The PI3K proteins family
\r\n\tThe present book intends to provide to the reader a comprehensive overview of the state of art in empathy studies, embracing the different theoretical points of view and illustrating the advanced research such as the application of new technologies to promote perspective-taking. The critical aspects and the future directions of the study on empathy will also be presented.
",isbn:"978-1-80356-612-2",printIsbn:"978-1-80356-611-5",pdfIsbn:"978-1-80356-613-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"4c1042dfe15aa9cea6019524c4cbff38",bookSignature:"Ph.D. Sara Ventura",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11443.jpg",keywords:"Theoretical Model, Skill, Perspective Taking, Training Programs, Practical Implications, Advanced Research, Future Directions, Virtual Reality, Augmented Reality, New Trends, Assistive Technology",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 1st 2022",dateEndSecondStepPublish:"June 8th 2022",dateEndThirdStepPublish:"August 7th 2022",dateEndFourthStepPublish:"October 26th 2022",dateEndFifthStepPublish:"December 25th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Passionate researcher in the application of new technologies to psychological treatments, neuro-rehabilitation, human behavior, and the evolution of the human-computer interaction. In 2017 Dr. Ventura won a competitive grant (Santiago Grisolia) at the University of Valencia at LABPSITEC group, where she was awarded her Ph.D. degree, supervised by Prof. Rosa Baños at the University of Valencia, and co-directed by Prof. Giuseppe Riva of the Catholic University of Milan.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"227763",title:"Ph.D.",name:"Sara",middleName:null,surname:"Ventura",slug:"sara-ventura",fullName:"Sara Ventura",profilePictureURL:"https://mts.intechopen.com/storage/users/227763/images/system/227763.jpg",biography:"Sara Ventura gained a B.Sc in Psychology at the University of Padua (Italy) in 2013 and an M.Sc. in Ergonomic Psychology at the Catholic University of Milan (Italy) in 2015. In 2016, she carried out a postgraduate training at Universidad Nacional Autónoma de Mexico (Mexico) at the Ciberpsychology lab, working on a rehabilitation protocol for people with acquired brain injury through Virtual Reality. In 2020, Sara gained the Ph.D. in Clinical Psychology at University of Valencia (Spain) working with the LabPsitec group and focusing her research on the study of embodiment and empathy with the support of Virtual Reality. Actually, she is working both with Alma Mater Studiorum – University of Bologna (Italy), and the University of Valencia (Spain) on the fields of embodiment, stroke rehabilitation, empathy and patient care. Her research interests mainly focus on the adoption of new technologies, particularly Virtual/Augmented Reality and Artificial Intelligence for the psycho-social wellbeing with clinical and non-clinical populations, the study of human-computer interaction, and the user experience. She is the author of several scientific papers and various presentations at national and international conferences.",institutionString:"University of Valencia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Valencia",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"21",title:"Psychology",slug:"psychology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"455410",firstName:"Dajana",lastName:"Jusic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/455410/images/20500_n.jpeg",email:"dajana.j@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6494",title:"Behavior Analysis",subtitle:null,isOpenForSubmission:!1,hash:"72a81a7163705b2765f9eb0b21dec70e",slug:"behavior-analysis",bookSignature:"Huei-Tse Hou and Carolyn S. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"49340",title:"Targeting the PI3K/AKT/mTOR Pathway in Cancer Cells",doi:"10.5772/61676",slug:"targeting-the-pi3k-akt-mtor-pathway-in-cancer-cells",body:'The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical regulator of many essential physiological processes, but it also plays a key role in the malignant transformation of human tumors and their subsequent growth, metabolism, proliferation, and metastasis [1]. Previous studies have demonstrated that the PI3K/AKT/mTOR pathway is frequently activated in human cancers due to the somatic mutation and amplification of genes encoding key components [2,3]. In addition, aberrant PI3K/AKT/mTOR signaling activation also confers resistance to conventional therapies and is a poor prognostic factor for many types of cancers [4,5]. Several agents that target the PI3K/AKT/mTOR cascade elements are undergoing evaluation in preclinical and clinical studies. These include PI3K inhibitors, AKT inhibitors, mTOR catalytic site inhibitors, and dual PI3K-mTOR inhibitors. This chapter focuses on recent preclinical and clinical data on the efficacy of PI3K/AKT/mTOR pathway inhibitors either as monotherapy or in combination with conventional chemotherapy or others target drugs. Herein, we review four different classes of PI3K pathway inhibitors: PI3K inhibitors, AKT inhibitors, mTOR catalytic site inhibitors, and dual PI3K-mTOR inhibitors.
The PI3K/AKT/mTOR constitutes an important pathway downstream of growth factor tyrosine kinase receptors, thus regulating a plethora of biological processes as angiogenesis, proliferation, metabolism, survival, and differentiation [3]. Accumulating evidences indicate, therefore, that alterations in the PI3K/AKT/mTOR axis play critical and multifaceted role in cancer pathogenesis and progression. Indeed, systematic analysis performed in 3.281 tumors from 12 cancer types of the Cancer Genome Atlas Pan-Cancer effort has revealed that elements of the PI3K/AKT/mTOR signaling pathway are among the highest frequently mutated genes in cancer, such as uterine corpus endometrioid, breast, colon, lung, head and neck, and ovarian carcinomas [4,5].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Class I Class IA | \n\t\t\t\n\t\t\t | \n\t\t |
Catalytic | \n\t\t\tp110α | \n\t\t\tPIK3CA | \n\t\t
\n\t\t\t | p110β | \n\t\t\tPIK3CB | \n\t\t
\n\t\t\t | p110δ | \n\t\t\tPIK3CD | \n\t\t
Regulatory | \n\t\t\tp50α, p55α, p85α | \n\t\t\tPIK3R1 | \n\t\t
\n\t\t\t | p85β | \n\t\t\tPIK3R2 | \n\t\t
\n\t\t\t | p55γ | \n\t\t\tPIK3R3 | \n\t\t
Class IB | \n\t\t\t\n\t\t\t | \n\t\t |
Catalytic | \n\t\t\tp110γ | \n\t\t\tPIK3CG | \n\t\t
Regulatory | \n\t\t\tp101 | \n\t\t\tPIK3R5 | \n\t\t
\n\t\t\t | p84, p87 | \n\t\t\tPIK3R6 | \n\t\t
Class II | \n\t\t\t\n\t\t\t | \n\t\t |
Catalytic | \n\t\t\tPI3KC2α | \n\t\t\tPIK3C2A | \n\t\t
\n\t\t\t | PI3KC2β | \n\t\t\tPIK3C2B | \n\t\t
\n\t\t\t | PI3KC2γ | \n\t\t\tPIK3C2G | \n\t\t
Class III | \n\t\t\t\n\t\t\t | \n\t\t |
Catalytic | \n\t\t\tVps34 | \n\t\t\tPIK3C3 | \n\t\t
Regulatory | \n\t\t\tVps15 | \n\t\t\tPIK3R4 | \n\t\t
The PI3K proteins family
PI3K is a heterodimer of its catalytic and regulatory subunits and has been classified as class I, II, and III. Class I PI3K is constituted by four 110-kDa catalytic subunits and two main regulatory domains, which is subdivide in class IA and IB. Class IA PI3K (PI3K α, β, and δ) is activated by receptors with tyrosine kinase activity, and class IB PI3K (PI3K γ) is activated by G protein-coupled receptors. The class IA enzymes are dimers of p110α, p110β, or p110δ catalytic subunits and the regulatory subunits p85α (or its splice variants p55a and p50a), p85β, p55γ, p101, or p84 [6,7]. In turn, class IB enzymes are dimers of p110γ catalytic subunit and either p101 or p84 (also known as p87PIKAP) regulatory subunits [8]. The four class I catalytic isoforms share overlapping but distinct functions. Although the expression of p110c and p110d isoforms seems to be confined to immune cells, p110a and p110b are ubiquitously expressed but exhibit isoform-specific cell-type- and context-dependent requirements, thus being involved in a wide range of cellular effects [9–13]. Class II PI3K (PI3KC2) subfamily has additional domains in both N- and C-terminal extensions and exists as 3 isoforms, PI3K-C2α, PI3K-C2β, and PI3K-Cγ [14]. On the other hand, class III PI3K occurs as a single isoform constituted by the catalytic subunit Vps34p and regulatory subunit Vps15 [14] (Table 1).
