\r\n\tThe book “Metamaterials” is devoted to exhibiting the current state of the art of the dynamic and vibrant field of different kinds of metamaterials reaching across various disciplines, suggesting exciting applications in chemistry, material science, biology, medicine, and engineering. It will illuminate recent advances in the wider metamaterials field, such as (to mention a few) active metamaterials and metasurfaces, plasmonic nanocavities.
",isbn:"978-1-78984-891-5",printIsbn:"978-1-78984-890-8",doi:null,price:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"e8d12e1027982a946bcaab4fc21afb0f",bookSignature:"Prof. Tatjana Gric",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8717.jpg",keywords:"metamaterials, photonics, absorption, dispersion, coupling, surface waves, slow light, stopped light, cloaking, invisibility, nanoplasmonic metamaterials, effective electric metamaterials",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 11th 2019",dateEndSecondStepPublish:"February 1st 2019",dateEndThirdStepPublish:"April 2nd 2019",dateEndFourthStepPublish:"June 21st 2019",dateEndFifthStepPublish:"August 20th 2019",remainingDaysToSecondStep:"18 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,editors:[{id:"212653",title:"Prof.",name:"Tatjana",middleName:null,surname:"Gric",slug:"tatjana-gric",fullName:"Tatjana Gric",profilePictureURL:"https://mts.intechopen.com/storage/users/212653/images/system/212653.jpg",biography:"Dr. Gric’s research career has been focused on the investigation of waveguide devices (waveguide modulators, filters etc.), namely on proposing their electrodynamical analysis. Applied research includes the design of microwave frequency selective structures, waveguide modulators, filters. Fundamental research is primarily concerned with developing rigorous computational methods for the electrodynamical analysis of the waveguide structures. Another major goal of her studies is plasmonics as the examination of the interaction between electromagnetic field and free electrons in a metal. The optically-active nanostructures have been simulated and their fundamental photonic properties have been explored. Moreover, the broad scope of research carried out by Dr. Gric has included investigations into the new fascinating properties of novel materials. Dr. Gric is involved in development of unusual materials and structures that can manipulate the flow of light in ways that are useful in optical sensing, photovoltaics, solid state lighting, fiber optics and other applications. Dr. Gric also has a record of effective teaching in the rank of Associate Professor. She has been conducting independent research projects for the past eight years. Dr. Gric has published extensively in her field of investigation with more than 40 peer-reviewed papers in top journals in physics, electrodynamics, and optics. It is worth noting that her recent publication rate is getting even higher with her being the first author.",institutionString:"Vilnius Gediminas Technical University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"20",title:"Physics",slug:"physics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247041",firstName:"Dolores",lastName:"Kuzelj",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247041/images/7108_n.jpg",email:"dolores@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6861",title:"Plasmonics",subtitle:null,isOpenForSubmission:!1,hash:"e33a5b5eaffb8edd2de62ce2a21486ea",slug:"plasmonics",bookSignature:"Tatjana Gric",coverURL:"https://cdn.intechopen.com/books/images_new/6861.jpg",editedByType:"Edited by",editors:[{id:"212653",title:"Prof.",name:"Tatjana",surname:"Gric",slug:"tatjana-gric",fullName:"Tatjana Gric"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7730",title:"Atomic Energy Science And Technology",subtitle:null,isOpenForSubmission:!0,hash:"40a7b7327b1f8c3e5392ea8641a70797",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7730.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8226",title:"Optical Anisotropy",subtitle:null,isOpenForSubmission:!0,hash:"96f9be3797ab3c4b5265803386aafc00",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/8226.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8416",title:"Non-Equilibrium Particle Dynamics",subtitle:null,isOpenForSubmission:!1,hash:"2c3add7639dcd1cb442cb4313ea64e3a",slug:null,bookSignature:"Prof. Albert S. 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1. Introduction
Recent developments in biotechnology for agro- /agro-industrial waste utilization have identified a plethora of agricultural waste (agrowaste) that is suitable for microbial proliferation and production of a variety of high value biological products, which are useful in industrial as well as environmental applications. About 1.6 billion tons of agrowaste is reportedly generated globally per annum [25]. Considering the environmental degeneration caused by such waste, and the fact that they are readily available, research studies have been geared toward assessing the feasibility of converting such waste into value added products. Studies into the chemical and nutritional composition of agrowaste have equally identified some of them as suitable substrates for microbial cultivation [54, 40, 63, 69, 5].
In environmental bioremediation applications, microorganisms can be supported on solid agrowaste to provide the required macro- and micro-nutrients required for biofilm formation, which usually enhances the metabolic activities of the microorganisms for solubilization and biodegradation of contaminants, some of which are known to be potential human carcinogens [18, 22]. The paradigm shift from conventional substrates such as refined glucose, to unconventional substrates such as solid agrowaste or agro-industrial waste could be due to the fact that the latter mitigates operational costs, particularly for large-scale processes. Nutrients are considered the largest expense in industrial bioprocesses whereby the fermentation medium can account for a large proportion of fermentation costs [10, 39, 60]. Suitable agrowaste such as orange peel, apple pomace, wheat bran, sugar cane bagasse, wheat bran, soybean oil cake, jatropha curcas, whey waste, and Beta vulgaris, have been identified to support microbial growth and the synthesis of metabolites which can catalyze a number of reactions under suitable conditions[46, 42, 62, 5].
One of the most common wastewater pollutants is cyanide. It is usually released through various anthropogenic activities in the form of industrial effluent discharged from numerous industries. Another incessant anthropogenic source of cyanide deposition into the environment is through petroleum oil processing and its derivatives. Naturally, hydrocarbon oils such as petroleum contain cyano group compounds, which react with metals during thermal cracking operations to form metal cyanide complexes that culminate in wastewater [14]. Many of these cyanide complexes are known to be highly unstable, mainly due to thermal instability, thus releasing free cyanide into the environment under high temperature. It has been reported by Acheampong et al. [1] that, cyanide concentrations from facilities that serve industrialized areas could have cyanide concentration higher than 21.6 mg F-CN/L. Cyanide exposure is known to result in neurological disorders and thyroid abnormalities in humans [69, 55]; hence, a robust and economically feasible bioremediation process using renewable resources (agrowaste), i.e. an environmentally benign approach, is necessary to ensure a sustainable and an effective bioremediation process for cyanide deposited into the environment.
