTable 1\n [1].
The main phenolic pollutants more detected in effluents.
\n
Phenols are compounds derived from aromatic hydrocarbons by replacing hydrogen atoms with hydroxyls. These compounds are generally solids and are obtained from coal tar distillation and heating of chloro-benzene with water [6]. Phenols can be classified according to the number of hydroxyls into monophenols, diphenols and triphenols. Phenol is less volatile than water and sparingly soluble in it, since the phenol-water system forms an azeotrope to 9.2% by mass of phenol [7].
\n
The toxicity of these organic substances contaminants in different water bodies, including wastewater, surface water, groundwater and drinking water, at environmental levels of mg L−1significantly affect the organoleptic properties of water [8]. Resolution 430 of the Conselho Nacional do Meio Ambiente—CONAMA (National Council on the Environmental), Brazil set a maximum of total phenols concentration at 0.5 mg L−1 for all effluents originating from any polluting source that can be disposed of in water bodies as of 13 May 2011 [9].
\n
According to literature review, phenolic and petroleum wastewater are recalcitrant compounds. Wastewater is generally characterized by the biological oxygen demand (BOD), chemical oxygen demand (COD), pH and total organic carbon (TOC) [10]. Petroleum wastewater contains a COD range from 850 to 1020 mg L−1, a BOD range from 570 mg L−1, a TOC range from 300 to 440 mg L−1 and a pH range from 8 to 8.2, showing that it contains large amounts of non-biodegradable organic matter [11]. Petro-chemical wastewater contains an initial COD range of 300–600 mg L−1, a BOD range of 150–360 mg L−1 and a pH range of 7–8 [12]. Conventional treatment of these substances is difficult because biologically resistant organic compounds do not induce oxygen depletion in receiving water [13].
\n
Several biological and chemical methods have shown a low efficiency to degrade the contaminants completely. As biological and chemical methods degrade only up to 60% of the recalcitrant components and in addition they require larger operation area and more chemical processes to reduce the sludge [14].
\n
There are a number of studies of industrial effluents treatments via conventional methods that are combined with chemical, biological and physical methods and also advanced oxidation processes (AOPs), shared with reactors for complete degradation of highly recalcitrant industrial wastewater. Section 2 discusses the AOP theory and the possibility of enhancement in reactor performance when implemented in the processes.
\n
\n
\n
2. Theory of advanced oxidation processes (AOPs)
\n
The need for an efficient treatment of phenolic compounds in water is very important. When conventional treatment methods such as biological processes fail due to the recalcitrant nature of the contaminants, physical and chemical methods are a good solution. Therefore, oxidation processes are preferred to degrade such organics present. For example, the chemical processes are commonly used to degrade recalcitrant substances. High degradation efficiencies are possible with direct oxidation methods. However, pollution load, process limitation and operation condition are the more important factors considered during the selection for most oxidation processes [15]. The main treatment methods of industrial effluents with biological processes are aerobic, anaerobic and enzymatic. The physical processes are decantation, filtration and adsorption. The chemical methods are incineration, electrochemical and advanced oxidation processes(AOP), for example, photocatalysis, ozonation, Fenton/photo-Fenton and direct contact thermal treatment (DiCTT) [4].
\n
The AOPs have been a viable alternative method for the wastewater treatment containing toxic and refractory organic pollutants, being studied in various combinations and are mainly based on intermediate reactions of hydroxyl radicals (•OH), an unstable and very reactive species, resulting in the degradation of toxic organic contaminants due to its high oxidizing potential of 2.8 V under acidic conditions and these processes have the major advantage of being a destructive treatment. Depending on the species to be degraded the hydroxyl radicals of reactive species, which attack the main part of organic molecules with a rate constant frequently in the order of 106–109 L mol−1s−1, and reacts 106–1012 times faster than ozone [16]. According to Tisa et al. [10] apud Bach et al. [17] and Garrido-Ramírez et al. [18], the principles of •OH generation is based on various combinations of strong oxidants, such as oxygen, ozone, hydrogen peroxide (H2O2), ultra-violet (UV) and electron beam.
\n
The AOPs are classified according to the reactive phase (homogeneous and heterogeneous). The homogeneous including: ozone (O3), ozone/ultraviolet (O3/UV), ozone/hydrogen peroxide (O3/H2O2), (O3/H2O2/UV), and (H2O2/UV) processes, as well as Fenton (Fe2+/H2O2), Fenton-like (Fe3+/mn+/H2O2), photo-Fenton (UV/Fe2+/H2O2), sono-Fenton (US/Fe2+/H2O2), electro-Fenton, sono-electro-Fenton, photo-electro-Fenton, sono-photo-Fenton. The heterogeneous includes: (TiO2/ZnO/CdS+UV), (TiO2/H2O2), (H2O2+Fe2+/Fe3+/mn+-solid), (H2O2+Fe0/Fe-nano-zero valente iron) and (H2O2+immobilized nano-zero valente iron). The non-conventional AOPs include ionizing radiation, microwaves and pulsed plasma techniques. Depending on the matrix and on the pollutant, degradation kinetics of AOPs can be zero order, first order and second order. First-order kinetics constant is achieved for pollutant degradation due to concentration of hydroxyl radicals within 1–10−4 s−1 [15, 4]. The mechanisms of different AOPs are presented in \nTable 2\n.
\n
\n
\n
\n
\n
\n
\n\n
\n
Name of the AOP
\n
Types
\n
Mechanism reaction
\n
Highlights
\n
References
\n
\n\n\n
\n
Fenton oxidation
\n
Homogeneous
\n
H2O2 + Fe2+ → Fe3+ + •OH + OH−\n
\n
-Degradation of pollutant happens in acidic aqueous mixture
Mechanisms of different advanced oxidation processes.
\n
In the AOPs, oxygen and their reactive species (O\nx\n, HO\nx\n, x = 1, 2, 3, 4) act as main precursors during the oxidation that occurs in step of degradation of the organic component [23].
\n
Devlin and Harris [24] proposed in their experimental trials that levels of O2 decrease quickly in accordance with the rates of degradation of aromatic compounds, due to the high concentrations of phenol, in the temperature range from 420 to 498 K, near or above the stoichiometric conditions. These results led to demonstrate that the concentration of radicals (•O) is the dominant mechanism for this temperature range, in which the intermediate rings resulting from the oxidation of phenol are degraded.
\n
Section 3 indicates that the direct contact thermal treatment technology is recent, with a limited investigation and was initially developed in Canada by Benali et al. [25, 26], being the unique experimental results available in the literature, until this moment. The DiCTT process provides a promising novel means to induce degradation and mineralization of organic pollutants in water being an AOP treatment method with respective advantages and limitations. Since combining AOP treatment process with reactors can be more promising in industrial applications, this research area needs to be explored further. Section 3 describes the DiCTT technique with applications in degradation and mineralization of the organic pollutant, being elaborated to highlight the important factors and their effects, as also a detailed investigation of the effective design and operating parameters are summarized.
\n
The actual work evaluated the liquid phase flow rate (Q\n\nL\n) of 100 and 170 L h−1 and the effect of initial phenol concentration (C\nPh0) of 500, 2000 and 3000 mg L−1. The experiments studies were performed using a molar stoichiometric ratio of phenol/hydrogen peroxide (R\nP/H) of 50%, an air excess (E) of 40%, a recycle rate of gaseous thermal wastes (Q\nRG) of 50%, and, a natural gas flow (Q\nGN) of 4 m3 h−1, on the oxidation of phenolic effluents by DiCTT process. The phenol concentration and mineralization content were obtained by high-performance liquid chromatography (HPLC) and mineralization Total Organic Carbon (TOC), respectively. A new data bank was compiled in this work by optimizing the operation conditions for the degradation/mineralization of phenol by the DiCTT process. (Phenol was used as a model compound for liquid organic wastes.)
\n
\n
\n
3. Concepts of DiCTT-AOPs in degradation and mineralization of organic pollutants
\n
\n
3.1. Pilot plant and experimental procedure
\n
Currently, a non-conventional AOP called Direct Contact Thermal Treatment (DiCTT) process has been investigated, whose main attraction are the use of natural gas as the energy source, the demonstrated ability to oxidize phenolic compounds at low temperatures and atmospheric pressure, and the generation of free radicals (•OH, •H, •CH3 and •CHO) resulting from combustion of natural gas (methane). The installation of the DiCTT technology presents a compact reactor configuration that involves maintaining the reactor in a vertical position, favouring the immediate application of this technology in off-shore oil platforms, where natural gas is available and space is limited [4, 27].
