Surgical early results after pericardiectomy for chronic constrictive pericarditis.
\r\n\tb. The growth of digital environments which can educate and empower as well as exploit and destroy (mobile learning, STEM education, tablets, etc.).
\r\n\tc. Social, racial, class, and gender-based discriminations that restrict the developmental potential and the prosperity perspectives
\r\n\td. Health hazards and illnesses such as the laters COVID-19 pandemic.
\r\n\te. Armed conflicts with casualties and displacements of populations seeking refuge
\r\n\tf. Lack of physical spaces that will support and nourish development and learning, etc.
\r\n\tEducation in the post-modern era strives to address the above issues and develop policies, curricula, methodologies, and strategies to contribute to an environmentally and socially sustainable future. It embraces multiple perspectives and worldviews and seeks to touch on inequalities and discriminations in favor of equity. In this direction, children’s s agency lies at the heart of democratic approaches. Educational processes adopt forms of interactions that actualize learning as “becoming” and place it in a continuum between past, present, and future. This book intends to feature innovative approaches that employ transformative elements (targets, methods, materials, ideas, etc.) and embrace the concept of child development as “becoming” in an ever-changing and challenging world.
\r\n\r\n\tWe invite authors to contribute original research or research review papers that present innovative approaches addressing personal and social transformation. All aspects of early childhood education will be considered, including research methodology for the early years.
",isbn:"978-1-80355-949-0",printIsbn:"978-1-80355-948-3",pdfIsbn:"978-1-80355-950-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"351c41dca5c8c997f15e758f2e035178",bookSignature:"Dr. Maria Ampartzaki and Associate Prof. Michail Kalogiannakis",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11281.jpg",keywords:"Early Childhood Education, Preschool, STEAM, Environmental Sustainability, Social Sciences, Social Sustainability, ICT, Digital Devices, Education for Equity, Gender Issues, Post-modern Epistemology, Social Constructivism",numberOfDownloads:65,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 16th 2021",dateEndSecondStepPublish:"December 14th 2021",dateEndThirdStepPublish:"February 12th 2022",dateEndFourthStepPublish:"May 3rd 2022",dateEndFifthStepPublish:"July 2nd 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"8 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Maria Ampartzaki is an Assistant Professor in Early Childhood Education in the Department of Preschool Education at the University of Crete. Her research interests include ICT in education, science education in the early years, inquiry-based and art-based learning, teachers’ professional development, action research, and the Pedagogy of Multiliteracies, among others. She has run and participated in several funded and non-funded projects on the teaching of Science, Social Sciences, and ICT in education.",coeditorOneBiosketch:"Michail Kalogiannakis is an Associate Professor of the Department of Preschool\r\nEducation, University of Crete in Greece. He graduated from the Physics Department\r\nof the University of Crete and continued his post-graduate studies at the University\r\nParis-7 and University Paris-5 and received his Ph.D. degree at the University Paris 5.\r\nHis research interests include science education in early childhood, science teaching\r\nand learning, e-learning, the use of ICT in science education, and games simulations.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"422488",title:"Dr.",name:"Maria",middleName:null,surname:"Ampartzaki",slug:"maria-ampartzaki",fullName:"Maria Ampartzaki",profilePictureURL:"https://mts.intechopen.com/storage/users/422488/images/system/422488.jpg",biography:"Dr Maria Ampartzaki is an Assistant Professor in Early Childhood Education in the Department of Preschool Education at the University of Crete. Her research interests include ICT in education, science education in the early years, inquiry-based and art-based learning, teachers’ professional development, action research, and the Pedagogy of Multiliteracies, among others. She has run and participated in several funded and non-funded projects on the teaching of Science, Social Sciences, and ICT in education. She also has the experience of participating in five Erasmus+ projects.",institutionString:"University of Crete",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}}],coeditorOne:{id:"260066",title:"Associate Prof.",name:"Michail",middleName:null,surname:"Kalogiannakis",slug:"michail-kalogiannakis",fullName:"Michail Kalogiannakis",profilePictureURL:"https://mts.intechopen.com/storage/users/260066/images/system/260066.jpg",biography:"Michail Kalogiannakis is an Associate Professor of the Department of Preschool Education, University of Crete, and an Associate Tutor at School of Humanities at the Hellenic Open University. He graduated from the Physics Department of the University of Crete and continued his post-graduate studies at the University Paris 7-Denis Diderot (D.E.A. in Didactic of Physics), University Paris 5-René Descartes-Sorbonne (D.E.A. in Science Education) and received his Ph.D. degree at the University Paris 5-René Descartes-Sorbonne (PhD in Science Education). His research interests include science education in early childhood, science teaching and learning, e-learning, the use of ICT in science education, games simulations, and mobile learning. 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\nPericardium and pericardial diseases, especially constrictive pericarditis, have always been a concern for physicians and surgeons in cardiovascular field. Some remarkable landmarks [1, 2] are as follows: the first anatomical description of the pericardium has been done by Hippocrates in 460 BC. Centuries after, surgical treatment started in the seventeenth century by Riolan, who performed a pericardotomy for an effusion in 1649. Then, Vieussens, some years later in 1679 and 1715, observed some cases of pericardial adhesions; from that step, the concept of constrictive pericarditis was born. Afterward, in 1728, Lancisi confirmed the existence of constrictive pericarditis and its risks such as cardiac compression and death via necropsy studies. Those observations were also mentioned by Morgagni (1761), Senac (1749), Laennec (1819), and Cheevers (1842). Clinical patterns related to the right atrium and ventricle compression, mainly as the most important source in the compression process, has been emphasized by Wilkes (1870). Based on anatomical findings, clinical pictures were then clarified: Kussmaul (1873) pointed out the venous pressure elevation in case of constrictive pericarditis; Pick (1896) described a new entity named “Pericarditis pseudocirrhosis of the liver.” Since then, Pick Syndrome was recognized as a component of constrictive pericarditis clinical presentation. From that, surgical treatment was considered as the most efficient therapy for releasing heart compression due to pericardium thickness and fibrosis. By then, Rhen and Sauerbruck (1913) in Germany, Hallopeau in France (1921), Schmieden and Fisher (1926) in Germany, Churchill (1929) and Beck (1931) in USA performed the first cases of pericardiectomy for constrictive pericarditis successfully.
\nThe pericardium is a solid fibro-serous sac that maintains the heart in the anterior mediastinum in a closed thoracic cavity called the “pericardial cavity.” The pericardium has two main components: (1) an external, fibrous pericardium ensuring the fixity of the pericardium and (2) an internal serous pericardium with two principal layers: the visceral and the parietal pericardium. In a normal heart, the parietal and visceral pericardium release the pericardial cavity filled with a fluid up to 50 ml allowing easy systolic and diastolic heart movements. Pericardium prevents the heart from inflammation, infection, damage, and excessive dilatation; it also ensures heart stabilization and anchoring [1, 2, 3].
\nIn case of constrictive pericarditis, restricted diastolic heart distensibility does exist and may provoke a right and a left ventricular preload decrease with a reduction of stroke volume and cardiac output [2, 3]. In Africa, we use to face on late clinical presentation of patients with massive pericardial thickness and calcifications inducting myocardial atrophy, fibrosis, and severe systolic dysfunction that significantly affect the results after pericardiectomy.
\nKey observations are described:
Impairment of ventricular distensibility and filling coexisting with ventricular stroke volume reduction.
Abnormal rapid diastolic ventricular filling and abnormal venous pressure elevation followed by an early diastolic ventricular dip.
High diastolic plateau due to a small expansion of the ventricular volume at the late diastolic period.
All those consequences determine the so called “Dip-and-plateau waveform.”
\nClassically, constrictive pericarditis appears as a complication of acute or effusive pericarditis. From Yadav’s study [4], approximately 9% of patients with acute pericarditis will contract a pericardial constriction. In Africa, the frequency of acute pericarditis varies widely with geographical location ranging from 2 to 11.3% among patients admitted in a hospital for cardiovascular diseases [5, 6, 7]; it affects mostly young male population with an average age between 26 and 42 years old and tuberculosis as the most frequent etiology from 33 to 69.5% in sub-Saharan Africa [5, 6, 8]. Over the past decades, the incidence of tuberculous pericarditis has risen up because of the HIV epidemic in sub-Saharan Africa [8, 9]. Noubiap et al. [10] have reported a comprehensive understanding of the epidemiology of pericardial diseases in Africa confirming clearly that tuberculosis remains as the leading cause of pericardial diseases in African Resource-Limited Settings with poor outcome marked by a mortality rate between 18 and 25% including a very high one of 40% within 6 months among patients with HIV/AIDS positive. However, pericardial tuberculosis frequency is variable according to authors such as Mayosi [11] and Thwaites [12] who found, respectively, pericardial tuberculosis in 69.5% of cases admitted for pericardiocentesis and in 10% of all hospitalized patients with heart failure. Moreover, the risk for developing constrictive is very high for tuberculosis or purulent pericarditis: 20–30% and in almost all the cases of tuberculous pericarditis as reported by Gupta [13]. In their prospective study on 500 consecutive cases, Imazzio et al. [14] have demonstrated that the evolution from non-constrictive pericarditis to constriction is different according to pericarditis etiology: the risk of constriction is greater for bacterial etiologies (tuberculosis or purulent pericarditis) than viral or idiopathic acute pericarditis; the incidence rate of constriction is, respectively, 31.65 cases per 1000 person-years for tuberculous pericarditis and 52.74 person-years for purulent pericarditis versus 0.76 person-years for viral or idiopathic pericarditis. The same observation has been described by Permanyer-Miralda et al. [15] in a prospective study of patients with occurrence of constriction in 56 and 35% of patients with tuberculous and purulent pericarditis, respectively, and in 17% of patients with neoplastic pericarditis after an acute pericarditis. In Africa, and in literature overall, the epidemiological pattern, incidence, and prevalence of CCP are not well elucidated. Nevertheless, it is known that tuberculosis is the most frequent etiology of constrictive pericarditis in Africa and emerging countries (40–90%) [16] versus other rare etiology in our practice such as constrictive pericarditis after surgery. In a recent study, Gaudino et al. [17] have concluded their study insisting on the fact that constrictive pericarditis after surgery has its own pathophysiological characteristics, but we still be ignorant on its real origin and pathogenesis. Therefore, we should be vigilant and keep in mind that any cardiac symptoms without explanation must be suspected and be treated surgically as soon as possible if there is any doubt of pericardial constriction.