It is common to use oxidation methods for cyanide degradation and its complexes, such as the use of metal catalyzed hydrogen peroxide, and alkaline chlorination processes, including removal by ion-exchange resin [17]. This approach, though effective, has some drawbacks that are of major concern. The excess reagents used in the treatment tend to further pollute the environment, as well as increase operational costs. In addition, due to municipal regulations in some countries, the application of chemical methods on a large scale is not permissible. Considering that cyanide in wastewater is undesirable, if present, it must not exceed the discharge limit of 0.01 mg F-CN/L [23]. Thus, cyanide degradation using biotechnological processes is desirable.
It has been shown that several microorganisms such as algae, bacteria, and fungi, can produce enzymes that are capable of degrading free cyanide, cyanide complexes and by-products produced [3, 24, 33, 59]. Recently, studies have established sustainable cyanide biodegradation processes using various microorganisms such as Klebsiella sp.,\n\t\t\t\tPseudomonas sp., Acinetobacter sp., Bacillus sp., and many others [41, 58]. A fungal specie - Fusarium oxysporum, has equally been reported for its ability to produce enzymes such as nitrilase which readily hydrolyses cyano-compounds into a corresponding weak acid and ammonium-nitrogen, thus bioremediating the contaminated wastewater, with both the acid and ammonium-nitrogen produced being consumed for metabolic functions [37, 32]. Several agrowaste have also shown to be effective substrates for the cultivation of microorganisms and for the biodegradation of cyanic compounds [15, 30, 49].
The application of agrowaste as a substrate in cyanide biodegradation systems is particularly promising, as reported by Santos et al. [62]. Having a readily accessible waste material, microorganisms will be able to produce enzymes suitable for bioremediating contaminants in wastewater [59]. Besides their application as effective biosorbents, agrowaste can serve as a sole substrate for bioremediation purposes, on condition that it is compatible to the microbial community to be used [67, 45, 17, 16]. In South Africa, approximately 10 million tons of agrowaste is generated per annum [53], of which 96% is classified as pre-consumer waste (Figure 1). This is a large quantity of waste for a developing economy and should be put into profitable use to safe our environment.
Figure 1.
Classification of agrowaste production in South Africa [53]
2. Application of Fusarium\n\t\t\t\tsp. and Beta vulgaris in cyanide biodegradation
Fusarium sp. are widely distributed in environmental samples, particularly in soil. They can cause spoilage of agricultural produce and produce mycotoxins which contaminate cereal crops, affecting human and animal health, if the mycotoxins enter the food chain. Fusarium sp. has also been found useful in the hydrolysis of starch. The hydrolysed agricultural produce can be used to sustain the production of extracellular enzymes such as pectinase, cellulase, xylanase, amylase, and organic acids [43]. The fungus is also known for the production of cyanide hydratase and nitrilase including cyanidase. Fusarium sp. has been identified as having the ability to degrade cyanides through hydrolysis at varying temperature and pH, then metabolise the by-products as either nitrogen and carbon sources, respectively [52, 31]. The cyanide hydratase, converts the cyanide to amide products and ammonium-nitrogen while the nitrilase hydrolyse cyanide to produce a carboxylic acid [50]. Compared with other enzymes derived from bacteria, nitrilase and cyanide hydratase are of higher activity and can degrade various cyanides [59].
Beta vulgaris waste consists of water, carbohydrates, minerals and proteins which makes it a suitable substrate for microbial growth in the production of high value compounds [5, 45]. However, limited studies have shown its potential as a feed stock and solid support in a bioreactor for the biodegradation of cyanide in the presence of heavy metals [46]. Additionally, hydroxyl functional groups found in B. vulgaris waste can act as pseudo-catalysts for the conversion of cyanide to ammonium-nitrogen. Alhough the free hydroxyl functional group is a weak acid, they are able to deprotonate to produce alkoxides in the presence of a strong base like cyanides especially at high alkaline pH (Figure 2) [31, 62].
Figure 2.
Pseudo-catalyst conversion of cyanide by free hydroxyl functional groups [61]
3. Biodegradation of cyanide by Fusarium oxysporum grown on Beta vulgaris
A number of different studies report on the application of cyanide degrading fungi. For instance, white rot fungi, Trametes versicolor, have been shown by Cabuk et al. [9] to tolerate cyanide concentration up to 130 mg F-CN/L, with complete degradation observed within 42 hours to produce minute quantities of ammonium-nitrogen (5.24 mg NH4+-N/L). Fourteen cyanide degrading fungi were examined by Pereira et al. [57] such as Fusarium sp. including Aspergillus sp. by Santos et al. [57, 62], and were found to tolerate cyanide concentration up to 520 mg F-CN/L. A list of other cyanide degrading species including degradation conditions are shown in Table 1.
There has been limited emphasis on the effect of carbon or nitrogen sources used in the biodegradation of cyanide. The viability of the agrowaste depends on the type of bioremediation required and the microorganism used. When the cultivating conditions are conducive, the minerals, proteins, carbohydrates and water in the agrowaste become easily accessible to the microorganisms [46]. Monosaccharides such as mannose, glucose and fructose present in the agrowaste can effectively support and/or enhance microbial growth [2]. Other overriding factors which directly influence cyanide degradation include exposure to direct sunlight, temperature and pH. Cyanide compounds are soluble in water, thus dissociate and evaporate easily at low pH (i.e. pH<9) while under high salinity, the solubility decreases. Also at neutral pH, weak-acid dissociable (WAD) cyanides such as copper or zinc cyanide complexes, if present in a high concentration, dissociate, releasing a cyano group. Similarly, the reduction in temperature reduces the activity of microorganisms used in bioremediation. A number of studies have proven that, at low temperature (below 10oC), growth of microorganisms is inhibited, resulting in low removal rates of contaminants such as ammonium-nitrogen, nitrates and cyanide [72, 29, 73].
In this study, the biodegradation of cyanide in the presence of heavy metals (arsenic, copper, lead, iron and zinc), using Fusarium oxysporum grown on B. vulgaris waste as the sole carbon source, without any buffer solution, was investigated. The effect of temperature and pH on cyanide degradation with minimal ammonium-nitrogen production was studied using a response surface methodology.
