\r\n\tThe human microbiota consists of a wide variety of bacteria, viruses, fungi, and other single-celled animals that live in the body while microbiome is the name given to all of the genes inside these microbial cells. Recently, there has been renewed interest in the role played by microbiota and microbiome in both human health and human disease. A correct equilibrium between the human host and their microorganisms is important for an appropriate physiological function. \r\n\tMicroorganisms have evolved alongside humans and form an integral part of life, carrying out a range of vital functions. They are implicated in both health and disease, and research has found links between bacterial populations, whether normal or disturbed, and the following diseases: asthma, cancer, diabetes, obesity, heart disease and, neurological and neurodegenerative diseases. \r\n\tThe chapters of this book aim to present outstanding research on biochemical, genetics, clinical, molecular and behavioral fields about microbiota-gut-brain axis with emphasis in how neuropeptides such as brain derived factor (BDNF), substance P, calcitonin gene-related peptide and neuropeptide Y (NPY), vasoactive intestinal polypeptide, somatostatin and corticotropin-releasing factor are also likely to play a role in the bidirectional gut-brain communication. In this capacity they may influence the activity of the gastrointestinal microbiota and its interaction with the gut-brain axis. \r\n\tIt will be shown evidence that neuropeptides represents a challenge in understanding the complex interactions between gut and brain. Although their precise role in the microbiota-gut-brain axis has not yet been defined, neuropeptides play an important role in this respect. For instance, a growing field of work is implicating the microbiota-microbiome in a variety of psychological processes and neuropsychiatric disorders. These include mood and anxiety disorders, neurodevelopmental disorders such as autism spectrum disorder and schizophrenia, and even neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. These brain disturbances have been linked to molecular and biochemical alterations in the course of neurodevelopment so, the research in this area has established different approaches (nutritional, immunological, energy homeostasis), to find the role played by the gut microbiota-microbiome in the etiology of the aforementioned brain disorders.
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National Autonomous University of Mexico (UNAM). School of Sciences. B. S. in Biology. \n1995-1997. National Autonomous University of Mexico (UNAM). Cell Physiology Institute. Master in Basic Biomedical Sciences Research\n1998-2000. National Autonomous University of Mexico (UNAM). Cell Physiology Institute. PhD in Biomedical Sciences (Neuroscience) \n2002-2004. Postdoctoral Fellow. Laboratory of Cell Biology: Mitosis, Ciliogenesis, Intracellular Transport and Motor Protein Functions. University of California, Davis- Dept. of Molecular & Cellular Biology, One Shields Ave. Davis, CA 95616. \n2005-2008. Postdoctoral Fellow. Laboratory of Neuropharmacology. National Institute of Psychiatry “Ramón de La Fuente Muñiz”. Calzada México-Xochimilco #101, Col. San Lorenzo Huipulco, CP 14370 México City, México. \n2009-present. Teaching Professor in Biochemistry. Bachelor in Biology Program. School of Sciences. National Autonomous University of Mexico (UNAM). Av. Insurgentes Sur 3000, Circuito Exterior. Ciudad Universitaria, Mexico D.F. C.P. 04510.\n2006-present. Consultant and Assessor Researcher. \nLaboratory of Psychiatric and Neurodegenerative Diseases. National Institute of Genomic Medicine (INMEGEN-SAP). Periferico Sur 4809, Arenal Tepepan, 14610 México City, México.\nLaboratory of Molecular Basis of Addictions. 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1. Introduction
Malignant glioma (MG), consisting of anaplastic glioma (AA, WHO grade III) and glioblastomamultiforme (GBM, WHO grade IV, 60-70%), is the most common and destructive brain tumor [1]. Despite systemic treatment, surgical resection followed by radiotherapy and chemotherapy, the prognosis of patients with GBM remains poor with a median survival of 12 to 15 months and a 5-year survival rate of 9.8% [2, 3]. The dismal outcome fuels the need to understand the molecular basis of gliomagenesis and identify novel therapeutic targets for MG treatment.
With a developing understanding of core aberrant signaling pathways in MG, molecular targeted therapy has shown certain promise as a more rational strategy. Established targets, including receptor tyrosine kinases (RTK) such as EGFR, PDGFR and VEGFR, as well as mTOR, farnesyl transferase and PI3K, have drawn particular interests both in fundamental and clinical research. However, single targeted agents so far have not displayed desirable clinical outcomes as expected, with response rates of 0 to 15% and no prolongation of 6-month progression-free survival [4–6]. This disappointing outcome is primarily due to the nature of cancer with multi-genetic abnormality and inter/intra-tumor heterogeneity. Therefore, multiple targeting strategies are essential to achieve better clinical benefits.
MicroRNA (miRNA), a type of endogenous small non-coding RNA which negatively modulates gene expression in post-transcriptional level, has rapidly become a topical issue since it was firstly discovered in C. elegans two decades ago[7]. Increasing researches have reported that dysregulation of miRNA is closely associated with tumorigenesis and tumor progression. In gliomas, a group of miRNAs have been characterized as oncogenic and tumor-suppressive molecules. With a unique feature of multi-targeting, miRNA may become a new powerful weapon fighting against MG. Although much remains to be learned about formulating miRNAs as nucleic acid drugs, we feel that identification of miRNAs as therapeutic targets for gliomas is now within sight.
In this chapter, we will critically review issues relevant to contemporary researches on miRNAs and MG. Based upon other teams’ and our data, this review will present findings on oncogenic and tumor-suppressive properties of miRNA in MG, focusing on the mechanisms of dysregulation, the involvement with core pathways of MG and the functional heterogeneity in different context. Besides, we will formulate evidences for miRNA-based clinical application in diagnosis and therapeutics of MG. The developing cognition of miRNAs will ultimately lead to innovative clinical approaches for MG.
2. Oncogenic and tumor-suppressive miRNAs in malignant gliomas
The very first oncogenic miRNA indentified in GBM is miR-21 as early as 2005 [8], although whose target genes were not fully understood at that time. In 2008, another group identified a set of targets of this miRNA which constitute a tumor-suppressive network including TGF-β, p53 and mitochondrial-apoptotic pathways [9]. This is one of the examples showing the multi-targeting nature of miRNAs in oncology. Beyond multi-targeting, these findings also prompt a hypothesis that miRNAs may have pathway preference in some cases.
Coincidently, also in 2005, S.A. Ciafreet al. firstly described that brain-enriched miR-128 and miR-181 family were frequently down-regulated in primary GBMs and cell lines [10], whose tumor-suppressive roles of these miRNAs were subsequently validated in the next few years [11–14].
In 2008, a milestone has been made in glioma research, accomplished by The Cancer Genome Atlas (TCGA) Research Network. Through integrative analysis of DNA copy number, gene expression and DNA methylation aberrations, TCGA defined three major pathways in GBM, which are RTK, p53 and RB signaling pathways, as shown in Figure 1 [15]. These pathways cannot be more familiar to every oncologist: frequently activated RTK signaling in cancer supports cell proliferation and survival, whereas p53 and RB signaling monitor cell cycle transition and couple to apoptosis and senescence pathways, which are commonly suppressed in cancer. To date, increasing oncogenic and tumor-suppressive miRNAs in MGs have been uncovered. In combination with genomic sketch of GBM described by TCGA, we have a deeper insight into the interactions within the core pathways of MG, which are controlled in coding and non-coding levels (Figure 1).
Here we do not pay our attention to the detail of each single miRNA, since several reviews have provided considerable details about their expression and function [16–18]. In this paper, we prefer to focus on how these miRNAs become aberrant, and which malignant phenotypes they contribute to.
As well as every protein coding gene, non-coding miRNA genes may similarly undergo over or lost expression, amplification, deletion, insertion, translocation and mutation, which lead to aberration of miRNAs. The mechanisms of miRNA aberration have not yet been extensively studied. Nevertheless, there have been some clues showing that transcriptional activity, single nucleotide polymorphism (SNP) and chromosome deletion contribute to aberrant genotype and malignant phenotype of MG.
