The PI3K proteins family
\r\n\tThis book aims to comprise the current state of the art of the drying operations, at a laboratory and industrial scale, through the presentation of chapters that cover the fundamentals and applications of the different drying methods such as convective, freeze (lyophilization), osmotic, supercritical, vacuum- and irradiation-assisted drying. The comparison, analysis, modeling, and scale-up of the diverse type of dryers are also topics under the scope of the book. Besides, the engineering aspects of drying are considered, specifically the drying kinetics and the transport phenomena during the process, as well as energy consumption, operating costs, equipment safety, and environmental controls.
",isbn:"978-1-83880-110-6",printIsbn:"978-1-83880-109-0",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"3ebb761607fa27f2d32dd269ee2f2c0f",bookSignature:"Dr. Israel Pala-Rosas",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8540.jpg",keywords:"convective drying, freeze drying, supercritical drying, cabinet tray dryer, drum dryer, equilibrium moisture, bound moisture, drying kinetics, drying constant, dryer design, dryer scale-up",numberOfDownloads:97,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 1st 2019",dateEndSecondStepPublish:"August 22nd 2019",dateEndThirdStepPublish:"October 21st 2019",dateEndFourthStepPublish:"January 9th 2020",dateEndFifthStepPublish:"March 9th 2020",remainingDaysToSecondStep:"4 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,editors:[{id:"284261",title:"Dr.",name:"Israel",middleName:null,surname:"Pala-Rosas",slug:"israel-pala-rosas",fullName:"Israel Pala-Rosas",profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:"Israel Pala-Rosas is Biochemical Engineer by the Instituto Tecnológico de Tehuacán (ITT), Master in Chemical Engineering by the Benemérita Universidad Autónoma de Puebla (BUAP) and Doctor in Sciences in Chemical Engineering by the Escuela Superior de Ingeniería Química e Industrias Extractivas del Instituto Politécnico Nacional (ESIQIE-IPN). \r\n\r\nCurrently, Israel Pala develops research at ESIQIE-IPN and at the Laboratorio de Procesos Catalíticos of the Universidad Autónoma Metropolitana-Azcapotzalco (UAM-A).\r\n\r\n His interest lies in, but is not limited to, the research and development of catalytic and biotechnological processes for the transformation of biomass to value-added compounds and biofuels, regarding the synthesis, characterization, and testing of catalysts, as well as the design and analysis of (bio)chemical reactors. Areas related to the catalytic processes, such as chemical thermodynamics and unit operations, are also under his scope.",institutionString:"Instituto Politécnico Nacional",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Instituto Politécnico Nacional",institutionURL:null,country:{name:"Mexico"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:[{id:"69858",title:"The Study of Fabric Drying Using Direct-Contact Ultrasonic Vibration",slug:"the-study-of-fabric-drying-using-direct-contact-ultrasonic-vibration",totalDownloads:8,totalCrossrefCites:0,authors:[null]},{id:"69050",title:"Convective Drying in the Multistage Shelf Dryers: Theoretical Bases and Practical Implementation",slug:"convective-drying-in-the-multistage-shelf-dryers-theoretical-bases-and-practical-implementation",totalDownloads:71,totalCrossrefCites:0,authors:[null]},{id:"69796",title:"Kinetics of Drying Medicinal Plants by Hybridization of Solar Technologies",slug:"kinetics-of-drying-medicinal-plants-by-hybridization-of-solar-technologies",totalDownloads:25,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"270941",firstName:"Sandra",lastName:"Maljavac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/270941/images/7824_n.jpg",email:"sandra.m@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:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],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"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.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"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3794",title:"Swarm Intelligence",subtitle:"Focus on Ant and Particle Swarm Optimization",isOpenForSubmission:!1,hash:"5332a71035a274ecbf1c308df633a8ed",slug:"swarm_intelligence_focus_on_ant_and_particle_swarm_optimization",bookSignature:"Felix T.S. Chan and Manoj Kumar Tiwari",coverURL:"https://cdn.intechopen.com/books/images_new/3794.jpg",editedByType:"Edited by",editors:[{id:"252210",title:"Dr.",name:"Felix",surname:"Chan",slug:"felix-chan",fullName:"Felix Chan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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"}}]},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\tSubunit\n\t\t\t | \n\t\t\t\n\t\t\t\tProtein\n\t\t\t | \n\t\t\t\n\t\t\t\tGene name (human)\n\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 in vitro and in xenograft models [51,52].
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 Penicillium wortimannin that irreversibly inhibits p110 by reacting covalently with the catalytic site [57], and LY294002, a synthetic, competitive, and reversible inhibitor of the ATP binding site of PI3K [58]. Both agents achieve significant antiproliferative and pro-apoptotic effects in preclinical in vitro and in vivo studies. However, unfavorable pharmacokinetic properties, insolubility in water, high levels of toxicity, and lack of selectivity for oncogenic isoforms of Class I PI3K limit its use in clinical trials [59,60]. Although this limiting features for their clinical use, wortmannin and LY294002 have served as important research tool for elucidating diverse signal transduction processes involving PI3K pathway and has spawned a new generation of PI3K inhibitors [61] (Table 2).
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 in vivo antitumor activity against numerous mouse xenograft models of human cancers [62,63]. In addition, a phase I study in eighty-four patients with advanced solid tumors showed that PX-866 is well tolerated. The most frequent study drug-related adverse events were gastrointestinal disorders, with diarrhea being the most common [64]. PX-866 is being currently tested in a combination phase I/II studies with cetuximab (NCT01252628) in squamous cell carcinoma of the head and neck (SCCHN) and in metastatic colorectal carcinoma. Furthermore, more two phase I/II studies with PX866 are ongoing: with docetaxel (NCT01204099) in non-small cell lung cancer and SCCHN and in combination with vemurafenib in patients with advanced melanoma (NCT01616199).
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]. In vivo studies have also shown that buparlisib potently inhibits the growth of human xenografts models and behaves synergistically when combined with cytotoxic agents such as temozolomide, alkylating agent, and docetaxel, antimitotic drug, or with targeted agents such as HER2 and mitogen-activated protein kinase kinase (MEK) inhibitors [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 vitro tests revealed that pilaralisib inhibits the formation of PIP3 in the membrane and phosphorylation of AKT and S6K-1 in multiple tumor cell lines with diverse genetic alterations in PI3K pathway [70]. Moreover, in mouse xenograft models, oral administration of pilaralisib results in significant tumor growth inhibition and combination with chemotherapeutic agents improved the growth-inhibitory effect observed with the single agents [71]. Based on this preclinical rationale, pilaralisib has been evaluated in phase I/II clinical trials.
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 vivo antitumor activity has also been observed when administered orally in combination with other anticancer drugs, for example, docetaxel and MEK inhibitor U0126 [77-80].
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 (PIK3CA mutations) in several cancers [82]. However, p110α is dispensable for PI3K pathway activation in tumors lacking PTEN. Thus, these cells depend largely on p110β to activate the pathway [82,83]. Preclinical tests showed that p110β-selective inhibitors had a significantly greater activity in cell lines with PTEN null than in those with PTEN intact, although, some PTEN-intact cell lines were sensitive and a number of cells lines lacking PTEN were resistant [84]. GSK-2636771 is a PI3K p110β-selective inhibitor currently in phase I studies in subjects with advanced solid tumors with PTEN deficiency (NCT01458067). Moreover, PI3Kδ is predominantly expressed in leukocytes and control immune responses [85]. Idelalisib (CAL-101), a highly specific PI3Kδ inhibitor, was the first isoform-specific PI3K inhibitors approved for cancer treatment [86].