\nIn African countries [18, 19, 20, 21, 22, 23, 24, 25, 26], the diagnosis of constrictive pericarditis is usually obvious for patients present late after the development of the constrictive process characterized mostly by advanced clinical manifestations of right-sided heart failure (50–100%), progressive New York Heart Association (NYHA) Functional Class III or IV (42–100%) associated with an evident antecedent pulmonary and extra-pulmonary tuberculosis such as tuberculous pericarditis (26–99%). Duration of illness prior to surgery may range from 1 month to 25 years with an average of 15 or 30 months found, respectively, by Ali et al. [26] and Yangni-Angate et al. [21]. Generally, male gender predominance is noted (60–80%), patients have an average age below 40 years; for instance in Morocco (32 years) [18], Ghana (33 years) [22], Senegal (23 years) [20], Gabon (36 years) [23], Cote d’Ivoire (28.8 years) [21], and Ethiopia (24.3 years) [26]. Main clinical findings often due to severe constriction include: hepatomegaly (74–100%), raised jugular venous pressure (76–100%), hepato-jugular reflux (67–100%), ascite (50–76%), peripheral edema (46–79%), complete “Pick Syndrome”(50–76%). Kussmaul sign is less detected (9.8%). In African setting, frequent radiographical findings at chest X-ray are as follows: enlarged cardiothoracic ratio or cardiomegaly (88–47%), calcifications (36–52.5%), and pleural effusion (44–63%); electrocardiography shows invariable modifications such as low QRS voltage (32.5–82.5%), atrial fibrillation (18–46%), and T wave abnormality up to 87.5%. Echocardiography is largely available and is useful for accurate assessment in revealing in most cases a thickened pericardium (56 and 100%), pericardial calcifications in 30.2%, 47.4% of cases according to authors and left ventricular septal motion abnormality (63.6%) with reduced ejection fraction below 0.60 in Rabat, Morocco [19]; cardiac catheterization performed only in a very few centers [21, 24, 25, 27] documents elevation and equalization of diastolic heart pressures with the typical dip-plateau waveform of constrictive pericarditis and evaluate the stroke volume, cardiac output, and myocardial systolic function. It still prevails to be the most final diagnostic assessment in sub-Saharan Africa. In his study, Yangni-Angate et al. [21] reported that cardiac catheterization confirmed a dip-and-plateau (square root sign), an equalization of end-diastolic pressures in right and/or left cardiac chambers ranged between 10 and 40 mmHg, a mean cardiac index (CI): 2.3 l/min/m2 (extremes: 1.3–3.6). From this author, the constriction was limited to the right cardiac cavities called right constriction (n = 54, 45%) or to the right and left cardiac cavities called bilateral constriction (n = 66, 55%) and hemodynamic parameters and cineangiograms confirmed the diagnosis of pericardial constriction in all the patients. Omboga in Nairobi [25] showed the same observation with elevation of intracardial pressures in all cases, raised mean right atrium, end-diastolic right and left ventricular, and elevated mean pulmonary artery pressures at 18, 18, 20, and 27mmHg, respectively. Other imaging studies such as computed tomography and magnetic resonance imaging are rarely prescribed because they are inexistent usually. Those modern imaging techniques could be heavily useful in diagnosing constrictive pericarditis. When done, pericardial biopsy can be contributive for constrictive pericarditis etiology. Laboratory investigations regarding protein-losing enteropathy in patients with chronic constrictive pericarditis are not yet done for Africans. Differential diagnosis is always considered, and distinction from both constrictive pericarditis and restrictive cardiomyopathy due to endomyocardial fibrosis is really the usual situation to be clarified. Endomyocardial fibrosis (EMF) is a tropical heart disease with fibrous endocardial lesions lying in the right and/or the left ventricle. Endoventricular fibrosis is shown and confirmed in all cases by bi-dimensional echocardiography and angiocardiography [28].
\nConstrictive pericarditis occurs mostly in our African context after a non-diagnosed, untreated tuberculous or pyogenic pericarditis or even as a sequel of a treated tuberculous pericarditis. Constrictive process starts with an acute pericarditis; then a subacute and chronic pericarditis marked in most of the cases by a fusion of the two layers of the pericardium and an occlusion of the pericardial cavity [3].
\nThe delay from onset clinical symptoms to constriction is widely flexible from 1 month to 10 years even 25 years [2].
\nWhen diagnosis of constrictive pericarditis is confirmed and surgery is indicated, a pericardiectomy should not be delayed; surgery remains the only efficient and comprehensive treatment option. Pericardiectomy is frequently performed via a median sternotomy approach or a left anterolateral thoracotomy approach; it may be partial or complete. From the African teams’ surgical experiences, cardiopulmonary bypass has not been used in all cases and excellent early surgical outcomes were reported.
\nYangni-Angate in Cote d’Ivoire [21], in his retrospective study related to 120 patients with CCP who underwent pericardiectomy through a median sternotomy approach (n = 117; 97.5%) found 15 early deaths (12.5%); the cause of hospital deaths was due to a low cardiac output (n = 12) and to a hepatic failure (n = 3). Class III or IV (NYHA) (p = 0.01), mitral regurgitation (p < 0.05), persistent a diastolic syndrome after surgery (p < 0.05) and low cardiac index (p < 0.02) were the important risk factors (Table 1). Age, size of cardiac X-ray silhouette, right and left ventricular diastolic pressures, ejection fraction, atrial fibrillation, and pericardial calcifications had no impact on early survival (Table 2).
\nAuthor | \nCountry | \nStudy period | \nCases (n) | \nAetiology | \nEarly deaths (%) | \nCauses of deaths | \nEarly risk factors | \n
---|---|---|---|---|---|---|---|
Omboga et al. [25] | \nKenya | \n1973–1981 | \n51 | \nTB (30%) Idiopathic (70%) | \n8.5 | \n\n
| \n− | \n
Yangni−Angate et al. [21] | \nCote d’Ivoire | \n1977–2012 | \n120 | \n\nTB (99%) | \n12.5 | \n\n
| \n\n
| \n
Ondo N’Dong et al. [23] | \nGabon | \n1986–1999 | \n18 | \nTB (50%) Idiopathic (33%) Infection (17%) | \n22.2 | \nLow cardiac output (n=4) | \nClass IV (NYHA) | \n
Mutyaba et al. [24] | \nSouth Africa | \n1990–2012 | \n121 | \nTB (91%) Idiopathic (5%) Miscellaneous (4%) | \n14 | \nLow cardiac output (n=11) Acute kidney injury (n=6) | \nClass IV (NYHA) | \n
Zamani et al. [27] | \nMorocco | \n1994–2009 | \n23 | \nTB (43%) Idiopathic (57%) | \n17 | \nLow cardiac output (n=2) Severe dysarythmia (n=1) Haemorrhage (n=1) | \nClass IV (NYHA) | \n
Ali et al. [26] | \nEthiopia | \n1996–2005 | \n19 | \nTB (31.6%) Infection (10.5%) Miscellaneous (67.9%) | \n5.3 | \n− | \n− | \n
Ciss et al. [20] | \nSenegal | \n1996–2008 | \n32 | \nTB (63.6%) \n | \n6.25 | \nLow cardiac output (n=1) | \nClass IV (NYHA) | \n
Nzondo et al. [19] | \nMorocco | \n1996–2010 | \n11 | \nTB (45.5%) Idiopathic (54.5%) | \n9.1 | \nLow cardiac output (n=1) | \nClass IV (NYHA) | \n
Tettey et al. [22] | \nGhana | \n2000–2004 | \n11 | \nTB (63.6%) | \n0 | \n\n | \n |
Hind et al. [18] | \nMorocco | \n2003–2013 | \n43 | \nTB (58%) Idiopathic (48%) | \n4.6 | \nLow cardiac output (n=2) | \nClass IV (NYHA) | \n
Surgical early results after pericardiectomy for chronic constrictive pericarditis.
TB: Tuberculosis.
Risk factors for immediate deaths | \nAlive (n = 105) | \nDeceased (n = 15) | \nP | \n||
---|---|---|---|---|---|
Average | \nExtremes | \nAverage | \nExtremes | \n||
Age (years) | \n30.4 ± 16.6 | \n10–51 | \n28.4 ± 10.1 | \n8–46 | \n0.09 | \n
CTR | \n0.55 ± 0.05 | \n0.45–0.70 | \n0.53 ± 0.3 | \n0.50–0.59 | \n0.34 | \n
RVEDP | \n20.6 ± 7.8 | \n7–40 | \n16.2 ± 10.3 | \n15–40 | \n0.12 | \n
LVEDP | \n20.1 ± 6.1 | \n10–30 | \n24.6 ± 7.7 | \n16–35 | \n0.07 | \n
EF | \n50.4 ± 16 | \n31–67 | \n54.3 ± 5 | \n49–59 | \n0.24 | \n
CI | \n2.42 ± 0.7 | \n1.3–3.6 | \n1.63 ± 0.2 | \n1.4–2 | \n0.02 | \n
WPAP | \n20.6 ± 9.9 | \n10–40 | \n25 ± 10.4 | \n18–37 | \n0.36 | \n
SPAP | \n27.3 ± 11.1 | \n21–66 | \n38.2 ± 17.9 | \n21–66 | \n0.08 | \n
Functional class NYHA III–IV | \n42/105 | \n15/15 | \n0.01 | \n||
Atrial fibrillation | \n18/105 | \n3/15 | \n0.10 | \n||
Calcifications | \n54/105 | \n6/15 | \n0.07 | \n||
Mitral insufficiency | \n6/105 | \n9/15 | \n0.00 | \n||
Persistence of post-operative constriction | \n9/105 | \n5/15 | \n0.00 | \n||
Bilateral constriction | \n61/105 | \n15/15 | \n0.04 | \n
Risk Factors for immediate deaths after pericardiectomy for constrictive chronic pericarditis—from Yangni-Angate et al. study [21].