The most interesting research addressing miRNA transcriptional regulation machinery in MGs is the TP53 and miR-25/32 feedback circuitry [19]. Carlo M. Croce’s and co-workers found that miR-25 and miR-32 are negatively regulated by TP53 via repressing their transcriptional factors MYC and E2F1. Intriguingly, by directly targeting MDM2 and TSC1, these miRNAs help stabilize P53 protein and suppress tumorigenicity in U87 GBM cells. Thus, a fine tuned recurrent autoregulatory circuit form. However, in the non-functional mutant TP53 context, miR-25/32 support cell proliferation per contra. These findings not only provide insights into the interaction between miRNAs and TP53 tumor-suppressive pathway, but also hint that a given miRNA may have distinct function in different genetic and biochemical status.
It is unexpected that miRNA genes rarely exhibit SNP or mutation within the major mature sequence segment, although which can be commonly found in the precursor (including the minor mature sequence which is formerly called the star sequence) and primary miRNA segments. Through mining human SNP database, Peng Jin’s group identified a G>U polymorphism located in the eighth nucleotide of the mature miR-125a-5p. The U allele blocks the processing from pri-miRNA to miRNA precursor by altering the secondary structure, and impairs miRNA-mediated translational suppression [20]. MiR-125s have been demonstrated to be tumor-suppressive in GBM [21–23]. However, such nucleotide alteration has not yet been described in glioma clinical data. The rs11614913 SNP, which locates in the segment producing minor mature miR-196a-3p (termed miR-196a* previously), was firstly found to be associated with the risk of glioma in Chinese population [24]. Recent clinical study indicates that the rs2910164 in segment containing minor mature miR-146a-3p sequence is also relative to the risk and prognosis in adult glioma [25]. These findings improve our understandings of miRNA-related pathogenesis and diagnostics in gliomas. Further research is required to fully comprehend the exact mechanisms underlying the relationship between miRNA gene SNPs and clinical outcomes, which may have huge clinical potential.
Chromosome alteration undoubtedly contributes to miRNA aberration. Particularly in diffuse astrocytoma (DA, WHO II) and AA, chromosome 7q32 is a hotspot that frequently amplifies. This region embraces eight miRNAs: miR-593, miR-129-1,miR-335, miR-182, miR-96, miR-183, miR-29a and miR-29b-1. Among these miRNAs, our group recently reported that miR-335 is the most striking target in AA [26]. We have demonstrated that miR-335 confers invasive and proliferative malignant phenotype on astrocytoma via targeting DAAM1. Disrupting miR-335 by cholesterylated miRNA inhibitor abrogates invasion and elicits apoptosis both in vitro and in vivo. Chromosome amplification in cancer often creates abnormal high level of coding and non-coding products that subsequently infests the well-balanced signaling. Currently, drug screening and discovery in oncology specifically focus on over-expressed protein and over-activated kinase. We believe that miRNA, such as miR-335, may also be the target for drug development in the future.
Figure 1.
Interaction between microRNAs and core pathways in malignant gliomas.
3. Dual scripts for a miRNA
In the last session we have mentioned that miR-25/32 functions differently depended on TP53 status in GBM. It is not the sole evidence that a given miRNA plays distinct roles in respective models. In fact, miRNAs show complicated functional heterogeneity.
One of the examples is miR-135a/b. Remco Nagel et al. found increased expression levels of miR-135a and miR-135b during colorectal cancer progression, which target the tumor suppressor gene Adenomatous Polyposis Coli (APC)[27]. The oncogenic role of miR-135a was further confirmed by BR Zetter’s group. They demonstrated that paclitaxel resistance is associated with up-regulation of miR-135a in multiple solid tumor cell lines. Knocking-down of miR-135a acquires susceptibility to paclitaxel[28]. However, in classic Hodgkin lymphoma (cHL), miR-135a directly regulates JAK2, thus suppressing the expression of BCL2L1 (also known as BCL-XL) and inducing apoptosis. Furthermore, higher level of miR-135a indicates better disease-free survival in cHL patients [29]. Likewise our group has also characterized that miR-135a functions as a selective killer of MG. We have reported that glial cell-enriched miR-135a is frequently down-regulated in MG and negatively correlates with the pathological grading of gliomas. Ectopic delivery of miR-135a selectively triggers mitochondrial dependent apoptosis in MG in vitro and in vivo. Interestingly, this lethal effect is neutral in normal glial cells and neurons [30].
MiR-335 gives us another example of the dual role nature of miRNAs. An early study identified that miR-335 suppresses breast cancer metastasis and migration through targeting SOX4 and TNC [31]. However, as mentioned above, our recent research found that this miRNA promotes invasion and proliferation in AA [26]. In this way, miRNAs seems to have cell-type-dependent functional heterogeneity. The definition of “tumor-suppressive” and “oncogenic” should be carefully employed depended on the cell types and diseases.
Even within the same cell type, the functional behavior of a given miRNA can also be diverse. Previously we have reported that activation of cAMP/PKA pathway, manipulated by Cholera toxin, induces cellular differentiation of MG, showing malignant phenotype reversion and potent GFAP (glial fibrillary acidic protein) expression [32]. As it has been well characterized, we found that IL-6/JAK2/STAT3 contributes to GFAP expression in this model [33]. Notably, epigenetic mechanism is also involved. In this context, the so-called oncogenic miR-335 in MG induced by Cholera toxin enhances GFAP expression in MG cell lines and primary cultures [34]. Multi-targeting is one of the natures of miRNAs. Signaling networks composed of target genes and their relative molecules may both contribute to tumor-suppressive and oncogenic function. It seems that the oncogenic functions of miR-335 are hindered under a high endogenous level of cAMP, rewiring to pro-differentiation pathways.
To sum up, the role of a given miRNA depends on the script which is assigned by the cell type, the genomic context and in part the cellular biochemical status. These observations remind that disease state as well as the genomic subclass of MGs should be considered in the preclinical study especially for drug discovery involved miRNAs.
4. Involvement of miRNAs as novel biomarkers in malignant gliomas
Biomarkers are distinctive biological indicators that serve for diagnosis, prognosis and medication. Traditional biomarkers include mRNAs, proteins and metabolites. At present, miRNAs are emerging as novel and practical biomarkers in oncology. Due to their surprising stability, miRNAs can not only be detected in fresh and frozen tissues, but also in body fluids and even formalin-fixed paraffin-embedded samples. In the study of Roland Schroers, miR-15b and miR-21 are found in cerebrospinal fluid and demonstrated to be markers of glioma [35]. Although much remains to be studied, e.g. to discover more accurate and specific markers for respective glioma types, this finding provides a new opportunity to develop less invasive and early diagnostic approach for gliomas.
Besides diagnosis, miRNAs may be promising biomarkers for prognosis. Jun Li’s group has reported that miR-182 is markedly up-regulated in various glioma cell lines and primary glioma specimens. Furthermore, higher level of miR-182 is associated with poor overall survival of patients with malignant glioma [36]. A more comprehensive study was recently carried out by Sujaya Srinivasan, et al. They analyzed miRNA expression profile of GBM patients (n = 222) from TCGA database and found a ten-miRNA expression signature that predicts survival for GBM. In detail, three miRNAs (miR-20a, miR-106a and miR-17-5p) were identified as protective markers and seven miRNAs (hsa-miR-31, hsa-miR-222, hsa-miR-148a, hsa-miR-221, hsa-miR-146b, hsa-miR-200b and hsa-miR-193a) were risky [37].
Recent studies have raised a possibility that miRNAs may function as predictive markers for therapeutics. Temozolomide (TMZ) is a well-known alkylating agent against gliomas, which methylates guanines in the O-6 position. Accumulating O-6 methyl guanines lead to DNA mismatch during replication and ultimately result in cell death. Although MGMT (methyl-guanine methyl transferase) promoter methylation has been proved to be a strongest marker to predict the TMZ response in low-grade and high-grade gliomas [38–40], it may not be the only indicator. Recent research indicates that miR-181b/c, miR-195, miR-455-3p and miR-10a-3p, rather than MGMT promoter methylation, predict response to concomitant chemoradiotherapy and acquired TMZ resistance in GBM cell line and patients [41, 42]. In addition, increasing evidences indicate that miRNAs also contribute to other drug response. For instance, up-regulated miR-21 confers teniposide and paclitaxel resistance on GBM cells [43, 44]. Various highly efficient MGMT inhibitors have been developed for sensitizing tumor to TMZ [45]. The emerging roles of miRNAs in drug resistance of TMZ and other antineoplastic agents give us a novel angle to include miRNAs as therapeutic targets.