The PI3K family recruits effector proteins, altering their localization, activity, and conformation. There are some binding proteins domains that mediate such events [14]. The best-characterized domains among them are FYVE (Fab 1, YOTB, Vac 1, EEA1) [15–17], PH (pleckstrin homology) [18], and PX (Phox) [19-23]. Nonetheless, the peculiar composition of the three PI3K subfamilies results in the activation of distinct cellular functions.
In brief, after activation by receptor tyrosine kinases, including members of platelet-derived growth factor receptor, the insulin and insulin-like growth factor 1 (IGF-1) receptors and human epidermal growth factor receptor family (EGFR and HER2), PI3K phosphorylates phosphatidylinositol 4,5-trisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) [24]. In physiological conditions, the level of PIP3 is strictly regulated by PTEN (phosphatase and tensin homolog), a phosphatase that specifically catalyzes the dephosphorylation of PIP3, converting PIP3 back to PIP2, thus constituting an important endogenous-negative feedback loop of the PI3K signaling pathway [25,26]. The lipid product of PI3K, PIP3, recruits a subset of signaling proteins with PH domains to the membrane, including 3-phosphoinositide-dependent protein kinase (PDK1) and AKT, resulting in its phosphorylation at threonine-308 and activation [24].
In both physiological and pathological conditions, AKT exists in three isoforms in mammals: AKT1, AKT 2, and AKT 3 [27,28]. AKT phosphorylates tuberous sclerosis complex 2 (TSC2), thereby inhibiting the GTPase activity of the TSC1/TSC2 complex and enabling mTOR activation by RAS homologue enriched in brain (RHEB), thus allowing signal propagation [26,29]. mTOR exists in two different structural protein complex: mTORC1 and mTORC2, each of which is expressed in different subcellular compartments, therefore affecting their activation and function. mTORC1 complex is composed of a catalytic subunit mTOR, regulatory-associated protein of mTOR (RAPTOR), mammalian lethal with SEC13 protein 8 (MLST8), and the noncore components PRAS40 and DEP domain-containing mTOR-interacting protein (DEPTOR). Once activated, mTORC1 leads to increased protein synthesis via its effectors, named translation-regulating factors ribosomal S6 kinase-1 (S6K-1) and eukaryote translation initiation factor 4E binding protein-1 (4EBP-1). S6K-1 and 4EBP1 are major regulators of protein translation [30]. On the other hand, mTORC2 is composed by rapamycin-insensitive companion of mTOR (RICTOR), MLST8, and mammalian stress-activated protein kinase interacting protein 1 (SIN1). The function of mTORC2 remains not fully understood, but it is required to phosphorylate AKT at serine-473, thus resulting in its maximal activation [31]. Of clinical relevance, differently from mTORC1, mTORC2 is insensitive to rapamycin inhibition, opening an avenue for drug discovery in face of the development of resistance by cancer cells against first-generation mTOR inhibitors (rapalogs) that particularly target mTORC1 [32] (Figure 1).
Overview of Pl3K/AKT/mTOR signaling pathway and some inhibitors of this pathway in clinical studies. The activation of the PI3K by receptor tyrosine kinases promotes conversion of PIP2 to PIP3. PTEN dephosphorylates PIP3, negatively regulating the PI3K signaling. The phosphorylation and activation of AKT impacts many downstream effectors, such as mTORCI, and finally leads to multiple cellular processes.
Somatic mutations and/or gains and losses of genes are possible genetic alterations affecting the PI3K/AKT/mTOR pathway in different solid and hematological tumors [33,34]. Indeed, PI3K pathway can be activated by direct upstream signs and can be intrinsically activated due to gain of functional mutations or amplifications in PIK3CA (p110 subunit), mutations in PIK3R (p85 subunit), and mutations or amplifications in one of the AKT isoforms or loss of PTEN [35]. Loss of PTEN via inactivating mutations, due to either copy number loss or homozygous deletions, is associated with both resistance to chemotherapy and reduced survival of human patients [3].
PIK3CA mutations in primary breast tumors have been associated with lymph node metastases and overexpression of ER, PR, and HER2 [36]. Furthermore, the presence of activating PI3KCA mutations and loss of PTEN in HER2-overexpressing cancers is correlated with a lower response to trastuzumab and lapatinib [37]. In non-small cell lung cancer, the downregulation of PTEN is also related with poor prognosis [38,39]. In ovarian cancer, PI3K/AKT/mTOR molecular alteration appears to be histological subtype specific. Studies have described amplifications in PIK3CA, amplifications of one of the AKT isoforms, and PTEN deletions in 20%, 15%, and 5% of the high grade serous ovarian cancer (HGSOC) cases, respectively [40,41]. The individual mutations, rare events in HGSOC, are prevalent in low grade serous, mucinous, endometrioid, and clear cell ovarian cancer; 20% of endometrioid and 35% of clear cell ovarian tumors display these PIK3CA mutations [42,43]. Besides, copy number changes in the genes encoding PIK3CA and PIK3CB subunits have been associated with a poor prognosis, and the inhibition of PI3K/mTOR was found to delay tumor growth and prolong survival [44,45].
Moreover, mutations of mTOR itself and/or in components of mTOR-related signaling pathways have frequently been described in human malignant diseases [46-48]. Different genetic lesions that mediate mTORC1 activation have diverse consequences: PTEN loss uncouples mTORC1 activation from growth factor signaling; liver kinase B1/serine/threonine kinase 11 (LKB1/STK11) mutations allow mTORC1 activation despite nutrient deprivation in poorly vascularized tumors; P53 mutations uncouple DNA damage from the inhibition of bioenergetic processes and cell cycle arrest [49]; and hyperactivation of S6K-1, 4EBP1 and eIF4E, and cancer growth by activating the lipid and protein biosynthesis. Furthermore, the increased phosphorylation of mTOR is associated with acquired cisplatin resistance, and AKT signaling has been implicated in primary platinum resistance [50]. In fact, AKT or mTOR inhibitors likely restore chemosensitivity to platinum derivates
These molecular alterations, in addition to the druggability of the components of the PI3K/AKT/mTOR signaling cascade, suggest that targeting the pathway might represent a useful treatment strategy in the fight against cancer.
As aforementioned, PI3K/AKT/mTOR pathway has been implicated in tumorigenesis, promotion of cell survival, angiogenesis, cellular invasion, tumor growth, and the acquisition of chemoresistant phenotype by cancer cells [1]. Currently, more than fifty PI3K/AKT/mTOR axis inhibitors are in different stages of development, with a great number of such inhibitors reaching clinical trials [53]. Analogs of rapamycin (inhibitors of mTORC1), temsirolimus and everolimus, are currently in the lead, having already been approved by the Food and Drug Administration (FDA) as anticancer agents [54-56]. The PI3K/AKT/mTOR pathway inhibitors are summarized in Table 2.
PI3K inhibitors can be divided in isoform-specific inhibitors or pan-PI3K inhibitors. pan-PI3K inhibitors target all class IA PI3Ks in tumor cells, whereas isoform-specific inhibitors were developed to decrease toxicity and might be particularly effective in cancers with PIK3CA mutations, for example.
The first-generation of PI3K inhibitors include wortmannin, a fungal metabolite isolated from
Currently, water-soluble wortmannin conjugates are being developed to overcome this issue. PX-866 is a semisynthetic analog of wortmannin with potent, irreversible, pan-class I PI3K inhibitory property against p110-α, p110-δ, and p110-γ enzymes in biochemical assays [62]. In preclinical studies, the compound alone or in combination with chemotherapy (cisplatin), radiotherapy, and targeted cancer drugs (gefitinib) exhibited
Buparlisib (NVP-BKM120) is an oral highly specific pan-class I PI3K inhibitor with inhibitory property against p110-α, p110-β, p110-δ, and p110-γ enzymes [65]. The compound is also active against activating p110α somatic mutations but does not significantly inhibit the related class III and class IV PI3K kinases. In preclinical cancer studies, buparlisib has shown antiproliferative and proapoptotic activity against a panel of 353 cell lines that display different genetic abnormalities that promote PI3K pathway activation [66].