\n
The experimental unit used is mainly composed of a vertical stainless steel reactor, being 1.359 mm high and 203 mm internal diameter, a gas-liquid separator, a first tank (Tank 1) for preparation of phenol synthetic solutions, 400 L volume, a second tank (Tank 2) for feeding in polluted waters, also of 400 L volume, and a natural gas burner with 50 kW maximum power. The combustion air is provided by an axial fan with 0.3 HP power. The output pressure of the natural gas supply is 2 × 105 Pa, followed by a reduction to 1 × 105 Pa for combustion in the burner.
\n
In this process, the effluent is tangentially injected into the reactor to produce a helical flow in its inner walls. The helical flow allows an intimate contact between the effluent and free radicals produced in the combustion flame of the natural gas, resulting in a thermochemical oxidation in the liquid phase, while avoiding their incineration. The high flame temperature contributes to the oxidation performance of the effluent in the presence of free radicals and works for the oxidation process to be carried out in completely liquid phase, by transferring some of the excess oxygen present in the flame.
\n
The DiCTT process is a thermochemical oxidation method in aqueous medium, and generating free radicals resulting from the combustion of natural gas (methane) according to the reaction mechanism described by the whole of Eq. (1) following [27]:
This technique presents operational and capital costs 2.5 times lower than those of wet air oxidation (WAO) and 4.1 times lower than those of electric plasma oxidation (EPO) [27].
\n
\n\nFigure 1\n show a schematic representation of the pilot plant used in the experiments that was composed of a vertical, stainless-steel reactor and a gas-liquid separator.
\n
Figure 1.
Pilot plant using the DiCTT process.
\n
The phenol solution was prepared in Tank 1. The operation of the system was stabilized by heating the water to almost 70°C for an hour and a half; phenol was subsequently added to Tank 1, and the synthetic effluent was transferred from Tank 1 to Tank 2. The reactor had an internal helical groove with a rectangular shape, in the axial direction, through which the liquid effluent flowed. Wastewater polluted with phenol was injected into the reactor tangentially to produce a liquid helical stream on its inner walls. The combustion gases were vented to the atmosphere through a chimney; a fraction of recycled combustion gases (of the total flow rate Q\nRG) was immediately injected into Tank 2 by adjusting an open valve to heat the solution in the recirculation tank (Tank 2) more rapidly and to dissolve a fraction of the residual oxygen from combustion into the reaction liquid, thereby inducing the thermochemical oxidation of the phenolic compounds. For the experiments, 250L of effluent was prepared. For each experiment 250mL samples of effluent in black plastic bottles were collected at previously chosen points and put to cool in a refrigerator. For the analyses, 250mL of treated drinking water was employed as a reference. To initiate the oxidation reaction, some millilitres of phenol/hydrogen peroxide with a mole ratio, RPH was introduced into Tank 2. Liquid samples were withdrawn for analysis through a collector located at the entrance of the tubes connecting the feed tank (Tank 2) to the reactor inlet (\nFigure 1\n).
\n
\n
\n
3.2. Analytical methods
\n
For the experiments, a phenol solution of analytical grade and oxygenated water 35% PA were employed. For the chromatographic analysis, methanol UV/HPLC grade and for TOC analysis phosphoric acid 25% PA were used.
\n
The concentrations of phenol, catechol and hydroquinone were monitored using an HPLC instrument (Shimadzu, model LC-20AT, with integrated data acquisition using a UV detector and a CLC-ODS column (M)/(C-18) that was 250 mm in length and 4.6 mm in diameter, also from Shimadzu). An isocratic elution mode was used under the following conditions: oven temperature of 35°C; flow rate of 0.75 mL min−1 for the mobile phase; injection volume of 20 μL; mobile phase consisting of 10% methanol and 90% phosphoric acid/deionised water with pH adjusted to 2.2; and operation of the UV detector at a wavelength of 270 nm to detect phenol, catechol and hydroquinone [4].
\n
The TOC content was measured using a TOC analyser (TOC-Vcsh model, Shimadzu) to analyse phenolic mineralisation quantitatively [28].
\n
\n
\n
3.3. Parameters and calculated data
\n
Phenol oxidation is a common reaction stoichiometry described in Eq. (2):
Molar ratios other than 100% were calculated proportionally using the reaction stoichiometry in Eq. (2).
\n
In this work, natural gas (89.24% of methane) supplied by COPERGAS (Pernambuco, Brazil) was employed [29]. Stoichiometrically 9.881 mol of air reacts with one mol of methane. So, the excess air (E) in the combustion and the equivalent ratio (Φ) may be evaluated employing Eqs. (3) and (4) [30, 31].
where Q\n\nL\n represents the volumetric flow rate, C\nph0, the initial phenol concentration, C\nph, the phenol concentration at time t, F\n\nG\n the dry air mass flow rate, C\nphv, the phenol concentration in the condensate at time t. TOC conversion was evaluated via Eq. (7).
\n
The TOC conversion (X\n\nT\n) was evaluated via Eq. (7):
where TOC0 denotes the initial total organic carbon concentration, TOC and TOCV denote the total organic carbon and the total organic carbon in the condensate, respectively, at a time point t of the process and TOCB denotes the total organic carbon in the blank.
\n
\n
\n
3.4. Effect of the liquid phase flow rate
\n
This work was to evaluate the influence of the liquid phase flow rate on the level of phenol oxidation, settling other process variables. These operational parameters are listed in \nTable 3\n.
\n
\n
\n
\n
\n
\n
\n
\n
\n\n
\n
Tests
\n
QL(L h−1)
\n
QGN(m3 h−1)
\n
E(%)
\n
Cph0(mgL−1)
\n
QRG(%)
\n
RP/H(%)
\n
\n\n\n
\n
E1
\n
170
\n
4
\n
40
\n
500
\n
50
\n
50
\n
\n
\n
E2
\n
100
\n
4
\n
40
\n
500
\n
50
\n
50
\n
\n\n
Table 3.
Operational parameters for the study of the influence of the liquid phase flow rate.
\n
\nFigure 2a and b show, respectively, the evolution of the temperature and pH of the liquid effluent present in the feed tank (Tank 2) during the process, varying the volumetric flow of the same.
\n
Figure 2.
(a) Evolution of temperature of the liquid effluent as a function of the operating time. (b) Evolution of pH as a function of the operating time. E = 40%, Q\nGN = 4 m3 h−1, C\nPh0 = 500 mg L−1, R\nP/H = 50% and Q\nRG = 50%.
\n
\n\nFigure 2a\n indicates that the elevation of effluent flow affects the heating curve of liquid effluent, getting it faster to obtain steady-state temperature in Tank 2. \nFigure 2a\n also show that for the larger effluent flow (170 L h−1), the same reaches a maximum temperature of 348 K, quite greater than the temperature of the effluent flow of the 100 L h−1 (344 K), featuring a small effect, since the difference in these temperatures reaches an order of magnitude lower than the measurement uncertainty by thermocouples.
\n
The oxidation process indicates that the heating profile is characterized by two distinct steps, a first, approximately 110 min, characterized by a rapid temperature rise and a second, after 110 min of operation, showing a temporal increase rate of low temperature. \nFigure 2b\n show that the evolution of pH also identifies these two steps, the first of about 110 min, characterized by a decreased less than hydrogen potential as a function of time, and the second-fastest where the temporal decay profile of pH is more significant. It is shown a low influence in liquid flow in the dynamics of acid formation [24].
\n
\nFigure 3a and b show, respectively, the profile of phenol degradation and residual fraction of the TOC as a function of time for the two flows of liquid effluent studied, 100 and 170 L h−1.
\n
Figure 3.
(a) Evolution of phenol degradation as a function of the operating time. (b) Evolution of TOC conversion as a function of the operating time. E = 40%, Q\nGN = 4 m3 h−1, C\nPh0 = 500 mg L−1, R\nP/H = 50% and Q\nRG = 50%.
\n
\n\nFigure 3a\n indicates that, in the range studied, the variation of the effluent flow does not affect the profile of phenol degradation and total degradation of the same is almost completely achieved in 180 min of operation, reaching values of 99.5 and 97.4%, respectively, at effluent flow of 100 and 170 L h−1. \nFigure 3b\n indicates that the increase of the effluent flow of 100 to 170 L h−1 allows a higher speed of phenol mineralization, due the acceleration of the lowest value of the pH, but not interfering in the maximum value TOC conversion, around 28% with an operating time of 210 min.