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. In vivo studies have demonstrated dose-dependent antitumor activity of NVP-BYL719 in PIK3CA-mutant or PIK3CA-amplified tumor xenograft models, such as ovarian, breast, and head and neck cancers [88, 89]. Preliminary results of phase I study performed in patients with advanced solid tumors carrying PIK3CA gene alterations demonstrated that NVP-BYL719 has a favorable safety profile with manageable toxicities, as hyperglycemia, nausea, diarrhea, decreased appetite, vomiting, and fatigue [90]. To date, more than fifteen clinical trial is ongoing in order to evaluate the combination of NVP-BYL719 with several agents, such conventional cytotoxic drugs (paclitaxel, cisplatin, and irinotecan) and target drugs (cetuximab, olaparib, and trastuzumab) in a subset of cancers (NCT02051751, NCT01822613, NCT01602315, NCT01623349, and NCT02167854)
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 in vitro and in vivo against several human cancers such as breast, osteosarcoma, ovarian, multiple myeloma, leukemia, and glioma [100,101]. Additional in vitro data demonstrate synergistic effects of perifosine and traditional chemotherapeutic agents such as paclitaxel and cisplatin in ovarian cancer [102,103], etoposide in leukemia cells [104], doxorubicin in multiple myeloma cells [105], and gemcitabine in pancreatic cells [106].
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 in vitro and in vivo models of ovarian, breast, and prostate cancer [114]. The compound has entered phase I trials for refractory hematologic malignancies but was withdrawn prior to enrolment (NCT00666081).
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 Streptomyces hygroscopicus, and it has clinical applications including antifungal, immunosuppressant, and anticancer proprieties [117,118]. FDA approved this drug in 1997 for prevention of host-rejection during kidney transplants [119]. Preclinical studies have shown that rapamycin presents strong antiangiogenic and antiproliferative properties against a variety of human cancers such as the phase II study, which showed rapamycin potentiates the effect of paclitaxel in endometrial cancer cell lines [120].
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 in vivo [137]. This drug was valued with bevacizumab or in combination with chemotherapeutic agents in endometrial cancer cell lines, and results showed the increase progesterone mRNA expression and inhibition of ER mRNA expression [138,139]. Also, preliminary phase II study using temsirolimus in patients with metastatic cervical cancer showed positives results [140]. Another phase II clinical study (NCT01196429) evaluates additional effects of the temsirolimus combined with paclitaxel/carboplatin therapy have been conducted in patients with stages III/IV clear cell adenocarcinoma [141]. However, some studies failed to show the efficiency of temsirolimus in patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer showing a modest activity of this mTOR inhibitor, and the results were insufficient to justify further study in a phase III [142].
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 in vitro and in vivo showed decrease cell growth alone or in combination with MEK inhibitors [156]. Another ATP competitive inhibitor, Torin2, was developed to overcome the pharmacological limitations of Torin1 and it is a potent inhibitor of ATR, ATM, and DNA-PK [157,158]. Lung cancer cell treatment with Torin2 resulted in a prolonged block in negative feedback and consequent threonine-308 phosphorylation on AKT. These effects were associated with strong growth inhibition in vitro [159].
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. In vivo studies indicated that AZD8055 can inhibit tumor growth and AZD8055 showed promise as a therapeutic agent.
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 in vivo [183].
\n\t\t\t\tInhibitor\n\t\t\t | \n\t\t\t\n\t\t\t\tTrade name (company)\n\t\t\t | \n\t\t\t\n\t\t\t\tDrug target\n\t\t\t | \n\t\t\t\n\t\t\t\tDevelopment stage\n\t\t\t | \n\t\t\t\n\t\t\t\tTumor types\n\t\t\t | \n\t\t\t\n\t\t\t\tReference\n\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 in vitro and in vivo\n\t\t\t | \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 in vitro and in vivo\n\t\t\t | \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.
Noise is one of the important properties in optical amplifiers [1]. The intrinsic noise characteristic is determined by quantum mechanics, especially Heisenberg’s uncertainty principle. This chapter describes quantum noise in optical amplifiers in terms of quantum mechanics. After brief introduction of a classical treatment usually used in the optical communication field, properties of an optically amplified light, such as the mean amplitude, the mean photon number, and their variances, are derived based on first principles of quantum mechanics. Two kinds of optical amplifiers are treated: amplifiers based on two-level interaction in a population-inverted medium, i.e., an Erbium-doped fiber amplifier and a semiconductor optical amplifier, and those based on parametric interaction in an optical nonlinear medium. The results presented here provide the quantum mechanical basis to a phenomenological classical treatment conventionally employed for describing amplifier noise.
A classical treatment of amplifier noise is widely employed in the optical communication field [1, 2], whereas it originates from quantum mechanics. Before presenting a quantum mechanical treatment, we briefly introduce the classical treatment. We first consider the light intensity or the photon number outputted from an amplifier. A photon-number rate equation for light propagating through a population-inverted medium can be expressed as
where n is the number of photons, N2 and N1 are the numbers of atoms at the higher and lower energy states in the medium, respectively, and g is a constant representing the photon emission/absorption efficiency. The first, second, and third terms represent stimulated emission, absorption, and spontaneous emission, respectively. The efficiency g is common in this phenomenon in a simple two-level model [3]. Assuming that N1 and N2 are uniform along the medium length, the photon number at the output is calculated from Eq. (1) as
where L is the medium length. The first term represents amplified signal photons with a signal gain of exp[g(N2 – N1)L] ≡ G. The second term represents amplified spontaneous emission (ASE) photons, which can be rewritten as nsp(G – 1) with nsp ≡ N2/(N2 – N1). The parameter nsp is called “population inversion parameter” or “noise factor.” Note that the above equations are for the photon number in one mode in terms of the frequency and the polarization.
Eq. (2) shows that the output photon number is composed of amplified signal photons and ASE photons. Accordingly, the output amplitude is supposed to be a summation of amplitudes of amplified signal and ASE lights as
where Eout, Ein, and EASE are the amplitudes of the output light, the input signal light, and ASE light, respectively. The second term provides the ASE power as <|EASE|2> = nsp(G – 1)hfΔf, where < > denotes the mean value, hf is one photon energy, and Δf is the ASE bandwidth. Regarding the ASE phase, it is supposed to be completely random because spontaneous emission occurs randomly. Thus, the average of the ASE amplitude is supposed to be zero: <EASE> = 0. Here, we decompose EASE into the real and imaginary parts, which are supposed to be isotropic because the phase is random: <{Re[EASE]}2> = <{Im[EASE]}2> = <|EASE|2>/2 = nsp (G –1)hfΔf/2. Subsequently, the variance of each amplitude component is <{Re[EASE]}2> − <Re[EASE]>2 = <{Im[EASE]}2> − <Im[EASE]>2 = nsp(G – 1)hfΔf/2.
Intensity noise is evaluated using Eq. (3). The output intensity is given by Iout = |Eout|2, and its fluctuation is evaluated by the variance of Iout as
where the postulate of the ASE light phase being random is used in averaging. The first term represents 2 × <signal output intensity> × <ASE intensity>, which is called the “signal-spontaneous beat noise.” The second and third terms represent the intensity variance of the ASE light, which is called the “spontaneous-spontaneous beat noise.”
As an indicator for the amplifier noise performance, the “noise figure (NF)” is usually used. It is defined as the ratio of the signal-to-noise ratios (SNRs) at the input and output of an amplifier in terms of the optical intensity: NF ≡ (SNR)in/(SNR)out where SNR ≡ (mean intensity)2/(variance of the intensity) in the signal mode. The square of the mean intensity at the output is calculated from Eq. (3) as <|Eout|2> = G|Ein|2 + <|EASE|2>, and the output variance is expressed as Eq. (4); thus the output SNR is expressed as
On the other hand, the input SNR is evaluated for pure monochromatic light in the definition of the noise figure. In quantum mechanics, such a light is called “coherent state,” whose photon-number variance is equal to the mean photon number: <n2> − <n>2 = <n>. Thus, <|Ein|4> − <|Ein|2>2 = |Ein|2hf where hf is attached for the dimension to be matched. Subsequently, the input SNR is given by <|Ein|2>2/(<|Ein|4> − <|Ein|2>2) = |Ein|2/hf. Therefore, the NF is expressed as
where G|Ein|2 > > |EASE|2 is assumed, and <|EASE|2> = nsp(G – 1)hf is substituted because the signal mode is considered here.