CTR, cardiothoracic ratio; RVEDP, right ventricle end-diastolic pressure; SPAP, systolic pulmonary arterial pressure; WPAP, wedged pulmonary artery pressure; LVEPD, left ventricle end-diastolic pressure; CI, cardiac index; EF, ejection fraction.
Tettey in Ghana [22] reviewed the surgical management of constructive pericarditis and the post-operative challenges of 11 patients who had pericardiectomy via a median sternotomy in all patients with no early mortality and a significant improvement of functional capacity of all of the patients followed-up.
\nMutyaba in South Africa [24] through a retrospective study of 121 patients who had undergone total (n = 105; 88.2%) or partial (n = 14; 11.8%) pericardiectomy for constrictive pericarditis at Groote Schuur Hospital, noted an early mortality of 14% (n = 14) mainly due to a low cardiac output syndrome. In this work, it has been statistically attested that serum sodium and pre-operative New York Heart Association Class IV versus combined Class I–III were independent predictors of early mortality. He also showed that early mortality after pericardiectomy was not influenced by HIV status and that of New York Heart Association Functional Class IV and hyponatremia were predictable factor for early mortality after pericardiectomy.
\nAli in Ethiopia [26] has done a retrospective study at the Thoracic Surgical Unit, Tikur Anbessa Hospital, Department of Surgery, Medical Faculty, Addis Ababa University, Addis Ababa on 19 patients who underwent pericardiectomy for CCP by a median sternotomy approach (n = 15; 79%) often. One early post-operative mortality was registered. The author emphasized the benefit of pericardiectomy in terms of physical exercise improvement.
\nOndo N’Dong in Gabon [23] has published his series on 18 patients with constrictive pericarditis treated surgically. All of them underwent a partial pericardiectomy via a left anterior thoracic incision in 17 patients and a median sternotomy incision in 1 patient. Four patients died in the early post-operative period due to low cardiac output; this study revealed pre-operative severe heart failure as a principal predictable risk factor for early death after pericardiectomy. This finding has been also noted In Rabat, Morocco by Nzondo [19]; in Fes, Morocco by Hind [18] and in Senegal by Ciss [20].
\nNzondo [19] has retrospectively analyzed 11 patients who had undergone partial pericardiectomy via a median sternotomy approach for constrictive pericarditis. Early mortality was of 9.1% related to acute heart and multi-organs failure. Hind in Fes, Morocco [18] on a study of 43 patients with constrictive pericarditis focused on 41 who had a partial pericardiectomy through a median sternotomy approach; hospital mortality was 4.6% (n = 2).
\nFinally, Ciss et al. [20] in their study on 32 patients with constrictive pericarditis undergoing partial pericardiectomy via a median sternotomy approach reported an early mortality of 6.25% in 2 patients out of 32 caused by hemodynamic and severe instability added to a poor NYHA functional class pre-operatively.
\nOmboga in Nairobi [25] in his study of 47 patients out of 51 who underwent surgery through median sternotomy (82.9%) and left lateral thoracic (17.1%) approaches has mentioned 8.5% of hospital mortality not due to acute failure as mentioned in previous studies in Africa but attributable to massive hemorrhage in the operative table (n = 1) and pulmonary embolism (n = 3) secondary to deep venous thrombosis.
\nNone of African teams mentioned above used robotic approach; this minimally invasive modern approach seems to be less painful, more adequate for a complete release of the pericardial constriction [29].
\nCompared to African series, where the most common etiology of CCP is TB, in developed world CCP etiology profile is different with idiopathic as most frequent. However, there is no significant difference among either surgical operative approach and hospital mortality or risk factors for early deaths. This fact is on the same line with McCaughan’s consideration cited by Kirklin and Barratt-Boyes [2] who demonstrated in 1985 that most of early deaths are due to acute heart failure and that of pre-operative NYHA class III and IV are significant risk factor for early death after pericardiectomy as noted in African surgical experiences. Chowdhury et al. [30] in a study including 338 patients (85.6%) who underwent total pericardiectomy (group I), and 57 patients (14.4%) undergoing partial pericardiectomy (group II), has demonstrated better perioperative and late mortality rates after total pericardiectomy; in addition, duration of symptoms, advanced functional class, partial pericardiectomy, pre-operative high right atrial pressure, hyperbilirubinemia, renal dysfunction, atrial fibrillation, pericardial calcification, thoracotomy approach, were significant risk factors for death.
\nIn a recent study from Porta-Sanchez in Spain [31], 140 consecutive patients who underwent pericardiectomy for constrictive pericarditis over a 34-year period in a single center were analyzed. Most frequent etiology found was idiopathic in 76 patients (54%). Median sternotomy was done in all patients. Perioperative mortality was 11%. There was no difference in mortality between etiologies.
\nMayo Clinic Experience with pericardiectomy for constrictive pericarditis over eight decades [32] related to 1071 pericardiectomies in 1066 individual patients. Patients were divided into two intervals: an historical (pre-1990) group (n = 259) and a contemporary (1990–2013) group (n = 807). This study showed a significant change in constrictive pericarditis etiology with a similar overall survival over decades and a significant decrease of 30-day mortality from 13.5% in the historical era to 5.2% in the contemporary era (p < 0.001). Another article from North America with no significant disparity is the Montreal Heart Institute Experience over a 20-year period [33]; it involved 99 consecutive patients with constrictive pericarditis; idiopathic was the most frequent etiology (61%) and hospital mortality 7.9% after isolated pericardiectomy.
\nBusha et al. [34] revealed an higher mortality death of 18.6% after pericardiectomy in 97 consecutive patients with constrictive pericarditis and no different risk factors for early death such as reduced left ventricular ejection fraction (LVEF) (35% < LVEF <55%) and right ventricular dilatation on multivariable analysis. He also found no difference in early mortality between patients with isolated pericardiectomy and those with concomitant surgery (p = 0.62).
\nIn African context, lack of substantial late outcomes after pericardiectomy is observed due to a significant number of patients lost to follow-up in general; however, in his series from Cote d’ivoire, Yangni-Angate [21], after an average follow-up of 4 years (extremes: 1–10 years), no late death was observed. A functional class I or II (NYHA) was mentioned in all survivors. Among them, those who underwent cardiac catheterization late post-operatively, a significant reduction even a normalization of the right and/or the left ventricular end-diastolic pressures, of the pulmonary capillary wedge pressure (p < 0.05) and of the right atrial pressure (p < 0.05) and absence of the dip-and-plateau after pericardiectomy were certified (Table 3).
\nHemodynamic measurements | \nAverage | \nExtremes | \nP | \n||
---|---|---|---|---|---|
Preop. | \nPostop. | \nPreop. | \nPostop. | \n||
RAP | \n16 | \n7.4 | \n10–36 | \n5–10 | \n0.04 | \n
RVEDP | \n21 | \n10 | \n7–40 | \n5–15 | \n0.02 | \n
SPAP | \n29 | \n23 | \n8–66 | \n17–30 | \n0.09 | \n
WPAP | \n21 | \n14 | \n10–40 | \n9–19 | \n0.00 | \n
LVEDP | \n21 | \n13 | \n10–35 | \n4.5–20 | \n0.02 | \n
CI | \n2.3 | \n2.7 | \n1.2–36 | \n1.92–3.5 | \n0.15 | \n
Comparison of hemodynamic measurements: pre-operative versus post-operative in patients who underwent pericardiectomy for chronic constrictive pericarditis—from Yangni-Angate et al. study [21].
Significant (P < 0.05); Non-significant (P ≥ 0.05); Preop., Pre-operative; Postop., Post-operative; RAP, right atrial pressure; RVEDP, right ventricle end-diastolic pressure; SPAP, systolic pulmonary arterial pressure; WPAP, wedged pulmonary artery pressure; LVEPD, left ventricle end-diastolic pressure; CI, cardiac index.
Significant reduction of right atrial mean pressure from 17 ± 6 mmHg pre-operatively to 7.1 ± 4.2 mmHg after pericardiectomy for CCP has been also shown by an African team work published by Zamani in Rabat, Morrocco [27].
\nA similar experience as African teams series has been published by Bicer et al. [35] with a predominance of tuberculous constrictive pericarditis (48.8%); other etiologies were: idiopathic (31.9%), malignancy (6.4%), prior cardiac surgery (4.3%), non-tuberculosis bacterial infections (4.3%), radiotherapy (2.1%), uremia (2.1%), and post-traumatic (2.1%). They had performed pericardiectomy in all patients via a sternotomy approach with a very low early mortality of 2.1%, while late mortality was 23.4%, and actuarial survival rates at 1, 5, 10 years were 91, 85, and 81%, respectively. Those rates are closed to the Montreal Heart Institute experience [33] characterized by tolerable long-term clinical outcome: 79% of patients were in NYHA class I or II post-operatively with an overall survival rate of 87% at 5 years and 78% at 10 years. At 10 years survival, Bicer et al. [35] estimated rate was worse (64%) because of poor prognosis of pericardiectomy after constrictive pericarditis post-mediastinal irradiation.
\nIn a 24-year experience on pericardiectomy in patients with constrictive pericarditis, based on Kaplan-Meier survival curves demonstration, Szaboa et al. [36] have confirmed poor prognosis of post-irradiation constrictive pericardiectomy and shown better and comparable long-term survival after in other etiologies as idiopathic tuberculosis myocardial infarction, and uremia; the author noted no survival after 5 years with post-radiation constrictive pericarditis; it is widely accepted radiation etiology is a negative factor affecting long-term survival results as well indicated by Nishimura in Japanese population [37] and Avgerinos et al. [38]. On his study related to 46 patients with a mean age of 59 years and various classic etiologies, Nishumuna et al. [37] have described the very high severity of radiation etiology with death within only 1 year after pericardiectomy confirming overall literature results.