\n
\nFigure 4a and b indicates, respectively, the time profiles of the hydroquinone and catechol formed by thermochemical phenol oxidation, for the two flows of liquid effluent, 100 and 170 L h−1. Analysing the same figures, it can be seen that the rate of formation of these species becomes appreciable after the induction period, approximately 110 min, previously observed by the curves of the evolution of pH, phenol degradation and TOC conversion.
\n
Figure 4.
(a) Evolution of hydroquinone formation as a function of the operating time. (b) Evolution of catechol formation as a function of the operating time. E = 40%, Q\nGN = 4 m3 h−1, C\nPh0 = 500 mg L−1, R\nP/H = 50% and Q\nRG = 50%.
\n
The evolution of the hydroquinone and catechol concentrations happened quickly because of the thermochemical oxidation reaction of phenol with high speed, regardless of the flows of liquid effluent studied. It has been observed that hydroquinone and catechol concentrations are reached when phenol consumption rate is maximum, which is identified in the process time between 140 and 150 min. After reaching the maximum hydroquinone and catechol formation, an immediate reduction in the concentration of these two species is observed, indicating that to achieve the maximum consumption of phenol, the oxidation rate of these two organic compounds becomes greater than its rate of formation, enabling to be degraded, thus favouring the formation of other organic compounds that are not acids, because the pH remained almost constant at 2.5−2.8, after 140−150 min of operation. The products resulting from the oxidation of hydroquinone and catechol are probably aldehydes (Glyoxal, for example, in the case of hydroquinone and catechol) and alkenes (1,4-dioxo-2-butene, for example, in the case of hydroquinone) [24].
\n
\n\nFigure 4a\n and presents the results obtained in the quantification of concentrations of hydroquinone and catechol, respectively. It also show a speed of formation and consumption of these species not significantly affected by variation of the flows of liquid effluent. It is also observed a rate of production and disappearance slightly larger (especially in the case of catechol) with use of effluent flow rate 170 L h−1, similarly what was evidenced in the evolution of pH, being less for the flow rate of 170 L h−1, allowing more oxidation of phenol to hydroquinone and catechol. However, regardless of the flow of the liquid studied, catechol concentrations were approximately two times higher compared to those obtained in relation to the hydroquinone.
\n
\n
\n
3.5. Effect of initial phenol concentration
\n
In order to evaluate the effect of initial concentration of the organic pollutant on the efficiency of the process DiCTT on thermochemical phenol oxidation, three initial concentrations of the aromatic contaminant (C\nPh0): 500, 2000 and 3000 mg L−1, were employed keeping all other variables constant. The operating conditions used in this study are presented in \nTable 4\n.
\n
\n
\n
\n
\n
\n
\n
\n
\n\n
\n
Tests
\n
CPH0(mgL−1)
\n
QGN(m3 h−1)
\n
E(%)
\n
QL(Lh−1)
\n
QRG(%)
\n
RP/H(%)
\n
\n\n\n
\n
E3
\n
500
\n
4
\n
40
\n
170
\n
50
\n
50
\n
\n
\n
E4
\n
2000
\n
4
\n
40
\n
170
\n
50
\n
50
\n
\n
\n
E5
\n
3000
\n
4
\n
40
\n
170
\n
50
\n
50
\n
\n\n
Table 4.
Operational parameters for the study of the influence of the initial concentration of phenol.
\n
\nFigure 5a and b presents, respectively, the evolution of the temperature and pH of the liquid effluent in the perfect mixing tank (Tank 2) during the process, varying only the initial concentration of phenol. From \nFigure 5a\n it can be seen that the concentration of phenol does not influence the heating curve of the liquid phase, reaching a temperature of approximately 350 K (77°C). An expected behaviour since the variation of concentration, in different experiments, it is not enough to significantly change the chemical and thermophysical properties of the effluent, since the natural gas flow in the process is the same for all cases, as well as the excess air and effluent flow which remained constant during these essays.
\n
Figure 5.
(a) Evolution of temperature of the liquid effluent as a function of the operating time. (b) Evolution of pH as a function of the operating time. E = 40%, Q\nGN = 4 m3 h−1, Q\n\nL\n = 170 L h−1, R\nP/H = 50% and Q\nRG = 50%.
\n
\n\nFigure 5b\n show the curves of the evolution of pH for concentrations of phenol 2000 and 3000 mg L−1. It can be seen that the initial pH value already show low values, 4 and 3, respectively, while for a C\nPh0 equal 500 mg L−1, pH presents an initial value of 8. This can be explained due to the amount of hydrogen peroxide added. In the procedure adopted for the preparation of the synthetic effluent, the peroxide is mixed with the phenol solution in the preparation tank, causing uncontrolled reactions. As the molar stoichiometric ratio of the mix is kept constant, to higher concentrations of phenol oxidant availability in the reaction medium is greater, increasing the effect and decreasing the initial pH due to a possible premature oxidation of phenol to form organic acids.
\n
\nFigure 6a and b presents, respectively, the profile of phenol degradation and TOC conversion as a function of time, for different initial concentrations of phenol studied.
\n
Figure 6.
(a) Evolution of phenol degradation as a function of the operating time. (b) Evolution of TOC conversion as a function of the operating time. E = 40%, Q\nGN = 4 m3 h−1, Q\n\nL\n = 170 L h−1, R\nP/H = 50% and Q\nRG = 50%.
\n
\n\nFigure 6a\n show that the increase of the initial concentration of phenol from 500 to 3000 mg L−1 does not affect the duration of the first step of the reaction, called induction period, and does not have a significant effect on the phenol degradation after a time of approximately 130 min. After the induction period, around 110 min, the speed of the reaction becomes more pronounced, as was expected, reaching values of XF practically the same after an operating time of around 130 min, regardless of the initial concentration of phenol. Phenol degradation around 99% is obtained after an operating time of 180 min.
\n
\n\nFigure 6b\n show the evolution of TOC conversion, identifying a time of induction period also approximately 110 min, and show a slight increase in the TOC conversion with increasing of the initial phenol concentration, reaching XT values of 27.5; 31.5 and 33.5% to initial concentration of phenol of 500, 2000 and 3000 mg L−1, respectively, after an operating time of 210 min. Regardless of the value of the initial phenol concentration, the process presents maximum rates of phenol degradation almost 100% after 170 min of operation, in addition to providing a TOC conversion, between a range of 27.5–33.5%, after 210 min, within the range of the initial concentration of phenol, being the air excess used of 40% and a combustion gases recycling rate of 50%.
\n
\nFigure 7a and b show, respectively, the results obtained in the quantification of the concentrations of hydroquinone and catechol formation. The evolution of the concentration profiles of hydroquinone and catechol in function of the time confirm clearly the induction time of reaction, around 110 min, identified initially by the curves of time evolution of the phenol degradation (\nFigure 6a\n) and TOC conversion (\nFigure 6b\n). It can be that maximum values of hydroquinone and catechol concentration formed in approximately 140 min operating time, reaching the maximum speed of phenol degradation and TOC conversion and that the catechol concentrations are always higher than the hydroquinone concentration.
\n
Figure 7.
(a) Evolution of hydroquinone formation as a function of the operating time. (b) Evolution of catechol formation as a function of the operating time. E = 40%, Q\nGN = 4 m3 h−1, Q\n\nL\n = 170 L h−1, R\nP/H = 50% and Q\nRG = 50%.
\n
After 140 min, both hydroquinone and catechol concentrations decrease, thus allowing the formation of other organic compounds that are not acids, because the pH becomes practically constant (pH = 3) after 140 min of operation (\nFigure 5b\n). It can be that the products resulting from the oxidation of hydroquinone and catechol are possibly aldehydes (Glyoxal, for example, in the case of hydroquinone and catechol) and alkenes (1,4-dioxo-2-butene, for example, in the case of hydroquinone).
\n
The phenol oxidation produces catechol and hydroquinone [20]. Analyses indicated a higher catechol production then hydroquinone. This may be explained by the mesomeric effect. This signifies an electron re-distribution to the ortho position, which increases its reactivity at this position of the molecule due to the proximity of opposing charges [4, 27].
\n
\n
\n
\n
4. Conclusions and recommendations
\n
The Advanced Oxidation Processes (AOPs) are found to be an environmental friendly process for the degradation and mineralization of refractory compounds. The limitations of conventional processes in wastewater treatment necessitate study on the AOPs. Thus, applications of the Direct Contact Thermal Treatment (DiCTT) process is a promising technique increasingly used to remove phenolic compounds in water. The method advantages are operational and capital costs lower than other process and ability to allow total degradation and higher mineralization of target compounds when compared to conventional AOPs. On the other hand, further efforts are conducted to overcome the empirical aspect by studying the operating parameters, as well as the optimization of the process.