4. Materials and methods
The experiments were carried out in batch cultures. B. vulgaris waste was milled to ≤ 100 μm. A broth of 0.5 g of milled waste in 10 mL distilled water was autoclaved at 116°C for 15 min to prevent thermal breakdown of reducing sugars [51]. To the waste broth, wastewater (20 mL) with 1 mL of a spore solution (2.25 x 106 spore/mL) of Fusarium oxysporum was added to the B. vulgaris broth. The wastewater used had characteristics similar to the goldmine wastewater reported by Acheampong et al. [1] having metals such as arsenic, iron, copper, lead and zinc. The mixture was incubated for 48 hours in a rotary shaker at 70 rpm at the desired temperature and pH (- see Table 2). After this, KCN in distilled water, was added to make a final cyanide concentration of 500 mg CN-/L in the mixture. Thereafter, the mixture was incubated for a further 72 hours at 70 rpm at the desired temperature (- see Table 2). All experiments were carried out in duplicate in airtight multiport round bottom Erlenmeyer flasks (n = 28; final volume of 51 mL). Cyanide (CN) (09701) and ammonium-nitrogen (NH4+-N) (00683) test kits (MERCK®) were used to quantify the residual free cyanide and ammonium-nitrogen concentrations using a NOVA 60 spectroquant. Free cyanide volatilised was accounted for using the mass balance equations below:
CN-s- (CN-r+ CN-v) = CN-bE1
\n\t\t\t
CN-v= CN-vo– CN-vfE2
\n\t\t\t
where CN-s is the initial free cyanide concentration in the culture broth; CN-r is the measured residual free cyanide after incubation; CN-v is the volatilised free cyanide during incubation; CN-b is the bioremediated free cyanide; CN-vo is the initial free cyanide in control cultures (500 mg F-CN/L); and CN-vf is the final free cyanide in control cultures. The control was prepared under the same conditions as other cultures without the Fusarium oxysporum.
Cyanide degrading microbial species using different nutritional sources under different temperature and pH conditions
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tRun\n\t\t\t
\n\t\t\t
\n\t\t\t\tTemperature (oC)\n\t\t\t
\n\t\t\t
\n\t\t\t\tpH\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
1
\n\t\t\t
19.5
\n\t\t\t
8.5
\n\t\t
\n\t\t
\n\t\t\t
2
\n\t\t\t
9
\n\t\t\t
11
\n\t\t
\n\t\t
\n\t\t\t
3
\n\t\t\t
19.5
\n\t\t\t
8.5
\n\t\t
\n\t\t
\n\t\t\t
4
\n\t\t\t
30
\n\t\t\t
11
\n\t\t
\n\t\t
\n\t\t\t
5
\n\t\t\t
30
\n\t\t\t
6
\n\t\t
\n\t\t
\n\t\t\t
6
\n\t\t\t
19.5
\n\t\t\t
8.5
\n\t\t
\n\t\t
\n\t\t\t
7
\n\t\t\t
9
\n\t\t\t
6
\n\t\t
\n\t\t
\n\t\t\t
8
\n\t\t\t
19.5
\n\t\t\t
8.5
\n\t\t
\n\t\t
\n\t\t\t
9
\n\t\t\t
19.5
\n\t\t\t
12.04
\n\t\t
\n\t\t
\n\t\t\t
10
\n\t\t\t
34.35
\n\t\t\t
8.5
\n\t\t
\n\t\t
\n\t\t\t
11
\n\t\t\t
4.65
\n\t\t\t
8.5
\n\t\t
\n\t\t
\n\t\t\t
12
\n\t\t\t
19.5
\n\t\t\t
4.96
\n\t\t
\n\t\t
\n\t\t\t
13
\n\t\t\t
19.5
\n\t\t\t
8.5
\n\t\t
\n\t\t
\n\t\t\t
14
\n\t\t\t
19.5
\n\t\t\t
8.5
\n\t\t
\n\t
Table 2.
Experimental variation of pH and temperature
The response surface methodology was used for the statistical design of the experiments to assess the influence of temperature and pH for optimal degradation of cyanide. A central composite design was used for the determination of optimal operating conditions with a minimum residual ammonium-nitrogen as one of the objectives. Design Expert software® version 6.0.8 (Stat-Ease Inc., USA) was used to generate the experimental runs.
Coded experimental design variables and the corresponding response
A and B represent coded level of variables.
The results (Table 3) indicated a variation in responses measured. There was appreciable degradation of cyanide in Runs 9, 4, 1, 3, 6, 8, 13, and 14, with the highest cyanide degraded being 263 mg F-CN/L (Run 9) and the lowest (83 mg F-CN/L) being observed for Run 11. However, both cases had a high residual ammonium-nitrogen of 210 mg NH4+-N/L and 120 mg NH4+-N/L, respectively. Both Runs 9 and 11 were axial points. Run 9 with an extremely high pH resulted in high residual ammonium-nitrogen while Run 11 with an extremely low temperature was observed to have minimal microbial activity despite the presence of a suitable quantity of B. vulgaris used as a carbon source. A similar scenario had earlier been reported by Zilouei et al. [72] and Zou et al. [73], whereby a low temperature was found to inhibit the growth of microorganisms, thus resulting in low removal of contaminants (ammonium-nitrogen, nitrate and nitrite). On the other hand, Runs 1, 3, 4, 6, 7, 8, 13 and 14 had up to 99% correlation with the predicted values for cyanide degradation which indicated a high accuracy of the model (Equation 4) used for predicting cyanide degradation. However, only Runs 4 and 7, which showed minimal residual ammonium-nitrogen presence, can be used for optimisation for a pilot scale process.
5. Statistical model analysis
The statistical model summary clarifies the fitness of the mean and quadratic models for the two responses based on the Sequential Model Sum of Squares and Lack of Fit Test. The responses were analysed using ANOVA to assess the significance of the variables in the model. A quadratic model was found to give the best fit for the experimental results.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tFactor\n\t\t\t
\n\t\t\t
\n\t\t\t\tCoeff. Estimate\n\t\t\t
\n\t\t\t
\n\t\t\t\tDF\n\t\t\t
\n\t\t\t
\n\t\t\t\tStandard Error\n\t\t\t
\n\t\t\t
\n\t\t\t\t95% CL Low\n\t\t\t
\n\t\t\t
\n\t\t\t\t95% CL High\n\t\t\t
\n\t\t\t
\n\t\t\t\tF Value\n\t\t\t
\n\t\t\t
\n\t\t\t\tProb > F\n\t
\n\t
\n\t\tSignificance\n\t
\n
\n
\n\t
Intercept
\n\t
239
\n\t
1
\n\t
10.03
\n\t
215.27
\n\t
262.73
\n\t
11.41
\n\t
0.0029
\n\t
S
\n
\n
\n\t
A
\n\t
23.6
\n\t
1
\n\t
8.69
\n\t
3.05
\n\t
44.50
\n\t
7.37
\n\t
0.0300
\n\t
S
\n
\n
\n\t
B
\n\t
38.09
\n\t
1
\n\t
8.69
\n\t
17.54
\n\t
58.63
\n\t
19.21
\n\t
0.0032
\n\t
S
\n
\n
\n\t
A2\n\t
\n\t
-49.87
\n\t
1
\n\t
9.05
\n\t
-71.26
\n\t
-28.49
\n\t
30.40
\n\t
0.0009
\n\t
S
\n
\n
\n\t
B2\n\t
\n\t
-3.62
\n\t
1
\n\t
9.05
\n\t
-25.01
\n\t
17.76
\n\t
0.16
\n\t
0.7005
\n\t
NS
\n
\n
\n\t
AB
\n\t
3.25
\n\t
1
\n\t
12.29
\n\t
-25.81
\n\t
32.31
\n\t
0.07
\n\t
0.7991
\n\t
NS
\n
\n
Table 4.