\nAvgerinos et al. [38] reported his 36 patients study who underwent pericardiectomy for constrictive pericarditis over 15 years; he has no hospital mortality and 1-, 5-, 10-, and 15-year survival rates were 97.2, 94.6, 86.5, and 78.3%, respectively; he fund risk factors for increased long-term mortality such as: pre-operative heart failure, elevated pre-operative total bilirubin (>2.7 mg/dl, hazard ratio 6.8, p = 0.02), and elevated creatinine (>1.4 mg/dl, hazard ratio 3.1, p = 0.05). Subsequently, he demonstrated from Kaplan-Meier survival analysis a significant decrease in survival of all the patients with post-radiation etiology associated (p = 0.05) or with impaired cardiac, hepatic or renal dysfunction.
\nAccording to Porta-Sanchez et al. [31], from a Cox-regression analysis in his study, age at surgery, advanced New York Heart Association Functional Class (III–IV) and previous acute idiopathic pericarditis were associated with increased mortality during follow-up ranging from 0.1 to 33.0 years with a mean follow-up of 12 years.
\nPredictor factors of prognosis and mortality after pericardiectomy have been largely documented by many studies; one of them from Kang [39] has even stipulated that an echocardiographical measurement of higher early diastolic mitral inflow velocity in predicting mortality after pericardiectomy was 71 cm/s (sensitivity of 84.6% and specificity of 52.2%); that value may also be useful in predicting late survival (p = 0.029).
\nBecause of satisfactory long-term results, pericardiectomy can be considered as a safe and efficient technical procedure [40]; it can be achieved in most cases with minimal hospital mortality, post-operative functional class significant improvement and substantial reduction of heart diastolic pressures and absence of any recurrence if completely performed.
\nGlioblastoma multiforme (GBM), classified as grade IV glioma, is highly invasive, heterogeneous, and malignant primary brain tumor. It accounts for ~57% of all gliomas and ~ 48% of all primary malignant central nervous system (CNS) tumors [1, 2]. Such tumors are associated with poor quality of life of the patient due to progressive decline in neurologic function, thus making a huge impact on the patients, care givers, and their families. The standard treatment includes multimodal approach involving maximal surgical resection followed by radiotherapy, systemic therapy (chemotherapy, targeted therapy), and supportive care; however, long-term survival is exceptional. Despite the treatment, these tumors regrow and that too with aggressive phenotype, which worsen the symptoms leading to prognosis with average overall survival time < 14.6 months for primary GBM patients and < 6.9 months for recurrent GBM patients [3]. Understanding the molecular mechanism involved in therapeutic resistance and tumor regrowth despite standard treatment is imperative.
In this regard, researchers have identified existence of cancer stem cells (CSCs) in a variety of cancers that play crucial role in tumor initiation, maintenance, resistance to therapy, recurrence, metastasis, and generation of more aggressive phenotype [4]. These properties of CSC are manifested by their potential to self-renew, proliferate, ability to differentiate in multiple phenotypes, plasticity, quiescence, and dormancy. It is suggested that these CSCs originate either from normal stem cells that were already present in tissue or can be generated from dedifferentiation of somatic cells from bulk of tumor. Based on the properties of CSCs, they pose not only a barrier for anticancer therapy but also are responsible for recurrence into more aggressive phenotype. Various researchers have shown that CSC escape anticancer therapy due to their ability to enter dormancy, plasticity, renewal, and regrowth into heterogeneous group of tumor cells. Of interest, recent evidences have suggested that these CSCs are further enriched in response to standard radio-chemotherapy, which may be responsible for tumor regrowth and aggressive phenotype. These enriched CSCs might be result from the existing population of CSCs that evades the therapy or as per recent evidences, can be generated from non-CSCs from the bulk of tumor in response to therapy. Of note, CSCs have been identified in HGG cases also known as glioma stem cells (GSCs) that contribute to tumor heterogeneity and resistance to therapies, thus a major contributor of tumor recurrence. These GSCs are considered as a potential therapeutic target, therefore understanding the molecular pathways that drive GSCs becomes imperative [5]. In this book chapter, we have discussed about the properties of cancer stem cells, cell surface markers, signaling pathways, and mechanism of resistance to therapies and ways by which these pathways can be targeted using different chemotherapeutic agents.
Stem cells are specialized cells present in our body that possess properties such as capacity to self-renew, proliferate, and differentiate into multiple cell types. This quality of self-renewal along with associated signaling pathways is shared between both stem cells and cancer stem cells with added feature of oncogenicity in CSCs. The most common pathways that drive multipotency and self-renewal of stem cells include the Notch, Sonic hedgehog (Shh), and Wnt signaling pathways [4]. Due to activation of oncogenic pathways, CSCs can give rise to tumor mass consisting of heterogeneous cell population. Initially, Bonnet and Dick characterized CSCs in acute myeloid leukemia as leukemia-initiating cell that possessed properties of leukemia stem cell [6]. Later, such cells were also identified in a variety of solid tumors, including prostate [7], colon [8], lung [9], ovarian [10], and brain [11] tumors. It is hypothesized that CSCs are the seed of a tumor that are responsible for tumorigenesis by initiation, maintenance, propagation, resistance to therapy, recurrence as well as progression of the tumor [12].
In brain tumors, presence of CSC has been identified and characterized by various groups and are defined as GSCs or glioma initiating cells [11]. When cultured, these cells grown into neurospheres that constitute of cells that express SC markers including Nestin and CD133. When these cells are injected into nude mice, they lead to tumor formation due to their SC properties [13]. To add further, various groups have utilized properties of stem cells that are present in brain predominantly in subventricular zone (SVZ) to initiate tumor by exposure to chemicals (ethylnitrosourea) or viruses (avian sarcoma virus) in animals that strongly support the importance of stem cells in tumor formation [7, 14, 15]. These cells contribute to tumor heterogeneity and plasticity and have shown resistance to therapies and thus have emerged as a major contributor of tumor recurrence [5, 16, 17]. These CSCs are also influenced by micro environmental conditions such as nutrient deprivation, hypoxia, pH, vasculature, radiation, and chemotherapeutic treatment (explained in detail in coming sections) [16, 17, 18, 19].
Several putative GSC surface markers, such as CD133, CD15, and CD44, and GSC transcription factors, such as SRY-box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and NANOG, have been discovered [20, 21]. However, before its clinical implication, higher sensitivity and specificity of these GSC markers need to be established [21, 22].
In order to maintain stemness properties, GSCs depend upon number of signaling pathways that also support them to sustain under adverse conditions during tumorigenesis [23, 24, 25]. To understand the process of stemness in GSC, the signaling pathways that are also a part of normal neuronal stem cells are discussed. These pathways mainly include Notch, bone morphogenic proteins (BMPs), NF-
Notch signaling pathway is crucial in developmental process and plays a major role during embryonic development. This pathway regulates cellular proliferation, differentiation, apoptosis, and cell lineage decisions. In GSCs, Notch signaling pathways are highly active, which in turn maintain stemness by inhibiting differentiation. Notch signaling is also involved in oncogenic transformation. It has been identified that inhibition of Notch signaling decreases oncogenic potential of GSCs [26, 27].
BMP group of molecules belongs to the transforming growth factor-β (TGF-β) superfamily of proteins. BMPs plays role during embryogenesis, development as well as adult tissue homeostasis. It interacts with different signaling molecules including Wnt/
Wnt/β-catenin signaling is a highly conserved pathway that regulates cellular proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. This pathway also regulates NSC expansion and promotes astroglial lineage differentiation during neural development [33, 34]. In GSC,
The EGFR pathway is one of the most crucial pathways involved in cellular processes including proliferation, differentiation, migration, and apoptosis in a variety of cells including stem cells. Dysregulation of this pathway has been linked to cancer. Critical role of EGFR has been identified in NSCs as well [40, 41, 42]. In GSC EGFR works through activation of
The Shh signaling pathway is crucial for proper embryonic development as it governs tissue polarity, patterning maintenance, cellular proliferation, intercellular communication, and differentiation [44, 45]. Persistent Shh pathway signaling has been observed in the subventricular zone of adult brain where it plays a critical role in regional specification and maintenance of NSCs [46]. Aberrant regulation of the Shh pathway due to mutation has been identified to cause tumorigenesis in a wide variety of cancer tissues including gliomas and GSCs. This pathway is highly active in GSCs where it regulates stemness genes and thus maintains self-renewal of GSC and promotes tumorigenesis and inhibition of Shh signaling reduces both stemness as well as
Resistance of CSCs toward therapies resulting in their enrichment and regrowth of tumor due to proliferation of these cells has been suggested by various researchers [48, 49, 50]. In HGG, despite the effectiveness of TMZ in removing the bulk tumor cells, regrowth with a more aggressive phenotype is inevitable, and researchers have identified critical role of CSCs in such regrowth. For instance, in HGG, treatment with therapeutic doses of temozolomide (TMZ) leads to expansion of GSCs pool in both patient-derived and established glioma cell lines. Such expansions are reported not only due to enrichment and proliferation of existing CSCs but also due to interconversion between differentiated tumor cells and GSCs [18]. Similarly, bevacizumab (VEGF antibody) although reduces GBM tumor growth, it is followed by tumor regrowth where the role of autocrine signaling through the VEGF-VEGFR2-Neuropilin-1 (NRP1) axis leads to enrichment of active VEGFR2 GSC subset in human GBM cells [51]. It is evident that the therapeutics evoke enrichment of CSCs involving multiple mechanisms. Thus, understanding various ways by which CSCs escape the radio- and chemotherapy, more effective treatment modalities can be developed. Broadly, in CSCs various different mechanism such as epithelial-mesenchymal transition (EMT), multiple drug resistance (MDR) dormancy, tumor environment contribute to resistance toward therapeutics and other adverse conditions faced by them in tumor microenvironment and are discussed as follows.