\n
The complete degradation of phenol (almost 100%) was obtained independently of the flows of liquid effluent, 100 and 170 L h−1, and, of the initial phenol concentrations, 500, 2000 and 3000 mg L−1 over a 180-min period. A TOC conversion of almost 35% was observed corresponding to an operational time of approximately 210 min at a Q\n\nL\n of 170 L h−1, which allows the speed of phenol mineralization is faster, but without interfering in the final value of almost 28% TOC conversion after 210 min of operation process. The flows of liquid effluent of 170 L h−1 was considered to be the best operating condition for the DiCTT process. An induction time of approximately 110 min was identified from the concentration profiles of hydroquinone and catechol. The concentrations of these intermediates tented to decrease independently of the flows of liquid effluent and of the initial phenol concentrations, indicating the formation of the other organic compounds, which were not acids (constant pH) according to data reported in the literature.
\n
\n
Acknowledgments
\n
The authors wish to thank the Financiadora de Estudos e Projetos—FINEP/Ministry of Science and Technology—MCT—Brazil and PETROBRÁS for providing financial support during the development of this work and the Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq for awarding the research grants.
\n
\n',keywords:"phenolic compounds, natural gas, AOP, DiCTT, TOC",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/53444.pdf",chapterXML:"https://mts.intechopen.com/source/xml/53444.xml",downloadPdfUrl:"/chapter/pdf-download/53444",previewPdfUrl:"/chapter/pdf-preview/53444",totalDownloads:1141,totalViews:456,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"June 1st 2016",dateReviewed:"October 17th 2016",datePrePublished:null,datePublished:"March 15th 2017",readingETA:"0",abstract:"This chapter aims the state of the art concerning the development of advanced oxidation processes (AOPs) for treatment of organic-aqueous effluent for the reuse of liquid water. It presents the major oxidative processes applied for industrial and domestic treatment, where the effluents are often contaminated by phenolic compounds. A special emphasis is given to a relatively new technique called direct contact thermal treatment (DiCTT) that has the advantages of conventional AOP without its inconveniences. The DiCTT process is characterized by the generation of hydroxyl radicals (•OH) by combustion of natural gas, its compact installation and easy operation, being able to be used in offshore oil-exploration platforms, where natural gas is available and the space is reduced. Also, in this chapter, original results on the treatment of the DiCTT technique are presented, which are considered unconventional, by evaluating the oxidation and the conversion of the total organic carbon (TOC) of phenolic compounds at low temperature and atmospheric pressure, with identification and quantification of the intermediate compounds, using high-performance liquid chromatography (HPLC), which may be more toxic than the original pollutants.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/53444",risUrl:"/chapter/ris/53444",book:{slug:"phenolic-compounds-natural-sources-importance-and-applications"},signatures:"Yana Batista Brandão, Julierme Gomes Correia de Oliveira and\nMohand Benachour",authors:[{id:"192946",title:"Dr.",name:"Yana",middleName:null,surname:"Brandão",fullName:"Yana Brandão",slug:"yana-brandao",email:"yanabatista@yahoo.com.br",position:null,institution:null},{id:"194009",title:"Prof.",name:"Mohand",middleName:null,surname:"Benachour",fullName:"Mohand Benachour",slug:"mohand-benachour",email:"mbena.br@gmail.com",position:null,institution:{name:"Federal Rural University of Pernambuco",institutionURL:null,country:{name:"Brazil"}}}],sections:[{id:"sec_1",title:"1. Introduction, definitions and concepts",level:"1"},{id:"sec_2",title:"2. Theory of advanced oxidation processes (AOPs)",level:"1"},{id:"sec_3",title:"3. Concepts of DiCTT-AOPs in degradation and mineralization of organic pollutants",level:"1"},{id:"sec_3_2",title:"3.1. Pilot plant and experimental procedure",level:"2"},{id:"sec_4_2",title:"3.2. Analytical methods",level:"2"},{id:"sec_5_2",title:"3.3. Parameters and calculated data",level:"2"},{id:"sec_6_2",title:"3.4. Effect of the liquid phase flow rate",level:"2"},{id:"sec_7_2",title:"3.5. Effect of initial phenol concentration",level:"2"},{id:"sec_9",title:"4. Conclusions and recommendations",level:"1"},{id:"sec_10",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\nRodrigues, GD, Silva, LHM, Silva, MCH. Green alternatives for the preparation of sample and determination of phenolic pollutants in water, Química Nova, 2010: 33, 1370–1378.\n'},{id:"B2",body:'\nSemrany, S, Favier, L, Djelal, H, Taha, S, Amrane, A. Bioaugmentation: possible solution in the treatment of Bio-Refractory Organic Compounds (Bio-ROCs). Biochem. Eng. J., 2012: 69, 75–86.\n'},{id:"B3",body:'\nMishra, VS, Mahajani, VV., Joshi, JB. Wet air oxidation. Ind. Eng. Chem. Res., 1995: 34, 2-48.\n'},{id:"B4",body:'\nBrandão, Y, Teodosio, J, Dias, F, Eustáquio, W, Benachour, M. Treatment of phenolic effluents by a thermochemical oxidation process (DiCTT) and modelling by artificial neural networks. Fuel, 2013: 110, 185-195.\n'},{id:"B5",body:'\nLuna, AJ, Rojas, LOA., Melo, DMA., Benachour, M, de Souza, JF. Total catalytic wet oxidation of phenol and its chlorinated derivates with MnO2/CeO2 catalyst in a slurry reactor. Brazil. J. Chem. Eng., 2009: 26, 493–502.\n'},{id:"B6",body:'\nExperimental and kinetic diffusional resistance on wet oxidation of phenolic compounds using metal catalysts [Master of Science, Dissertation]. Natal, RN: UFRN; 2003.\n'},{id:"B7",body:'\nHackbart LM. Liquid-liquid equilibrium of Systems Containing Phenol-Water-solvent:Obtaining and Thermodynamic Modelling [Master of Science, Dissertation]. Curitiba, PR: UFPR; 2007.\n'},{id:"B8",body:'\nBritto, JM, Rangel, MC. Advanced oxidation processes of phenolic compounds in industrial effluents. Química Nova, 2008: 31, 114–122.\n'},{id:"B9",body:'\nNational Council for the Environment (CONAMA). Resolution, 2011: 43.\n'},{id:"B10",body:'\nTisa, F, Raman, AAA, Daud, WMAW. Applicability of fluidized bed reactor in recalcitrant compound degradation through advanced oxidation processes: a review. J. Environ. Manage., 2014: 46, 260–275.\n'},{id:"B11",body:'\nCoelho, A, Castro, AV, Dezotti, M. Treatment of petroleum refinery sour-water by advanced oxidation processes. J. Hazard Mater., 2006: 137, 178–184.\n'},{id:"B12",body:'\nMa, F, Guo, J-B, Zhao, L-J, Chang, C-C, Cui, D. Application of bioaugmentation to improve the activated sludge system into the contact oxidation system treating petrochemical wastewater. Bioresour. Technol., 2009: 100, 597–602.\n'},{id:"B13",body:'\nGuo, J-B, Al-Dahhan, M. Catalytic wet air oxidation of phenol in concurrent downflow and upflow packed-bed reactors over pillared clay catalyst. Chem. Eng. Sci., 2005: 60, 735–746.\n'},{id:"B14",body:'\nOller, S, Malato, JA, Sánchez-Pérez. Combination of advanced oxidation processes and biological treatments for wastewater decontamination—a review. Sci. Total Environ., 2011: 409, 4141–4166.\n'},{id:"B15",body:'\nBabuponnusami, A, Muthukumar, K. A review on Fenton and improvements to the Fenton process for wastewater treatment. J. Environ. Chem. Eng., 2014: 2, 557–572.\n'},{id:"B16",body:'\nHoigne, J. Inter-calibration of OH radical sources and water quality parameters. Water Sci. Technol., 1997: 35, 1–8.\n'},{id:"B17",body:'\nBach, A, Shemer, H, Semiat, R. Kinetics of phenol mineralization by Fenton-like oxidation. Desalination, 2010: 264, 188−192.\n'},{id:"B18",body:'\nGarrido-Ramírez, EG, Theng, BKG, Mora, ML. Clays and oxide minerals as catalysts and nanocatalysts in Fenton-like reactions—a review. Appl. Clay Sci., 2010: 47, 182−192.