ANOVA for F-CN Reponse Surface Quadratic Model
S = significant; NS = Not significant; CL = Confidence Level; DF = Degree of freedom; “Prob > F” less than 0,05 indicates the model term is significant while values greater than 0.1 indicates the model term is not significant; Std. Dev. = 24.58; R2 = 0.8907; Adj. R2 = 0.8127; Pred. R2 = -0.1858; Adeq. Precision = 10.341
The predicted response (Y) for the biodegradation of free cyanide in terms of the coded values was:
where A and B are the coded values of temperature and pH, respectively. When coefficients with significant effects were considered, Eq. (3) became;
Y = 239 + 23.6A + 38.09B – 49.87A2E4
\n\t\t\t
A model reduction was appropriate since there were many insignificant model terms. Excluding these terms improved the model. The Model F-value of 11.41 for the cyanide biodegradation was significant; therefore, there was only a 0.29% chance that a "Model F-Value" this large could occur due to noise for the quadratic model. Statistically, an adequate ratio greater than 4 is desireable for measuring a signal to noise ratio; therefore, the adequate precision of 10.341 observed in this study indicates a passable signal that can be used to further navigate the design space. Figure 3 further justifies the fitness of the model with normality in the error term.
6. Representation of the response surface model
The interaction between independent variables can be studied by plotting three dimensional (3-D) curves of the response against the variables. It allows for the interpretation of experimental results and determination of optimal conditions. Elliptical contour shows the interaction between the independent variables is perfect while a circular contour indicates the variables are non-interactive [44, 47].
Figure 3.
Normal probability plot of the residual F-CN
Figure 4.
D plot showing interaction of independent variables on cyanide degradation
Figure 5.
D plot showing interaction of independent variables on ammonium-nitrogen formation
7. Cyanide biodegradation optimisation
The optimisation was done using the Design-Expert software® numerical optimisation option where input factors were selected to achieve a desired perfomance. The numerical optimisation can maximise, minimise or achieve a targeted value: a single response; a single response subjected to upper and/or lower boundaries on other responses; and combinations of two or more responses. The desired goal for each variable and response is selected and the weight is chosen to show the degree of importance of individual goals. In this analysis, temperature and pH were set within range, cyanide degradation response was set at maximum while ammonium-nitrogen formation response was set at a minimum. The software gave three different solutions for this criteria with different desirability. The optimum point with the highest desirability was selected as shown in Fig.6 and 7. The optimal point with the maximum cyanide degradation of 250.436 mg F-CN/L and minimum ammonium-nitrogen formation of 74.285 mg NH4+-N /L was found to be at temperature of 30oC and pH of 11.
Figure 6.
Desirability ramp for the numerical optimisation of cyanide degradation and ammonium-nitrogen formation
Figure 7.
Desirability histogram for numerical optimisation of cyanide degradation and ammonium-nitrogen formation
8. Conclusion
Fusarium oxysporum cultures were grown on B. vulgaris waste to facilitate the biodegradation of cyanide, with the initial concentration of the cyanide being 500 mg CN-/L. The wastewater used was similar to the effluent discharged into ponds by goldmines having metals such as arsenic, copper, lead, iron and zinc.
The response surface plot identified temperature as a more significant factor affecting both the cyanide degradation and ammonium-nitrogen formation. The ammonium-nitrogen produced can be used as a nitrogen source by the fungus.
The optimum condition for maximum cyanide degradation and minimum ammonium-nitrogen formation was found at temperature 30oC and pH of 11 where cyanide of 250.436 mg F-CN/L was degraded and ammonium-nitrogen of 74.285 mg NH4+-N/L was formed.
Acknowledgments
The authors acknowledge the CPUT University Research Fund RK 16 for funding this research.
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Ojumu",authors:[{id:"160162",title:"Dr.",name:"Olusola",middleName:"Solomon",surname:"Amodu",fullName:"Olusola Amodu",slug:"olusola-amodu",email:"os.amodu@yahoo.com",position:null,institution:null},{id:"161195",title:"Prof.",name:"Seteno",middleName:"Karabo Obed",surname:"Ntwampe",fullName:"Seteno Ntwampe",slug:"seteno-ntwampe",email:"ntwampes@cput.ac.za",position:"Senior Lecturer: Biotechnology",institution:{name:"Cape Peninsula University of Technology",institutionURL:"http://www.cput.ac.za/",country:{name:"South Africa"}}},{id:"161208",title:"Prof.",name:"T.V.",middleName:null,surname:"Ojumu",fullName:"T.V. Ojumu",slug:"t.v.-ojumu",email:"OjumuT@cput.ac.za",position:null,institution:null},{id:"172353",title:"BSc.",name:"Ncumisa",middleName:null,surname:"Mpongwana",fullName:"Ncumisa Mpongwana",slug:"ncumisa-mpongwana",email:"mpongwanancumisa@yahoo.com",position:null,institution:null},{id:"172354",title:"M.Sc.",name:"Enoch",middleName:"Akinbiyi",surname:"Akinpelu",fullName:"Enoch Akinpelu",slug:"enoch-akinpelu",email:"biyipelu@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Application of Fusarium\n\t\t\t\tsp. and Beta vulgaris in cyanide biodegradation",level:"1"},{id:"sec_3",title:"3. Biodegradation of cyanide by Fusarium oxysporum grown on Beta vulgaris",level:"1"},{id:"sec_4",title:"4. Materials and methods",level:"1"},{id:"sec_5",title:"5. Statistical model analysis",level:"1"},{id:"sec_6",title:"6. Representation of the response surface model",level:"1"},{id:"sec_7",title:"7. Cyanide biodegradation optimisation",level:"1"},{id:"sec_8",title:"8. Conclusion",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Acheampong M, Paksirajan K, Lens PL. Assessment of the effluent quality from a gold mining industry in Ghana. Environmental Science and Pollution Research 2013; 20(6) 3799-3811.'