GSCs possess better DNA repair capacity as compared with bulk tumor cells [52]. These cells express higher levels of DNA repair enzymes such as O6-methylguanine-methyltransferase (MGMT), which are responsible for therapy resistance against DNA alkylating agents such as TMZ [53, 54, 55, 56]. However, there are contradictory studies that also suggest that TMZ resistance in GSCs is independent of MGMT status and alternate pathways might be involved [57, 58]. Further, preferential expression of DNA checkpoint kinases 1 (Chk1) and 2 (Chk2) lead to more efficient repair of DNA damage in CD133-positive glioma cells than CD133-negative glioma cells [54]. Other transcriptional regulators such as BMI, DNA-PK, poly (ADP-ribose) polymerase-1, hnRNP U, and histone H1, which play a role in DNA double-strand break repair, are highly expressed in CD133-positive GBM cells and play pivotal role in GSCs’ functions [59, 60].
EMT involves phenotypic changes in cells from epithelial to mesenchymal type involving high expression of markers such as N-cadherin and vimentin under various physiological as well as pathological conditions including cancer [61]. Interestingly, CSCs also share the EMT-like cell features [62], and it is believed that the link between EMT and CSCs might be responsible for cancer drug resistance acquisition and plasticity resulting in cancer cells transformation into the malignant cells and
As the understanding of CSC biology has improved, it has been identified that CSCs can exist in proliferative or dormant state. Dormant CSCs maintain a low metabolic activity, however, show similarities with the normal proliferative counterpart in terms of stemness and other signaling pathways. For instance, dormant stem cells are low in metabolic activity that preferentially utilize the glycolytic pathway and produce low levels of levels of reactive oxygen species (ROS) [68]. However, these dormant/quiescent cells demonstrate high plasticity and can be reactivated to reenter proliferative stage and lead to tumor formation. Such dormant cells are also chemoresistant due to their dormant nature; interestingly, proliferative CSC can also enter dormancy in response to chemotherapeutics agents. In GBM, existence of a relatively quiescent subset of GSCs has been observed, which is responsible for maintaining the long-term tumor growth and responsible for recurrence by entering into highly proliferative cells upon receiving proper signals [69].
Various anti-apoptotic protein such as B-cell lymphoma-2 (BCL-2), BCL2 like 1 (BCL2L1), myeloid cell leukemia-1, MCL1 and BCL-xL are highly expressed in GSCs than differentiated bulk tumor cells. These proteins not only play role in GSCs maintenance but also provide survival advantage to these cells against various chemotherapeutic agents [70]. Other mediator of GSCs resistance includes BMI1, a GSC-enriched protein that inhibits p53-mediated apoptosis against TMZ [71]. Inhibition of such anti-apoptotic pathways can increase sensitivity of GSCs against different therapeutic agents.
Stem cells express higher levels of several ATP-binding cassette (ABC) transporters resulting in efflux ability for various antineoplastic drugs [72]. In GSCs, increased
GSCs show metabolic adaptations to survive adverse conditions of tumor microenvironment that includes low pH, hypoxia, and low nutrient supply; at the same time they proliferate at a high rate to maintain their stemness [16, 17]. Majority of GSCs rely on glucose uptake via high-affinity glucose transporter 3 (GLUT3) to provide carbon source for nucleotide biosynthesis for rapid proliferating cells along with high energy demands [78, 79, 80]. These cells also highly express glutamine synthetase as compared with differentiated glioma cells for higher glutamine uptake, which acts as preferential source for
Autophagy is a catabolic pathway which is a cellular stress response under physiological as well as pathological conditions. This pathways acts by removal of damaged macromolecules such as proteins, nucleic acid, and lipids and recycles them for cellular processes and thus promotes cell survival; however, defect or dysregulation of such pathway may lead to cell death [84]. Role of autophagy is well established in a variety of cancers including GBM where it can play a role in cell survival or cell death [84, 85]. Autophagy also contributes to the maintenance of stemness characteristics of GSCs as well as provides chemoresistance to CSC against therapeutic agents [19, 86]. Inhibition of autophagy sensitizes GSCs towards a variety of therapeutic agents [19, 87, 88, 89]. Interestingly, other studies demonstrated that induction of autophagy by mammalian target of rapamycin (mTOR) inhibitors as well as curcumin-induced autophagy shows anti proliferative effect, induces differentiation and also improves sensitivity of GSC towards DNA damaging agents [90, 91, 92]. Together, these results suggest that GSCs require a balanced level of autophagy, too much or too little can significantly affect their stemness potential and resistance toward therapeutics. Further, role of autophagy has also been shown to support motility/migration capacity of GSCs [93]. However, role of autophagy in suppression of the self-renewal ability and tumorigenicity of GSCs has also been demonstrated where autophagy mediates Notch1 degradation [94]. Thus, role of autophagy in GSCs is crucial for maintenance of stemness as well as chemotherapeutic agents; targeting such pathway appears as a p These cells also highly express glutamine synthetase otential strategy to make the existing treatment more effective.
Besides the signaling pathways and genetic signature of GSCs, extracellular environment also called as microenvironment in which these cells resides also plays crucial role in its functions and determines response towards therapeutic agents [95]. It has been identified that GSCs reside in inner tumor mass where rapid growth and high energy requirement of these cells along with neovasculature result in hypoxic conditions as well as low pH [29, 96]. These adverse conditions further promote expression of GSC markers and associated phenotype [97]. Various hypoxia and acidic pH-induced genes such as hypoxia-inducible factor (HIF) 1 and 2alpha and vascular endothelial growth factor (VEGF) are highly expressed in GSCs that contribute to GSC functions [98, 99]. It has been shown that in GSCs Notch signaling and MGMT expression are also regulated by HIF-1α, resulting in GSC stemness and also resistance toward TMZ [100, 101]. Further, hypoxic GSCs release extracellular vesicles that deliver HIF-1α induced miR-30b-3p that further activates STAT3 pathway and promotes TMZ resistance [102]. Further, it has been identified that TMZ increases the GSC pool in non-GSC subpopulations, indicating that non-GSC shows plasticity and can be converted to GSCs that might be responsible for resistance as well as regrowth of the tumor [18, 19]. Together, these findings suggest that
Various signaling pathways such as Notch and SHH are active in GSCs compared with bulk tumor cells [103]. Further, in response to TMZ treatment of GSCs from primary GBM cells resulted in upregulation of
Despite extensive research in oncology, the target is being missed leading to recurrence in a variety of high-grade tumors including malignant gliomas. With advancement in understanding of GSCs and its capacity of initiation, progression, resistance as well as recurrence of tumor, they appear as most promising target to treat cancers such as HGG. The drugs that can target GSC are being developed using multiple strategist including molecular targeting, autophagy inhibition, drug repositioning, and indirect targeting of GSC niches [17, 21, 106].
GSCs are regulated by various pathways involving differential expression of epidermal growth factor receptor (EGFR), Notch1, sonic hedgehog (Shh), and STAT3, as well as related signaling pathways.
As discussed earlier, CD133 is the most well-characterized cell surface marker for GSCs, which has become a potential target for antibody-based therapy. Different immunotherapeutic approaches such use of synthetic monoclonal antibody, dual-antigen T cell engager, and chimeric antigen receptor (CAR) T cell have been utilized to target CD133+ GSCs. RW03 (anti-CD133 antibody) targets self-renewal ability of GSCs without effecting its proliferative capacity and could be a promising strategy in targeting GSCs [107]. Further, photothermal therapy has also shown selective efficacy in diminishing CD133-positive cells both
EGFR, a receptor tyrosine kinase, which is highly expressed in GSCs, is crucial for its survival, self-renewal, and tumorigenicity. Of importance, EGFR variant III (EGFRvIII) mutation is most commonly detectable (25–33%) in GBM cases [109]. Thus, EGFR inhibition becomes a potential target to inhibit GSCs proliferation, self-renewal, and induction of apoptosis [110]. EGFR inhibition in fact enhanced chemo- and radio-sensitivity of human glioma CSCs. Various reversible and irreversible inhibits of EGFR are available that can bind EGFR alone or along with its co-receptor HER2 [111, 112]. First-generation EGFR TKIs include gefitinib and erlotinib that can reversibly bind EGFR along with HER2; however, less than 20% of patients presented a response to these treatments [112, 113]. Irreversible inhibitor of EGFR, osimertinib, has shown efficiency in crossing the blood-brain barrier (BBB) and significantly inhibits GBM tumorigenesis
Various signaling pathways such as Notch and SHH are active in GSCs compared with bulk tumor cells [114]. Further, in response to TMZ treatment of GSCs from primary GBM cells resulted in upregulation of
Shh/Gli signaling that regulates GSCs cell proliferation, stem cell fate determination, and differentiation has also appeared as potential target for GSCs therapeutics [124]. Inhibition of hedgehog pathway by LDE225 induces autophagic cell death in GSCs with higher sensitivity of CD133-positive cells than CD133-negative cells [125]. LDE225 inhibits expression and nuclear translocation of Gli proteins, a transcriptional effectors of the Shh signaling pathway [126]. Casein kinase 2 (CK2) is another target to inhibit Shh/Gli signaling via transcriptional activation of β-catenin [127] and inhibition of CK2 by, CX-4945 (silmitasertib), reduces MGMT expression and sensitized tumor cells to TMZ [128].