\n'},{id:"B19",body:'\nLucas, MS, Peres, JA. Degradation of Reactive Black 5 by Fenton/UV-C and ferrioxalate/H2O2/solar light processes. Dyes Pigments, 2007: 74, 622−629.\n'},{id:"B20",body:'\nEsplugas, S, Gimenez, J, Contreras, S, Pascual, E, Rodrigues, M. Comparison of diferente advanced oxidation processes for phenol degradation. Water Res., 2001: 36, 1034−1042.\n'},{id:"B21",body:'\nAyoub, K, Nelieu, S, van Hullebusch, ED, Maia-Grondard, A, Cassir, M, Bermond, A. TNT oxidation by Fenton reaction: reagent ratio effect on kinetics and early stage degradation pathways. Chem. Eng. J., 2011: 173, 309−317.\n'},{id:"B22",body:'\nNidheesh, PV, Gandhimathi, R, Ramesh, ST. Degradation of dyes from aqueous solution by Fenton processes: a review. Environ. Sci. Pollut. Res. 2013: 20, 2099−2132.\n'},{id:"B23",body:'\nOppenländer T. Photochemical purification of water and air—Advanced Oxidation Processes (AOPs): principles, reaction mechanisms, reactor concepts. Wiley-VCH: Weinheim, 2003. 368p.\n'},{id:"B24",body:'\nDevlin, HR, Harris, IJ. Mechanism of the oxidation of aqueous phenol with dissolved oxygen. Ind. Eng. Chem. Res., 1984: 23, 387–92.\n'},{id:"B25",body:'\nGuy, C, Benali, M and Ostiguy, E. Free radical oxidation process and installation for treating liquid effluents contaminated by organic substances. Canadian Patent, 2002, no. 2187982.\n'},{id:"B26",body:'\nBenali, M and Guy, C. Thermochemical oxidation of phenolic-laden liquid effluent models. J. Environ. Eng. Sci., 2007: 6, 543-552.\n'},{id:"B27",body:'\nBrandão, Y, Teodosio, J, Benachour, M, Oliveira, J, Marinho, I, Figueirêdo, F, Anselmo-Filho, P. Study of the effect of excess air and dissipation of the burner on the capabilities of the DiCTT process in liquid phenolic wastewater treatment. Revista Iberoamericana Sistemática—Cibernética e Informática, 2010: 7, 1–9.\n'},{id:"B28",body:'\nFonseca, JCL, Silva, MRA, Bautitz, IR. Nogueira, RFP, Marchi, MRR. Evaluation of the reliability of analytical determinations of total organic carbon (TOC). Ecletica Quim, 2006: 31, 47–52.\n'},{id:"B29",body:'\nPernambuco Gas Company (COPERGÁS) [Internet]. 2009. Available from: http://www.copergas.com.br/site/ctudoconteudo.asp?idsecao=4 [Accessed: 2009-04-03].\n'},{id:"B30",body:'\nOliveira, JGC. Theoretical study via CFD-computational and experimental study of the combustion of natural gas for liquid organic effluent treatment by applying the new technology DICTT [Master of Science, Dissertation]. Recife, PE: UFPE; 2007.\n'},{id:"B31",body:'\nBaukal, Jr. Charles, E, Schwartz, RE. The John Zink combustion handbook. Boca Raton, FL: CRC Press; 2001, 354 p.\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Yana Batista Brandão",address:null,affiliation:'
Department of Engineering, University Federal Rural of Pernambuco, Cabo de Santo Agostinho, Pernambuco, Brazil
'},{corresp:null,contributorFullName:"Julierme Gomes Correia de Oliveira",address:null,affiliation:'
Department of Engineering, College of Boa Viagem, Recife, Pernambuco, Brazil
Department of Chemical Engineering, University Federal of Pernambuco, Recife, Pernambuco, Brazil
'}],corrections:null},book:{id:"6029",title:"Phenolic Compounds",subtitle:"Natural Sources, Importance and Applications",fullTitle:"Phenolic Compounds - Natural Sources, Importance and Applications",slug:"phenolic-compounds-natural-sources-importance-and-applications",publishedDate:"March 15th 2017",bookSignature:"Marcos Soto-Hernandez, Mariana Palma-Tenango and Maria del Rosario Garcia-Mateos",coverURL:"https://cdn.intechopen.com/books/images_new/6029.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"65790",title:"Prof.",name:"Marcos",middleName:null,surname:"Soto-Hernández",slug:"marcos-soto-hernandez",fullName:"Marcos Soto-Hernández"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"53295",title:"Chemical Structure of Phenols and Its Consequence for Sorption Processes",slug:"chemical-structure-of-phenols-and-its-consequence-for-sorption-processes",totalDownloads:1525,totalCrossrefCites:2,signatures:"Magdalena Sobiesiak",authors:[{id:"193105",title:"Dr.",name:"Magdalena",middleName:null,surname:"Sobiesiak",fullName:"Magdalena Sobiesiak",slug:"magdalena-sobiesiak"}]},{id:"53530",title:"Phenolic Compounds from the Natural Sources and Their Cytotoxicity",slug:"phenolic-compounds-from-the-natural-sources-and-their-cytotoxicity",totalDownloads:2234,totalCrossrefCites:0,signatures:"Shagufta Perveen and Areej Mohammad Al-Taweel",authors:[{id:"192992",title:"Associate Prof.",name:"Shagufta",middleName:null,surname:"Perveen",fullName:"Shagufta Perveen",slug:"shagufta-perveen"},{id:"192994",title:"Dr.",name:"Areej",middleName:null,surname:"Al-Taweel",fullName:"Areej Al-Taweel",slug:"areej-al-taweel"}]},{id:"53539",title:"Phenolics in Foods: Extraction, Analysis and Measurements",slug:"phenolics-in-foods-extraction-analysis-and-measurements",totalDownloads:2397,totalCrossrefCites:4,signatures:"Alfredo Aires",authors:[{id:"175895",title:"Dr.",name:"Alfredo",middleName:null,surname:"Aires",fullName:"Alfredo Aires",slug:"alfredo-aires"}]},{id:"53529",title:"Synthesis and Characterization of Phenolic Lipids",slug:"synthesis-and-characterization-of-phenolic-lipids",totalDownloads:1391,totalCrossrefCites:3,signatures:"Mohamed Hussein Hamdy Roby",authors:[{id:"193349",title:"Dr.",name:"Mohamed",middleName:null,surname:"Roby",fullName:"Mohamed Roby",slug:"mohamed-roby"}]},{id:"53528",title:"Anthocyanin Pigments: Importance, Sample Preparation and Extraction",slug:"anthocyanin-pigments-importance-sample-preparation-and-extraction",totalDownloads:4688,totalCrossrefCites:0,signatures:"Julia Martín, María José Navas, Ana María Jiménez-Moreno and\nAgustín G. 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1. Introduction
CD4+FOXP3+ regulatory T cells (Treg) have an indispensable role in maintaining immune homeostasis and immune tolerance. They control unwanted immune responses that are involved in the regulation of immune tolerance to self as well as to foreign antigens. Loss-of-function mutation in FOXP3 locus, a gene encoding Treg lineage transcription factor FOXP3, leads to multiorgan associated autoimmunity. Abnormal numbers of Treg and/or impaired suppressive function of Treg are often found in various autoimmune diseases like type 1 diabetes (T1D) [1], multiple sclerosis (MS) [2], rheumatoid arthritis (RA) [3], psoriasis [4, 5, 6], and systemic lupus erythematosus (SLE) [7, 8, 9]. On the other hand, tumor-infiltrating Treg generally show potent suppressive functions, indicating that they regulate tumor-specific immune responses and might help tumor immune escape [10]. It seems logical to use Treg as a therapeutic target for diseases where the immune balance is impaired and could benefit from the regulation of Treg properties. Nevertheless, due to the intrinsic properties of Treg, i.e. heterogeneity and plasticity, several key questions need to be clarified before making Treg an ideal candidate for clinical applications.
Tumor necrosis factor (TNF) is initially expressed on cell surface as a membrane bound cytokine (mTNF), which can be cleaved by a metalloprotease TNF converting enzyme (TACE) to generate soluble form of TNF (sTNF) [11]. TNF binds to receptors, TNF receptor 1 (TNFR1) and 2 (TNFR2). In contrast to TNFR1, TNFR2 expression is restricted in certain cell types including lymphocytes [12]. TNF-TNFR1 interaction mostly induces proinflammatory reactions, whereas TNFR2 generally leads to the suppressive function of TNF [13]. It is known that TNFR2 is constitutively expressed on both murine and human Treg, and TNFR2+ Treg are the most suppressive Treg subpopulation [14, 15, 16, 17]. The effect of TNF on Treg suppressor function remains controversial. In this chapter, we will describe in detail the TNF-mediated signal transduction pathways, its effect on Treg cells, and the potential clinical applications in various immunopathologies.