The above-mentioned classical treatment is widely used for noise in optical amplifiers. However, it is based on phenomenological assumptions. (i) Eq. (3) is phenomenologically provided. Though the solution of the photon-number rate equation indicates that the output photon number is composed of amplified signal photons and ASE photons (Eq. (2)), this result does not logically conclude that the output amplitude is a linear summation of the amplified signal and the ASE amplitudes as Eq. (3). (ii) The phase of ASE light is assumed to be random, which is a phenomenological postulate, not logically derived from first principles. Although the above classical treatment is correct and useful in fact, we need quantum mechanics for theoretically confirming its validity, which is presented in the following sections.
In this section, we briefly review quantum mechanics, especially the Heisenberg picture [4]. The basic concept of quantum mechanics is that a physical state is probabilistic and the theory only provides mean values of physical quantities, which is given by a quantum mechanical inner product of a physical quantity operator
where
The most important operator in discussing quantum mechanical properties of light is the “annihilation operator,”
We discuss quantum noise of optical amplifiers in the following sections, using the above-mentioned framework of quantum mechanics. Note that the above operator
Erbium-doped fiber amplifiers (EDFAs) are widely used in optical communications. Optical semiconductor amplifiers are also being developed for compact and integrated amplifying devices. They amplify signal light through interaction between light and a two-level atomic system with population inversion. This section discusses quantum noise in population-inversion-based amplifiers [5].
The Hamiltonian for a light-atom interacting system can be expressed as [4]
The first and second terms are the Hamiltonians of light and atoms without interaction, respectively, where
Applying the above Hamiltonian to the Heisenberg equations for
Employing the variable translations
where Δωj ≡ ω – ωa(j), i.e., the frequency detuning between light and a two-level system.
We solve Eq. (10) by an iterative approximation. First, the first-order solutions are derived by substituting the initial values {
The solutions of these equations are
Next, these first-order solutions are substituted into the right-hand side of Eq. (10a), and the second-order solution is calculated as
We regard Eq. (13) as the time evolution of the field operator during a short time τ, and rewrite it as
where
Eq. (14) is the basic expression for discussing quantum properties of light that travels through an amplifier. For the discussion, we also need an initial state of the system at t0. It can be expressed as
where |Ψ(t0)> denotes the initial state of light, |Ψa(t0)> denotes that of atoms, and c1 and c2 are the probability amplitudes of an atom being in the lower and upper states, respectively, satisfying |c1|2 + |c2|2 = 1. We use Eqs. (14) and (16) in the following calculations.
We first discuss the mean amplitude. The mean amplitude, denoted as
The average of the transition operator
Assuming that the energy levels of each atom are densely distributed, the summation in this equation can be replaced by an integral in the frequency domain, and the real part of Eq. (18) is further calculated as
where Ω is the frequency detuning; ρ is the density of atoms in the frequency domain and is assumed to be constant around a resonant frequency Ω = 0 as ρ0; {κ, |c2|2, and |c1|2} are assumed to be identical for any atom; and N1 ≡ ρ0|c1|2 and N2 ≡ ρ0|c2|2 are the numbers of atoms at the lower and upper energy states, respectively. On the other hand, the imaginary part of Eq. (18) can be rewritten as
In this expression, the contents of the integral is an odd function around the resonant frequency Ω = 0. Thus, the imaginary part equals 0. Regarding the average of
Eq. (21) describes the time evolution of the mean amplitude of light traveling through an amplifying medium, i.e., the time evolution in a frame moving along with the light, during a short time. This expression can be translated to the spatial evolution along the medium length as
where g ≡ 2κ2π/v with v being the light velocity. Applying a Taylor expansion x(z0 + Δz) = x(z0) + [dx/dz](z0) × Δz to this equation, we obtain the following differential equation:
Eq. (23) includes (N2 – N1), which depends on the atoms’ state at a local position. Here, we assume that the atoms’ state is uniform along the medium length independent of z, and this condition is satisfied in uniformly pumped amplifiers with no gain saturation. With this assumption, Eq. (23) can be analytically solved, and the mean amplitude at the amplifier output is expressed as
where G ≡ exp[g(N2 – N1)L] with L being the amplifier length. This result, derived from the Heisenberg equation, is equivalent to the classical expression, i.e., Eq. (3) with <EASE > = 0, and confirms that the mean amplitude of ASE light is zero.
We next discuss the mean photon number. The short-time evolution of the photon-number operator is expressed from Eq. (14) as
from which the short-time evolution of the mean photon number is obtained as
In deriving Eq. (26), higher-order interaction terms are neglected, because the short-time evolution is considered here. This short-time evolution is translated to the short-length evolution along the medium length as
from which the following spatial differential equation is obtained:
This equation is equivalent to the photon-number rate equation given in Eq. (1). Therefore, similar to Eq. (1), the output of the mean photon number is calculated as
The first and second terms represent amplified signal photons and ASE photons, respectively. It is noted that ASE photons appear at the output even though there is no such light in the mean amplitude as shown in Eq. (24).
We next discuss amplitude fluctuations or noise. The light amplitude has two quadratures, i.e., the real and imaginary components. The operators representing each component are
From Eq. (14), the short-time evolution of the mean square of the real component is expressed as
where O(τ2) terms are neglected. On the other hand, the square of the average of the real component is expressed as
From Eqs. (30) and (31), the short-time evolution of the variance of the real component is obtained as
This equation is translated to the short-length evolution as
from which the following differential equation is obtained:
From Eq. (34), the variance of the real component at the output is calculated as
The variance of the imaginary component is similarly calculated as σx22(L) = Gσx22 (0) + (1/4)(2nsp – 1)(G – 1). The first term in Eq. (35) represents amplified fluctuations from the incident light, with a gain G whose square root equals the amplitude gain [Eq. (24)], and the second term represents additional fluctuations that are superimposed onto the amplified fluctuation through the amplification process. This input and output relationship of amplitude fluctuations can be schematically illustrated in the complex amplitude space (constellation) as shown in Figure 1.
Constellation diagram of amplified light.
For a coherent incident state, i.e., whose amplitude variances is σx12 (0) = σx22 (0) = 1/4 [4], Eq. (35) is rewritten as
The first term 1/4 corresponds to the inherent quantum noise of a coherent state, and the second term represents amplitude fluctuations at the amplifier output in a classical picture. Recalling that the mean amplitude at the amplifier output is that amplified from the incident light with no addition mean field, as indicated in Eq. (24), Eq. (36) suggests that the amplifier output can be regarded as a summation of a clean signal light (i.e., coherent state), displaced from the initial mean amplitude position, and fluctuating light, whose mean value and variance are 0 and nsp(G – 1)/2, respectively, in one quadrature. Figure 2 illustrates this output condition in the complex amplitude space. Noting that the variance of the fluctuating light equals half of the spontaneous photon number indicated in the second term in Eq. (28), we can say that the above picture illustrated in Figure 2 is equivalent to the classical picture of amplitude noise described in Section 2, where the ASE power is given by <|EASE|2> = nsp(G – 1)hfΔf and the variance of the real component of ASE light is given by <{Re[EASE]}2> − <Re[EASE]> = nsp(G – 1)hfΔf/2. Therefore, the classical picture introduced in Section 2 is confirmed by the quantum mechanical treatment presented here, except for the inherent quantum noise of 1/4. This noise 1/4 is sometimes called “vacuum fluctuation” or “zero-point fluctuation,” that appears owing to quantum mechanics.
Decomposition of amplified light in the constellation diagram.