Signal transducer and activator of transcription 3 (STAT3) that regulates multiple processes such as cell cycle and survival, regulation, immune response, and differentiation, tumorigenic transformation has also been implicated in GSC maintenance [129, 130]. Resveratrol (RV), a polyphenol present in grapes, a tumor preventive agent targets STAT3 signaling. In glioma, RV has shown antineoplastic actions by apoptosis induction and improving radio sensitivity of GSCs CD133+ cell population along with reducing of tumorigenic potential. Furthermore, RV also modulates Wnt signaling pathway and EMT activators, thereby regulating stemness of GSCs and reducing cellular motility [131, 132]. Another molecule that inhibits STAT pathway is WP1066, which is an analog of the natural product caffeic acid benzyl ester and targets GSCs. This molecule has shown promising results in clinical trial for patients with recurrent malignant glioma [133]. Other STAT3 inhibitors, STX-0119 and WP1066 have shown ability to suppress GSC proliferation
GSCs are localized in specific niches, which have been identified as protective microenvironments in GBM. Five types of GSC niches have been identified where different cell types exists and have specific singling pathways: peri-vascular, peri-arteriolar, peri-hypoxic, peri-immune, and extracellular matrix out of which peri-vascular niche is the most frequently described GSC [135]. GSC microenvironment lacks organizations and has compromised BBB, higher levels of hypoxia, and excessive angiogenesis making it a target for anti-angiogenic therapy [136, 137].
Drug repositioning also called as repurpose drugs is a growing concept that explores pre-existing a well-established drug to treat diseases aside from the intended ones. This concept results in lowering the overall developmental cost, time and risk assessments, as the efficacy and safety of the original drug have already been well accessed and approved by regulatory authorities [138]. In case of GSCs, repurpose drugs are being tested and have shown encouraging results. Especially, anti-diabetes drugs have been most well studied with promising results in GSCs targeting. Metformin, successfully used for type 2 diabetes mellitus, has entered phase I clinical trial for GBM in combination with TMZ [139]. Metformin preferentially acts in GSCs by inhibiting Akt activation and also induces conversion on GSCs to non-GSCs [140, 141]. Similarly glimepiride, another anti-diabetes drug, impairs GSCs by targeting glycolytic flux and increases its radio sensitivity to GBM [791]. Further, more repurpose drugs need to be identified that can effectively target GSCs along with its associated mechanism before it can be used in clinical application [138].
Autophagy is a cellular stress response, which can either promote survival or cell death. Our laboratory along with others has identified that autophagy is required for maintenance of GSCs and also plays a role in resistance of GSCs toward chemotherapy [19, 142, 143]. Targeting autophagy by commonly used agent chloroquine (CQ), which blocks the fusion of autophagosomes with lysosomes, has been shown to inhibit GSCs as well as sensitized them toward chemotherapeutic agents [19, 144]. This drug has also entered multiple clinical trials as an adjuvant treatment for GBM; where its antitumor effects of CQ are not limited to GSCs [145]. Further, combination of autophagy inhibitors with radiation effectively induced apoptosis and inhibited tumorosphere formation in GSCs [146, 147]. More selective autophagy inhibitor NSC185058, antagonist of autophagy-related 4B, inhibits tumorigenic potential of GSCs and enhances GBM sensitivity to radiotherapy in xenograft mouse models [148].
Treatment of HGG remains challenging. With identification of GSCs and their properties to resist treatment and repopulate the original tumor, a big momentum has been created in the development of novel therapeutics. Such therapeutic will involve a combination of drugs that controls the bulk tumor mass along with CSCs-directed agents. It has been identified that GSCs are responsible for tumorigenesis, therapeutic resistance, and tumor recurrence, and thus GSC-targeting drugs are being developed for improvement of treatment regime. These GSCs can survive cancer treatment by activating multiple mechanisms such as EMT, signaling pathways to regulate self-renewal, its interaction with tumor microenvironment, higher expression of drug transporters or detoxification proteins, plasticity, autophagy induction, anti-apoptotic mechanism, induction of dormant phenotype, and many others to overcome the toxic effects of therapeutics. With knowledge of these pathways, anticancer therapeutics are targeted against GSCs, which includes directing specific and pathways that regulate GSCs and protect them from therapeutic stress. Such GSC-directed drugs can be combined with agents that are currently in use to achieve better survival rates of cancer patients.
Identification of bioactive products and their molecular mechanisms that can modulate GSCs needs to be incorporated in treatment regime of HGG patients. With recent advancements in the field of high-throughput screening and genetic and epigenetic signatures, specific targeted drugs that can target bulk tumor with minimal generation of induced GSCs along with combination of drug that can target GSCs can be developed. Furthermore, tumor microenvironment that significantly regulates GSCs is also a potential target to prevent rate of dedifferentiation. It is important to consider that current therapeutic can result in conversion of non-GSC to GSCs; therefore, newer drugs or combinations need to be developed that can prevent this detrimental conversion. More stringent strategies involving GSC-targeted therapy along with glioma molecular subtypes need to be designed for selective and effective clinical trials.
However, most therapeutic agents have failed to be approved for clinical application or during clinical trials due to lack of understanding of the underlying mechanisms or failure to consider individual characteristics of the tumor. Further investigation of the molecular pathways that drive GSCs and make them resistant to therapies along with subtype-specific pathways of GSCs is required. Such studies will significantly improve not only the understanding of disease but will also direct the development of highly specific drugs with minimal side effects along with improved patient outcome.
The authors would like to acknowledge the funding support from Department of Biotechnology Bio-CARe grant, Govt. of India (BT/P19357/BIC/101/927/2016 to M.T.) and Intramural Research Grant by SGPGIMS (PGI/DIR/RC/36/2021) to LKS.
The authors declare that they have no conflict of interest.
Authors are listed below with their open access chapters linked via author name:
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\\n\\nJim Van Os 2015-18
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\\n\\nFei Wei 2016-18
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\\n\\nQi Xie 2016-18
\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
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Over the past few decades, no major new types of antibiotics have been produced and almost all known antibiotics are increasingly losing their activity against pathogenic microorganisms. The levels of multi-drug resistant bacteria have also increased. It is known that worldwide, more than 60% of all antibiotics that are produced find their use in animal production for both therapeutic and non-therapeutic purposes. The use of antimicrobial agents in animal husbandry has been linked to the development and spread of resistant bacteria. Poultry products are among the highest consumed products worldwide but a lot of essential antibiotics are employed during poultry production in several countries; threatening the safety of such products (through antimicrobial residues) and the increased possibility of development and spread of microbial resistance in poultry settings. This chapter documents some of the studies on antibiotic usage in poultry farming; with specific focus on some selected bacterial species, their economic importance to poultry farming and reports of resistances of isolated species from poultry settings (farms and poultry products) to essential antibiotics.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Christian Agyare, Vivian Etsiapa Boamah, Crystal Ngofi Zumbi and\nFrank Boateng Osei",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"261271",title:"MSc.",name:"Crystal Ngofi",middleName:null,surname:"Zumbi",slug:"crystal-ngofi-zumbi",fullName:"Crystal Ngofi Zumbi"},{id:"261272",title:"MSc.",name:"Frank Boateng",middleName:null,surname:"Osei",slug:"frank-boateng-osei",fullName:"Frank Boateng Osei"},{id:"261273",title:"Dr.",name:"Vivian Etsiapa",middleName:null,surname:"Boamah",slug:"vivian-etsiapa-boamah",fullName:"Vivian Etsiapa Boamah"}]},{id:"49246",doi:"10.5772/61300",title:"Chitosan as a Biomaterial — Structure, Properties, and Electrospun Nanofibers",slug:"chitosan-as-a-biomaterial-structure-properties-and-electrospun-nanofibers",totalDownloads:4727,totalCrossrefCites:27,totalDimensionsCites:63,abstract:"Chitosan is a polysaccharide derived from chitin; chitin is the second most abundant polysaccharide in the world, after cellulose. Chitosan is biocompatible, biodegradable and non-toxic, so that it can be usedin medicalapplications such as antimicrobial and wound healing biomaterials. It also used as chelating agent due to its ability to bind with cholesterol, fats, proteins and metal ions.",book:{id:"4648",slug:"concepts-compounds-and-the-alternatives-of-antibacterials",title:"Concepts, Compounds and the Alternatives of Antibacterials",fullTitle:"Concepts, Compounds and the Alternatives of Antibacterials"},signatures:"H. M. Ibrahim and E.M.R. El- Zairy",authors:[{id:"90645",title:"Dr.",name:"Hassan",middleName:null,surname:"Ibrahim",slug:"hassan-ibrahim",fullName:"Hassan Ibrahim"},{id:"175694",title:"Dr.",name:"Enas",middleName:null,surname:"El- Zairy",slug:"enas-el-zairy",fullName:"Enas El- Zairy"}]},{id:"70919",doi:"10.5772/intechopen.90891",title:"Antimicrobial Effect of Titanium Dioxide Nanoparticles",slug:"antimicrobial-effect-of-titanium-dioxide-nanoparticles",totalDownloads:1817,totalCrossrefCites:21,totalDimensionsCites:47,abstract:"The widespread use of antibiotics has led to the emergence of multidrug-resistant bacterial strains, and therefore a current concern for food safety and human health. The interest for new antimicrobial substances has been focused toward metal oxide nanoparticles. Specifically, titanium dioxide (TiO2) has been considered as an attractive antimicrobial compound due to its photocatalytic nature and because it is a chemically stable, non-toxic, inexpensive, and Generally Recognized as Safe (GRAS) substance. Several studies have revealed this metal oxide demonstrates excellent antifungal and antibacterial properties against a broad range of both Gram-positive and Gram-negative bacteria. These properties were significantly improved by titanium dioxide nanoparticles (TiO2 NPs) synthesis. In this chapter, latest developments on routes of synthesis of TiO2 NPs and antimicrobial activity of these nanostructures are presented. Furthermore, TiO2 NPs favor the inactivation of microorganisms due to their strong oxidizing power by free radical generation, such as hydroxyl and superoxide anion radicals, showing reductions growth against several microorganisms, such as Escherichia coli and Staphylococcus aureus. Understanding the main mechanisms of antimicrobial action of these nanoparticles was the second main purpose of this chapter.",book:{id:"9521",slug:"antimicrobial-resistance-a-one-health-perspective",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A One Health Perspective"},signatures:"Carol López de Dicastillo, Matias Guerrero Correa, Fernanda B. Martínez, Camilo Streitt and Maria José Galotto",authors:[{id:"244902",title:"Dr.",name:"Carol",middleName:null,surname:"Lopez De Dicastillo",slug:"carol-lopez-de-dicastillo",fullName:"Carol Lopez De Dicastillo"},{id:"315494",title:"Mr.",name:"Matias",middleName:null,surname:"Guerrero Correa",slug:"matias-guerrero-correa",fullName:"Matias Guerrero Correa"},{id:"315495",title:"Ms.",name:"Fernanda",middleName:null,surname:"B. Martínez",slug:"fernanda-b.