5. Perspectives on miRNAs as nucleic acid drugs in malignant gliomas
5.1. MiRNAs replacement therapy and suppressive therapy
Human body has an extremely complicated internal environment, relying on balance and stability of which human keep their health. Once the homeostasis is disrupted by down-regulation or up-regulation of some important molecules including miRNAs, human will suffer from all kinds of diseases. Based on the disequilibrium status, the ideal protocols to cure diseases are believed to replace what is lost and to repress what is excessive, which are respectively called replacement therapy and suppressive therapy. For the former, estrogen replacement therapy is the most representative example, which is generally used in menopausal women with menopausal syndrome caused by ovarian hormones loss and has shown a positive effect [46]. For the latter, a typical case is a famous anti-angiogenesis drug Avastin, the humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody for cancer therapy [47]. Besides, Gefitinib and Glivec specially inhibiting EGFR tyrosine kinase, have both achieved high clinical benefit rates in treating cancer especially lung carcinoma and chronic myelocytic leukemia[48,49], further indicating the efficacy of suppressive therapy via targeting core molecules in tumorigenesis.
Notably, increasing evidences demonstrated that gliomagenesis is also closely associated with deregulation of miRNAs, such as up-regulation of oncogenic miRNAs and down-regulation of tumor suppressive miRNAs. Therefore, targeting these aberrant miRNAs has tremendous potential as a therapeutic strategy by down- or up-regulating altered genes. Specially, miRNA mimics can be synthesized to replace lessened ones critical in gliomagenesis, and miRNA inhibitors can be designed to suppress the function of up-regulated oncogenic miRNAs. Just less than two decades after discovering the role of miRNAs in oncology, the replacement and suppressive therapies of miRNA are already being used in preclinical researches. We have proved that artificially rectification of abnormally expressed miRNAs inhibited growth of glioma xenografts in mice and prolonged the median survival of rat with orthotopic glioma[26,30], opening a new sight for glioma treatment.
5.2. MiRNA-targeting cocktail therapy
Glioma is a complicated disease of altered genes. TCGA has reported multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that construct three core pathways (as shown in Figure 1] [15]. Furthermore, glioma is a disease of altered miRNAs. A genome-wide expression profiling of 26 GBMs, 13 AAs and 7 normal brain samples identifies multiple deregulated miRNAs in MGs [50]. In addition, large scale of sequencing analysis of GBMs has identified extensive genetic heterogeneity between GBM samples from different patients [51], implying the possibility of miRNA\'s heterogeneity. The multiplicity of deregulated miRNAs and the heterogeneity of deregulated miRNAs expression profiling may foster therapeutic failure and tumor adaptation to solo miRNA-targeting therapy.
To date, researchers just verified the efficiency of targeting solo miRNA as if by prior agreement. What will happen if target several pivotal miRNAs simultaneously? Given the multiplicity of deregulated miRNAs in glioma, a cocktail consisting of special miRNA mimics and/or inhibitors may kill multiple birds with one stone. In another word, components in cocktail may have an additive effect or even a synergistic effect against MGs. Furthermore, considering individual differences, one cocktail may not fit for each patient with MGs. If we can design a specific miRNA cocktail based on individual deregulated miRNAs, miRNA individualized treatment will be within our sights. Certainly, additional preliminary evidences are needed to verify the feasibility and availability of miRNA-targeting cocktail therapeutics.
5.3. Engineering miRNA
Engineering miRNA (emiRNA) is artificially designed in sequence, endowed with functional similarity to natural miRNA and functional specificity according to human’s will. In a sense, emiRNA is a branch of small interfering RNA (siRNA) that possesses multi-targeting power just as natural miRNA.
Leastwise, there are two strategies to design emiRNA: (a) adjustment based on the natural miRNA sequence; (b) de novo design.
In the sessions above, we have discussed the fact that a given miRNA may play distinct role in different models, e.g. different genetic background, different cell type and different second messenger level. Even in a “conclusive”circumstance that a certain miRNA strongly kills a type of cancer cell, we still need to evaluate its pharmacodynamics in the cancer tissue and toxic side effect to the normal tissue before clinical application. If a natural sequence miRNA shows remarkable antitumor effect but exhibits unsatisfying selectivity, does it mean we should totally abandon this target? The problem may be solved by emiRNA technology. Different dominant target genes and their roles in different models determine the functional heterogeneity of a given miRNA. If we are able to find out the undesired targets that lead to unsatisfying selectivity, perhaps by keeping the seed region of the miRNA and adjusting its 3’ nucleotide sequence, we could either avoid the interaction between the miRNA and the undesired target genes, or enhance the binding to our goal targets.
In broader context, we could design an artificial miRNA in a de nove way. Cancers are known as a type of multigenic disease. By comprehensive sequencing, RTK/RAS/PI[3]K, p53 and RBsignalings are characterized as the core pathways in GBM [15]. In virtue of bioinformatics, it is possible to design a miRNA that contemporaneously targets the key components of two or more pathways by carefully examining their mutual microRNA recognition elements (MREs).
However, numbers of scientific problems need to be addressed before putting emiRNA into practice. We still have limited knowledge about the details of miRNA biogenesis and the MRE language passing on along evolution. Someday the secret will be unlocked and emiRNA may be a practical weapon against cancers.
5.4. MiRNA formulation
Another attractive issue of translating miRNA into clinical application is formulation. Although whose length is quite short in the RNA world, miRNA as well as siRNA is a type of high molecular weight drug in pharmaceutical point of view. Additionally, electric charge contributed by phosphate groups of the nucleic acid backbone make it inadequate for CNS delivery. Fortunately, new technical progress brings miRNA formulation within sight.
In the earlier period, viral vector including retrovirus, adenovirus, herpes simplex virus and adeno-associated virus were broadly used due to their high efficiency for both gene delivery and expression. However, limitations associated with safety, genomic stability and immunogenicity motivate scientists to focus on non-viral systems. At present, remarkable achievements have been made in chemical modifications and conjugations of small RNA. For example, locked nucleic acid (LNA) technology not only increases melting temperature of RNA-RNA duplex thus enhancing the binding affinity between small RNA and target transcript, but also improves the half-life of small RNA in serum, which is critical for therapeutic use [52]. Cholesterylation, viz. modification with cholesteryl functionality, which improves the cellular uptake of small RNA, is now extensively used for miRNA mimics/inhibitors and siRNA in preclinical research [53]. Two reviews have provided clear and comprehensive introduction of the progress on chemical small RNA encapsulation [54, 55]. Particularly, a recent study from Paula Hammond and colleagues reported a self-assembled microsponges of small RNA hairpin polymersin corporated more than half a million copies of siRNA in a single nanoparticle [56]. This novel technology allow one thousand times lower concentration to achieve same degree of gene silencing efficiency as conventional strategies, showing great clinical application potential. In the near future, small RNA formulation will further benefit from evolution of nanotechnology and biomaterial technology.
6. Concluding remark
Glioma is not the type of high incidence disease; however the depressive clinical outcomes still threaten human health. Special location, rapid proliferation, invasive growth and massive angiogenesis are the key issues that limit treatment for MG. In addition, extremely complicated histopathological and genomic classifications perplex fundamental and clinical research.
With the evolution of new generation high through-put sequencing technology, clearer insights of driver mutations and core pathways in various cancers are gradually revealed in the recent period [57–59]. According to these cancer genomic studies, we realize that not only aberrant coding genes lead to cancers, but also non-coding components underneath the iceberg. Twenty-year’s research on miRNA opens a new world of genetics and oncology. More and more groups are dedicated to study the role of miRNA in cancer including glioma. Albeit fragmentary, accumulating data will offer deeper insights of glioma with more systematic considerations.