We next discuss photon-number fluctuations. These fluctuations are evaluated employing the variance of the photon number as
where higher-order interaction terms are neglected as before. This expression can be translated to the short-length evolution as
from which the following differential equation is obtained:
with
Here,
From this equation and Eq. (29), the photon-number variance at the amplifier output is expressed as
Recalling that the mean photon numbers of the amplified signal and the spontaneous emission are
The first and second terms in Eq. (42) correspond to the classical intensity noise represented by Eq. (4), as described above, supporting the classical treatment. In addition, the inherent quantum noises are included in Eq. (42), owing to the full quantum mechanical treatment, and the amplified excess noise is simultaneously included as well. Sometimes in the classical treatment, the inherent quantum noise is phenomenologically added as the shot noise arising at the electrical stage after direct detection [2]. In fact, however, it exists in the optical stage as derived above. Therefore, the inherent quantum noise is sometimes called “optical shot noise.”
The noise figure, defined as the ratio of the signal-to-noise ratios (SNRs) at the input and output of an amplifier in terms of the light intensity or the photon number, is usually used as an indicator for the noise performance of an amplifier. Based on the above results, we describe the noise figure of population-inversion-based amplifiers in this subsection. The output SNR is obtained from Eqs. (29) and (42) as
where only the signal power and the signal-spontaneous beat noise are taken into account, assuming that the amplified signal is sufficiently larger than the spontaneous emission. On the other hand, the input SNR is evaluated for a coherent state, according to the definition of the noise figure, which is
This expression equals the classical result given by Eq. (6).
The noise figure is proportional to the population inversion parameter nsp = N2/(N2 – N1), as shown above. The minimum value of nsp is 1, which is achieved when N1 = 0, i.e., the fully inverted condition where all atoms are in the upper states. Under this condition, NF = 3 dB for G >> 1. This is the quantum-limited noise figure of population-inversion-based optical amplifiers. Near-quantum-limited noise figure has been demonstrated experimentally in Erbium-doped fiber amplifiers [6, 7].
The fact that the noise performance is determined by the population inversion parameter can be intuitively understood as follows. The source of amplifier noise is spontaneous emission. A small amount of spontaneous emission suggests a good noise performance. However, spontaneous emission is roughly proportional to the signal gain (Eq. (29)), which is desired to be high as an amplifier. Thus, the amount of spontaneous emission normalized to the signal gain, (ASE power)/(signal gain), can be an indicator for the noise performance. The spontaneous emission rate is proportional to the number of atoms in the upper energy level N2, i.e., (ASE power)∝N2, and the signal gain is determined by the balance between stimulated emission and absorption and thus is proportional to the difference between the numbers of atoms in the upper and lower states, roughly speaking, i.e., (signal gain)∝(N2 – N1). Subsequently, (ASE power)/(signal gain)∝N2/(N2 – N1) = nsp, which suggests that the amplifier noise performance is determined by the population inversion parameter nsp.
Whereas population-inversion–based amplifiers are widely used, there is another type of optical amplifiers, that is an optical parametric amplifier (OPA) based on optical nonlinearity [8]. When signal light is incident onto a nonlinear medium along with intense pump light, a signal and idler photons are created from one pump photon in case of second-order nonlinearity, satisfying the energy conservation of ℏωs + ℏωi = ℏωp (ωs, ωi, and ωp are the angular frequencies of the signal, idler, and pump lights, respectively), or they are created from two pump photons in case of third-order nonlinearity, satisfying ℏωs + ℏωi = ℏωp1 + ℏωp2. Through this photon exchange phenomenon, the signal light is amplified. This signal amplification scheme also offers optical signal processing functions such as wavelength conversion and generation of phase-conjugated light [9]. This section describes quantum noise in OPAs [10].
The Hamiltonian for parametric interaction between signal and idler via pump light(s) can be expressed as [11]
The first and second terms are the Hamiltonians of signal and idler lights without interaction, respectively, where
From the Heisenberg equation with the above Hamiltonian, temporal differential equations for the field operators are obtained as
These temporal differential equations can be translated to spatial ones as
where β = n (ω/c) is the propagation constant (n: the refractive index, c: the light velocity in the vacuum). The above equations can be simplified by the variable translation
Here, we consider the propagation phase of the right-hand term in the above equations. The coefficient χ includes the pump light amplitude as χ ∝Ep or Ep1Ep2, and the pump amplitude can be expressed as Ep = Ep (0)exp(−iβpz) under no pump-depletion condition (βp is the propagation constant of the pump light). Subsequently, χ ∝Ep (0)exp(−iβpz) or Ep1(0)Ep2(0) exp[−i(βp1 + βp2)z]. From these considerations, Eq. (48) can be rewritten as
where κ is the coupling coefficient in the spatial domain, excluding exp(−iβpz) or exp[−i(βp1 + βp2)z], and Δβ ≡ βs + βi – βp or βs + βi – βp1 – βp2. This parameter Δβ is called “phase mismatch,” and determines the signal gain of an OPA as shown later. As for κ, its absolute value is |κ| = dγ|Ep1| |Ep2| when an optical fiber is used as a nonlinear medium, where γ is the nonlinear coefficient, and d is the degeneracy factor that takes 2 and 1 for fp1 ≠ fp2 and fp1 = fp2, respectively. Regarding the phase of κ, it is determined by the incident phase(s) of the pump light(s).
From Eq. (49), the signal field operator at the output is calculated as
where g ≡ {|κ|2 – (Δβ/2)2}1/2, L is the medium length, and φ ≡ arg(κ). Eq. (50a) includes the field operators of signal and idler lights, i.e., the signal and the idler are treated separately. For particular frequency conditions such as 2ωs = ωp for the second-order nonlinearity or 2ωs = ωp1 + ωp2 for the third-order nonlinearity, the idler frequency equals to the signal frequency, ωi = ωs, and the signal and the idler are degenerate. Under such conditions, Eq. (50a) is rewritten as
As shown later, degenerate and nondegenerate OPAs have definitely different characteristics. For simplifying mathematical expressions, hereafter, we rewrite Eq. (50) as
with
The mean values of the physical quantities after amplification can be evaluated using Eq. (51). In the evaluation, we need the initial state in addition. Here, we assume that only signal light is incident to an OPA, and express the initial state as
The mean amplitude and photon number at the output are evaluated by
Eq. (53) indicates that the signal field is simply amplified while preserving the phase state, with no additional field on average. On the other hand, Eq. (54) shows that the output photons consist of two components. The first term is proportional to the incident photon number, which corresponds to the amplified signal photons with a gain of
It is noted in this expression that parameter g = {|κ|2 – (Δβ/2)2}1/2 is equivalent to the gain coefficient. When Δβ = 0, g is maximum and the signal gain is maximum. Therefore, it is important to satisfy the condition Δβ = 0, that is called the “phase matching condition,” in implementing an OPA [9]. The second term in Eq. (54) is independent on the signal input, and represents spontaneously emitted photons. The above results, i.e., the spontaneous light does not appear in the mean amplitude while it does in the photon number, suggest that the amplitude of the spontaneous emission is completely random. However, we do not know how random it is at this stage. The photon number of the spontaneous emission is expressed from the second term in Eqs. (54) and (52c) as
where Eq. (55) is applied. This expression is equivalent to the spontaneous photon number in population-inversion-based amplifiers indicated in Eq. (29) with nsp = 1. This correspondence suggests that nondegenerate OPAs can offer the ideal noise performance achievable in EDFAs, which is shown later.
Regarding degenerate OPA, on the other hand, its mean output amplitude is calculated as
where θ0 is the phase of the incident signal light. The mean output amplitude does not have a simple form as in nondegenerate OPA (Eq. (53)). Under the condition where Δβ = 0 and the gain coefficient g is so large as cosh(gL) ≈ sinh(gL) ≈ egL/2, Eq. (57) is approximated as
where Δ ≡ θ0 + (φ – ϕ)/2 is introduced. This expression indicates that the phase state of the incident signal light is not transferred to the output.
The mean photon number in degenerate OPA is calculated from Eq. (51) as
Unfortunately, this equation cannot be further developed, because we cannot readily calculate
In this expression, the first term represents amplified signal photons, and the second term represents spontaneous emission whose mean amplitude is zero as indicated in Eq. (57).