-martinez",fullName:"Fernanda B. 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Aggregation continues with the maturation of biofilm. Dispersion is started by certain conditions such as phenol-soluble modulins (PSMs). By this way, sessile bacteria turn back into planktonic form. Bacteria embedded in biofilm (sessile form) are more resistant to antimicrobials than planktonic bacteria. So it is hard to treat biofilm-embedded bacteria than planktonic forms. For this reason, it is important to detect biofilm. There are a few biofilm detection and biofilm production methods on prosthetics, methods for screening antibacterial effect of agents against biofilm-embedded microorganism and antibiofilm effect of agents against biofilm production and mature biofilm. The aim of this chapter is to overview direct and indirect methods such as microscopy, fluorescent in situ hybridization, and Congo red agar, tube method, microtiter plate assay, checkerboard assay, plate counting, polymerase chain reaction, mass spectrometry, MALDI-TOF, and biological assays used by antibiofilm researches.",book:{id:"8427",slug:"antimicrobials-antibiotic-resistance-antibiofilm-strategies-and-activity-methods",title:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods",fullTitle:"Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods"},signatures:"Sahra Kırmusaoğlu",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"}]},{id:"63397",doi:"10.5772/intechopen.80624",title:"Antibiotic Resistance in Lactic Acid Bacteria",slug:"antibiotic-resistance-in-lactic-acid-bacteria",totalDownloads:2486,totalCrossrefCites:12,totalDimensionsCites:21,abstract:"Most starter cultures belong to the lactic acid bacteria group (LAB) and recognized as safe by the US Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA). However, LAB may act as intrinsic or extrinsic reservoirs for antibiotic resistance (AR) genes. This fact may not constitute a safety concern itself, as the resistance gene transfer is vertical. Nevertheless, external genetic elements may induce changes that favor the horizontal transfer transmission of resistance from pathogens as well as from the human intestinal microbiota, which represents a severe safety issue. Some genus of AR LAB includes Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, and Streptococcus isolated from fermented meat and milk products. Currently, the WHO recommends that LAB used in the food industry should be free of resistance. Therefore, the objective of this chapter is to present an overview of the LAB antibiotic resistance and some methods to determine the same.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Yenizey M. 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After attachment, aggregation of bacteria is started by cell-cell adhesion. Aggregation continues with the maturation of biofilm. Dispersion is started by certain conditions such as phenol-soluble modulins (PSMs). By this way, sessile bacteria turn back into planktonic form. Bacteria embedded in biofilm (sessile form) are more resistant to antimicrobials than planktonic bacteria. So it is hard to treat biofilm-embedded bacteria than planktonic forms. For this reason, it is important to detect biofilm. There are a few biofilm detection and biofilm production methods on prosthetics, methods for screening antibacterial effect of agents against biofilm-embedded microorganism and antibiofilm effect of agents against biofilm production and mature biofilm. 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Over the past few decades, no major new types of antibiotics have been produced and almost all known antibiotics are increasingly losing their activity against pathogenic microorganisms. The levels of multi-drug resistant bacteria have also increased. It is known that worldwide, more than 60% of all antibiotics that are produced find their use in animal production for both therapeutic and non-therapeutic purposes. The use of antimicrobial agents in animal husbandry has been linked to the development and spread of resistant bacteria. Poultry products are among the highest consumed products worldwide but a lot of essential antibiotics are employed during poultry production in several countries; threatening the safety of such products (through antimicrobial residues) and the increased possibility of development and spread of microbial resistance in poultry settings. 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Kocazeybek",authors:[{id:"179460",title:"Associate Prof.",name:"Sahra",middleName:null,surname:"Kırmusaoğlu",slug:"sahra-kirmusaoglu",fullName:"Sahra Kırmusaoğlu"},{id:"248288",title:"Prof.",name:"Bekir",middleName:null,surname:"Kocazeybek",slug:"bekir-kocazeybek",fullName:"Bekir Kocazeybek"},{id:"406463",title:"Dr.",name:"Nesrin",middleName:null,surname:"Gareayaghi",slug:"nesrin-gareayaghi",fullName:"Nesrin Gareayaghi"}]},{id:"63397",title:"Antibiotic Resistance in Lactic Acid Bacteria",slug:"antibiotic-resistance-in-lactic-acid-bacteria",totalDownloads:2486,totalCrossrefCites:12,totalDimensionsCites:21,abstract:"Most starter cultures belong to the lactic acid bacteria group (LAB) and recognized as safe by the US Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA). However, LAB may act as intrinsic or extrinsic reservoirs for antibiotic resistance (AR) genes. This fact may not constitute a safety concern itself, as the resistance gene transfer is vertical. Nevertheless, external genetic elements may induce changes that favor the horizontal transfer transmission of resistance from pathogens as well as from the human intestinal microbiota, which represents a severe safety issue. Some genus of AR LAB includes Enterococcus, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, and Streptococcus isolated from fermented meat and milk products. Currently, the WHO recommends that LAB used in the food industry should be free of resistance. Therefore, the objective of this chapter is to present an overview of the LAB antibiotic resistance and some methods to determine the same.",book:{id:"6978",slug:"antimicrobial-resistance-a-global-threat",title:"Antimicrobial Resistance",fullTitle:"Antimicrobial Resistance - A Global Threat"},signatures:"Yenizey M. 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It also used as chelating agent due to its ability to bind with cholesterol, fats, proteins and metal ions.",book:{id:"4648",slug:"concepts-compounds-and-the-alternatives-of-antibacterials",title:"Concepts, Compounds and the Alternatives of Antibacterials",fullTitle:"Concepts, Compounds and the Alternatives of Antibacterials"},signatures:"H. M. Ibrahim and E.M.R. El- Zairy",authors:[{id:"90645",title:"Dr.",name:"Hassan",middleName:null,surname:"Ibrahim",slug:"hassan-ibrahim",fullName:"Hassan Ibrahim"},{id:"175694",title:"Dr.",name:"Enas",middleName:null,surname:"El- Zairy",slug:"enas-el-zairy",fullName:"Enas El- Zairy"}]}],onlineFirstChaptersFilter:{topicId:"897",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81704",title:"Quorum Sensing Inhibition Based Drugs to Conquer Antimicrobial Resistance",slug:"quorum-sensing-inhibition-based-drugs-to-conquer-antimicrobial-resistance",totalDownloads:22,totalDimensionsCites:0,doi:"10.5772/intechopen.104125",abstract:"Quorum sensing is the cell to cell communication mechanism in microorganism through signalling molecules. Regulation of virulence factor, sporulation, proteolytic enzymes production, biofilm formation, auto-inducers, cell population density are key physiological process mediated through quorum-sensing (QS) signalling. Elevation of innate immune system and antibiotic tolerance of pathogens is highly increased with perspective of quorum-sensing (QS) activity. Development of novel drugs is highly attractive scenario against cell-cell communication of microbes. Design of synthetic drugs and natural compounds against QS signal molecules is vital combat system to attenuate microbial pathogenicity. Quorum sensing inhibitors (QSIs), quorum quenchers (QQs), efflux pump inhibitors (EPIs) act against multi-drug resistance strains (MDR) and other pathogenic microbes through regulation of auto-inducers and signal molecule with perceptive to growth arrest both in-vitro and in-vivo. QQs, QSIs and EPIs compounds has been validated with various animal models for high selection pressure on therapeutics arsenal against microbe’s growth inhibition. Promising QSI are phytochemicals and secondary metabolites includes polyacetylenes, alkaloids, polyphenols, terpenoids, quinones.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Kothandapani Sundar, Ramachandira Prabu and Gopal Jayalakshmi"},{id:"82372",title:"Unlocking the Potential of Ghost Probiotics in Combating Antimicrobial Resistance",slug:"unlocking-the-potential-of-ghost-probiotics-in-combating-antimicrobial-resistance",totalDownloads:20,totalDimensionsCites:0,doi:"10.5772/intechopen.104126",abstract:"Antimicrobial resistance is a global concern that requires immediate attention. Major causes of development of antimicrobial resistance in microbial cells are overuse of antimicrobials along the food chain especially in livestock, in preventing infections as well as misuse of antimicrobials by patients. Probiotics could be a viable alternative to antibiotics in the fight against antimicrobial resistance. Probiotic strains can act as a complement to antimicrobial therapy, improving antimicrobial function and enhancing immunity. However, there are safety concerns regarding the extensive use of live microbial cells especially in immunocompromised individuals; these include microbial translocation, inhibition of other beneficial microorganisms and development of antimicrobial resistance, among other concerns. Inevitably, ghost probiotics have become the favored alternative as they eliminate the safety and shelf-life problems associated with use of probiotics. Ghost probiotics are non-viable microbial cells (intact or broken) or metabolic products from microorganisms, which when administered in adequate amounts have biologic activity in the host and confer health benefits. Ghost probiotics exert biological effects similar to probiotics. However, the major drawback of using ghost probiotics is that the mechanism of action of these is currently unknown, hence more research is required and regulatory instruments are needed to assure the safety of consumers.