Compared with other non-coding protagonists, e.g. histone modification and DNA methylation, miRNA is the easiest role to be specifically manipulated, either by over-expression or inhibition, which determines miRNA to be the star with enormous clinical potential. Although we have not drawn an elaborate picture of miRNA biogenesis, especially how primary sequence and intra-cellular microenvironment influence secondary structure and eventually contribute to processing and maturation, as well as the communication principles between miRNA and MRE, we believe that technologies nowadays are poised to uncover the law of miRNA in oncology. We envision that this intrinsic biomolecule will be the therapeutic target for cancer.
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Introduction",level:"1"},{id:"sec_2",title:"2. Oncogenic and tumor-suppressive miRNAs in malignant gliomas",level:"1"},{id:"sec_3",title:"3. Dual scripts for a miRNA",level:"1"},{id:"sec_4",title:"4. Involvement of miRNAs as novel biomarkers in malignant gliomas",level:"1"},{id:"sec_5",title:"5. Perspectives on miRNAs as nucleic acid drugs in malignant gliomas",level:"1"},{id:"sec_5_2",title:"5.1. MiRNAs replacement therapy and suppressive therapy",level:"2"},{id:"sec_6_2",title:"5.2. MiRNA-targeting cocktail therapy",level:"2"},{id:"sec_7_2",title:"5.3. Engineering miRNA",level:"2"},{id:"sec_8_2",title:"5.4. MiRNA formulation",level:"2"},{id:"sec_10",title:"6. Concluding remark",level:"1"}],chapterReferences:[{id:"B1",body:'Louis, D.N., Ohgaki, H., Wiestler, O.D., Cavenee WK. WHO Classification of Tumours of the Central Nervous System. IARC Press; 2007. '},{id:"B2",body:'Meyer M a. Malignant Gliomas in Adults. New England Journal of Medicine. 2008 Oct 23;359(17):1850–1850. 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Zhongshan School of Medicine, Sun Yat-sen University, People’s Republic of China
Zhongshan School of Medicine, Sun Yat-sen University, People’s Republic of China
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Souweidane",authors:[{id:"45389",title:"Dr.",name:"Mark",middleName:"M.",surname:"Souweidane",fullName:"Mark Souweidane",slug:"mark-souweidane"},{id:"158907",title:"Dr.",name:"Zhiping",middleName:null,surname:"Zhou",fullName:"Zhiping Zhou",slug:"zhiping-zhou"}]},{id:"43963",title:"Chemotherapeutic Agent for Glioma",slug:"chemotherapeutic-agent-for-glioma",signatures:"Shinji Kohsaka and Shinya Tanaka",authors:[{id:"49655",title:"Prof.",name:"Shinya",middleName:null,surname:"Tanaka",fullName:"Shinya Tanaka",slug:"shinya-tanaka"},{id:"161991",title:"Dr.",name:"Shinji",middleName:null,surname:"Kohsaka",fullName:"Shinji Kohsaka",slug:"shinji-kohsaka"}]},{id:"43965",title:"Topoisomerase Therapy in the Treatment of Brain Tumors",slug:"topoisomerase-therapy-in-the-treatment-of-brain-tumors",signatures:"George Theodore, Niramol Savaraj and Lynn Feun",authors:[{id:"162096",title:"Dr.",name:"George",middleName:null,surname:"Theodore",fullName:"George Theodore",slug:"george-theodore"},{id:"162110",title:"Dr.",name:"Lynn",middleName:null,surname:"Feun",fullName:"Lynn Feun",slug:"lynn-feun"}]},{id:"43966",title:"Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research",slug:"primary-central-nervous-system-lymphoma-recent-advance-on-clinical-research",signatures:"Ryuya Yamanaka",authors:[{id:"41282",title:"Dr.",name:"Ryuya",middleName:null,surname:"Yamanaka",fullName:"Ryuya Yamanaka",slug:"ryuya-yamanaka"}]},{id:"43967",title:"Contributions to the Understanding of the Neural Bases of the Consciousness",slug:"contributions-to-the-understanding-of-the-neural-bases-of-the-consciousness",signatures:"Leon Dănăilă and Mihail Lucian Pascu",authors:[{id:"41760",title:"Dr.",name:"Mihail - Lucian",middleName:null,surname:"Pascu",fullName:"Mihail - Lucian Pascu",slug:"mihail-lucian-pascu"}]},{id:"43969",title:"The Stance of Antioxidants in Brain Tumors",slug:"the-stance-of-antioxidants-in-brain-tumors",signatures:"Pinar Atukeren and M. Ramazan Yigitoglu",authors:[{id:"54960",title:"Dr.",name:"Pınar",middleName:null,surname:"Atukeren",fullName:"Pınar Atukeren",slug:"pinar-atukeren"},{id:"163866",title:"Dr.",name:"M.Ramazan",middleName:null,surname:"Yigitoglu",fullName:"M.Ramazan Yigitoglu",slug:"m.ramazan-yigitoglu"}]},{id:"43971",title:"Management of Brain Tumor in Pregnancy — An Anesthesia Window",slug:"management-of-brain-tumor-in-pregnancy-an-anesthesia-window",signatures:"Hala M. Goma",authors:[{id:"42540",title:"Dr.",name:"Hala",middleName:"Mostafa",surname:"Goma",fullName:"Hala Goma",slug:"hala-goma"},{id:"162798",title:"Prof.",name:"Amr",middleName:null,surname:"Abo Ela",fullName:"Amr Abo Ela",slug:"amr-abo-ela"}]},{id:"44038",title:"Interdisciplinary Surgical Management of Orbital and Maxillo- Ethmoidal Complex Disorders",slug:"interdisciplinary-surgical-management-of-orbital-and-maxillo-ethmoidal-complex-disorders",signatures:"Jarosław Paluch, Jarosław Markowski, Jan Pilch, Agnieszka Piotrowska – Seweryn, Robert Kwiatkowski, Joanna Lewin-Kowalik, Czesław Zralek and Agnieszka Gorzkowska",authors:[{id:"46014",title:"Prof.",name:"Jarosław",middleName:null,surname:"Markowski",fullName:"Jarosław Markowski",slug:"jaroslaw-markowski"},{id:"55851",title:"Dr.",name:"Jarosław",middleName:null,surname:"Paluch",fullName:"Jarosław Paluch",slug:"jaroslaw-paluch"},{id:"165065",title:"Dr.",name:"Agnieszka",middleName:null,surname:"Piotrowska - Seweryn",fullName:"Agnieszka Piotrowska - Seweryn",slug:"agnieszka-piotrowska-seweryn"},{id:"166896",title:"Prof.",name:"Joanna",middleName:null,surname:"Lewin-Kowalik",fullName:"Joanna Lewin-Kowalik",slug:"joanna-lewin-kowalik"},{id:"166897",title:"Dr.",name:"Włodzimierz",middleName:null,surname:"Dziubdziela",fullName:"Włodzimierz Dziubdziela",slug:"wlodzimierz-dziubdziela"},{id:"166944",title:"Dr.",name:"Maciej",middleName:null,surname:"Kajor",fullName:"Maciej Kajor",slug:"maciej-kajor"},{id:"166955",title:"Dr.",name:"Czesław",middleName:null,surname:"Zralek",fullName:"Czesław Zralek",slug:"czeslaw-zralek"},{id:"166968",title:"Dr.",name:"Robert",middleName:null,surname:"Kwiatkowski",fullName:"Robert Kwiatkowski",slug:"robert-kwiatkowski"},{id:"167226",title:"Prof.",name:"Jan",middleName:null,surname:"Pilch",fullName:"Jan Pilch",slug:"jan-pilch"}]},{id:"43805",title:"The Epidemiology of Paediatric Brain Cancer — Descriptive Epidemiology and Risk Factors",slug:"the-epidemiology-of-paediatric-brain-cancer-descriptive-epidemiology-and-risk-factors",signatures:"Adrianna Ranger",authors:[{id:"40865",title:"Dr.",name:"Adrianna",middleName:null,surname:"Ranger",fullName:"Adrianna Ranger",slug:"adrianna-ranger"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"73426",title:"Emerging Compounds in Mexico: Challenges for Their Identification and Elimination in Wastewater",doi:"10.5772/intechopen.93909",slug:"emerging-compounds-in-mexico-challenges-for-their-identification-and-elimination-in-wastewater",body:'\n
\n
1. Introduction
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Currently one of the greatest challenges worldwide is the conservation of the quality of water resources. On a daily basis, a large amount of waste from different industrial, urban and livestock activities is discharged into water bodies, mainly through wastewater. According to UNESCO, 59% of total water consumption in developed countries is destined for industrial use, 30% for agricultural consumption and 11% for domestic activities [1]. It has been reported that more than 80% of hazardous waste in the world is produced in industrialized countries; it is also known that in developing countries 70% of the waste generated in industry is dumped to bodies of water without any type of previous treatment [1]. Specifically in Mexico, 54% of wastewater is not treated, which has become one of the biggest public health problems, since this type of water is reused for agricultural activities and in some cases for human consumption [2]. Table 1 shows the percentage proportions of water uses according to their origin in Mexico.