},{id:"B2",body:'Adjei MD, Ohta Y. Factors affecting the biodegradation of cyanide by Burkholderia cepacia strain C-3. Journal of Bioscience and Bioengineering 2000; 89(3) 274-277.'},{id:"B3",body:'Akcil A. Destruction of cyanide in gold mill effluents: biological versus chemical treatments. Biotechnology Advances 2003; 21(6) 501-511.'},{id:"B4",body:'Akcil A, Karahan AG, Ciftci H, Sagdic O. Biological treatment of cyanide by natural isolated bacteria (Pseudomonas sp.). Minerals Engineering 2003; 16(7) 643 - 649.'},{id:"B5",body:'Amodu OS, Ntwampe SK, Ojumu TV. Emulsification of Hydrocarbons by Biosurfactant: Exclusive Use of Agrowaste. 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Faculty of Engineering, Department of Chemical Engineering, Cape Peninsula University of Technology, Cape Town, South Africa
Bioresource Engineering Research Group, Cape Peninsula University of Technology, Cape Town, South Africa
Faculty of Engineering, Department of Chemical Engineering, Cape Peninsula University of Technology, Cape Town, South Africa
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Luke, Claire Roulston, Jens Tilsner and Martin D. Ryan",authors:[{id:"171775",title:"Dr.",name:"Garry",middleName:null,surname:"Luke",fullName:"Garry Luke",slug:"garry-luke"},{id:"172385",title:"Dr.",name:"Martin",middleName:null,surname:"Ryan",fullName:"Martin Ryan",slug:"martin-ryan"}]},{id:"48297",title:"Synthetic Biology and Intellectual Property Rights",slug:"synthetic-biology-and-intellectual-property-rights",totalDownloads:1531,totalCrossrefCites:0,signatures:"Rajendra K. 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Elnakish and Hamdy H. Hassanain",authors:[{id:"95760",title:"Prof.",name:"Hamdy",middleName:null,surname:"Hassanain",fullName:"Hamdy Hassanain",slug:"hamdy-hassanain"},{id:"102836",title:"MSc.",name:"Mohammad",middleName:null,surname:"Elnakish",fullName:"Mohammad Elnakish",slug:"mohammad-elnakish"}]},{id:"30565",title:"E. coli Alpha Hemolysin and Properties",slug:"e-coli-alpha-hemolysin-and-properties",signatures:"Bakás Laura, Maté Sabina, Vazquez Romina and Herlax Vanesa",authors:[{id:"95151",title:"Dr.",name:"Vanesa",middleName:null,surname:"Herlax",fullName:"Vanesa Herlax",slug:"vanesa-herlax"},{id:"101968",title:"Dr.",name:"Laura",middleName:null,surname:"Bakás",fullName:"Laura Bakás",slug:"laura-bakas"},{id:"101969",title:"Dr.",name:"Sabina",middleName:null,surname:"Maté",fullName:"Sabina Maté",slug:"sabina-mate"},{id:"101970",title:"Ms.",name:"Romina",middleName:null,surname:"Vazquez",fullName:"Romina Vazquez",slug:"romina-vazquez"}]},{id:"30566",title:"Human ERα and ERβ Splice Variants: Understanding Their Domain Structure in Relation to Their Biological Roles in Breast Cancer Cell Proliferation",slug:"human-er-and-er-splice-variants-understanding-their-domain-structure-in-relation-to-their-biological",signatures:"Ana M. Sotoca, Jacques Vervoort, Ivonne M.C.M. Rietjens and Jan-Åke Gustafsson",authors:[{id:"99101",title:"Dr.",name:"Ana",middleName:null,surname:"Sotoca",fullName:"Ana Sotoca",slug:"ana-sotoca"},{id:"102772",title:"Dr.",name:"Jacques",middleName:null,surname:"Vervoort",fullName:"Jacques Vervoort",slug:"jacques-vervoort"},{id:"102773",title:"Prof.",name:"Ivonne McM",middleName:null,surname:"Rietjens",fullName:"Ivonne McM Rietjens",slug:"ivonne-mcm-rietjens"},{id:"102774",title:"Prof.",name:"Jan-Åke",middleName:null,surname:"Gustafsson",fullName:"Jan-Åke Gustafsson",slug:"jan-ake-gustafsson"}]},{id:"30567",title:"GPCRs and G Protein Activation",slug:"gpcrs-and-g-protein-activation",signatures:"Waelbroeck Magali",authors:[{id:"95679",title:"Dr.",name:"Magali",middleName:null,surname:"Waelbroeck",fullName:"Magali Waelbroeck",slug:"magali-waelbroeck"}]},{id:"30568",title:"Application of Quantitative Immunogold Electron Microscopy to Determine the Distribution and Relative Expression of Homo- and Heteromeric Purinergic Adenosine A1 and P2Y Receptors",slug:"distribution-and-relative-expression-of-homo-and-heteromeric-purinergic-adenosine-a1-and-p2y-recepto",signatures:"Kazunori Namba",authors:[{id:"87656",title:"Dr.",name:"Kazunori",middleName:null,surname:"Namba",fullName:"Kazunori Namba",slug:"kazunori-namba"}]},{id:"30569",title:"Carbonic Anhydrase and Heavy Metals",slug:"carbonic-anhydrase-and-heavy-metals",signatures:"Maria Giulia Lionetto, Roberto Caricato, Maria Elena Giordano, Elisa Erroi and Trifone Schettino",authors:[{id:"95101",title:"Dr.",name:"Maria Giulia",middleName:null,surname:"Lionetto",fullName:"Maria Giulia Lionetto",slug:"maria-giulia-lionetto"}]},{id:"30570",title:"Enzymology of Bacterial Lysine Biosynthesis",slug:"enzymology-of-bacterial-lysine-biosynthesis",signatures:"Con Dogovski, Sarah. C. Atkinson, Sudhir R. Dommaraju, Matthew Downton, Lilian Hor, Stephen Moore, Jason J. Paxman, Martin G. Peverelli, Theresa W. Qiu, Matthias Reumann, Tanzeela Siddiqui, Nicole L. Taylor, John Wagner, Jacinta M. Wubben and Matthew