From the first term in Eq. (60), the signal gain is expressed as
which is dependent on the relative phase Δ = θ0 + (φ−ϕ)/2. Hence, degenerate OPA is called “phase-sensitive amplifier (PSA).” The maximum gain is obtained when Δ = 0 as
Next, we evaluate the amplitude noise in OPAs. For the evaluation, the light amplitude is decomposed into two quadratures and the variance of each quadrature is calculated, as in Section 4.3. In case of OPAs, the output field operator is phase-shifted by (φ + ϕ)/2, as indicated by Eq. (51). Accordingly, we introduce a phase-shifted field operator defined as
The calculation result for nondegenerate OPA is expressed as
where Eqs. (55) and (56) are applied. The first term represents noise amplified from the incident light, and the second term represents additional noise superimposed via OPA. Note that Eq. (63) is equivalent to the amplitude variance of population-inversion-based amplifiers shown by Eq. (35) with nsp = 1, suggesting that the ideal noise performance achievable in EDFAs can be obtained in OPA. Similar to Eq. (35), Eq. (63) is rewritten for a coherent incident state as
The first term is the inherent quantum noise of a coherent state, and the second term represents noise superimposed via OPA in a classical picture. The sum of the second terms of the two quadratures equals the photon number of spontaneous emission light indicated in Eq. (56). This consideration supports the classical noise treatment, described in Section 2, where spontaneous emission with random phase is superimposed onto signal light at the amplifier output.
For degenerate OPA, on the other hand, the amplitude variances are calculated as
where G0 ≡ G(Δ = 0) is the phase-synchronized gain introduced in Eq. (62). The results show that the output variances are unequal in the two quadratures, such that σx12 is enhanced while σx22 is depressed. Since
Constellation diagram of amplified light in a phase-synchronized degenerate OPA.
Next, we discusses photon-number fluctuations in OPAs, which are evaluated through the photon-number variance as σn2 = <Ψ0|
Subsequently, the photon-number variance is obtained as
where Eqs. (55) and (56) are applied. Recalling that the mean photon number of the amplified signal is
Next, we consider degenerate OPA. As indicated by Eq. (59), properties of the photon number in degenerate OPA are hard to evaluate for an arbitrary initial state. Thus, we assume a coherent incident state here. From Eq. (51), the average of the square of the photon-number operator for the initial state |Ψ0> = |α>s ⊗ |0>i is calculated as
Subsequently, the photon-number variance at the output is
where Eq. (61) is applied. This expression cannot be decomposed and interpreted as that of nondegenerate OPA indicated by Eq. (68), which could be because the amplitude distribution is not simply isotropic in two quadratures, unlike nondegenerate OPA.
The noise figure can be evaluated from the results obtained above. For nondegenerate OPA, it is obtained as
where only the signal-spontaneous beat noise is considered for the output SNR, according to the definition on the noise figure. This noise figure equals that of ideal population-inversion–based amplifiers indicated by Eq. (44) with nsp = 1. For the degenerate case, on the other hand, it is expressed as
For Δ = 0, NF = 1 (0 dB), suggesting no SNR degradation in phase-synchronized degenerate OPA. In fact, a noise figure of less than 3 dB in a phase-sensitive amplifier has been experimentally demonstrated [12, 13].
This chapter describes quantum noise of optical amplifiers. Full quantum mechanical treatment based on the Heisenberg equation for physical quantity operators was presented, by which quantum properties of optical amplifiers were derived from first principles. The obtained results are consistent with a conventional classical treatment, except for the inherent quantum noise or the zero-point fluctuation, providing the theoretical base to the conventional phenomenological treatment.
"I work with IntechOpen for a number of reasons: their professionalism, their mission in support of Open Access publishing, and the quality of their peer-reviewed publications, but also because they believe in equality. Throughout the world, we are seeing progress in attracting, retaining, and promoting women in STEMM. IntechOpen are certainly supporting this work globally by empowering all scientists and ensuring that women are encouraged and enabled to publish and take leading roles within the scientific community." Dr. Catrin Rutland, University of Nottingham, UK
",metaTitle:"Advantages of Publishing with IntechOpen",metaDescription:"We have more than a decade of experience in Open Access publishing. \n\n ",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"We have more than a decade of experience in Open Access publishing. The advantages of publishing with IntechOpen include:
\\n\\nOur platform – IntechOpen is the world’s leading publisher of OA books, built by scientists, for scientists.
\\n\\nOur reputation – Everything we publish goes through a two-stage peer review process. We’re proud to count Nobel laureates among our esteemed authors. We meet European Commission standards for funding, and the research we’ve published has been funded by the Bill and Melinda Gates Foundation and the Wellcome Trust, among others. IntechOpen is a member of all relevant trade associations (including the STM Association and the Association of Learned and Professional Society Publishers) and has a selection of books indexed in Web of Science's Book Citation Index.
\\n\\nOur expertise – We’ve published more than 4,200 books by more than 116,000 authors and editors.
\\n\\nOur reach – Our books have more than 125 million downloads and more than 84,800 Web of Science citations. We increase citations via indexing in all the major databases, including the Book Citation Index at Web of Science and Google Scholar.
\\n\\nOur services – The support we offer our authors and editors is second to none. Each book in our program receives the following:
\\n\\nOur end-to-end publishing service frees our authors and editors to focus on what matters: research. We empower them to shape their fields and connect with the global scientific community.
\\n\\n"In developing countries until now, advancement in science has been very limited, because insufficient economic resources are dedicated to science and education. These limitations are more marked when the scientists are women. In order to develop science in the poorest countries and decrease the gender gap that exists in scientific fields, Open Access networks like IntechOpen are essential. Free access to scientific research could contribute to ameliorating difficult life conditions and breaking down barriers." Marquidia Pacheco, National Institute for Nuclear Research (ININ), Mexico
\\n\\nInterested? Contact Ana Pantar (book.idea@intechopen.com) for more information.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'We have more than a decade of experience in Open Access publishing. The advantages of publishing with IntechOpen include:
\n\nOur platform – IntechOpen is the world’s leading publisher of OA books, built by scientists, for scientists.
\n\nOur reputation – Everything we publish goes through a two-stage peer review process. We’re proud to count Nobel laureates among our esteemed authors. We meet European Commission standards for funding, and the research we’ve published has been funded by the Bill and Melinda Gates Foundation and the Wellcome Trust, among others. IntechOpen is a member of all relevant trade associations (including the STM Association and the Association of Learned and Professional Society Publishers) and has a selection of books indexed in Web of Science's Book Citation Index.
\n\nOur expertise – We’ve published more than 4,200 books by more than 116,000 authors and editors.
\n\nOur reach – Our books have more than 125 million downloads and more than 84,800 Web of Science citations. We increase citations via indexing in all the major databases, including the Book Citation Index at Web of Science and Google Scholar.
\n\nOur services – The support we offer our authors and editors is second to none. Each book in our program receives the following:
\n\nOur end-to-end publishing service frees our authors and editors to focus on what matters: research. We empower them to shape their fields and connect with the global scientific community.
\n\n"In developing countries until now, advancement in science has been very limited, because insufficient economic resources are dedicated to science and education. These limitations are more marked when the scientists are women. In order to develop science in the poorest countries and decrease the gender gap that exists in scientific fields, Open Access networks like IntechOpen are essential. Free access to scientific research could contribute to ameliorating difficult life conditions and breaking down barriers." Marquidia Pacheco, National Institute for Nuclear Research (ININ), Mexico
\n\nInterested? Contact Ana Pantar (book.idea@intechopen.com) for more information.