In recent decades, the use of new chemical products has intensified in different anthropic activities, which has caused the degradation of water resources throughout the planet [3]. Within this set of compounds, a new range of compounds that are characterized by their high persistence and low degradation have been identified, called emerging compounds (EC). The term EC is used to refer to compounds of different origin and chemical nature, whose presence in the environment is not considered significant in terms of distribution and/or concentration, so they go unnoticed. What constitutes a high risk for the environment and the health of the population [4]. Emerging pollutants include a wide variety of products for daily use of different structures, domestic and industrial applications, such as: pesticides, industrial and personal hygiene products, hormones, and drugs, most of which are toxic, persistent and bioaccumulative. Figure 1 briefly describes the classification of this type of compound by families.
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Figure 1.
Classification of emerging compounds by family. (Adapted from [5]).
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It has been established that these compounds enter the environment through different sources, such as domestic and industrial wastewater [6], from waste, treatment plants [7], hospital effluents [8], agricultural and livestock activities [9] and septic tanks, among others [10], which are produced at different concentrations in surface waters, whose environmental quality criteria have not yet been specified [11].
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One of the main problems of this type of pollutant is that the current wastewater treatment plants are unable to eliminate them. They are designed to remove organic matter and nutrients in higher concentrations (g L−1). Therefore, emerging pollutants are present in surface water, groundwater and in purified water. In addition, the primary degradation of some of these compounds in wastewater treatment plants or in the environment itself, generate more persistent and more dangerous products, and synergistic effects may even occur if the compounds share the mechanisms of action [12].
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This situation has been a matter of concern for the scientific community and for regulatory environmental entities, given the multiple impacts that they can cause on the environment and human health [11].
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Since 1989, the World Health Organization (WHO) has developed guidelines for the safe use of wastewater, and on this basis, each country has established its own regulatory framework. In this sense, Mexico has implemented a decentralized policy framework for managing water resources. In particular, the National Water Commission (CONAGUA, by its acronym in Spanish) was created, whose main function is the management of water resources, likewise is responsible for the formulation of public policies for water management. Water management legally incorporates Integrated Water Resources Management (IWRM), whose purpose is to promote stakeholder participation in coordinating the development and management of water, land and related resources [13]. Within the functions of the IWRM is the management of wastewater treatment and its reuse. However, the treatment and reuse of wastewater has not yet been adequately implemented within the sanitation services in terms of comprehensive water management, this is partly due to the fact that sanitation is not defined within the water legislation, in addition to institutional fragmentation, making it difficult to carry out such activity [14].
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2. Challenges in the management of water resources in Mexico
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Until now, all strategies and policies for the administration of water resources in Mexico have been ineffective, mainly because of the economic and political interests of some groups in society, which has not allowed the application of the principles established in IWRM, considering the participation of interest groups. This situation has not allowed the investment of resources to address the environmental problem generated by the presence of EC in water bodies. Currently only a few very specific studies have been carried out in a few states of the republic which indicates that there are many pending tasks on the part of the entities responsible for the management of water resources, in terms of the diagnosis of water quality and the development of advanced technologies to face such problem.
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2.1 Identification of emerging compounds
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Some examples of these contaminants are drugs, products for personal use and care, surfactants, fire retardants, steroids, hormones and derivatives of disinfection processes. These products correspond in most of the cases to contaminants that may be candidates for regulation; however, extensive research is required on its potential health effects [15, 16]. In some cases it is assumed that several of the EC have been discharged into the environment for periods prolonged but not detected due to the little information and a lack of analytical methods to detect low concentrations in different matrices [16].
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The identification of this family of compounds in all types of waters has become a challenge for the scientific community, which requires highly sensitive analytical techniques for detection at nanograms per liter (ngL−1) scales. Therefore, the development of rapid and sensitive analytical methods for EC monitoring is important [17].
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The analytical techniques most used today are gas and liquid chromatography, both coupled to mass spectrometry. Coupling to mass spectrometry for the identification of EC in environmental matrices has shown significant results, mainly due to its high sensitivity, specificity and selectivity [17].
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The detection of this type of compounds in environmental matrices requires efficient sample treatment procedures to concentrate analytes of interest and eliminate interferences [17].
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Sample preparation techniques include solid phase extraction, solid phase microextraction, liquid-liquid extraction, microwave assisted extraction, liquid phase microextraction techniques, stir bar sorption extraction, and pressurized liquid extraction, among others [18].
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However, access to these techniques requires large investments of money and highly specialized personnel for the development and validation of adequate methodologies. This situation has not made it possible to carry out diagnoses of the real situation of the presence of these compounds and in the main water bodies of the republic, since the states do not have the necessary resources.
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In Mexico, there are few studies that have determined the concentration levels of this type of compounds in wastewater, groundwater, and surface water, almost all made in the center of the country (Guanajuato, Hidalgo, Jalisco, Morelos states, and Mexico city). Among the reported compounds are estradiol, ethinylestradiol, 4-nonylphenol, bisphenol A, 4-tert-octylphenol, naproxen, acetaminophen, diclofenac, bezafibrate, atenolol and carbamazepine, among others. This situation is worrying if we consider the great industrial and agricultural activity that takes place in a large part of the republic (Table 2).
Emergent compounds concentrations detected in surface and wastewater in different states of the Mexican Republic.
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2.2 Removal of EC from wastewater
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The pollution of water bodies is a technical, social, and environmental challenge, attributable to continuous population increase and limited waste elimination strategies coupled with poor public management of water contaminants [24, 25]. The treatment of wastewater has been carried out for a long time, with the intention of reducing adverse effects on the environment and human health.
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Although wastewater treatment plants are designed to remove solid materials, dissolved organic matter, nutrients and reduce the levels of metals, bacteria, and other pathogens. Most are not designed to efficiently remove organic pollutants, since the presence of different ECs has been detected in the wastewater and in sludge at high concentrations of up to thousands of μg/L or μg/kg [26].
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In this context, contamination of water with EC represents a technical problem for its treatment and purification, since conventional treatments: aerobic biological, anaerobic, coagulation-flocculation, inverse osmosis filtration and disinfection with chlorine are not enough to completely eliminate or degrade this type of compounds [27, 28].
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For this reason, the latest technological developments have focused on advanced oxidation processes (AOP), which focus on the generation of hydroxyl radicals (° OH), which have a greater oxidation potential than ozone or chlorine. The interactions with the compounds of interest are controlled mainly by diffusion and eventually result in the fragmentation of organic compounds and mineralization to CO2 [29].
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In order to provide these radicals, several processes have been implemented that are based on the application of electrical energy (electrochemical oxidation), radiation (UV), ultrasound (US), chemical additives (O3, H2O2) photo-fenton (Fe2+/UV/H2O2) or a combination of these methods (Table 3). A consequence of the high reactivity of the oxidizing agent (° OH) is its low selectivity; which is a desirable feature in the case of wastewater pollutant removal.