2. Regulatory T cells and its plasticity
Treg exert their function in primary and secondary lymphoid organs and nonlymphoid tissues. FOXP3, as the lineage transcription factor of Treg, facilitates Treg thymic development by stabilizing its own expression and inhibiting transcription factors needed for the development of other helper T-cell (Th) lineages like T-bet for Th1, GATA3 for Th2, and RORγt for Th17 cells [18]. Next to FOXP3, Treg constitutively express a high level of the IL-2 receptor α chain (CD25) and a low level of the IL-7 receptor α chain (CD127) compared to human activated non-Treg. The combination of CD4+, CD25high, and CD127low has been used to isolate Treg for functional studies and for adoptive immunotherapy [19]. However, no unique Treg marker has been identified so far, although many molecules are proposed. These Treg-related cell markers include CD27 [20], CD62L [21], CTLA4 (cytotoxic T-lymphocyte-associated protein) [22], CD39 and CD73 ectoenzymes [23], Helios [24], Neuropilin-1 [25], HLA-DR [26], and the most recently identified combination of TIGIT and FcRL3, which results in the identification of human Helios+ memory Treg [27].
Compelling evidence indicates that both mouse and human Treg consist of various subpopulations and have a more or less plastic phenotype depending on the microenvironment they are in [28]. Based on the site of Treg generation, two major Treg subsets are classified, namely, thymus-derived Treg (tTreg) that develop in the thymus from CD4 single positive thymocytes which in general display high-affinity self-reactive T-cell receptors (TCRs), and peripherally induced Treg (pTreg) which emerge in the periphery from conventional CD4+ T lymphocytes (Tconv) in response to environmental antigens and tolerogenic stimuli. Studies in mice have shown that pTreg and tTreg are both required for full protection against colitis and lymphoproliferative disease [29, 30], indicating that these two Treg subsets play distinct roles in protecting against immunopathology. However, the relative contribution of tTreg and pTreg in human immune tolerance remains a major unresolved issue, partially due to the lack of specific markers to definitively distinguish them. In fact, the transcription factor Helios was the first marker proposed to distinguish both mice and human tTreg from pTreg [31]. However, this has been disputed by studies showing that Helios can also be expressed by activated Tconv [32] and by pTreg upon in vitro and in vivo stimulation [33], precluding its use as tTreg-specific marker. Another cell surface marker that has been proposed to harbor the specificity necessary to distinguish between murine tTreg and pTreg is the coreceptor Neuropilin-1 [25]. Unfortunately, human Treg do not uniquely express Neuropilin-1 [34].
3. TNF/TNFR signaling pathways
TNF is firstly discovered as an inflammatory cytokine that is induced by the endotoxin [35]. Various immune cells produce TNF including macrophages, monocytes, dendritic cells, B cells, activated natural killer cells, and activated T cells. TNF is initially expressed on the cell surface as a trimeric type II transmembrane protein mTNF, which is then cleaved by the metalloproteinase TACE (also known as ADAM17) and released as soluble extracellular sTNF [36]. Both forms of TNF are present as bioactive homotrimers. There exist two structurally related but functionally distinct receptors, TNFR1 (p55) and TNFR2 (p75). TNFR1 is ubiquitously expressed on most mammalian cell types, and it binds to mTNF as well as sTNF, whereas TNFR2 expression is restricted to immune cells, neurons, and endothelial cells. TNFR2 binds with higher affinity to mTNF than sTNF compared to TNFR1.
TNFR1 and TNFR2 share the similar extracellular TNF-binding motifs but differ in their intracellular domains. Both receptors lack intrinsic enzyme activity; thus, upon the ligand binding, they need to recruit the cytosolic proteins to initiate the intracellular signal transduction. Specifically, TNFR1 contains a homologous intracellular region called “death domain”, which preferentially interacts with the adaptor protein named TNFR1-associated death-domain (TRADD) protein [37]. TRADD further recruits another two adaptor proteins, receptor interacting protein kinase 1 (RIPK1) and TNFR-associated factor (TRAF) 2, thus forming an enzymatic complex signalosome, which is also known as signaling complex 1. One of the main targets of the complex 1 is the enzyme complex called IkB kinase (IKK). Phosphorylation of IKK in turn leads to the canonical activation of the transcription factor NFkB as well as members of the family of MAPKs such as c-jun kinase (JNK) and p38 MAPK. The TRADD containing signaling complex 1 may further be converted to a death-inducing signaling complex, so-called complex 2, by adaptor protein Fas-associated protein with death domain (FADD). The complex 2 is able to further initiate downstream caspase cascades, thus inducing cell apoptosis and cell death [37].
The pathways induced by TNFR2 are slightly different from TNFR1. Due to the lack of death domain, TNFR2 is unable to recruit TRADD protein, but it can directly interact with TRAF2 [38]. In contrast to TNFR1 that drives apoptosis and cell death, TNFR2 induces the noncanonical activation of NFκB via the activation of the NFκB-inducing kinase (NIK), which further leads to the phosphorylation of IKKα and the processing of p100, a crucial step in the nuclear translocation of p52/RelB [38, 39]. Interestingly, TRAF2 binding to TNFR2 is considerably weaker than its binding to TRADD protein. Upon binding to TRAF2, TNFR2 could also recruit cIAP1/2 proteins [39] that are involved in the TNFR1-mediated NFκB activation, indicating that there exists a crosstalk between TNFR1 and TNFR2 pathways. Another interesting adaptor protein called endothelial/epithelial protein tyrosine kinase (Etk) interacts with the C-terminal domain of TNFR2 in a ligand-independent manner [40]. TNFR2-mediated Etk phosphorylation is able to partially activate the growth factor receptor VEGFR2, which in turn results in the activation of PI3K/Akt pathway and cell survival.
A number of proteins are essential for the negative regulation of the TNF-TNFR pathways. A20, also named as TNF alpha-induced protein 3, is one of the most studied negative regulatory proteins. A20 is an ubiquitin editing enzyme. It limits NFκB signaling after activation by TNF [41]. Consistent with this, A20-deficient mice are hypersensitive to TNF exposure and die perinatally because of severe inflammation and multiorgan failure [42]. Intriguingly, A20 is recently shown to regulate the de novo generation of tTreg in a cell-intrinsic manner, while the suppressor function of A20-deficient Treg is unchanged in vitro [43].
4. Effect of TNFR2 on Treg
Although TNFR1 expression is not different between Treg and non-Treg cells, human Treg constitutively express high levels of TNFR2 compared to CD25- Tconv. Moreover, TNFR2+ Treg reveal the most potent suppressive capacity [14, 44]. The effect of TNF on Treg suppressor function remains controversial. Several groups including ours demonstrated that sTNF preserved or even increased FOXP3 expression as well as Treg suppressive capacity in both mice and humans [15, 45, 46, 47]. The TNF-TNFR2 is crucial for sustaining FOXP3 expression and maintaining the stability of murine Treg in an inflammatory environment [44]. A similar phenomenon is also observed for human Treg in vitro [48]. There is also evidence for the negative effects of TNF on Treg function. Studies show that TNF impairs Treg function by reducing FOXP3 expression or enhancing its dephosphorylation [47, 49]. In clinical practices, RA patients responding to anti-TNF antibody adalimumab showed an increased percentage of FOXP3 + cells as well as the restored regulatory function [50]. It should be noted that the nature of the TNFR2 antibodies used in these studies was likely different (agonistic versus antagonistic) [46]. Recent studies highlight that TNFR2 agonisms and antagonisms might regulate the phenotype and the suppressor function of Treg in a complete different way [46].