A phase I dose-escalation study in thirty-five patients with advanced-stage solid tumors showed that buparlisib is a safe and well-tolerated drug with favorable pharmacokinetic properties. The major treatment-related adverse events included rash, hyperglycemia, diarrhea, anorexia, mood alteration, nausea, fatigue, pruritus, and mucositis [67]. Importantly, hyperglycemia was more common at higher doses and represents a class effect of the inhibition of PI3K signaling, commonly observed with other PI3K/AKT/mTOR pathway inhibitors [67]. Later, phase I dose-escalation and expansion study of buparlisib was performed in eighty-three patients with advanced solid tumors demonstrating that buparlisib was well tolerated up to 100 mg/day and showed preliminary activity in patients with advanced cancers [68]. This subsequently led to the initiation of several clinical trials in multiple cancer types, such as non-small cell lung cancer, prostate cancer, breast cancer, colon cancer, and glioblastoma multiform (GBM).
BASALT-1, an ongoing phase II trial (NCT01297491), is investigating the efficacy of single-agent buparlisib in patients with metastatic non-small cell lung cancer with PI3K pathway activation. Furthermore, phase Ib/II is under evaluation in patients with advanced non-small cell lung cancer of different histotype, testing buparlisib in combination with other targeted agents such as everolimus (NCT01470209), erlotinib (NCT01487265), MEK inhibitor (NCT01363232), or in combination with standard chemotherapeutic drugs, such as docetaxel (NCT01911325), gemcitabine, and cisplatin (NCT01971489) and carboplatin and paclitaxel (NCT01820325).
At present, several active, not recruiting, and recruiting clinical trials are being conducted in all the biological subsets of breast cancer, including combinations with endocrine therapy, anti-HER2 agents, poly (ADP-ribose) polymerase (PARP) inhibitors, and chemotherapy with buparlisib. Two large phase III studies (BELLE-2 and BELLE-3) (NCT01610284, NCT01633060) are investigating the combination of buparlisib plus fulvestrant in postmenopausal women with hormone receptor-positive/HER2-negative breast cancer after failure of aromatase inhibitor alone or aromatase inhibitor plus mTOR inhibitor treatment, respectively. Another ongoing clinical study is BELLE-4, a placebo-controlled phase II trial of buparlisib with paclitaxel in the first-line treatment of HER2-negative metastatic breast cancer (NCT01572727). Buparlisib has also been evaluated in a phase II study of paclitaxel plus trastuzumab in HER2-overexpressing breast cancer (NCT01816594).
Pilaralisib (XL147) is an oral pan-class I PI3K inhibitor (α, β, γ, and δ) through reversible, competitive inhibition with ATP for p110-α, -δ, -γ, and -β enzymes [69].
In a phase I dose-escalation trial of sixty-nine patients with advanced solid tumors, pilaralisib was tolerable at doses associated with PI3K pathway inhibition, and the most frequent drug-related adverse events included dermatologic toxicities, diarrhea, nausea, and decreased appetite [72]. However, a phase I dose-escalation study of pilaralisib with erlotinib in patients with solid tumors showed that combination had limited antitumor activity with moderate inhibition of PI3K, MAPK and EGFR pathways [73]. Moreover, phase I/II study of pilaralisib in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer related that no responses were observed in patients treated with pilaralisib plus trastuzumab while clinical activity was observed in paclitaxel arm [74]. Additional clinical evaluation of this PI3K inhibitor is ongoing in phase I/II studies (NCT01587040).
Pictilisib (GDC-0941) is another potent, selective, and orally bioavailable inhibitor of pan-class I PI3K. In biochemical assays, pictilisib demonstrates selectivity over a large panel of protein kinases and PI3K family kinases, including mTOR and DNA-dependent protein kinase (DNA-PK) [75]. Interestingly, pictilisib induces apoptosis in a subset of human tumor cell lines and potently inhibited tumor growth in xenograft models, including those with mutations in PI3K, PTEN, and K-Ras [76]. Significant
In a first-in-human phase I study of pictilisib in sixty patients with advanced solid tumors, the most frequently reported drug-related adverse events were nausea, fatigue, and rash [81]. Importantly, one patient with V600E BRAF-mutant melanoma and another with platinum-refractory ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response [81]. Pictilisib is currently under evaluation in several phase I/II clinical trials, mainly in non-small cell lung cancer and breast cancer (NCT01918306, NCT01740336, NCT01493843, and NCT00974584).
One strategy to achieve significant pathway inhibition clinically with tolerable adverse effect profile is the use of isoform-specific PI3K inhibitors. As aforementioned, each isoform has distinct role in normal physiological processes and disease (Table 1). PI3K catalytic subunit p110α is predominantly responsible for mediating growth factor signaling from receptor tyrosine kinases and is a frequent genetic driver (
Alpelisib (NVP-BYL719) is an oral inhibitor that selectively targets PI3K p110α equipotent against the wild type and the most common somatic mutations of p110α [87]. NVP-BYL719 has been the first PI3Kα-selective inhibitor to enter in clinical trials after positive preclinical investigations.
Taselisib (GDC-0032) is a PI3K inhibitor with higher affinity for mutated PI3Kα with reduced inhibitory activity against PI3Kβ [91]. Preclinical studies show that taselisib has enhanced activity against PI3Kα isoform mutant cancer cell lines [92]. In an ongoing phase I study, taselisib has been well tolerated with hyperglycemia and fatigue being the dose-limiting toxicities [93]. This selectivity profile and excellent pharmacokinetic properties allowed fewer clinical studies with GDC-0032. Currently, several clinical studies are ongoing to evaluate the combination of taselisib with endocrine therapy, trastuzumab, and conventional chemotherapy in breast cancer (NCT02285179, NCT02390427, and NCT01862081). In addition, a phase I study is currently ongoing in taselisib with CDK4/6 inhibitor, palbociclib, in advanced solid tumors and breast cancer (NCT02389842).
Idelalisib was approved in 2014 in the United States and European Union for the treatment of three indolent B-cell neoplasms: relapsed chronic lymphocytic leukemia, in combination with rituximab, relapsed follicular B-cell non-Hodgkin’s lymphoma, and relapsed small lymphocytic lymphoma (as monotherapy) [94]. In lymphoid cell lines and primary patient samples, idelalisib abrogates PI3K/AKT/mTOR signaling and promotes apoptosis [95,96]. The first phase I trial in healthy volunteers established the bioavailability and safety of idelalisib [97]. Another phase I study in patients with relapsed/refractory mantle cell lymphoma reported the most common adverse events, which includes diarrhea, nausea, pyrexia, fatigue, rash, upper respiratory infection, pneumonia and alanine transaminase, or aspartate transaminase elevations [98]. To date, about twenty-five clinical trials are ongoing with idelalisib. A phase I/II trial studies aimed evaluated idelalisib in combination with lenalidomide and rituximab in patients with relapsed or refractory mantle cell lymphoma (NCT01838434). In addition, idelalisib is being evaluated in combination with rituximab in adults with previously treated indolent non-Hodgkin lymphoma (NCT01732913).
AKT inhibitors constitute another class of drugs that has gained recent interest. As discussed previously, AKT is involved in the regulation of various signaling downstream pathways involved in cell survival, growth, proliferation, metabolism, and angiogenesis. AKT inhibition promotes decreasing cancer cell survival by preventing signal transduction through its downstream effectors. In addition, targeting AKT is an interesting pharmacological approach due to the AKT activation in consequence of the feedback loop release when mTOR is inhibited.
AKT inhibitors can be grouped into three classes, including lipid-based phosphatidylinositol (PI) analogs, ATP-competitive inhibitors (catalytic inhibitors), and allosteric inhibitors. To date, the most developed inhibitor of AKT is perifosine (KRX-0401), a lipid-based inhibitor. Perifosine is an allosteric inhibitor that targets the PH domain of AKT, thereby preventing its translocation to the plasma membrane required for pathway activation [99]. Perifosine has demonstrated great efficacy
Despite these encouraging preclinical studies, results from phase I/II clinical trials of perifosine as single agent in a various tumor types (metastatic breast cancer, metastatic head and neck cancer, locally advanced soft tissue sarcoma, prostate cancer, and metastatic
In behalf of the poor efficacy of perifosine as a single agent observed in most tumor types evaluated thus far, efforts have been made to combine this drug with target agents and chemotherapy. Phase I studies have now confirmed the safety of these combinations with different agents, including sorafenib in patients with Hodgkin lymphoma and taxanes in high-grade epithelial ovarian cancer [112,113]. Currently, one clinical trial with perifosine is recruiting patients, a phase II study with perifosine and temsirolimus in patients with malignant gliomas (NCT02238496).