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:null},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5313},{group:"region",caption:"Middle and South America",value:2,count:4819},{group:"region",caption:"Africa",value:3,count:1468},{group:"region",caption:"Asia",value:4,count:9362},{group:"region",caption:"Australia and Oceania",value:5,count:837},{group:"region",caption:"Europe",value:6,count:14778}],offset:12,limit:12,total:108153},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"0",sort:"dateEndThirdStepPublish",topicId:"16"},books:[{type:"book",id:"7927",title:"Selected Topics in Child and Adolescent Mental Health",subtitle:null,isOpenForSubmission:!0,hash:"d0afa3f41927509c4a21502c591726b8",slug:null,bookSignature:"Dr. Maria Rosaria Muzio",coverURL:"https://cdn.intechopen.com/books/images_new/7927.jpg",editedByType:null,editors:[{id:"286957",title:"Dr.",name:"Maria",surname:"Rosaria Muzio",slug:"maria-rosaria-muzio",fullName:"Maria Rosaria Muzio"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8710",title:"Eosinophils",subtitle:null,isOpenForSubmission:!0,hash:"310c9d9e1510937f3bec11533ead88be",slug:null,bookSignature:"Dr. Seyyed Shamsadin Athari and Dr. Entezar Mehrabi Nasab",coverURL:"https://cdn.intechopen.com/books/images_new/8710.jpg",editedByType:null,editors:[{id:"139889",title:"Dr.",name:"Seyyed Shamsadin",surname:"Athari",slug:"seyyed-shamsadin-athari",fullName:"Seyyed Shamsadin Athari"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7632",title:"Beyond LEO - Human Health Issues for Deep Space Exploration",subtitle:null,isOpenForSubmission:!0,hash:"800d9e65b9eca19dd1372fa0db7478cd",slug:null,bookSignature:"Dr. Robert J. Reynolds",coverURL:"https://cdn.intechopen.com/books/images_new/7632.jpg",editedByType:null,editors:[{id:"220737",title:"Dr.",name:"Robert",surname:"J. Reynolds",slug:"robert-j.-reynolds",fullName:"Robert J. Reynolds"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9133",title:"Hospital Acquired Infection and Legionnaires Disease",subtitle:null,isOpenForSubmission:!0,hash:"67e9b00ffb1203f7a41d2bb8507367c4",slug:null,bookSignature:"Dr. Salim Surani and Dr. Joseph Varon",coverURL:"https://cdn.intechopen.com/books/images_new/9133.jpg",editedByType:null,editors:[{id:"15654",title:"Dr.",name:"Salim",surname:"Surani",slug:"salim-surani",fullName:"Salim Surani"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9087",title:"Anemia",subtitle:null,isOpenForSubmission:!0,hash:"f94d3fb270e4af2b9813b12455424c22",slug:null,bookSignature:"Dr. Ota Fuchs",coverURL:"https://cdn.intechopen.com/books/images_new/9087.jpg",editedByType:null,editors:[{id:"36468",title:"Dr.",name:"Ota",surname:"Fuchs",slug:"ota-fuchs",fullName:"Ota Fuchs"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9451",title:"Learning Disabilities",subtitle:null,isOpenForSubmission:!0,hash:"9c7a717ecf24f759a2b2111dfca99960",slug:null,bookSignature:" Sandro Misciagna",coverURL:"https://cdn.intechopen.com/books/images_new/9451.jpg",editedByType:null,editors:[{id:"103586",title:null,name:"Sandro",surname:"Misciagna",slug:"sandro-misciagna",fullName:"Sandro Misciagna"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7966",title:"Diagnosis and Treatment of Osteomyelitis",subtitle:null,isOpenForSubmission:!0,hash:"764c30adac79d07c33b37020ee81218b",slug:null,bookSignature:"Prof. Mauricio S. Baptista and Dr. João Paulo Tardivo",coverURL:"https://cdn.intechopen.com/books/images_new/7966.jpg",editedByType:null,editors:[{id:"85863",title:"Prof.",name:"Mauricio S.",surname:"Baptista",slug:"mauricio-s.-baptista",fullName:"Mauricio S. Baptista"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7845",title:"Platelets",subtitle:null,isOpenForSubmission:!0,hash:"d33b20516d6ff3a5b7446a882109ba26",slug:null,bookSignature:"Dr. Steve W. W. Kerrigan and Prof. Niamh Moran",coverURL:"https://cdn.intechopen.com/books/images_new/7845.jpg",editedByType:null,editors:[{id:"73961",title:"Dr.",name:"Steve W.",surname:"Kerrigan",slug:"steve-w.-kerrigan",fullName:"Steve W. Kerrigan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9069",title:"Zinc and Human Health",subtitle:null,isOpenForSubmission:!0,hash:"b40ada91c760e960017f31af036f60e0",slug:null,bookSignature:"Dr. Andreas Grabrucker",coverURL:"https://cdn.intechopen.com/books/images_new/9069.jpg",editedByType:null,editors:[{id:"178792",title:"Dr.",name:"Andreas",surname:"Grabrucker",slug:"andreas-grabrucker",fullName:"Andreas Grabrucker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9464",title:"Health Benefits of Tea (Camellia sinensis)",subtitle:null,isOpenForSubmission:!0,hash:"f8945b63ec8437f5589e4168ff682e2d",slug:null,bookSignature:"Dr. Kula Kamal Senapati",coverURL:"https://cdn.intechopen.com/books/images_new/9464.jpg",editedByType:null,editors:[{id:"234221",title:"Dr.",name:"Kula Kamal",surname:"Senapati",slug:"kula-kamal-senapati",fullName:"Kula Kamal Senapati"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9056",title:"Multiple Chronic Conditions - Overview and Management of Chronic Disease Clusters",subtitle:null,isOpenForSubmission:!0,hash:"c842c2f3339a6a9290603393ab741253",slug:null,bookSignature:"Prof. Sevgi Akarsu",coverURL:"https://cdn.intechopen.com/books/images_new/9056.jpg",editedByType:null,editors:[{id:"182444",title:"Prof.",name:"Sevgi",surname:"Akarsu",slug:"sevgi-akarsu",fullName:"Sevgi Akarsu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9126",title:"Respiratory Physiology",subtitle:null,isOpenForSubmission:!0,hash:"e57374d11c8da9e7c70631881dcf55fa",slug:null,bookSignature:"Dr. Ketevan Nemsadze",coverURL:"https://cdn.intechopen.com/books/images_new/9126.jpg",editedByType:null,editors:[{id:"149748",title:"Dr.",name:"Ketevan",surname:"Nemsadze",slug:"ketevan-nemsadze",fullName:"Ketevan Nemsadze"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:35},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:32},{group:"topic",caption:"Business, Management and Economics",value:7,count:9},{group:"topic",caption:"Chemistry",value:8,count:29},{group:"topic",caption:"Computer and Information Science",value:9,count:26},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:14},{group:"topic",caption:"Engineering",value:11,count:75},{group:"topic",caption:"Environmental Sciences",value:12,count:13},{group:"topic",caption:"Immunology and Microbiology",value:13,count:3},{group:"topic",caption:"Materials Science",value:14,count:37},{group:"topic",caption:"Mathematics",value:15,count:14},{group:"topic",caption:"Medicine",value:16,count:142},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:5},{group:"topic",caption:"Neuroscience",value:18,count:6},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:8},{group:"topic",caption:"Physics",value:20,count:20},{group:"topic",caption:"Psychology",value:21,count:2},{group:"topic",caption:"Robotics",value:22,count:6},{group:"topic",caption:"Social Sciences",value:23,count:14},{group:"topic",caption:"Technology",value:24,count:10},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:3},{group:"topic",caption:"Intelligent System",value:535,count:1}],offset:12,limit:12,total:142},popularBooks:{featuredBooks:[{type:"book",id:"7878",title:"Advances in Extracorporeal Membrane Oxygenation",subtitle:"Volume 3",isOpenForSubmission:!1,hash:"f95bf990273d08098a00f9a1c2403cbe",slug:"advances-in-extracorporeal-membrane-oxygenation-volume-3",bookSignature:"Michael S. Firstenberg",coverURL:"https://cdn.intechopen.com/books/images_new/7878.jpg",editors:[{id:"64343",title:null,name:"Michael S.",middleName:"S",surname:"Firstenberg",slug:"michael-s.