TNF priming induces the proliferation and activation of Treg in vitro [15, 51] as well as in vivo via TNFR2 in an acute mouse GvHD model [52]. Our group have found that stimulation of human Treg with a TNFR2-agonist antibody preserved a stable Treg phenotype and function after ex vivo expansion [48]. Using TNFR2 agonist only was enough to prevent the loss of FOXP3 expression, whereas the sustained hypomethylation of TSDR (Treg-specific demethylated region) of FOXP3 gene locus required both rapamycin and TNFR2 agonist, suggesting that stabilization of FOXP3 expression requires both mTOR and NFκB signal pathways. In vitro restimulation of TNFR2 agonist plus rapamycin-expanded Treg led neither to the loss of FOXP3 protein nor the enhancement of IL-17A production, especially under proinflammatory conditions, indicating a well-preserved Treg stability. TNFR2 knockout CD4+ T cells have increased expression of RORγt and IL-17 production, which is dependent on the impairment of TNFR2-mediated activation of NFκB [53]. We speculate that a similar process of regulation may exist in human Treg where TNFR2/NFκB signaling might act as a double-edged sword to enhance FOXP3 but also to inhibit RORγt expression, thus contributing to Treg stability. Another possible explanation is that TNFR2 engagement results in an autocrine TNF-TNFR2 loop, which further regulates the expression of histone methyltransferase EZH2 [51], a subunit of the polycomb repressor complex 2 (PRC2). EZH2 is known to bind to FOXP3 thus helping FOXP3 to regulate the gene transcriptional repression [54].
5. TNFR2 agonists and autoimmune diseases
Defect in the function of Treg as well as the low numbers are the main properties of various autoimmune diseases. Therefore, restoring the proper functional Treg thus favoring the immune tolerance induction has become a final goal of treatment for patients with autoimmune diseases. As discussed above, ample studies show that either TNF and/or TNFR2 agonism has capacity to enhance Treg proliferation and activation. Furthermore, TNF-TNFR2 is essential to maintain the Treg function and stability in the inflammatory environment [44, 48]. Impaired TNF-TNFR signaling pathways occur in several human diseases including T1D, SLE, IBD, and MS. For instance, a single-nucleotide polymorphism (SNP) in the first intron is linked to a decreased level of TNFR2 in carriers of the SNP and a high risk of disease susceptibility [55]. T1D patients have higher TNFR2+ Treg compared to healthy controls. The rationale for using TNFR2 agonists as a therapeutic option for autoimmune diseases was first shown in T1D. Using blood from patients with T1D, a dose-response relationship between TNFR2 agonism and the destroying of pathogenic autoreactive CD8 T cells was observed [56], suggesting inducing of TNF-TNFR2 pathway is an effective approach of selectively killing autoreactive T cells.
Currently used biologics targeting TNF include the anti-TNF antibodies infliximab, adalimumab, certolizumab, and the decoy receptor etanercept that binds to sTNF. Although they have a good safety profile, with increasing use of these drugs, paradoxical adverse events involving the skin, joints, and lungs have been described [57]. Skin manifestations are the most common adverse event and occur in about 25% of patients receiving anti-TNFs. The underlying mechanism is recently attributed to the TNFR2/A20 signal axis which is specifically responsible for TNF-mediated IL-17A inhibition [58]. Termination of NFκB activation is critical to prevent aberrant inflammatory responses. In memory CD4 T cells, A20 is identified as one of the strongest TNF-responsive genes with a strong inverse correlation to IL-17A expression.
6. TNFR2 antagonists and cancer immunotherapy
Tumor microenvironment preferably recruits TNFR2+ Treg cells which possess a highly immunosuppressive capacity, thus facilitating tumor immune escape. That TNFR2 knockout mice show improved immune responses to tumors might be caused by the lack of TNFR2 expressing Treg or have failed to develop systemic autoimmunity [59] or the decreased numbers and the impaired function of MDSCs [60]. In humans, the high level of TNFR2+ Treg is found in the peripheral blood of lung cancer patients [10] and in the tumor-associated ascites in ovarian cancer patients [61]. Moreover, the increased TNFR2 gene expression on Treg cells has been shown to be associated with exhaustion of CD8 cytotoxic T lymphocytes in metastatic melanoma patients.
In addition to being an inducer of Treg expansion, TNFR2 also acts as an oncogene which has been identified on at least 25 tumor types. Enhanced expression of TNFR2 on tumor itself has been also reported but not limited in human renal cell carcinoma, multiple myeloma, colon cancer, ovarian cancer, and cutaneous T-cell lymphomas (CTCL) [62]. In general, the overexpression of TNFR2 exploits this cytokine receptor for increased tumor cell proliferation and tumor growth. Genetic mutation/genomic gains of TNFRSF1B, a gene encoding TNFR2 protein, occur in patients with Sézary syndrome (SS), a rare form of CTCL often refractory to treatment. SS is characterized with high expression of TNFR2 on the tumor cells and Treg. Such gain-of-function mutation in TNFR2 leads to the enhanced noncanonical NKκB activation [63], a pathway primarily involved in cell expansion and growth. It seems being desirable to apply one approach that could successfully inhibit potent suppressive Treg and also directly prevent tumor growth by using the antagonistic molecules against TNFR2. Such TNFR2-specific blocking molecules would ideally inhibit Treg and permit Tconv proliferation and function, thus enabling to restore the antitumor immune responses and to induce tumor regression.
7. Strategies for blocking of TNF/TNFR2 signaling
A number of agonistic or antagonistic biological agents targeting to TNF and/or TNFR2 have been developed. Two potent dominant TNFR2 antagonist antibodies are developed by Faustman et al. group [64]. They report that these TNFR2 antagonists lock the TNFR2 receptor in the form of antiparallel dimmers, which further prevents the TNF binding as well as the intracellular scaffolding. Consequently, these dominant TNFR2 antagonists, even in the presence of TNF, could kill Treg isolated from ovarian cancer ascites more potently than it kills Treg from healthy donors. Interestingly, TNFR2 antagonistic mAbs are also able to directly kill TNFR2-expression ovarian cancer cell lines in vitro [64]. Similar effect is observed in another in vitro study where the cancer cells and lymphocytes were isolated from the end-stage SS patients [65]. In mouse model of colon and breast cancers, combining a blocking TNFR2 antibody with a kind of immune stimulant markedly enhances the antitumor efficacy of immunotherapy through reducing the number of tumor-infiltrating TNFR2+ Treg and increasing the number of IFNγ-producing CD8 cells [66].
Some pharmacological agents are found to regulate TNF and/or its receptors expression. Thalidomide and its analogues prevent the surface expression of TNFR2 on activated T cells, which is associated with the inhibition of TNFR2 protein trafficking to the cell membrane [67]. Treating acute myeloid leukemia patients with azacitidine and lenalidomide, a thalidomide derivative can reduce TNFR2 expression on T cells as well as TNFR2+ Treg in vivo, leading to enhanced effector immune function [68]. Cyclophosphamide is a DNA alkylating agent. It is commonly used as a cytotoxic chemotherapy in cancer treatment. In a mouse model, it is shown that cyclophosphamide treatment depletes TNFR2+ Treg via inducing the death of replicating Treg that co-express TNFR2 and KI-67 [69]. A re-expansion of Treg from lymphodepletion suppresses the effective antitumor immunity developed after cyclophosphamide treatment. Intriguingly, blockade of TNF signaling using etanercept inhibits TNFR2+ Treg cell expansion during recovery from cyclophosphamide-induced lymphodepletion and markedly inhibits the growth of established CT26 tumors in mice [70]. Altogether, it suggests that a TNFR2-targeted approach to inactive host Treg, especially in only tumor microenvironment, may offer optimal options for antitumor immune reactions.
8. Conclusions
Many surface receptors of Treg are also expressed on other immune cells, with TNFR2 being a prominent exception with highest density in the tumor microenvironment. TNFR2 is a functional receptor on Treg. Cell surface expression of TNFR2 not only identifies the potent Treg subsets but also is the property of tumor-infiltrating Treg. TNFR2 expression on some cancer-infiltrating Treg is about 100 times higher than on circulating Treg in control subjects. In other types of cancer, the abundance of TNFR2+ Treg in peripheral blood is higher than healthy ones. Targeting TNFR2 using small molecule agonists or antagonists is a promising but also a challenging task. Considering the suppressive property of Treg and its impaired functions in various immunopathologies, there is no doubt that novel (tumor-specific) antagonists against TNFR2 are promising for cancer immunotherapy. From the clinical utilities point of view, combination of TNFR2 inhibition with immune checkpoint inhibitors seems to be an attractive approach in reshaping modern cancer immunotherapy.