A. Perugini",authors:[{id:"98807",title:"Dr.",name:"Matthew",middleName:null,surname:"Perugini",fullName:"Matthew Perugini",slug:"matthew-perugini"}]},{id:"30571",title:"Enzyme-Mediated Preparation of Flavonoid Esters and Their Applications",slug:"enzyme-mediated-preparation-of-flavonoid-esters-and-their-applications",signatures:"Jana Viskupicova, Miroslav Ondrejovic and Tibor Maliar",authors:[{id:"99039",title:"Dr.",name:"Miroslav",middleName:null,surname:"Ondrejovič",fullName:"Miroslav Ondrejovič",slug:"miroslav-ondrejovic"},{id:"102801",title:"Dr.",name:"Tibor",middleName:null,surname:"Maliar",fullName:"Tibor Maliar",slug:"tibor-maliar"},{id:"102802",title:"Dr.",name:"Jana",middleName:null,surname:"Viskupicova",fullName:"Jana Viskupicova",slug:"jana-viskupicova"}]},{id:"30572",title:"Glucose Metabolism and Cancer",slug:"glucose-metabolism-and-cancer",signatures:"Lei Zheng, Jiangtao Li and Yan Luo",authors:[{id:"95693",title:"Prof.",name:"Lei",middleName:null,surname:"Zheng",fullName:"Lei Zheng",slug:"lei-zheng"}]},{id:"30573",title:"HIV-1 Selectively Integrates Into Host DNA In Vitro",slug:"hiv-1-selectively-integrates-into-the-host-dna-in-vitro",signatures:"Tatsuaki Tsuruyama",authors:[{id:"94907",title:"Prof.",name:"Tatsuaki",middleName:null,surname:"Tsuruyama",fullName:"Tatsuaki Tsuruyama",slug:"tatsuaki-tsuruyama"}]},{id:"30574",title:"Distinct Role for ARNT/HIF-1β in Pancreatic Beta-Cell Function, Insulin Secretion and Type 2 Diabetes",slug:"distinct-role-for-arnt-hif1-in-pancreatic-beta-cell-function-insulin-secretion-and-type-2-diabetes",signatures:"Renjitha Pillai and Jamie W. Joseph",authors:[{id:"98663",title:"Ms",name:"Renjitha",middleName:null,surname:"Pillai",fullName:"Renjitha Pillai",slug:"renjitha-pillai"},{id:"99065",title:"Dr.",name:"Jamie",middleName:null,surname:"Joseph",fullName:"Jamie Joseph",slug:"jamie-joseph"}]},{id:"30575",title:"Modulation of EAAC1-Mediated Glutamate Uptake by Addicsin",slug:"modulation-of-eaac1-mediated-glutamate-uptake-by-addicsin-",signatures:"Mitsushi J. Ikemoto and Taku Arano",authors:[{id:"97618",title:"Dr",name:"Mitsushi",middleName:"J",surname:"Ikemoto",fullName:"Mitsushi Ikemoto",slug:"mitsushi-ikemoto"},{id:"97683",title:"MSc.",name:"Taku",middleName:null,surname:"Arano",fullName:"Taku Arano",slug:"taku-arano"}]},{id:"30576",title:"Functional Genomics of Anoxygenic Green Bacteria Chloroflexi Species and Evolution of Photosynthesis",slug:"functional-genomics-of-anoxygenic-green-bacteria-chloroflexi-species-and-evolution-of-photosynthesis",signatures:"Kuo-Hsiang Tang",authors:[{id:"91732",title:"Dr.",name:"Joseph",middleName:"KuoHsiang",surname:"Tang",fullName:"Joseph Tang",slug:"joseph-tang"}]},{id:"30577",title:"Mechanism of Cargo Recognition During Selective Autophagy",slug:"mechanism-of-cargo-recognition-during-selective-autophagy",signatures:"Yasunori Watanabe and Nobuo N. Noda",authors:[{id:"78180",title:"Dr",name:"Nobuo N.",middleName:"N.",surname:"Noda",fullName:"Nobuo N. Noda",slug:"nobuo-n.-noda"},{id:"101464",title:"MSc.",name:"Yasunori",middleName:null,surname:"Watanabe",fullName:"Yasunori Watanabe",slug:"yasunori-watanabe"}]},{id:"30578",title:"Role of Ceramide 1-Phosphate in the Regulation of Cell Survival and Inflammation",slug:"role-of-ceramide-1-phosphate-in-the-regulation-of-cell-survival-and-inflammation",signatures:"Alberto Ouro, Lide Arana, Patricia Gangoiti and Antonio Gomez-Muñoz",authors:[{id:"92925",title:"Prof.",name:"Antonio",middleName:null,surname:"Gómez-Muñoz",fullName:"Antonio Gómez-Muñoz",slug:"antonio-gomez-munoz"}]},{id:"30579",title:"Cholesterol: Biosynthesis, Functional Diversity, Homeostasis and Regulation by Natural Products",slug:"cholesterol-biosynthesis-functional-diversity-homeostasis-and-regulation-by-natural-products",signatures:"J. Thomas, T.P. Shentu and Dev K. Singh",authors:[{id:"91855",title:"Dr.",name:"Dev",middleName:"Karam",surname:"Singh",fullName:"Dev Singh",slug:"dev-singh"},{id:"96815",title:"Dr.",name:"Shentu",middleName:null,surname:"Tzu-Pin",fullName:"Shentu Tzu-Pin",slug:"shentu-tzu-pin"},{id:"96820",title:"Prof.",name:"Johnson",middleName:null,surname:"Thomas",fullName:"Johnson Thomas",slug:"johnson-thomas"}]},{id:"30580",title:"Stobadine – An Indole Type Alternative to the Phenolic Antioxidant Reference Trolox",slug:"stobadine-an-indole-type-alternative-to-the-phenolic-antioxidant-reference-trolox-",signatures:"Ivo Juranek, Lucia Rackova and Milan Stefek",authors:[{id:"92672",title:"Dr.",name:"Milan",middleName:null,surname:"Stefek",fullName:"Milan Stefek",slug:"milan-stefek"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"65408",title:"Introductory Chapter: Progress in Myelodysplastic Syndrome Area",doi:"10.5772/intechopen.84594",slug:"introductory-chapter-progress-in-myelodysplastic-syndrome-area",body:'\n
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1. Advances in our knowledge of cytogenetic abnormalities andgene mutations
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Myelodysplastic syndromes (MDS) constitute a group of age-associated heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis with peripheral cytopenias, dysplasia, and an increased risk of progression to acute myeloid leukemia (AML) [1, 2, 3, 4, 5, 6]. About 50% of cases of MDS are characterized by the presence of cytogenetic abnormalities. Losses of chromosomal material as del(5q), del(20q), monosomy 7 or del(7q), and del(Y) are most common cytogenetic abnormalities and are more frequent than gains of chromosomal material as trisomy 8 or trisomy 21 [7].