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Homogeneous processes
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\n\n\n
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(a) No external energy input
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\n
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\n
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* Ozonolysis in alkaline medium (O3/−OH)
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\n
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\n
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* Ozonolysis with hydrogen peroxide (O3/H2O2) and (O3/H2O2/−OH)
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\n
\n
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* Hydrogen peroxide and catalyst
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\n
\n
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(b) With external energy input
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\n
\n
\n
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(b1) Energy from UV radiation
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\n
\n
\n
\n
\n
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* Ozonolysis and UV radiation (O3/UV)
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\n
\n
\n
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* Hydrogen peroxide and UV radiation (H2O2/UV)
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\n
\n
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* Ozone, hydrogen peroxide and UV radiation (O3/H2O2/UV)
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\n
\n
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* Photo-fenton (Fe2+/H2O2/UV)
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(b2) Energy from ultrasound (US)
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\n
\n
\n
\n
\n
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* Ozonolysis and US (O3/US)
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\n
\n
\n
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* Hydrogen peroxide and US (H2O2/US)
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\n
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(b3) Electrochemistry
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\n
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* Electrochemical oxidation
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\n
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\n
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* Anodic oxidation
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\n
\n
\n
\n
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* Electro-fenton
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\n
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\n
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Heterogeneous processes
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\n
\n
\n
\n
\n
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* Catalytic ozonolysis (O3/TiO2)
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\n
\n
\n
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* Photocatalytic ozonolysis (O3/TiO2/UV)
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\n
\n
\n
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* Heterogeneous photocatalysis (H2O2/TiO2/UV)
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\n\n
Table 3.
Summary of the main AOPs used for the degradation of organic compounds.
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On the other hand, these are processes that use expensive reagents such as hydrogen peroxide or ozone, so its use should be restricted to situations in which other processes cheaper, such as biological, are not possible. Their full potential is exploited when they are achieved integrate with other treatments, such as adsorption or biological treatments, in order to achieve the maximum oxidant economy.
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Faced with this panorama, the challenge for Mexico is great if we consider that in the country there are 2540 wastewater treatment plants, of which 3.2% apply primary treatment, 96% secondary treatment and only 0.12% apply tertiary treatment (Table 4).
\n
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\n\n
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Type of treatment
\n
Process
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Number of plants
\n
Treated flow (m3/s)
\n
\n\n\n
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Primary
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Primary
\n
13
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0.035
\n
\n
\n
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Advanced primary
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10
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4.431
\n
\n
\n
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Imhoff tank
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58
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0.326
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\n
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Secondary
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Aerobic
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20
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1.849
\n
\n
\n
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Anaerobe
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100
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0.625
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Biodiscs
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30
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0.872
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\n
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Biological
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30
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0.737
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Dual
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24
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27.402
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\n
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Biological filters
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39
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5.13
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Septic tank
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100
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0.142
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Septic tank + biological filter
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40
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0.044
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\n
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Septic tank + wetland
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115
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0.207
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Wetlands
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74
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1.249
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Aerated lagoons
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29
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7.024
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Stabilization lagoons
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774
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13.739
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Activated sludge
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725
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70.239
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\n
\n
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UAR + biological filter
\n
62
\n
0.577
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\n
\n
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UAR + wetland
\n
34
\n
0.331
\n
\n
\n
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Upflow Anaerobic Reactor (UAR)
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133
\n
1.175
\n
\n
\n
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Enzymatic reactor
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44
\n
0.097
\n
\n
\n
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Sedimentation + wetland
\n
21
\n
0.04
\n
\n
\n
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Imhoff tank + biological filter
\n
26
\n
0.181
\n
\n
\n
\n
Imhoff tank + wetland
\n
6
\n
0.017
\n
\n
\n
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Oxidation trenches
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13
\n
0.985
\n
\n
\n
Tertiary
\n
Tertiary
\n
3
\n
0.044
\n
\n
\n
Not specified
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Others
\n
17
\n
0.203
\n
\n
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Total
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2540
\n
137.701
\n
\n\n
Table 4.
Main municipal wastewater treatment processes (source CONAGUA 2).
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In recent years, various government agencies responsible for carrying out research in the management processes and development of water remediation strategies have led to some studies aimed at the application of advanced technologies for the removal and/or degradation of organic compounds in wastewater. For example, since 2014 the Mexican Institute of Water Technology (IMTA, for its acronym in Spanish), has been developing different technologies for the removal of EC. Within these developments, they used biofiltration systems for biodegradation of two drugs, metformin and ciprofloxacin. Obtaining biodegradation efficiencies of 83 and 71% respectively, during 103 days of operation [30]. Likewise, in another study carried out in two wastewater treatment plants located in the states of Guanajuato and Mexico, they used a system integrated by oxidation ditches and UV light lamps, obtaining EC elimination efficiencies between 20% and 22% % (Guanajuato). Likewise, while in the other treatment that consisted of anaerobic / anoxic/aerobic tanks together with two disinfection processes; chlorine dioxide and ultraviolet lamps, the removal of EC was significant (up to 80%) (Mexico) [23].
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Also used a submerged membrane bioreactor for the degradation of compounds estrone, estradiol and 17α-ethinylestradiol, obtaining removals close to 96% for all compounds [31]. Meanwhile Flores and Mijaylova 2017, evaluated the removal of three pharmaceutical micropollutants (fluoxetine, mefenamic acid and metoprolol) from municipal wastewater, by using four aerated submerged attached growth bioreactors, with removal efficiencies of 95, 82 and 73% for fluoxetine, mefenamic acid and metoprolol, respectively [32]. In another study conducted by García-Espinosa et al. 2018, obtained degradation percentages of Carbamazepine in wastewater of 88.7%, using an electrochemical oxidation process [33].
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3. Conclusions
\n
The main challenge facing Mexico for the comprehensive management of water resources, to do with current legislation has some structural deficiencies, for example, the sanitation process is not defined within the water legislation, as well as to institutional fragmentation. On the other hand, it must be considered that decision-making is strongly influenced by political interests and social pressure, which makes it difficult to align common goals in public health and environmental protection between local authorities and different sectors of society. It is also important to note that many official guidelines for water management are generally prepared by new presidential administrations every six years, which prevents the continuity of plans and programs, which causes waste of economic resources, which accelerates the deterioration of water and sanitation services.
\n
As can be seen in scientific reports and publications, in Mexico there is little information on the real level of concentration levels of emerging compounds, which is worrisome considering that there are currently no laws that regulate said compounds in bodies of Water. Some of the studies carried out reveal alarming concentrations of some compounds. The foregoing suggests the implementation of intensive programs in the areas with the highest population, and regions with high industrial and agricultural activity; however, access to this type of methodologies requires highly qualified personnel, as well as high investments in the acquisition of supplies and equipment.
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Finally, the number of waste treatment plants is insufficient; in addition, the vast majority are concentrated in primary and secondary treatments, and only 0.12% apply tertiary treatments. Although some advanced methods have been implemented for the removal of organic compounds, some of them with high efficiencies, which is encouraging, however these technologies continue to be expensive, which suggests the participation of government and private companies to support projects, that yields mutual benefits for both parties; that is to say, environmental, social and economic.
\n
\n
Acknowledgments
\n
The authors wish to thank PRODEP (Program for the Development of Teachers), for the support in the financing of this publication. Likewise, they also wish to National Council for Science and Technology (CONACYT) for the grant awarded to José Gustavo Ronderos Lara.