GSK-690693 is a potent ATP-competitive AKT inhibitor selective for all three AKT isoforms versus the majority of kinases assessed by biochemical tests [114]. GSK690693 displayed antiproliferative activity
As discussed previously, mTOR is involved in many cell signaling pathways, and clinical trials for cancer treatment showed that tumor cells with mutations in p53 or PTEN are susceptible to mTOR inhibitors [115]. mTOR inhibitors are categorized in first- and second-generation presenting a wide variety of target and mechanism. The first-generation mTOR inhibitors include rapamycin and its analogs that employ allosteric mechanism to block, whereas the second-generation mTOR inhibitors (AZD8055, Torin1, PP242, and PP30) have as target ATP binding site to impede kinase activity of both mTORC1 and mTORC2 [116].
Rapamycin, discovered in 1975, is a macrocyclic lactone isolated from the soil bacterium
Three different mechanisms of action have been proposed: first, the binding of the FKBP-12–rapamycin complex to mTOR that could lead dephosphorylation of downstream effector molecules such as S6K-1 and 4EBP1 [121]; second, the FKBP-12–rapamycin complex competes with phosphatidic acid to bind to the FRB domain of mTOR, blocking mTOR kinase function [122]; and third, the FKBP-12–rapamycin complex bounds to mTOR and destabilizes the mTOR–raptor–4EBP1/S6K-1 scaffold complex, leading to dephosphorylation of S6K-1 and 4EBP1 [123,124].
This inhibitor has limited bioavailability due to its poor aqueous solubility. In an effort to improve its pharmacokinetics, several rapamycin analogs, named rapalogs, have been developed, such as temsirolimus (CCI-779), everolimus (RAD001), and ridaforolimus (MK-8669/AP23573) [125-127].
Some studies have shown that these compounds are able to disrupt the mTORC2 complex in a dose-, time-, and cell type-dependent manner [24,128,129]. A possible mechanism by which rapamycin and rapalogs could inhibit mTORC2 relies on the interaction of newly synthesized mTOR molecules and rapamycin/rapalogs-FKBP12 complexes. In turn, this interaction would prevent mTOR from the interaction with RICTOR, thus inhibiting mTORC2. Indeed, it has been shown that prolonged exposure of cancer cells to rapamycin can promote its binding to mTOR before the assembly of the mTORC2 complex, with subsequent inhibition of the AKT-mediated signaling [24].
Rapamycin and its derivates exhibit a safe toxicity profile, being the side effects of skin rashes and mucositis dose dependent [130]. Other symptoms commonly described are fatigue, nausea, anemia, hypertriglyceridemia, hypercholesterolemia, and neutropenia [131]. Furthermore, temsirolimus and sirolimus are associated with significant rate of pulmonary toxicity [130,131]. Rare side effects of the aforesaid drugs include interstitial lung disease, risk of secondary lymphoma, and reactivation of latent infections [35].
Everolimus (Afinitor®), the oral mTOR inhibitor, has been approved by the FDA in 2009 for advanced renal cell cancer. Everolimus exhibit strong antiangiogenic and antiproliferative activity against various human cancer such as metastatic or unresectable pancreatic neuroendocrine tumors, subependymal giant cell astrocytoma [132], metastatic renal cell carcinoma, and advanced estrogen receptor (ER)-positive [133] and human epidermal growth factor receptor-2 (HER2)-negative breast cancer [134].
Several studies have been conducted to analyze the effectiveness of rapamycin and rapalogs alone and in combination with standard chemotherapy, hormonal therapy such as anti-VEGF inhibitors in the treatment of several types of cancers such breast, ovarian, cervical, and endometrial. Phase II studies are ongoing in order to test everolimus in combination with chemotherapy (cisplatin and gemcitabine) in patients with metastatic triple negative breast cancer (NCT01939418 and NCT01931163). In addition, a recent study of breast cancer (BOLERO-3) demonstrated that the combination of everolimus with trastuzumab and vinorelbine significantly prolonged progression-free survival (PFS) in patients with trastuzumab-refractory and taxane-pretreated, HER2-positive advanced breast cancer [135]. Moreover, another breast cancer study, BOLERO-1, evaluated patients treated with paclitaxel and trastuzumab with or without everolimus as first-line therapy [136]. Furthermore, clinical studies have evaluated the aromatase inhibitor letrozole in combination with everolimus in patients with metastatic endometrial carcinoma (NCT01068249) and breast cancer (NCT00107016).
Temsirolimus (Torisel®), the first rapamycin analog to be FDA approved as an anticancer drug, is an intravenous injection drug and gets converted into rapamycin
Ridaforolimus (MK-8669/AP23573), a non-rapamycin prodrug, is available in both oral and intravenous formulations. This mTOR inhibitor is actively being evaluated as either monotherapy or in combination with other therapies for treatment of various cancers, including sarcomas, endometrial, prostate, breast, and non-small cell lung cancer [143]. Studies had been conducted in patients with advanced endometrial cancer and clinical benefit response was reported in 33% of the patients [144]. Another phase II study using oral ridaforolimus in patients with advanced or recurrent endometrial cancer also showed partial response in 7.7% patients [145].
Although clinically promising, the efficacy of rapalogs is partially limited by the negative feedback loops in the mTOR pathway. With this regard, the exclusive inhibition of the mTORC1 complex by the rapalogs compromises the S6K-1-mediated feedback loop towards IRS-1, resulting in the activation of both the PI3K/AKT and the mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERK) pathways, hence promoting compensatory cell survival, and the acquisition of chemoresistant phenotype [127,146,147]. Efforts have been made to overcome the previously mentioned clinical limitation by means of developing new generation mTOR inhibitors, which inhibit the catalytic activity of both mTORC1 and mTORC2 complexes.
Although rapamycin is a potent allosteric mTORC1 inhibitor with clinical applications, a second-generation ATP-competitive inhibitor have been developed, including Torin1, Torin2, PP242, PP30, KU0063794, WAY-600, WYE-687, WYE-354, XL-388, INK-128, AZD-2014, AZD8055, and OSI-027 [148-153]. The ATP-competitive inhibitors of mTOR directly inhibit the mTOR kinase activity, affecting both mTORC1 and mTORC2 complexes simultaneously and suppress AKT activity.
ATP-competitive mTOR inhibitors represent a promising new approach to target the pathway with potentially grater tolerability and efficacy than rapamycin. It has been shown that ATP inhibitors displayed dramatic antiproliferative activity across a range of cancer cell lines [151,154,155].
Studies have been conducted with PP242 in colon cancer cells
Studies conducted by Rodrik-Outmezguine and colleagues [160], comparing mTORC1 inhibition with rapamycin and AZD8055, revealed that rapamycin treatment led to an almost complete loss in the mTORC1 phosphorylation of S6K-1 (threonine-389) and increased phospho-AKT (serine-473). In contrast, AZD8055 treatment led to reductions in phospho-S6K-1 (threonine-389), phospho-4EBP1 (threonine-37/40, threonine-65, and threonine-70), and phospho-AKT (serine-473). Thereby, AZD8055 was a better inhibitor of mTORC1 in comparison to rapamycin.
At present, there are several clinical trials focused on the examination of new agents, such as AZD-8055 (NCT00731263), OSI-027 (NCT00698243), and INK128 (NCT02142803), in a variety of human hematological malignancies and solid tumors, including breast cancer. Also some studies were conducted using GSK795 in patients with advanced platinum-resistant ovarian and showed interesting results as tumor regressions and CA125 decreases [161]. Phase I study are ongoing to evaluate the safety and toxicity profile of AZD2014 in combination with paclitaxel in patients with ovarian cancer (NCT02193633).
Despite the clinical improvements observed with the ATP-competitive inhibitor when compared to the rapalogs, the literature still acknowledges significant limitations that outcome from compensatory cellular events. With this regard, it has been found that loss of the feedback on PI3K results in compensatory activation of the MAPK/ERK cascade by mTOR downstream effectors, such as 4EBP1/eIF4E, maintaining cell proliferation [162]. Furthermore, it has been shown that chronic inhibition of mTORC2 induces the activation of AKT by its phosphorylation mediated by PDK-1, even in the absence of the priming serine-473 phosphorylation. Altogether, the referred mechanisms ultimately drive the acquisition of the resistant phenotype by the cancer cells [154,163].