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MDS are caused by abnormalities in many genes. The great progress in analysis of these mutations and in elucidation of relationships between gene mutations and clinical phenotypes of these disorders was achieved. Somatic mutations were found in more than 90%. Next-generation sequencing (NGS) detected about 10 different mutations in almost every patient with MDS. The majority of these mutations are nonpathogenic passenger mutations. However, one or more driver mutations in most patients with MDS are associated with the pathogenesis of MDS. Gene mutations affect proteins involved in various important cell processes as RNA-splicing, DNA methylation, histone and chromatin modifications, signal transduction, transcription (transcription factors), tumor suppressor (TP53), RAS pathway, and separation of sister chromatids during cell division (cohesion complex) [4, 8, 9, 10].
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RNA-splicing and DNA methylation mutations occur early and are known as founding mutations. Other mutations are called subclonal mutations. No MDS-specific mutations exist. Strongly represented mutations in genes coding for proteins involved in DNA methylation, such as TET2, DNMT3A, and ASXL1, are common also in older individuals with normal blood count (clonal hematopoiesis of indeterminate potential/CHIP/) [11, 12]. Until now, mutations in TP53, EZH2, RUNX1, and SF3B1 predict independently overall survival (OS) of MDS patients. The first three mutations are associated with shorter OS but the last mutation is connected with better survival in refractory anemia with ring sideroblast (MDS-RS) and with thrombocytosis (RARS-T) [13, 14]. SF3B1 mutations are present in about 80% of MDS-RS and correlates with its development. SF3B1 mutations could alter the expression of the gene for ABCB7 transporter and abnormally regulate iron homeostasis in mitochondria mediating the phenotype of acquired MDS-RS [15]. Effects of other mutations are not clear up to now and results are often controversial.
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We lack clinical methods to stop clonal development from relatively benign state of CHIP to malignancy. Especially, TP53-mutant clones induce progress to therapy-related MDS/AML. Therapy-related myeloid neoplasms have mutations in TP53 and epigenetic modifying genes, instead of mutations in tyrosine kinase and spliceosome genes [16]. The possible treatments are now the use of hypomethylating agents or in future anti-inflammatory therapy and clonally selective immunotherapies.
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MDS are associated with genomic instability and extensive DNA damage caused by deficient repair mechanisms. Aberrations in DNA damage response/repair genes other than TP53 and some genes involved in DNA damage checkpoints are rare. Differential expression of homologous recombination DNA repair-associated genes during MDS progression was detected and could be confirmed as new biomarkers related to pathogenesis and poor prognosis in MDS [17, 18].
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2. Advance in our understanding of del(5q) myelodysplastic syndrome pathogenesis and its treatment with lenalidomide
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The greatest progress was achieved in the study of molecular pathogenesis of del(5q) MDS disease phenotype and its treatment by immunomodulatory or cereblon-binding drug lenalidomide [2, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35]. Ebert et al. described that impaired ribosome biosynthesis due to RPS14 (ribosomal protein 14 of the small ribosome subunit) gene haploinsufficiency leads to the E3 ubiquitin ligase HDM2 (human homolog to mouse double minute 2, major negative regulator of p53) inactivation by free ribosomal proteins, particularly RPL11 [36]. HDM2 degradation drives p53-mediated apoptosis of erythroid cells carrying the del(5q) aberration. This p53-mediated apoptosis of erythroid cells is a key effector of hypoplastic anemia in MDS patients with del(5q) [36]. RPS14 haploinsufficiency causes a block in erythroid differentiation mediated by calprotectin (the heterodimeric S100 calcium-binding proteins S100A8 and S100A9) [37]. Proinflammatory proteins, S100A9 and tumor necrosis factor-α, suppress the effect of erythropoietin in MDS [38]. Some patients originally considered as MDS patients without del(5q) can have a phenotype of atypical 5q− syndrome and can be sensitive to lenalidomide therapy because they have diminutive somatic deletions in the 5q region. These deletions were not identified by fluorescence in situ hybridization or cytogenetic testing but by single nucleotide polymorphism array genotyping [39]. Low RPS14 expression in 50–70% MDS patients without del(5q) confers higher apoptosis rate of nucleated erythrocytes and predicts prolonged survival [40, 41].
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What is the mechanism of lenalidomide in del(5q) MDS based on what has been achieved and elucidated to date? Lenalidomide stabilizes E3 ubiquitin ligase HDM2, thereby accelerating p53 degradation [42, 43]. Lenalidomide inhibits phosphatases PP2a and Cdc25c (coregulators of cell cycle which genes are very commonly deleted in del(5q) MDS) with consequent G2 arrest of del(5q) MDS progenitors and their apoptosis. PP2a and Cdc25c inhibition by lenalidomide suppress HDM2 autoubiquitination and subsequent degradation. Thus, lenalidomide has been shown to not only reverse apoptosis within the erythroid compartment, but also directly induce apoptosis of the myeloid clone in del(5q) MDS [44, 45]. Lenalidomide upregulates expression of other two haploinsufficient genes located on chromosome 5q, genes for microRNAs (miR-145 and miR-146a) [46]. These miRs are involved in Toll-like receptor pathway, IL-6 induction, and regulation of megakaryopoiesis [20].
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Ito et al. discovered that thalidomide (founding member of immunomodulatory drugs/IMiDs/) binds cereblon (CRBN) in the terminal C-region (parts of exons 10 and 11 of the CRBN gene code this IMiD binding region) [47]. Several researchers confirmed CRBN as target of lenalidomide in multiple myeloma (MM), lymphoma, chronic lymphocytic leukemia, and del(5q) MDS [48]. CRBN is the ubiquitously expressed 51 kDa protein with a putative role in cerebral development, especially memory and learning [49, 50].
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Our group found that del(5q) MDS patients (the so-called 5q minus syndrome) have higher levels of full-length CRBN mRNA than other patients with lower risk MDS, linking higher levels of a known lenalidomide target CRBN and del(5q) MDS subgroup known to be especially sensitive to lenalidomide [51].