Acknowledgments
The authors would like to thank the A FACTT network (Cost Action BM1305: http://www.afactt.eu) for supporting this work by positive discussion. XH is also supported by NSFC 61263039 and NSFC 11101321. XW is supported by NSFC 61263039, NSFC 11101321, and 2018-ZJ-776.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Nomenclature
IBD
Inflammatory bowel disease
CTCL
Cutaneous T-cell lymphomas
MS
Multiple sclerosis
MAPK
Mitogen-activated protein kinase
mTNF
Membrane-bound TNF
NFκB
Nuclear factor κB
RA
Rheumatoid arthritis
SNP
Single-nucleotide polymorphism
SS
Sézary syndrome
T1D
Type 1 diabetes
TACE
TNF-converting enzyme
TCR
T-cell receptor
TNFR
TNF receptor
TRAF
TNFR-associated factor
Treg
Regulatory T cells
TSDR
Treg-specific demethylated region
\n',keywords:"TNF, TNF receptor 2, regulatory T cells, immunotherapy, autoimmune disease, cancer immunotherapy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/66411.pdf",chapterXML:"https://mts.intechopen.com/source/xml/66411.xml",downloadPdfUrl:"/chapter/pdf-download/66411",previewPdfUrl:"/chapter/pdf-preview/66411",totalDownloads:221,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 12th 2018",dateReviewed:"March 4th 2019",datePrePublished:"April 8th 2019",datePublished:null,readingETA:"0",abstract:"TNF has both proinflammatory and antiinflammatory effects. It binds to two structurally related but functionally distinct receptors TNFR1 and TNFR2. Unlike TNFR1 that is ubiquitously expressed, TNFR2 expression is more limited to myeloid and lymphoid cell lineages including a fraction of regulatory T cells (Treg). In general, TNFR1 is responsible for TNF-mediated cell apoptosis and death, and mostly induces proinflammatory reactions. However, TNFR2 mainly leads to functions related to cell survival and immune suppression. Treg play an indispensable role in maintaining immunological self-tolerance and restraining excessive immune reactions deleterious to the host. Impaired Treg-mediated immune regulation has been observed in various autoimmune diseases as well as in cancers. Therefore, Treg might provide an ideal therapeutic target for diseases where the immune balance is impaired and could benefit from the regulation of Treg properties. TNFR2 is highly expressed on Treg in mice and in humans, and TNFR2+ Treg reveal the most potent suppressive capacity. TNF-TNFR2 ligation benefits Treg proliferation, although the effect on Treg suppressive function remains controversial. Here, we will describe in detail the TNF-mediated regulation of Treg and the potential clinical applications in cancer immunotherapy as well as in autoimmune diseases, with the focus on human Treg subsets.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/66411",risUrl:"/chapter/ris/66411",signatures:"Xuehui He and Xinhui Wang",book:{id:"7853",title:"Cytokines",subtitle:null,fullTitle:"Cytokines",slug:null,publishedDate:null,bookSignature:"Ph.D. Payam Behzadi",coverURL:"https://cdn.intechopen.com/books/images_new/7853.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"45803",title:"Ph.D.",name:"Payam",middleName:null,surname:"Behzadi",slug:"payam-behzadi",fullName:"Payam Behzadi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Regulatory T cells and its plasticity",level:"1"},{id:"sec_3",title:"3. TNF/TNFR signaling pathways",level:"1"},{id:"sec_4",title:"4. Effect of TNFR2 on Treg",level:"1"},{id:"sec_5",title:"5. TNFR2 agonists and autoimmune diseases",level:"1"},{id:"sec_6",title:"6. TNFR2 antagonists and cancer immunotherapy",level:"1"},{id:"sec_7",title:"7. Strategies for blocking of TNF/TNFR2 signaling",level:"1"},{id:"sec_8",title:"8. Conclusions",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"},{id:"sec_12",title:"Conflict of interest",level:"1"},{id:"sec_11",title:"Nomenclature",level:"1"}],chapterReferences:[{id:"B1",body:'Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Science Translational Medicine. 2015;7(315):315ra189'},{id:"B2",body:'Haas J, Fritzsching B, Trubswetter P, Korporal M, Milkova L, Fritz B, et al. 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Blood. 2016;128(12):1651-1659'},{id:"B53",body:'Miller PG, Bonn MB, McKarns SC. Transmembrane TNF-TNFR2 impairs Th17 differentiation by promoting Il2 expression. Journal of Immunology (Baltimore Md: 1950). 2015;195(6):2633-2647'},{id:"B54",body:'Arvey A, van der Veeken J, Samstein RM, Feng Y, Stamatoyannopoulos JA, Rudensky AY. Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nature Immunology. 2014;15(6):580-587'},{id:"B55",body:'Li D, Silverberg MS, Haritunians T, Dubinsky MC, Landers C, Stempak JM, et al. TNFRSF1B is associated with ANCA in IBD. Inflammatory Bowel Diseases. 2016;22(6):1346-1352'},{id:"B56",body:'Ban L, Zhang J, Wang L, Kuhtreiber W, Burger D, Faustman DL. Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(36):13644-13649'},{id:"B57",body:'Cleynen I, Vermeire S. 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Science Signaling. 2017;10(462). pii: eaaf8608'},{id:"B65",body:'Torrey H, Khodadoust M, Tran L, Baum D, Defusco A, Kim YH, et al. Targeted killing of TNFR2-expressing tumor cells and Tregs by TNFR2 antagonistic antibodies in advanced Sezary syndrome. Leukemia. 2018 Oct 24. pii: 10.1038/s41375-018-0292-9'},{id:"B66",body:'Nie Y, He J, Shirota H, Trivett AL, Yang KDM, et al. Blockade of TNFR2 signaling enhances the immunotherapeutic effect of CpG ODN in a mouse model of colon cancer. Science Signaling. 2018;11(511). pii: 11/511/eaan0790'},{id:"B67",body:'Marriott JB, Clarke IA, Dredge K, Muller G, Stirling D, Dalgleish AG. Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells. Clinical and Experimental Immunology. 2002;130(1):75-84'},{id:"B68",body:'Govindaraj C, Madondo M, Kong YY, Tan P, Wei A, Plebanski M. Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients. American Journal of Hematology. 2014;89(8):795-802'},{id:"B69",body:'van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW, et al. Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: A role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunology, Immunotherapy: CII. 2009;58(8):1219-1228'},{id:"B70",body:'Chang LY, Lin YC, Chiang JM, Mahalingam J, Su SH, Huang CT, et al. Blockade of TNF-alpha signaling benefits cancer therapy by suppressing effector regulatory T cell expansion. Oncoimmunology. 2015;4(10):e1040215'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Xuehui He",address:"xuehui.he@radboudumc.nl",affiliation:'
College of Computer Science, Qinghai Normal University, China
Department of Laboratory Medicine, Laboratory Medical Immunology, Radboud University Medical Center, The Netherlands
College of Computer Science, Qinghai Normal University, China
Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam University Medical Center, The Netherlands
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Amezcua-Guerra is a Professor of Rheumatology and Immunology at the Instituto Nacional de Cardiología in Mexico City, Mexico. He is a postgraduate in Rheumatology and Internal Medicine at the School of Medicine, Universidad Nacional Autónoma de México.\nHis work has been seminal to identify and characterize the immune mechanisms that underlie erosive arthritis in systemic lupus erythematosus, especially those related to the abnormal behavior of citrulline and C-reactive protein. He has also been involved in the study of kidney damage in Takayasu’s arteritis as well as in the existence of subclinical tissue damage in patients with asymptomatic hyperuricemia. 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Our business values are based on those any scientist applies to their research. The values of our business are based on the same ones that all good scientists apply to their research. We have created a culture of respect and collaboration within a relaxed, friendly, and progressive atmosphere, while maintaining academic rigour.
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IntechOpen is a dynamic, vibrant company, where exceptional people are achieving great things. We offer a creative, dedicated, committed, and passionate environment but never lose sight of the fact that science and discovery is exciting and rewarding. We constantly strive to ensure that members of our community can work, travel, meet world-renowned researchers and grow their own career and develop their own experiences.
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If this sounds like a place that you would like to work, whether you are at the beginning of your career or are an experienced professional, we invite you to drop us a line and tell us why you could be the right person for IntechOpen.
Integrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
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Openness - We communicate honestly and transparently. We are open to constructive criticism and committed to learning from it.
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Disruptiveness - We are eager for discovery, for new ideas and for progression. We approach our work with creativity and determination, with a clear vision that drives us forward. We look beyond today and strive for a better tomorrow.
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What makes IntechOpen a great place to work?
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IntechOpen is a dynamic, vibrant company, where exceptional people are achieving great things. We offer a creative, dedicated, committed, and passionate environment but never lose sight of the fact that science and discovery is exciting and rewarding. We constantly strive to ensure that members of our community can work, travel, meet world-renowned researchers and grow their own career and develop their own experiences.
\n\n
If this sounds like a place that you would like to work, whether you are at the beginning of your career or are an experienced professional, we invite you to drop us a line and tell us why you could be the right person for IntechOpen.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:null},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. 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I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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