Scientist have explored to shed light on strategies to overcome the limitations by concomitantly targeting two molecules in the PI3K/AKT/mTOR pathway, PI3K and mTOR, whereas the resistance mTOR inhibitors cloud arise via feedback PI3K activation. This molecular knowledge have stimulated the development of new inhibitors termed dual PI3K-mTOR inhibitors that include NVP-BEZ235, XL765, BGT226, PI-103, PF-04691502, PKI-587, and GDC-0980 [164-170]. Comparing with the other types of PI3K pathway inhibitors, dual PI3KmTOR inhibitors have the possible advantage of inhibiting all PI3K catalytic isoforms, mTORC1 and mTORC2 [171]. Therefore, these inhibitors may effectively turn off this pathway completely and display best efficacy in feedback inhibition normally observed with mTORC1 inhibitors [172]. However, it is not clear that dual PI3K-mTOR inhibitors will be tolerable at doses that effectively inhibit all p110 isoforms and mTOR [171].
The potential clinical value of the dual PI3K/mTOR inhibitors have been demonstrated by their significant inhibition of cell growth, the induction of apoptosis and/or autophagy [173] in a variety of tumor cancer cells [174-176]. In addition, these inhibitors have shown powerful effects in xenograft models of breast cancer [177], pancreatic cancer [178], melanoma [179], multiple myeloma [180], and RCC [181].
In agreement, dual PI3K/mTOR inhibitors have entered clinical trials either monotherapy or polytherapy. A single agent includes BEZ235/NVP-BEZ235 (NCT00620594) and BGT226 (NCT00600275 and NCT00742105) in advanced solid tumors and breast cancer, GDC-0980 (NCT00854126, NCT00854152, and NCT01455493) in non-Hodgkin lymphoma and endometrial carcinoma, and PF-04691502 (NCT00927823) and GSK2126458 (NCT00972686 and NCT01248858) in solid tumors. In combination with others agents, the treatment includes XL765 (Exelixis) with erlotinib (NCT00777699), letrozole (NCT01082068), and temozolomide (NCT00704080) in non–small cell lung cancer, breast cancer, and gliomas, respectively.
Both BEZ235 and XL765 have shown good tolerability, with adverse effects including diarrhea, anorexia, and nausea [49]. Furthermore, the combined therapy using rapamycin and dual PI3K/mTOR kinase inhibitor (PI-103) has been shown to be efficacious against human ovarian cells
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
LY294002 | \n\t\t\t- | \n\t\t\tPan-PI3K inhibitor | \n\t\t\tPreclinical | \n\t\t\t- | \n\t\t\t[57,58] | \n\t\t
Wortmannin | \n\t\t\t- | \n\t\t\tPan-PI3K inhibitor | \n\t\t\tPreclinical | \n\t\t\t- | \n\t\t\t[57,59,60] | \n\t\t
PX-866 | \n\t\t\t(Oncothyreon) | \n\t\t\tPan-PI3K inhibitor | \n\t\t\tPhase II | \n\t\t\tSolid cancers, prostate, colorectal, glioblastoma, SCCHN, non-small cell lung cancer | \n\t\t\t[62,64] | \n\t\t
NVP-BKM120 | \n\t\t\tBuparlisib (Novartis) | \n\t\t\tPan-PI3K inhibitor | \n\t\t\tPhase III | \n\t\t\tNon-small cell lung cancer, prostate, breast, GBM, colon | \n\t\t\t[65,66] | \n\t\t
XL147 | \n\t\t\tPilaralisib (Sanofi-Exelixis) | \n\t\t\tPan-PI3K inhibitor | \n\t\t\tPhase II | \n\t\t\tSolid cancers, breast, breast, endometrial, ovarian, non-small cell lung cancer, glioblastoma, lymphoma | \n\t\t\t[69,72] | \n\t\t
GDC-0941 | \n\t\t\tPictilisib (Genentech-Roche) | \n\t\t\tPan-PI3K inhibitor | \n\t\t\tPhase II | \n\t\t\tSolid cancers, breast, non-small cell lung cancer, glioblastoma, non-Hodgkin\'s lymphoma | \n\t\t\t[75,81] | \n\t\t
GSK-2636771 | \n\t\t\t(GlaxoSmithKline) | \n\t\t\tPI3Kβ inhibitor | \n\t\t\tPhase I | \n\t\t\tSolid cancers (PTEN deficient), prostate | \n\t\t\t[84] | \n\t\t
NVP-BYL719 | \n\t\t\tAlpelisib (Novartis) | \n\t\t\tPI3Kα inhibitor | \n\t\t\tPhase II | \n\t\t\tAdvanced solid tumors, SCCHN, breast, ovarian | \n\t\t\t[87,90] | \n\t\t
GDC-0032 | \n\t\t\tTaselisib (Genentech) | \n\t\t\tPI3Kα inhibitor | \n\t\t\tPhase III | \n\t\t\tSolid cancers, breast, non-small cell lung cancer | \n\t\t\t[91,93] \n\t\t\t | \n\t\t
CAL-101 | \n\t\t\tIdelalisib (Gilead Sciences) | \n\t\t\tPI3Kδ inhibitor | \n\t\t\tPhase III | \n\t\t\tLymphomas, multiple myelomas, chronic lymphocytic leukemia, acute myeloid leukemia | \n\t\t\t[94,97,98] | \n\t\t
KRX-0401 | \n\t\t\tPerifosine (Pfizer) | \n\t\t\tAKT inhibitors | \n\t\t\tPhase II | \n\t\t\tSolid tumors, non-small cell lung cancer, colon, kidney, breast, gliomas, multiple myeloma, leukemia, lymphomas | \n\t\t\t[107,111,112,113] \n\t\t\t | \n\t\t
GSK-690693 | \n\t\t\t(GlaxoSmithKline) | \n\t\t\tATP-competitive AKT inhibitor | \n\t\t\tPhase I | \n\t\t\tHematologic malignancies | \n\t\t\t[114] | \n\t\t
Rapamycin | \n\t\t\tSirolimus (Wyeth) | \n\t\t\tInhibits mTOR kinase by binding to FKBP12 | \n\t\t\tPhase I | \n\t\t\tGlioblastoma, non-small cell lung cancer | \n\t\t\t[182] | \n\t\t
RAD001 | \n\t\t\tEverolimus (Novartis) | \n\t\t\tInhibits mTOR kinase by binding to FKBP12 | \n\t\t\tPhase I/II/III (FDA has approved for RCC, 2009) \n\t\t\t | \n\t\t\tMetastatic renal cell carcinoma, breast cancer, melanoma, ovarian cancer, neuroendocrine tumors of the pancreatic origin (PNET), endometrial carcinoma | \n\t\t\t[56,133,134,135,136], NCT01939418, NCT01931163 | \n\t\t
CCI-779 | \n\t\t\tTemsirolimus (Wyeth/Pfizer) | \n\t\t\tInhibits mTOR kinase by binding to FKBP12 | \n\t\t\tPhase I/II/III (FDA and European Medicine Agency have approved for RCC, 2007) | \n\t\t\tNon-small cell lung cancer; advanced solid tumors, metastatic renal cell carcinoma, hepatocellular carcinoma, cervical cancer, clear cell adenocarcinoma | \n\t\t\t[138,139,141] \n\t\t\t | \n\t\t
MK-8669/AP23573 | \n\t\t\tRidaforolimus | \n\t\t\tInhibits mTOR kinase by binding to FKBP12 | \n\t\t\tPhase I/II/III \n\t\t\t | \n\t\t\tSarcoma, bone, endometrial cancer | \n\t\t\t[144,145] | \n\t\t
PP242 | \n\t\t\t\n\t\t\t | ATP competitive inhibitor of mTOR | \n\t\t\tStudies | \n\t\t\tColon cancer, acute myeloid leukemia | \n\t\t\t[156] | \n\t\t
Torin2 | \n\t\t\t\n\t\t\t | ATP competitive inhibitor of mTOR | \n\t\t\tStudies | \n\t\t\tLung cancer | \n\t\t\t[159] | \n\t\t
AZD8055 | \n\t\t\t\n\t\t\t | ATP competitive inhibitor of mTOR | \n\t\t\tPhase I \n\t\t\t | \n\t\t\tAdvanced solid tumors, lymphoma \n\t\t\t | \n\t\t\t[183,184] | \n\t\t
OSI-027 | \n\t\t\t\n\t\t\t | ATP competitive inhibitor of mTOR | \n\t\t\tPhase I \n\t\t\t | \n\t\t\tAdvanced solid tumors, lymphoma \n\t\t\t | \n\t\t\t[185] | \n\t\t
INK128 | \n\t\t\t\n\t\t\t | ATP competitive inhibitor of mTOR | \n\t\t\tPhase I | \n\t\t\tGlioblastoma, advanced solid tumors. | \n\t\t\tNCT02142803 | \n\t\t
GSK795 | \n\t\t\t\n\t\t\t | ATP competitive inhibitor of mTOR | \n\t\t\tPhase I \n\t\t\t | \n\t\t\tAdvanced solid tumors | \n\t\t\t[134] | \n\t\t
NVP-BEZ235 | \n\t\t\t(Novartis) | \n\t\t\tDual mTOR/PI3K | \n\t\t\tPhase I/II | \n\t\t\tAdvanced solid tumors, breast cancer, prostate cancer | \n\t\t\t[94], NCT00620594 | \n\t\t
BGT226 | \n\t\t\t(Novartis) | \n\t\t\tDual mTOR/PI3K | \n\t\t\tPhase I \n\t\t\t | \n\t\t\tAdvanced solid tumors, breast cancer | \n\t\t\t[169], NCT00600275, NCT00742105 | \n\t\t
GDC-0980 | \n\t\t\t(Genentech) | \n\t\t\tDual mTOR/PI3K | \n\t\t\tPhase I/II \n\t\t\t | \n\t\t\tNon-Hodgkin lymphoma, endometriose | \n\t\t\tNCT00854126, NCT00854152, NCT01455493 | \n\t\t
PF-04691502 | \n\t\t\t(Pfizer) | \n\t\t\tDual mTOR/PI3K | \n\t\t\tPhase I \n\t\t\t | \n\t\t\tAdvanced solid tumors | \n\t\t\tNCT00927823 | \n\t\t
GSK2126458 | \n\t\t\tGlaxoSmithKline | \n\t\t\tDual mTOR/PI3K | \n\t\t\tPhase I \n\t\t\t | \n\t\t\tAdvanced solid tumors | \n\t\t\tNCT00972686, NCT01248858 | \n\t\t