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CRBN is a member and substrate receptor of the cullin 4 RING E3 ubiquitin ligase complex (CRL4). CRBN recruits substrate proteins to the CRL4 complex for ubiquitination and the subsequent degradation in proteasomes. IMiDs binds to CRBN in CRL4 complex and block normal endogenous substrates (CRBN and the homeobox transcription factor MEIS2 in multiple myeloma/MM/) from binding to CRL4 for ubiquitination and degradation [52]. After IMID binding to CRBN, CRL4 complex is recruiting transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) for ubiquitination and degradation in MM cells [53]. Degradation of these transcription factors explains lenalidomide’s growth inhibition of MM cells and increased interleukin-2 (IL-2) release from T cells. However, it is unlikely that degradation of IKZF1 and IKZF3 accounts for lenalidomide’s activity in MDS with del(5q). Fink et al. identified a novel target casein kinase1A1 (CSNK1A1) by quantitative proteomics in the myeloid cell line KG-1 [54]. CSNK1A1 is encoded in the del(5q) commonly deleted region and the gene is haploinsufficient. Lenalidomide treatment leads to increased ubiquitination of the remaining CSNK1A1 and decreased protein abundance. CSNK1A1 negatively regulates β-catenin which drives stem cell self-renewal, and CSNK1A1 haploinsufficiency causes the initial clonal expansion in patients with the del(5q) MDS and contributes to the pathogenesis of del(5q) MDS. The further inhibition of CSNK1A1 in del(5q) MDS is associated with del(5q) failure and p53 activation. The inhibition of CSNK1A1 reduced RPS6 phosphorylation, induced p53 expression and growth inhibition, and triggered myeloid differentiation program. TP53-null leukemia did not respond to CSNK1A1 inhibition, strongly supporting the importance of the p53 expression for the yield of CSNK1A1 inhibition. CSNK1A1 mutations have been recently found in 5–18% of MDS patients with del(5q) [55]. These mutations are associated similarly to the effect of TP53 mutations with rise to a poor prognosis in del(5q) MDS [56]. Other studies did not find impact of CSNK1A1 mutations on lenalidomide treatment in del(5q) MDS [57, 58].
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Even if the treatment of del(5q) MDS patients with lenalidomide is very efficient, 50% of treated patients relapse after 2–3 years. Martinez-Hoyer et al. found that low platelet count and occurrence of additional mutations, mainly TP53 mutations induce lenalidomide resistance [59, 60, 61]. They used whole genome sequencing and observed in several resistant patients mutations in RUNX1 gene or decreased amount of RUNX1 transcript without aberration in TP53 [59]. Results were verified in model system of two human del(5q) lines, MDS-L and KG-1a. RUNX1 knock-out or RUNX1 shRNA increased proliferation and reduced apoptosis in lenalidomide-treated cells with decreased RUNX1 transcript. Therefore, effect of lenalidomide in del(5q) requires functional RUNX1. Similar results were obtained with TP53 knock-out cells. Both RUNX1 and TP53 transcripts cooperate and alter the activity of GATA2 transcriptional complex [59].
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3. Studies on lenalidomide use also in lower risk non-del(5q) MDS treatment and new possible therapies
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While CSNK1A1 is CRL4CRBN target in del(5q) MDS, CRL4CRBN targets in lower risk non-del(5q) remain to be determined. The mechanism of action of lenalidomide is still unclear in non-del(5q) MDS cells. Recent evidence shows that lenalidomide directly improves erythropoietin receptor (EPOR) signaling by EPOR upregulation mediated by a posttranscriptional mechanism [62]. Lenalidomide stabilizes the EPOR protein by inhibition of the E3 ubiquitin ligase RNF41 (ring finger protein 41, also known as neuregulin receptor degradation protein-1/Nrdp1/and fetal liver ring finger/FLRF/) responsible for EPOR polyubiquitination and next degradation [62] and induces lipid raft assembly to enhance EPOR signaling in MDS erythroid progenitors [63, 64].
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After failure of ESAs, lenalidomide yields red blood cell transfusion independence in 20–30% of lower risk non-del(5q) MDS. Indeed, several observations suggest an additive effect of ESA and lenalidomide in this situation [65, 66] and also in del(5q) MDS patients [67]. Synthetic corticosteroids (dexamethasone and prednisone) are also able to potentiate the effect of lenalidomide or combination of lenalidomide and erythropoietin [67, 68, 69].
\n
Basiorka et al. and Sallman et al. reported activation of the NLRP3 inflammasome in MDS [70, 71]. NRLP3 drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins. Activated NLRP3 complexes direct then activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX) and increasing levels of reactive oxygen species (ROS). ROS initiate cation influx, cell swelling, and β-catenin activation. Knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs cause a common redox-sensitive inflammasome circuit. They are new candidates for therapeutic intervention.
\n
Not only apoptosis and pyroptosis are involved in increased cell death in MDS. Recently, possible further mechanism of cell death, necroptosis, in MDS has been described [72, 73]. Necroptosis is like pyroptosis associated with membrane permeabilization and the release of damage-associated molecular patterns (DAMPs) such as alarmins. Alarmins bind Toll-like receptor 4 (TLR4) and activate the transcription factor NF-κB and inflammation [74].
\n
The effects of lenalidomide in non-del(5q) are thought to be secondary to modulation of the immune system. Hyperactivated T cells inhibit hematopoiesis. Immunosuppressive therapies with antithymocyte globulin alone and in combination with prednisone or cyclosporine show response rates between 25 and 40% [75, 76].
\n
The studies discussed in this and other chapters of this book will help to translate our knowledge of genetic aberrations and of pathophysiological mechanisms in MDS into clinical use in diagnosis, prognosis, and therapy. Novel agents developed on the basis of this knowledge (luspatercept, rigosertib, immune checkpoint inhibitors, venetoclax, and others) are in clinical trials and will help in relapsed/refractory MDS.
\n
The work of our group in this area was supported by the research project for conceptual development of research organization (00023736; Institute of Hematology and Blood Transfusion, Prague) from the Ministry of Health of the Czech Republic.
\n
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Advances in our knowledge of cytogenetic abnormalities andgene mutations",level:"1"},{id:"sec_2",title:"2. Advance in our understanding of del(5q) myelodysplastic syndrome pathogenesis and its treatment with lenalidomide",level:"1"},{id:"sec_3",title:"3. Studies on lenalidomide use also in lower risk non-del(5q) MDS treatment and new possible therapies",level:"1"}],chapterReferences:[{id:"B1",body:'Bejar R, Steensma DP. Recent developments in myelodysplastic syndromes. Blood. 2014;124(18):2793-2803. DOI: 10.1182/blood-2014-04-522136\n'},{id:"B2",body:'Pellagatti A, Boultwood J. The molecular pathogenesis of the myelodysplastic syndromes. European Journal of Haematology. 2015;95(1):3-15. DOI: 10.1111/ejh.12515\n'},{id:"B3",body:'Shastri A, Will B, Steidl U, Verma A. Stem and progenitor cell alterations in myelodysplastic syndromes. Blood. 2017;129(12):1586-1594. DOI: 10.1182/blood-2016-10-696062\n'},{id:"B4",body:'Nazha A, Sekeres MA. 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Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications. Cancer. 2017;123(10):1703-1713. DOI: 10.1002/cncr.30585\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ota Fuchs",address:"ota.fuchs@uhkt.cz",affiliation:'
Institute of Hematology and Blood Transfusion, Prague, Czech Republic
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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
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We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,000 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,000 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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