\n
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"emerging compounds, monitoring, wastewater, removal",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73426.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73426.xml",downloadPdfUrl:"/chapter/pdf-download/73426",previewPdfUrl:"/chapter/pdf-preview/73426",totalDownloads:47,totalViews:0,totalCrossrefCites:0,dateSubmitted:"June 23rd 2020",dateReviewed:"September 7th 2020",datePrePublished:"December 1st 2020",datePublished:null,dateFinished:"October 1st 2020",readingETA:"0",abstract:"In recent years, the presence of organic pollutants has received great attention due to their effects on public health and biota. Within this set of compounds, a new range of compounds that are characterized by their high persistence and low degradation have been identified, called Emerging Compounds. Emerging pollutants include a wide variety of products for daily use of different structures, domestic and industrial applications, such as: pesticides, industrial and personal hygiene products, hormones, and drugs, most of which are toxic, persistent and bioaccumulative. A characteristic of these types of pollutants is that current wastewater treatment plants are unable to remove them; they are designed to remove organic matter and nutrients in higher concentrations. In Mexico there is little information on the concentration levels of these compounds, due to the lack of public policies aimed at providing resources to institutions and researchers trained to carry out this type of study. On the other hand, the technological infrastructure of the wastewater treatment plants is insufficient for the country’s demand. This situation represents one of the greatest challenges for the authorities responsible for the management of water resources, in the immediate time if it is intended to preserve said resource and therefore take care of the health of the population.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73426",risUrl:"/chapter/ris/73426",signatures:"José Gustavo Ronderos-Lara, Hugo Saldarriaga-Noreña, Pedro Guillermo Reyes-Romero, Luis Alberto Chávez-Almazán, Josefina Vergara-Sánchez, Mario Alfonso Murillo-Tovar and César Torres-Segundo",book:{id:"10030",title:"Emerging Contaminants",subtitle:null,fullTitle:"Emerging Contaminants",slug:null,publishedDate:null,bookSignature:"Dr. Aurel Nuro",coverURL:"https://cdn.intechopen.com/books/images_new/10030.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"14427",title:"Dr.",name:"Aurel",middleName:null,surname:"Nuro",slug:"aurel-nuro",fullName:"Aurel Nuro"}],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. Challenges in the management of water resources in Mexico",level:"1"},{id:"sec_2_2",title:"2.1 Identification of emerging compounds",level:"2"},{id:"sec_3_2",title:"2.2 Removal of EC from wastewater",level:"2"},{id:"sec_5",title:"3. Conclusions",level:"1"},{id:"sec_6",title:"Acknowledgments",level:"1"},{id:"sec_9",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'\nUNESCO. Agua para todos, agua para la vida, s.l.: Ediciones UNESCO y Mundi-Prensa. 2003.\n'},{id:"B2",body:'\nCONAGUA. Estadísticas del Agua en México, s.l.: s.n. 2015.\n'},{id:"B3",body:'\nCherfi A, Achour M, Cherfic M, Otmani S. and Morsli A. Health risk assessment of heavy metals through consumption of vegetables irrigated with reclaimed urban wastewater in Algeria. Process Saf. Environ. Protec. 2015; 98: 245-252.\n'},{id:"B4",body:'\nBarceló D, and. L. M. Contaminación y calidad química del agua: el problema de los contaminantes emergentes. Panel científico-técnico de seguimiento de la política de aguas. 2007.\n'},{id:"B5",body:'\nMoyá-Llamas M. Tratamientos combinados para la degradación y eliminación de compuestos emergentes en aguas. 2a Reunión de la red Traguanet. 2016b.\n'},{id:"B6",body:'\nDaughton C G. "PPCPs in the Environment: Future Research — Beginning with the End Always in Mind," In Pharmaceuticals in the Environment, Kümmerer K (Ed.), 2nd edition, Springer, 2004, Chapter 33, pp. 463-495.\n'},{id:"B7",body:'\nDana W, Kolpin Edward T, Furlong Michael T, Meyer E, Michael Thurman Steven D, Zaugg Larry B, Barber and Herbert T. Buxton Pharmaceuticals, Hormones, and Other Organic Wastewater Contaminants in U.S. Streams, 1999−2000: A National Reconnaissance. Environmental Science & Technology 2002; 36 (6): 1202-1211.\n'},{id:"B8",body:'\nKümmerer K. Emerging contaminants. Treatise on Water Science, 2011; 3: 69-87.\n'},{id:"B9",body:'\nWatanabe N, Bergamaschi B.A, Loftin K.A, Meyer M.T, and Harter T. Use and environmental occurrence of antibiotics in freestall dairy farms with manured forage fields. Environ. Sci. Technol. 2010; 44: 6591– 6600.\n'},{id:"B10",body:'\nChristopher H Swartz, Sharanya Reddy, Mark J. Benotti, Haifei Yin, Larry B. Barber, Bruce J. Brownawell, and Ruthann A. Rudel. Environmental Science & Technology. 2006; 40 (16): 4894-4902.\n'},{id:"B11",body:'\nTrine Eggen, Monika Moeder, Augustine Arukwe. Municipal landfill leachates: A significant source for new and emerging pollutants, Science of The Total Environment. 2010; 408 (21): 5147-5157.\n'},{id:"B12",body:'\nGiger W, Brunner P.H. & Schaffner, C. 4-Nonylphenol in sewage sludge: accumulation of toxic metabolites from non-ionic surfactants. Science. 1984; 225: 623–625.\n'},{id:"B13",body:'\nAgarwal A, de los Angeles M.S., Bhatia R., Chéret I., Davila-Poblete S., Falkenmark M., González-Villarreal, F., Jønch-Clausen T., Kadi M.A., Kindler J. et al. Integrated Water Resources Management. Global Water Partnership (GWP); Tack Background Papers No. 4; Global Water Partnership Technical Advisory Committee (TAC): Stockholm, Sweden. 2000; p. 71. ISBN 91-630-9229-8.\n'},{id:"B14",body:'\nOECD. Getting It Right Una Agenda Estratégica Para las Reformas en México (An Strategic Agenda for the Mexican Reforms); OECD Publishing: Mexico City, Mexico, 2013; p. 312. ISBN 978-92-64-19036-8.\n'},{id:"B15",body:'\nUSEPA 2014. Contaminants of Emerging Concern including Pharmaceuticals and Personal Care Products.https://www.epa.gov/wqc/contaminants-emerging-concern-including-pharmaceuticals-and-personal-care-products. (Accessed Aug 2020).\n'},{id:"B16",body:'\nErickson M.L., Langer S.K., Roth J.L., and Kroening S.E. Contaminants of emerging concern in ambient groundwater in urbanized areas of Minnesota. 2009–12 U.S. Geological Survey Scientific Investigations Report 2014–5096, 38 p., with appendix, http://dx.doi.org/10.3133/sir20145096.\n'},{id:"B17",body:'\nAgüera Ana,AU - Martínez Bueno, María Jesús AU - Fernández-Alba, Amadeo R. PY. New trends in the analytical determination of emerging contaminants and their transformation products in environmental waters. Environmental Science and Pollution Research. 2013; 20 (6): 3496-3515.\n'},{id:"B18",body:'\nK. Mogolodi Dimpe, Philiswa N. Nomngongo. Current sample preparation methodologies for analysis of emerging pollutants in different environmental matrices, TrAC Trends in Analytical Chemistry. 2016; 82: 199-207.\n'},{id:"B19",body:'\nGibson R., Becerril-Bravo E., Silva-Castro V., and Jiménez B. Determination of acidic pharmaceuticals and potential endocrine disrupting compounds in wastewaters and spring waters by selective elution and analysis by gas chromatography-mass spectrometry. Journal of Chromatography A. 2007; 1169 (1-2): 31-39.\n'},{id:"B20",body:'\nDíaz-Torres E., Gibson R., González-Farías F. et al. Endocrine Disruptors in the Xochimilco Wetland, Mexico City. Water Air Soil Pollut. 2013: 224, 1586.\n'},{id:"B21",body:'\nRonderos-Lara J.G., Saldarriaga-Noreña H. Murillo-Tovar M.A., Vergara-Sánchez J. Optimization and Application of a GC-MS Method for the Determination of Endocrine Disruptor Compounds in Natural Water. Separations. 2018; (5), 33.\n'},{id:"B22",body:'\nJosé Abraham Rivera-Jaimes, Cristina Postigo, Rosa María Melgoza-Alemán, Jaume Aceña, Damia Barceló, Miren López de Alda, Study of pharmaceuticals in surface and wastewater from Cuernavaca, Morelos, Mexico: Occurrence and environmental risk assessment, Science of The Total Environment. 2018; (613–614): 1263-1274.