XL765 | \n\t\t\t(Exelixis) | \n\t\t\tDual mTOR/PI3K | \n\t\t\tPhase I/II \n\t\t\t | \n\t\t\tNon-small cell lung cancer, breast cancer, gliomas | \n\t\t\tNCT00777699, NCT01082068, NCT00704080 | \n\t\t
Overview of PI3K/AKT/mTOR pathway inhibitors.
Advances in molecular research have resulted in an improved understanding of cancer biology. There is strong preclinical rationale to support the continued development of PI3K/AKT/mTOR inhibitors, especially in some genetically defined cancer subtypes that may be the most sensitive to single-agent PI3K pathway inhibitors. These include cancers with PIK3CA activating mutations, mutations in PIK3R (p85 subunit), mutations or amplifications in one of the AKT isoforms or loss of PTEN. However, rational clinical trials design with a focus in identifying a patient population most likely to benefit from this strategy is imperative to the success of single-agent therapeutics.
The combination of PI3K/AKT/mTOR inhibitors with cytotoxic chemotherapy and other biological agents such as anti-HER2 compounds, EGFR inhibitors, and antiangiogenic agents may optimize the action of those agents in different pathways that control protein translation, cell growth, migration, metastasis, and angiogenesis. The successful development of the combinations will require determining the duration, doses, and schedules of targeted therapy and how to best incorporate it into standard treatment protocols. Several clinical trials are underway to prove the clinical use of the PI3K/AKT/mTOR inhibitors. The druggability of the components of the PI3K/AKT/mTOR signaling cascade, in addition to the enlightenment of the mutational landscape of human cancers, which points to the high frequency of genetic alterations and anomalous activation of the pathway, strongly suggests that targeting its elements might represent a useful treatment strategy in the fight against cancer.
Review of numerical and approximate methods for the modal analysis of general optical dielectric waveguides with emphasis on recent developments has been published [1]. In this review, interesting methods are given such as, the finite-difference and the finite-element methods. Review of numerical methods for the analysis of the homogeneous and inhomogeneous, isotropic and anisotropic, microwave and optical dielectric waveguides with arbitrarily-shaped cross sections has been published [2]. The main approaches as the integral equations, finite difference, and finite element have been discussed.
A fundamental and accurate approach to compute the attenuation of electromagnetic waves propagating has been proposed [3]. The propagation constant was found by substituting the values of transverse wave numbers into the dispersion relation. A Green’s dyadic for describing the propagating electromagnetic waves in a rectangular dielectric waveguide has been developed [4]. The use of Green’s dyadic developed in order to calculate the effect of small perturbations upon the system.
An analytical method for solution of one-dimensional optical systems, based on the differential transfer matrices has been presented [5]. An approach to solve the problem of the propagation of electromagnetic waves in unidimensional media with an arbitrary variation of their dielectric permittivity has been proposed [6]. This method was deduced from the Maxwell equations with a minimum of approximations and allows a full vectorial description of both the electric and magnetic fields through the direct calculation of their cartesian coordinates. The equations permit the simulation of materials with a continuous variation of their dielectric permittivity without approximating them by discontinuous layered media, reducing so the computational effort of the models.
An analytical method for solution of non-homogeneous anisotropic optical systems, based on the extension of transfer matrices into differential form has been presented [7]. This approach can be used for exact calculation of various functions including reflection and transmission coefficients, band structures and bound states. A full-wave analysis of lossy dielectric waveguides using a hybrid vector finite element method has been presented [8]. The direct matrix solution technique with minimum degree of reordering has been combined with the modified Lanczos algorithm to solve for the resultant sparse generalized eigenmatrix equation efficiently.
Three-dimensional finite-element method with edge elements for electromagnetic waveguide discontinuities has been proposed [9]. This paper shows that the finite-element method using edge elements succeeds in suppressing spurious solutions and moreover that this method succeeds in the analysis of three-dimensional electromagnetic waveguide problems with metal wedges. An analytical approach based on scalar wave approximation to estimate the modal dispersion characteristics and cutoff condition of an optical waveguide has been presented [10]. This approach has an arbitrary and uniform core cross-section. The structure represents the core of a circular waveguide which is compressed at both the ends of a diameter.
Propagation characteristics of modes in some rectangular waveguides using the finite-difference time-domain method have been studied [11]. The method in this paper was used to determine the modal characterization of rectangular waveguide structures by means of a least-square non-linear fitting to a theoretical modal expansion. Wave propagation along a rectangular waveguide with slowly varying width has been investigated [12] with the help of field theory and approximate circuit theory. Many properties of the modulated periodic structure, e.g., the frequency dependence of the propagation constant, group and phase velocities, and the electric field axial variation for the fundamental space harmonic and its filter-like property have been investigated.
A method for measuring samples using a partially-filled waveguide has been presented [13]. A mode-matching technique was used to determine the fields in the three regions. An advantageous finite element method for the rectangular waveguide problem has been developed [14] by which complex propagation characteristics may be obtained for arbitrarily shaped waveguide.
A method has been introduced for the frequency domain analysis of arbitrary longitudinally inhomogeneous waveguides [15]. The integral equations of the longitudinally inhomogeneous waveguides, converted from their differential equations, were solved using the method of moments. A method has been introduced for the frequency domain analysis of arbitrarily loaded lossy and dispersive nonuniform transmission lines [16]. In this method, all distributed primary parameters of the line and also the voltage and current distribution along the line were considered as a Taylor’s series.
A technique based on the two-dimensional Fourier transform has been presented [17] and applied to the study of nonlinear wave propagation phenomena in one-dimensional, finite, nonlinear transmission lines.
A method for calculating the modes of arbitrarily shaped dielectric waveguides has been presented [18]. It consists of expanding the field in a two-dimensional Fourier series. The expansion has been used to convert the scalar wave equation into a matrix eigenvalue equation. A transfer matrix function for the analysis of electromagnetic wave propagation along the straight dielectric waveguide with arbitrary profiles has been proposed [19]. This method is based on the Laplace and Fourier transforms and the inverse Laplace and Fourier transforms.