-firstenberg",fullName:"Michael S. Firstenberg"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7614",title:"Fourier Transforms",subtitle:"Century of Digitalization and Increasing Expectations",isOpenForSubmission:!1,hash:"ff3501657ae983a3b42fef1f7058ac91",slug:"fourier-transforms-century-of-digitalization-and-increasing-expectations",bookSignature:"Goran S. Nikoli? and Dragana Z. Markovi?-Nikoli?",coverURL:"https://cdn.intechopen.com/books/images_new/7614.jpg",editors:[{id:"23261",title:"Prof.",name:"Goran",middleName:"S.",surname:"Nikolic",slug:"goran-nikolic",fullName:"Goran Nikolic"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8299",title:"Timber Buildings and Sustainability",subtitle:null,isOpenForSubmission:!1,hash:"bccf2891cec38ed041724131aa34c25a",slug:"timber-buildings-and-sustainability",bookSignature:"Giovanna Concu",coverURL:"https://cdn.intechopen.com/books/images_new/8299.jpg",editors:[{id:"108709",title:"Dr.",name:"Giovanna",middleName:null,surname:"Concu",slug:"giovanna-concu",fullName:"Giovanna Concu"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7062",title:"Rhinosinusitis",subtitle:null,isOpenForSubmission:!1,hash:"14ed95e155b1e57a61827ca30b579d09",slug:"rhinosinusitis",bookSignature:"Balwant Singh Gendeh and Mirjana Turkalj",coverURL:"https://cdn.intechopen.com/books/images_new/7062.jpg",editors:[{id:"67669",title:"Prof.",name:"Balwant Singh",middleName:null,surname:"Gendeh",slug:"balwant-singh-gendeh",fullName:"Balwant Singh Gendeh"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7087",title:"Tendons",subtitle:null,isOpenForSubmission:!1,hash:"786abac0445c102d1399a1e727a2db7f",slug:"tendons",bookSignature:"Hasan Sözen",coverURL:"https://cdn.intechopen.com/books/images_new/7087.jpg",editors:[{id:"161402",title:"Dr.",name:"Hasan",middleName:null,surname:"Sözen",slug:"hasan-sozen",fullName:"Hasan Sözen"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7955",title:"Advances in Hematologic Malignancies",subtitle:null,isOpenForSubmission:!1,hash:"59ca1b09447fab4717a93e099f646d28",slug:"advances-in-hematologic-malignancies",bookSignature:"Gamal Abdul Hamid",coverURL:"https://cdn.intechopen.com/books/images_new/7955.jpg",editors:[{id:"36487",title:"Prof.",name:"Gamal",middleName:null,surname:"Abdul Hamid",slug:"gamal-abdul-hamid",fullName:"Gamal Abdul Hamid"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7701",title:"Assistive and Rehabilitation Engineering",subtitle:null,isOpenForSubmission:!1,hash:"4191b744b8af3b17d9a80026dcb0617f",slug:"assistive-and-rehabilitation-engineering",bookSignature:"Yves Rybarczyk",coverURL:"https://cdn.intechopen.com/books/images_new/7701.jpg",editors:[{id:"72920",title:"Prof.",name:"Yves",middleName:"Philippe",surname:"Rybarczyk",slug:"yves-rybarczyk",fullName:"Yves Rybarczyk"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7837",title:"Geriatric Medicine and Gerontology",subtitle:null,isOpenForSubmission:!1,hash:"e277d005b23536bcd9f8550046101979",slug:"geriatric-medicine-and-gerontology",bookSignature:"Edward T. Zawada Jr.",coverURL:"https://cdn.intechopen.com/books/images_new/7837.jpg",editors:[{id:"16344",title:"Dr.",name:"Edward T.",middleName:null,surname:"Zawada Jr.",slug:"edward-t.-zawada-jr.",fullName:"Edward T. Zawada Jr."}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,isOpenForSubmission:!1,hash:"61c627da05b2ace83056d11357bdf361",slug:"current-topics-in-neglected-tropical-diseases",bookSignature:"Alfonso J. Rodriguez-Morales",coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",editors:[{id:"131400",title:"Dr.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7610",title:"Renewable and Sustainable Composites",subtitle:null,isOpenForSubmission:!1,hash:"c2de26c3d329c54f093dc3f05417500a",slug:"renewable-and-sustainable-composites",bookSignature:"António B. Pereira and Fábio A. O. Fernandes",coverURL:"https://cdn.intechopen.com/books/images_new/7610.jpg",editors:[{id:"211131",title:"Prof.",name:"António",middleName:"Bastos",surname:"Pereira",slug:"antonio-pereira",fullName:"António Pereira"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8416",title:"Non-Equilibrium Particle Dynamics",subtitle:null,isOpenForSubmission:!1,hash:"2c3add7639dcd1cb442cb4313ea64e3a",slug:"non-equilibrium-particle-dynamics",bookSignature:"Albert S. Kim",coverURL:"https://cdn.intechopen.com/books/images_new/8416.jpg",editors:[{id:"21045",title:"Prof.",name:"Albert S.",middleName:null,surname:"Kim",slug:"albert-s.-kim",fullName:"Albert S. Kim"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8463",title:"Pediatric Surgery, Flowcharts and Clinical Algorithms",subtitle:null,isOpenForSubmission:!1,hash:"23f39beea4d557b0ae424e2eaf82bf5e",slug:"pediatric-surgery-flowcharts-and-clinical-algorithms",bookSignature:"Sameh Shehata",coverURL:"https://cdn.intechopen.com/books/images_new/8463.jpg",editors:[{id:"37518",title:"Prof.",name:"Sameh",middleName:null,surname:"Shehata",slug:"sameh-shehata",fullName:"Sameh Shehata"}],productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:4392},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"7878",title:"Advances in Extracorporeal Membrane Oxygenation",subtitle:"Volume 3",isOpenForSubmission:!1,hash:"f95bf990273d08098a00f9a1c2403cbe",slug:"advances-in-extracorporeal-membrane-oxygenation-volume-3",bookSignature:"Michael S. Firstenberg",coverURL:"https://cdn.intechopen.com/books/images_new/7878.jpg",editors:[{id:"64343",title:null,name:"Michael S.",middleName:"S",surname:"Firstenberg",slug:"michael-s.-firstenberg",fullName:"Michael S. Firstenberg"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7614",title:"Fourier Transforms",subtitle:"Century of Digitalization and Increasing Expectations",isOpenForSubmission:!1,hash:"ff3501657ae983a3b42fef1f7058ac91",slug:"fourier-transforms-century-of-digitalization-and-increasing-expectations",bookSignature:"Goran S. Nikoli? and Dragana Z. Markovi?