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Abigarl Ndudzo, Sakhile Ndlovu, Nesisa Nyathi and Angela Sibanda Makuvise"},{id:"82178",title:"Managing Antimicrobial Resistance beyond the Hospital Antimicrobial Stewardship: The Role of One Health",slug:"managing-antimicrobial-resistance-beyond-the-hospital-antimicrobial-stewardship-the-role-of-one-heal",totalDownloads:16,totalDimensionsCites:0,doi:"10.5772/intechopen.104170",abstract:"Infections caused by micro-organisms affect the health of people and animals, causing morbidity and mortality, with Asia and Africa as the epicenters. Some of the infectious diseases are emerging and re-emerging in nature. Examples include viral hepatitis, Lassa fever, Ebola, yellow fever, tuberculosis, covid-19, measles, and malaria, among others. Antimicrobials have been playing an important role in the treatment of infections by these microbes. However, there has been a development of resistance to these antimicrobials as a result of many drivers. This write-up used secondary data to explore the management of antimicrobial resistance (AMR) beyond the hospital antimicrobial resistance steward using the one health concept. The findings showed AMR to be a transboundary, multifaceted ecosystem problem affecting both the developed and developing countries. It is also one of the top ten global public health threats facing mankind. Globally, AMR will cost over US$100 trillion in output loss by 2050, about 700,000 deaths a year, and 4,150,000 deaths in Africa by 2050. About 2.4 million people could die in high-income countries between 2015 and 2050 without a sustained effort to contain AMR. The drivers of AMR are beyond the hospital and hospital AMR stewardship. Therefore, the need for one health concept to manage it.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Istifanus Anekoson Joshua, Mathew Bobai and Clement Sokfa Woje"},{id:"81918",title:"Machine Learning for Antimicrobial Resistance Research and Drug Development",slug:"machine-learning-for-antimicrobial-resistance-research-and-drug-development",totalDownloads:53,totalDimensionsCites:0,doi:"10.5772/intechopen.104841",abstract:"Machine learning is a subfield of artificial intelligence which combines sophisticated algorithms and data to develop predictive models with minimal human interference. This chapter focuses on research that trains machine learning models to study antimicrobial resistance and to discover antimicrobial drugs. An emphasis is placed on applying machine learning models to detect drug resistance among bacterial and fungal pathogens. The role of machine learning in antibacterial and antifungal drug discovery and design is explored. Finally, the challenges and prospects of applying machine learning to advance basic research on and treatment of antimicrobial resistance are discussed. Overall, machine learning promises to advance antimicrobial resistance research and to facilitate the development of antibacterial and antifungal drugs.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Shamanth A. Shankarnarayan, Joshua D. Guthrie and Daniel A. Charlebois"},{id:"81891",title:"Alternatives to Antibiotics in Semen Extenders Used in Artificial Insemination",slug:"alternatives-to-antibiotics-in-semen-extenders-used-in-artificial-insemination",totalDownloads:29,totalDimensionsCites:0,doi:"10.5772/intechopen.104226",abstract:"Antimicrobial resistance is a serious global threat requiring a widespread response. Both veterinarians and medical doctors should restrict antibiotic usage to therapeutic use only, after determining the sensitivity of the causal organism. However, the addition of antibiotics to semen extenders for animal artificial insemination represents a hidden, non-therapeutic use of antimicrobial substances. Artificial insemination for livestock breeding is a huge global enterprise with hundreds of million sperm doses prepared annually. However, reporting of antimicrobial resistance in semen is increasing. This review discusses the consequences of bacteria in semen samples, as well as the effect of antimicrobial substances in semen extenders on bacteria in the environment and even on personnel. Alternatives to antibiotics have been reported in the scientific literature and are reviewed here. The most promising of these, removal of the majority of bacteria by colloid centrifugation, is considered in detail, especially results from an artificial insemination study in pigs. In conclusion, colloid centrifugation is a practical method of physically removing bacteria from semen, which does not induce antibiotic resistance. Sperm quality in stored semen samples may be improved at the same time.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Jane M. Morrell, Pongpreecha Malaluang, Aleksandar Cojkic and Ingrid Hansson"},{id:"81699",title:"Efflux Pumps among Urinary E. coli and K. pneumoniae Local Isolates in Hilla City, Iraq",slug:"efflux-pumps-among-urinary-e-coli-and-k-pneumoniae-local-isolates-in-hilla-city-iraq",totalDownloads:13,totalDimensionsCites:0,doi:"10.5772/intechopen.104408",abstract:"Urinary tract infections (UTI) are the most common bacterial infections affecting humans. Escherichia coli and Klebsiella pneumoniae were common enterobacteria engaged with community-acquired UTIs. Efflux pumps were vital resistance mechanisms for antibiotics, especially among enterobacteria. Overexpression of an efflux system, which results in a decrease in antibiotic accumulation, is an effective mechanism for drug resistance. The ATP-binding cassette (ABC) transporters, small multidrug resistance (SMR), and multidrug and toxic compound extrusion (MATE) families, the major facilitator superfamily (MFS), and the resistance-nodulation- cell division (RND) family are the five superfamilies of efflux systems linked to drug resistance. This chapter highlights the results of studying the prevalence of efflux pump genes among local isolates of E. coli and K. pneumoniae in Hilla City, Iraq. class RND AcrAB-TolC, AcrAD-TolC, and AcrFE-TolC genes detected by conventional PCR of E. coli and K. pneumoniae respectively. The result revealed approximately all studied efflux transporter were found in both E. coli and K. pneumoniae in different percentages. Biofilm formation were observed in 50(100%) of K. pneumoniae and 49(98%) of E. coli isolates were biofilm former and follow: 30(60%), 20(40%) were weak, 12(24%), 22(44%) were moderate and 7(14%) and 8(16%) were Strong biofilm former for E. coli and K. pneumoniae, respectively.",book:{id:"11373",title:"The Global Antimicrobial Resistance Epidemic - Innovative Approaches and Cutting-Edge Solutions",coverURL:"https://cdn.intechopen.com/books/images_new/11373.jpg"},signatures:"Hussein Al-Dahmoshi, Sahar A. Ali and Noor Al-Khafaji"}],onlineFirstChaptersTotal:13},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:7,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"13633",title:"Prof.",name:"Abdelhamid",middleName:null,surname:"Mellouk",slug:"abdelhamid-mellouk",fullName:"Abdelhamid Mellouk",profilePictureURL:"https://mts.intechopen.com/storage/users/13633/images/1567_n.jpg",institutionString:null,institution:{name:"Paris 12 Val de Marne University",institutionURL:null,country:{name:"France"}}},{id:"109268",title:"Dr.",name:"Ali",middleName:null,surname:"Al-Ataby",slug:"ali-al-ataby",fullName:"Ali Al-Ataby",profilePictureURL:"https://mts.intechopen.com/storage/users/109268/images/7410_n.jpg",institutionString:null,institution:{name:"University of Liverpool",institutionURL:null,country:{name:"United Kingdom"}}},{id:"3807",title:"Dr.",name:"Carmelo",middleName:"Jose Albanez",surname:"Bastos-Filho",slug:"carmelo-bastos-filho",fullName:"Carmelo Bastos-Filho",profilePictureURL:"https://mts.intechopen.com/storage/users/3807/images/624_n.jpg",institutionString:null,institution:{name:"Universidade de Pernambuco",institutionURL:null,country:{name:"Brazil"}}},{id:"38850",title:"Dr.",name:"Efren",middleName:null,surname:"Gorrostieta Hurtado",slug:"efren-gorrostieta-hurtado",fullName:"Efren Gorrostieta Hurtado",profilePictureURL:"https://mts.intechopen.com/storage/users/38850/images/system/38850.jpg",institutionString:null,institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},{id:"239041",title:"Dr.",name:"Yang",middleName:null,surname:"Yi",slug:"yang-yi",fullName:"Yang Yi",profilePictureURL:"https://mts.intechopen.com/storage/users/239041/images/system/239041.jpeg",institutionString:null,institution:{name:"Virginia Tech",institutionURL:null,country:{name:"United States of America"}}}]},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"13818",title:"Dr.",name:"Asim",middleName:null,surname:"Bhatti",slug:"asim-bhatti",fullName:"Asim Bhatti",profilePictureURL:"https://mts.intechopen.com/storage/users/13818/images/system/13818.jpg",institutionString:null,institution:{name:"Deakin University",institutionURL:null,country:{name:"Australia"}}},{id:"151889",title:"Dr.",name:"Joao Luis Garcia",middleName:null,surname:"Rosa",slug:"joao-luis-garcia-rosa",fullName:"Joao Luis Garcia Rosa",profilePictureURL:"https://mts.intechopen.com/storage/users/151889/images/4861_n.jpg",institutionString:null,institution:{name:"University of Sao Paulo",institutionURL:null,country:{name:"Brazil"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",institutionURL:null,country:{name:"Turkey"}}}]},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"1177",title:"Prof.",name:"António",middleName:"J. R.",surname:"José Ribeiro Neves",slug:"antonio-jose-ribeiro-neves",fullName:"António José Ribeiro Neves",profilePictureURL:"https://mts.intechopen.com/storage/users/1177/images/system/1177.jpg",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"220565",title:"Dr.",name:"Jucheng",middleName:null,surname:"Yang",slug:"jucheng-yang",fullName:"Jucheng Yang",profilePictureURL:"https://mts.intechopen.com/storage/users/220565/images/5988_n.jpg",institutionString:null,institution:{name:"Tianjin University of Technology",institutionURL:null,country:{name:"China"}}},{id:"29299",title:"Prof.",name:"Serestina",middleName:null,surname:"Viriri",slug:"serestina-viriri",fullName:"Serestina Viriri",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYOalQAG/Profile_Picture_1620817405517",institutionString:null,institution:{name:"University of KwaZulu-Natal",institutionURL:null,country:{name:"South Africa"}}},{id:"315933",title:"Dr.",name:"Yalın",middleName:null,surname:"Baştanlar",slug:"yalin-bastanlar",fullName:"Yalın Baştanlar",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002qpr7hQAA/Profile_Picture_1621430127547",institutionString:null,institution:{name:"Izmir Institute of Technology",institutionURL:null,country:{name:"Turkey"}}}]},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"111683",title:"Prof.",name:"Elmer P.",middleName:"P.",surname:"Dadios",slug:"elmer-p.-dadios",fullName:"Elmer P. 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