In this chapter, we present some examples of dielectric structures as shown in Figure 1a–e. The method is based on Fourier transform, thus we need use with the image method and periodic replication for fulfilling the boundary conditions of the metallic waveguide. We relate also to the complementary shapes for different applications. The periodicity and the symmetry properties are chosen to force the boundary conditions at the location of the walls in real problem, by extending the waveguide region (
The image method and periodic replication for five examples. (a). The cross section entirely filled with the dielectric material, (b). The dielectric material is located in the center of the cross section, (c). The hollow waveguide where the hollow rectangle is located in the center of the cross section, (d). The cross section consists with four dielectric profiles, and (e). The hollow waveguide with four hollow rectangles.
Note that the geometries from Figure 1a–e become more complex. Calculating of the dielectric profile for Figure 1a is the simplest and for Figure 1e is the most complicated in relation to the examples described in these examples. The integrals of the dielectric profiles of the geometries described in Figure 1a and b can be calculated by analytical form and without solving numerical form. The calculation of the dielectric profile for the geometry of Figure 1c for a hollow rectangle in the center is interesting in the case of hollow waveguide, but it is more complicated than the case of Figure 1b. Therefore, in this case we should calculate the dielectric profile by substracting the dielectric profile of Figure 1b from the dielectric profile of Figure 1a. The calculation of the integrals of the dielectric profiles for the geometries depicted in Figure 1d and e are already more complicated, and in such cases the proposed techniques require that the integrals be solved numerically. We will explain the proposed technique for calculating the dielectric profile for each case.
Figure 2c represents an example of receiving a hollow waveguide where the hollow rectangle is located in the center by substracting the waveguide with dielectric material located at the center of the cross section (Figure 2b) from the waveguide entirely filled with the dielectric material (Figure 2a), and by using the image method (Figure 2d). Figure 3c represents an example of receiving a hollow waveguide with four hollow rectangles by substracting the four dielectric rectangles (Figure 3b) from the waveguide entirely filled with the dielectric material (Figure 3a), and by using with the image method (Figure 3d).
Example of receiving a hollow waveguide where the hallow rectangle is located in the center (c) by substracting the waveguide with dielectric material located at the center of the cross section (b) from the waveguide entirely filled with the dielectric material (a), and by using the image method (d).
Example of receiving a hollow waveguide with four hollow rectangles (c) by substracting the four dielectric rectangles (b) from the waveguide entirely filled with the dielectric material (a), and by using the image method (d).
This section presents a technique to calculate the dielectric profile for the two inhomogeneous geometries of the cross section, as shown in Figure 4a and b.
Two examples of the complementary shapes of profiles in the cross section and the periodic replication, (a). The dielectric material is located in the center of the cross section with the relevant parameters of
Figure 4a and b show the cross section of Figure 1b and c, respectively, with the relevant parameters. These figures represent two examples of the complementary shapes in the cross section. The periodic replication is shown in Figure 4c by using with the image method. The dielectric material in Figure 4a is located in the center of the cross section. The hollow rectangle in Figure 4b is located in the center of the cross section in the case of the hollow waveguide.
The dielectric profile
where
For the cross section as shown in Figure 4a and according to Figure 4c, the center of the dielectric rectangle is located at (a/2, b/2). According to Figure 4a and c, the Fourier components of the dielectric profile are given by
Similarly, for the cross section entirely filled with the dielectric material as shown in Figure 1a, the Fourier components of the dielectric profile are given by
The Fourier components of the dielectric profile (
Figure 5a and b show the cross section of Figure 1d and e, respectively, with the relevant parameters. These figures represent two examples of the complementary shapes in the cross section. The cross section consists with four dielectric profiles as shown in Figure 5a. The hollow waveguide with four hollow rectangles is shown in Figure 5b. The centers of the first, the second, the third and the firth dielectric rectangles in Figure 5a and hollow rectangles in Figure 5b are located at the points (a/4, b/4), (3a/4, b/4), (a/4, 3b/4), and (3a/4, 3b/4), respectively. The calculation of the elements of the matrix in Figure 5b is already more complicated. Thus, the Fourier components of the dielectric profile (
Two examples of the complementary shapes of profiles in the cross section and their relevant parameters. The centers of the first, the second, the third and the firth rectangles are located at the points (a/4, b/4), (3a/4, b/4), (a/4, 3b/4), and (3a/4, 3b/4), respectively: (a) the cross section consists with four dielectric profiles with the relevant parameters of
In order to calculate the elements of the dielectric profiles of the inhomogeneous geometry of the cross section in Figure 5a, we can use with the
The
It is good idea to calculate the dielectric profile of Figure 4a again, by using the
and
where
Similarly, we can calculate the rectangular dielectric profile according to the location of the profile in the cross section of the waveguide.
The elements of the matrix in Fourier space of the inhomogeneous geometry described in Figure 4a are given in the case of b
Figure 5a shows the cross section where the centers of the first, the second, the third and the firth rectangles are located at the points (a/4, b/4), (3a/4, b/4), (a/4, 3b/4), and (3a/4, 3b/4), respectively, and for
The dielectric profile of Figure 5a is given according to the
and
where
The elements of the matrix for the inhomogeneous geometry of the cross section of Figure 5a are calculated in Fourier space by
According to Ref. [19]. The cyclic matrix
Similarly, the
The proposed technique to calculate the elements of the matrix
This section presents several examples for the different geometries in the cross section. Five examples of the different discontinuous cross sections and complementary shapes are demonstrated in Figure 1a–e. All the next graphical results are demonstrated as a response to a half-sine (
Figure 7a–e shows the results of the output field as a response to a half-sine (
The output field as a response to a half-sine (
The results of Figure 7a–e are demonstrated for
The output field for the hollow rectangular waveguide where the dielectric material is located between the hollow rectangle and the metal is shown in Figure 8a–d, where a = b = 20 mm, and c = d = 14 mm. In this case the thickness of the dielectric layer is equal to 3 mm (e = f = 3 mm). The results are demonstrated for
The output field as a response to a half-sine (
We can find the relevant parameters to obtain the Gaussian behavior of the output field. We can show that the Gaussian behavior is obtained when the thickness of the dielectric layer is equal to 3 mm, as shown in the results of Figure 8a–d. The output results are strongly affected by the thickness of the dielectric layer.
Figure 9a–d shows the results of the output field as a response to a half-sine (
The output field as a response to a half-sine (
Figure 10a–d shows the results of the output field as a response to a half-sine (
The output field as a response to a half-sine (
By increasing only the parameter
The applications are useful for straight waveguides in millimeter regimes, in the cases where the dielectric profile is located in the center of the cross section, for the cases where the hollow rectangle is located in the center of the cross section, and also for complicated and discontinuous profiles in the cross section.
This chapter presents two interesting types of dielectric materials in the straight rectangular waveguides and their applications. Five examples of the different discontinuous cross section were demonstrated. The effective technique was proposed for all case of Figure 1a–e, in order to calculate the dielectric material in the specific cross section.
The proposed techniques are very important to understand the influence of the dielectric materials and the hollow rectangles in all case of discontinuous geometry in the cross section. All the graphical results are demonstrated as a response to a half-sine (
The method is based on Fourier transform, thus we need use with the image method to calculate the dielectric profile in the cross section. The image method and periodic replication are needed for fulfilling the boundary condition of the metallic waveguide.
Figure 8a–e relates to the hollow rectangular waveguide where the hollow rectangle is located in the center of the cross section as shown in Figure 4b. We can find the relevant parameters to obtain the Gaussian behavior of the output field. From the results of Figure 8a–e, the Gaussian behavior is obtained when the thickness of the dielectric layer is equal to 3 mm. The output results are strongly affected by the thickness of the dielectric layer.
By increasing only the parameter
The applications are useful for straight waveguides in millimeter regimes, in the cases where the dielectric profile is located in the center of the cross section, for cases where the hollow rectangle is located in the center of the cross section, and also for complicated and discontinuous profiles in the cross section.