\n'},{id:"B23",body:'\nEdson Baltazar Estrada-Arriaga, Juana Enriqueta Cortés-Muñoz, Arturo González-Herrera, César Guillermo Calderón-Mólgora, Ma. de Lourdes Rivera-Huerta, Esperanza Ramírez-Camperos, Leticia Montellano-Palacios, Silvia Lucila Gelover-Santiago, Sara Pérez-Castrejón, Lina Cardoso-Vigueros, Alejandra Martín-Domínguez, Liliana García-Sánchez, Assessment of full-scale biological nutrient removal systems upgraded with physico-chemical processes for the removal of emerging pollutants present in wastewaters from Mexico, Science of The Total Environment. 2016; (571): 1172-1182.\n'},{id:"B24",body:'\nCorcoran E. (Editor); Nellemann C. (Editor); Baker E. (Editor); Bos R. (Editor); Osborn D. (Editor); Savelli H. (Editor) (2010): Sick Water? The central role of wastewater management in sustainable development. A Rapid Response Assessment. United Nations Environment Programme (UNEP), UN-HABITAT, GRID-Arendal. URL [Accessed August 2020].\n'},{id:"B25",body:'\nM. Bilal, M. Asgher, R. ParraSaldivar, H. Hu, W. Wang, X. Zhang, H.M.N. IqbalImmobilized ligninolytic enzymes: an innovative and environmental responsive technology to tackle dye-based industrial pollutants–a review Sci. Total Environ. 2017; (576): 646-659.\n'},{id:"B26",body:'\nKlaus Kümmerer. Antibiotics in the aquatic environment – A review – Part I, Chemosphere. 2009; (75): 417-434.\n'},{id:"B27",body:'\nTeodora Basile, Andrea Petrella, Mario Petrella, Giancarlo Boghetich, Valentina Petruzzelli, Sara Colasuonno, and Domenico Petruzzelli. Review of Endocrine-Disrupting-Compound Removal Technologies in Water and Wastewater Treatment Plants: An EU Perspective. Industrial & Engineering Chemistry Research. 2011; 50 (14): 8389-8401.\n'},{id:"B28",body:'\nMark J. Benotti, Rebecca A. Trenholm, Brett J. Vanderford, Janie C. Holady, Benjamin D. Stanford, and Shane A. Snyder. Environmental Science & Technology. 2009; 43 (3): 597-603.\n'},{id:"B29",body:'\nGiri R.R., Ozaki H., Ota S. et al. Degradation of common pharmaceuticals and personal care products in mixed solutions by advanced oxidation techniques. Int. J. Environ. Sci. Technol. 2010; (7): 251–260.\n'},{id:"B30",body:'\nEstrada-Arriaga, E. Removal of emerging compounds through the biofiltration. (2014). Mexican Institute of Water Technology (IMTA). (Consulted August 2020).\n'},{id:"B31",body:'\nEstrada-Arriaga Edson Baltazar, Mijaylova-Nacheva Petia, Moeller-Chavez Gabriela, Mantilla-Morales Gabriela, Ramírez-Salinas Norma y Sánchez-Zarza Manuel. Presencia y tratamiento de compuestos disruptores endócrinos en aguas residuales. Ingeniería Investigación y Tecnología. 2013; (2) , abril-junio: 275-284.\n'},{id:"B32",body:'\nY. Flores Velázquez, P. Mijaylova Nacheva. Removal of pharmaceuticals from municipal wastewater by aerated submerged attached growth reactors, Journal of Environmental Management. 2017; (192): 243-253.\n'},{id:"B33",body:'\nJosué Daniel García-Espinoza, Petia Mijaylova-Nacheva, Martha Avilés-Flores. Electrochemical carbamazepine degradation: Effect of the generated active chlorine, transformation pathways and toxicity, Chemosphere. 2018; (192): 142-151.\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"José Gustavo Ronderos-Lara",address:null,affiliation:'
Chemical Research Center, Autonomous University of Morelos State, Mexico
Laboratory of Analysis and Environmental Sustainability, School of Higher Studies of Xalostoc, Autonomous University of Morelos State, Mexico
'}],corrections:null},book:{id:"10030",title:"Emerging Contaminants",subtitle:null,fullTitle:"Emerging Contaminants",slug:null,publishedDate:null,bookSignature:"Dr. Aurel Nuro",coverURL:"https://cdn.intechopen.com/books/images_new/10030.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"14427",title:"Dr.",name:"Aurel",middleName:null,surname:"Nuro",slug:"aurel-nuro",fullName:"Aurel Nuro"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"21210",title:"Dr.",name:"Amir",middleName:null,surname:"Amani",email:"aamani@sina.tums.ac.ir",fullName:"Amir Amani",slug:"amir-amani",position:null,biography:null,institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"1",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:null},booksEdited:[],chaptersAuthored:[{title:"Artificial Neural Networks: Applications in Nanotechnology",slug:"artificial-neural-networks-applications-in-nanotechnology",abstract:null,signatures:"Amir Amani and Dariush Mohammadyani",authors:[{id:"21210",title:"Dr.",name:"Amir",surname:"Amani",fullName:"Amir Amani",slug:"amir-amani",email:"aamani@sina.tums.ac.ir"},{id:"22996",title:"Dr.",name:"Dariush",surname:"Mohammadyani",fullName:"Dariush Mohammadyani",slug:"dariush-mohammadyani",email:"d.mohammadyani@gmail.com"}],book:{title:"Artificial Neural Networks",slug:"artificial-neural-networks-application",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"19110",title:"Dr.",name:"Daniel",surname:"Memmert",slug:"daniel-memmert",fullName:"Daniel Memmert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"19117",title:"Dr.",name:"Emad S.",surname:"Elmolla",slug:"emad-s.-elmolla",fullName:"Emad S. Elmolla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20400",title:"PhD.",name:"Michael",surname:"Štencl",slug:"michael-stencl",fullName:"Michael Štencl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20726",title:"Dr.",name:"Saro",surname:"Lee",slug:"saro-lee",fullName:"Saro Lee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20842",title:"Prof.",name:"Gaetano Bruno",surname:"Ronsivalle",slug:"gaetano-bruno-ronsivalle",fullName:"Gaetano Bruno Ronsivalle",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/20842/images/2217_n.jpg",biography:"Education\nG. Bruno Ronsivalle has a degree in Music, a degree in Philosophy, a Post-graduate Specialization in Didactics of Human Sciences, a Ph.D. in Philosophy and Fundaments of Physics, a Master in Digital Design, a Post-graduate Specialization in Instructional Design and a Master in Criminology and investigative sciences and security.\n\nJob\nSince 2003 he leads the Evaluation Systems Research Group of ABIFormazione (Italian Banking Association, Roma, Milano, Italy) and he is R&D Manager at L@belFormazione (Roma, Italy).\nAt present he is Professor at Faculty of Communication Sciences of “La Sapienza†University (Rome), he collaborates with ABI Sicurezza (Security) and with Italian Criminalpol for the creation of a neural network based predictive model to manage Bank Robbery Risk. \nHe has been involved in numerous national, European and internationally research and development projects for the application of e-learning standard and advanced assessment models to bank, industry, medicine, education and communications.",institutionString:null,institution:{name:"University of Verona",institutionURL:null,country:{name:"Italy"}}},{id:"22897",title:"Dr.",name:"Messias",surname:"Borges Silva",slug:"messias-borges-silva",fullName:"Messias Borges Silva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"23027",title:"Prof.",name:"Jiří",surname:"Šťastný",slug:"jiri-stastny",fullName:"Jiří Šťastný",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"23092",title:"Dr.",name:"Oswaldo Luiz Cobra",surname:"Guimarães",slug:"oswaldo-luiz-cobra-guimaraes",fullName:"Oswaldo Luiz Cobra Guimarães",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"23093",title:"Dr.",name:"Hélcio José",surname:"Izário Filho",slug:"helcio-jose-izario-filho",fullName:"Hélcio José Izário Filho",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Sao Paulo",institutionURL:null,country:{name:"Brazil"}}},{id:"23576",title:"Dr.",name:"Hyun-Joo",surname:"Oh",slug:"hyun-joo-oh",fullName:"Hyun-Joo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"our-story",title:"Our story",intro:"
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.
",metaTitle:"Our story",metaDescription:"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.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
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 4,200 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 4,200 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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