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Various environmental attributes in these seven KPIs in the workplace affect not only health but also performance and engagement of employees via their physical, mental, and social interactions within the environment. For instance, ergonomics, acoustics, lighting, thermal comfort, and olfactory comfort address the overall physical comfort while biophilic components contribute to employee cognitive functions as well as their capacity to cope with mental stress and fatigue. These seven KPIs of workplace health ultimately contribute to five positive organizational outcomes, including healthy organizational culture, higher productivity, improved individual health and safety, financial savings, and enhanced reputation of the organization. This chapter discusses critical health factors in the workplace and their contributions to the capacity of human capital at the individual as well as organizational levels.",book:{id:"8529",slug:"indoor-environment-and-health",title:"Indoor Environment and Health",fullTitle:"Indoor Environment and Health"},signatures:"Young Lee",authors:null},{id:"67890",title:"Air Quality and Airflow Characteristic Studies for Passenger Aircraft Cabins",slug:"air-quality-and-airflow-characteristic-studies-for-passenger-aircraft-cabins",totalDownloads:1217,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This chapter summarizes the work done at the Airliner Cabin Environment Research Lab (ACERL) related to air quality, airflow characteristics, and human thermal comfort inside aircraft cabins. The laboratory is part of the Institute for Environmental Research (IER) at Kansas State University. It has a Boing 767 mockup cabin, bleed air simulator, and a Boeing 737 actual aircraft section that were all utilized to conduct experimental studies to understand air quality inside aircraft cabins. The studies summarized in this chapter include particle image velocimetry (PIV) investigations, particle dispersion, computational fluid dynamics (CFD) simulations, tracer gas and smoke visualization studies, and bleed air investigations. The chapter also summarizes other related studies including virus dispersion, air quality monitoring devices, and related developed air quality standards. The scope of this chapter is to summarize the setup and results of each of the above categories. This summary along with the cited references provides results for full size aircraft cabin environments, helps validate data for CFD simulations, and provides comparison data for other similar studies. This helps improve the design of future aircraft cabins and their ventilation systems and recommends changes to maintenance practices done that can improve the health and safety of humans inside these enclosed compartments.",book:{id:"8529",slug:"indoor-environment-and-health",title:"Indoor Environment and Health",fullTitle:"Indoor Environment and Health"},signatures:"Maher Shehadi",authors:null},{id:"67373",title:"Noise Calculation Charts and Indoor Environmental Quality for Evaluating Industrial Indoor Environment and Health",slug:"noise-calculation-charts-and-indoor-environmental-quality-for-evaluating-industrial-indoor-environme",totalDownloads:1157,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Noise, defined as “a sensation of unwanted intensity of a wave,” is perception of a pollutant and a type of environmental stressor. An environmental stressor such as noise may have detrimental effects on various aspects of health. The unwanted intensity of a wave is a propagation of noise due to transmission of waves (viz. physical agents) such as sun, light, sound, heat, electricity, fluid, and fire. The effects of these physical agents on human health as noise-intruding elements in an industrial indoor environment are discussed. Noise characterization is discussed from indoor air quality and health perspective. The noise calculation charts are detailed for interference of noise waves based on a benchmark solution. These charts calculate positive and negative magnitudes of noise based on noise characterization of waves due to power difference of two intensities. The noise interference is calculated from newly devised noise measurement equations and their units. The grades and flag colors are notated to the noise calculation charts. Furthermore, illustrated examples of noise characterization calculations for indoor environment are presented using devised noise measurement equations. Indoor environmental quality and noise instrumentation are discussed. Adverse effects of pollutants on human health are summarized. Ventilation systems for dispersion of pollutants from industrial indoor environment are also elaborated.",book:{id:"8529",slug:"indoor-environment-and-health",title:"Indoor Environment and Health",fullTitle:"Indoor Environment and Health"},signatures:"Himanshu Dehra",authors:[{id:"12304",title:"Mr.",name:"Himanshu",middleName:null,surname:"Dehra",slug:"himanshu-dehra",fullName:"Himanshu Dehra"}]},{id:"19157",title:"Interaction of Urban Vegetation Cover to Sequester Air Pollutants from Ambient Air Environment",slug:"interaction-of-urban-vegetation-cover-to-sequester-air-pollutants-from-ambient-air-environment",totalDownloads:3906,totalCrossrefCites:4,totalDimensionsCites:5,abstract:null,book:{id:"488",slug:"air-pollution-new-developments",title:"Air Pollution",fullTitle:"Air Pollution - New Developments"},signatures:"Sharda Dhadse, D. G. Gajghate, P.R. 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For each site, two different locations were chosen to examine the coarse particles (PM10 and PM5.0) and fine particles (PM2.5, PM1.0, PM0.5 and PM0.25) concentrations and metal concentration of Zn, Pb, Ni, Fe, Cr, Cd, Mg and Cu in PM2.5 and for their related health effects. The exposure factor and health risk assessment for carcinogenic effects due to heavy metal contaminants have also been calculated for adults working in different microenvironment by following the methodology prescribed by US EPA.",book:{id:"8529",slug:"indoor-environment-and-health",title:"Indoor Environment and Health",fullTitle:"Indoor Environment and Health"},signatures:"Mahima Habil, David D. 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",coverUrl:"https://cdn.intechopen.com/series/covers/22.jpg",latestPublicationDate:"June 27th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"356540",title:"Prof.",name:"Taufiq",middleName:null,surname:"Choudhry",slug:"taufiq-choudhry",fullName:"Taufiq Choudhry",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000036X2hvQAC/Profile_Picture_2022-03-14T08:58:03.jpg",biography:"Prof. Choudhry holds a BSc degree in Economics from the University of Iowa, as well as a Masters and Ph.D. in Applied Economics from Clemson University, USA. In January 2006, he became a Professor of Finance at the University of Southampton Business School. He was previously a Professor of Finance at the University of Bradford Management School. He has over 80 articles published in international finance and economics journals. His research interests and specialties include financial econometrics, financial economics, international economics and finance, housing markets, financial markets, among others.",institutionString:null,institution:{name:"University of Southampton",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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Dr. Khalid\\'s research interests include leadership and negotiations, digital transformations, gamification, eLearning, blockchain, Big Data, and management of information technology. Dr. Bilal Khalid also serves as an academic editor at Education Research International and a reviewer for international journals.",institutionString:"KMITL Business School",institution:{name:"King Mongkut's Institute of Technology Ladkrabang",country:{name:"Thailand"}}},{id:"418514",title:"Dr.",name:"Muhammad",middleName:null,surname:"Mohiuddin",slug:"muhammad-mohiuddin",fullName:"Muhammad Mohiuddin",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038UqSfQAK/Profile_Picture_2022-05-13T10:39:03.jpg",biography:"Dr. Muhammad Mohiuddin is an Associate Professor of International Business at Laval University, Canada. He has taught at Thompson Rivers University, Canada; University of Paris-Est, France; Osnabruck University of Applied Science, Germany; and Shanghai Institute of Technology and Tianjin University of Technology, China. He has published research in Research Policy, Applied Economics, Review of Economic Philosophy, Strategic Change, International Journal of Logistics, Sustainability, Journal of Environmental Management, Journal of Global Information Management, Journal of Cleaner Production, M@N@GEMENT, and more. He is a member of CEDIMES Institut (France), Academy of International Business (AIB), Strategic Management Society (SMS), Academy of Management (AOM), Administrative Science Association of Canada (ASAC), and Canadian council of small business and entrepreneurship (CCSBE). He is currently the director of the Research Group on Contemporary Asia (GERAC) at Laval University. He is also co-managing editor of Transnational Corporations Review and a guest editor for Electronic Commerce Research and Journal of Internet Technology.",institutionString:"Université Laval",institution:{name:"Université Laval",country:{name:"Canada"}}},{id:"189147",title:"Dr.",name:"Hailan",middleName:null,surname:"Salamun",slug:"hailan-salamun",fullName:"Hailan Salamun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/189147/images/19274_n.jpeg",biography:"Hailan Salamun, (Dr.) was born in Selangor, Malaysia and graduated from Tunku Ampuan Jamaah Religious High School at Shah Alam. Obtained a degree from the International Islamic University (UIA), Gombak in the field of Islamic Revealed Knowledge and Heritage. Next, I furthered my studies to the professional level to obtain a Diploma in Education at UIA. After serving for several years in school, I furthered my studies to the Master of Dakwah and Leadership at Universiti Kebangsaan Malaysia (UKM), Bangi. 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