-Nikoli?",coverURL:"https://cdn.intechopen.com/books/images_new/7614.jpg",editors:[{id:"23261",title:"Prof.",name:"Goran",middleName:"S.",surname:"Nikolic",slug:"goran-nikolic",fullName:"Goran Nikolic"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8299",title:"Timber Buildings and Sustainability",subtitle:null,isOpenForSubmission:!1,hash:"bccf2891cec38ed041724131aa34c25a",slug:"timber-buildings-and-sustainability",bookSignature:"Giovanna Concu",coverURL:"https://cdn.intechopen.com/books/images_new/8299.jpg",editors:[{id:"108709",title:"Dr.",name:"Giovanna",middleName:null,surname:"Concu",slug:"giovanna-concu",fullName:"Giovanna Concu"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7062",title:"Rhinosinusitis",subtitle:null,isOpenForSubmission:!1,hash:"14ed95e155b1e57a61827ca30b579d09",slug:"rhinosinusitis",bookSignature:"Balwant Singh Gendeh and Mirjana Turkalj",coverURL:"https://cdn.intechopen.com/books/images_new/7062.jpg",editors:[{id:"67669",title:"Prof.",name:"Balwant Singh",middleName:null,surname:"Gendeh",slug:"balwant-singh-gendeh",fullName:"Balwant Singh Gendeh"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7087",title:"Tendons",subtitle:null,isOpenForSubmission:!1,hash:"786abac0445c102d1399a1e727a2db7f",slug:"tendons",bookSignature:"Hasan Sözen",coverURL:"https://cdn.intechopen.com/books/images_new/7087.jpg",editors:[{id:"161402",title:"Dr.",name:"Hasan",middleName:null,surname:"Sözen",slug:"hasan-sozen",fullName:"Hasan Sözen"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7955",title:"Advances in Hematologic Malignancies",subtitle:null,isOpenForSubmission:!1,hash:"59ca1b09447fab4717a93e099f646d28",slug:"advances-in-hematologic-malignancies",bookSignature:"Gamal Abdul Hamid",coverURL:"https://cdn.intechopen.com/books/images_new/7955.jpg",editors:[{id:"36487",title:"Prof.",name:"Gamal",middleName:null,surname:"Abdul Hamid",slug:"gamal-abdul-hamid",fullName:"Gamal Abdul Hamid"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7701",title:"Assistive and Rehabilitation Engineering",subtitle:null,isOpenForSubmission:!1,hash:"4191b744b8af3b17d9a80026dcb0617f",slug:"assistive-and-rehabilitation-engineering",bookSignature:"Yves Rybarczyk",coverURL:"https://cdn.intechopen.com/books/images_new/7701.jpg",editors:[{id:"72920",title:"Prof.",name:"Yves",middleName:"Philippe",surname:"Rybarczyk",slug:"yves-rybarczyk",fullName:"Yves Rybarczyk"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7837",title:"Geriatric Medicine and Gerontology",subtitle:null,isOpenForSubmission:!1,hash:"e277d005b23536bcd9f8550046101979",slug:"geriatric-medicine-and-gerontology",bookSignature:"Edward T. Zawada Jr.",coverURL:"https://cdn.intechopen.com/books/images_new/7837.jpg",editors:[{id:"16344",title:"Dr.",name:"Edward T.",middleName:null,surname:"Zawada Jr.",slug:"edward-t.-zawada-jr.",fullName:"Edward T. Zawada Jr."}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,isOpenForSubmission:!1,hash:"61c627da05b2ace83056d11357bdf361",slug:"current-topics-in-neglected-tropical-diseases",bookSignature:"Alfonso J. Rodriguez-Morales",coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",editors:[{id:"131400",title:"Dr.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7610",title:"Renewable and Sustainable Composites",subtitle:null,isOpenForSubmission:!1,hash:"c2de26c3d329c54f093dc3f05417500a",slug:"renewable-and-sustainable-composites",bookSignature:"António B. Pereira and Fábio A. O. Fernandes",coverURL:"https://cdn.intechopen.com/books/images_new/7610.jpg",editors:[{id:"211131",title:"Prof.",name:"António",middleName:"Bastos",surname:"Pereira",slug:"antonio-pereira",fullName:"António Pereira"}],productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"8463",title:"Pediatric Surgery, Flowcharts and Clinical Algorithms",subtitle:null,isOpenForSubmission:!1,hash:"23f39beea4d557b0ae424e2eaf82bf5e",slug:"pediatric-surgery-flowcharts-and-clinical-algorithms",bookSignature:"Sameh Shehata",coverURL:"https://cdn.intechopen.com/books/images_new/8463.jpg",editedByType:"Edited by",editors:[{id:"37518",title:"Prof.",name:"Sameh",middleName:null,surname:"Shehata",slug:"sameh-shehata",fullName:"Sameh Shehata"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7187",title:"Osteosarcoma",subtitle:"Diagnosis, Mechanisms, and Translational Developments",isOpenForSubmission:!1,hash:"89096359b754beb806eca4c6d8aacaba",slug:"osteosarcoma-diagnosis-mechanisms-and-translational-developments",bookSignature:"Matthew Gregory Cable and Robert Lawrence Randall",coverURL:"https://cdn.intechopen.com/books/images_new/7187.jpg",editedByType:"Edited by",editors:[{id:"265693",title:"Dr.",name:"Matthew Gregory",middleName:null,surname:"Cable",slug:"matthew-gregory-cable",fullName:"Matthew Gregory Cable"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7955",title:"Advances in Hematologic Malignancies",subtitle:null,isOpenForSubmission:!1,hash:"59ca1b09447fab4717a93e099f646d28",slug:"advances-in-hematologic-malignancies",bookSignature:"Gamal Abdul Hamid",coverURL:"https://cdn.intechopen.com/books/images_new/7955.jpg",editedByType:"Edited by",editors:[{id:"36487",title:"Prof.",name:"Gamal",middleName:null,surname:"Abdul Hamid",slug:"gamal-abdul-hamid",fullName:"Gamal Abdul Hamid"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7701",title:"Assistive and Rehabilitation Engineering",subtitle:null,isOpenForSubmission:!1,hash:"4191b744b8af3b17d9a80026dcb0617f",slug:"assistive-and-rehabilitation-engineering",bookSignature:"Yves Rybarczyk",coverURL:"https://cdn.intechopen.com/books/images_new/7701.jpg",editedByType:"Edited by",editors:[{id:"72920",title:"Prof.",name:"Yves",middleName:"Philippe",surname:"Rybarczyk",slug:"yves-rybarczyk",fullName:"Yves Rybarczyk"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7726",title:"Swarm Intelligence",subtitle:"Recent Advances, New Perspectives and Applications",isOpenForSubmission:!1,hash:"e7ea7e74ce7a7a8e5359629e07c68d31",slug:"swarm-intelligence-recent-advances-new-perspectives-and-applications",bookSignature:"Javier Del Ser, Esther Villar and Eneko Osaba",coverURL:"https://cdn.intechopen.com/books/images_new/7726.jpg",editedByType:"Edited by",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8256",title:"Distillation",subtitle:"Modelling, Simulation and Optimization",isOpenForSubmission:!1,hash:"c76af109f83e14d915e5cb3949ae8b80",slug:"distillation-modelling-simulation-and-optimization",bookSignature:"Vilmar Steffen",coverURL:"https://cdn.intechopen.com/books/images_new/8256.jpg",editedByType:"Edited by",editors:[{id:"189035",title:"Dr.",name:"Vilmar",middleName:null,surname:"Steffen",slug:"vilmar-steffen",fullName:"Vilmar Steffen"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7240",title:"Growing and Handling of Bacterial Cultures",subtitle:null,isOpenForSubmission:!1,hash:"a76c3ef7718c0b72d0128817cdcbe6e3",slug:"growing-and-handling-of-bacterial-cultures",bookSignature:"Madhusmita Mishra",coverURL:"https://cdn.intechopen.com/books/images_new/7240.jpg",editedByType:"Edited by",editors:[{id:"204267",title:"Dr.",name:"Madhusmita",middleName:null,surname:"Mishra",slug:"madhusmita-mishra",fullName:"Madhusmita Mishra"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8299",title:"Timber Buildings and Sustainability",subtitle:null,isOpenForSubmission:!1,hash:"bccf2891cec38ed041724131aa34c25a",slug:"timber-buildings-and-sustainability",bookSignature:"Giovanna Concu",coverURL:"https://cdn.intechopen.com/books/images_new/8299.jpg",editedByType:"Edited by",editors:[{id:"108709",title:"Dr.",name:"Giovanna",middleName:null,surname:"Concu",slug:"giovanna-concu",fullName:"Giovanna Concu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7062",title:"Rhinosinusitis",subtitle:null,isOpenForSubmission:!1,hash:"14ed95e155b1e57a61827ca30b579d09",slug:"rhinosinusitis",bookSignature:"Balwant Singh Gendeh and Mirjana Turkalj",coverURL:"https://cdn.intechopen.com/books/images_new/7062.jpg",editedByType:"Edited by",editors:[{id:"67669",title:"Prof.",name:"Balwant Singh",middleName:null,surname:"Gendeh",slug:"balwant-singh-gendeh",fullName:"Balwant Singh Gendeh"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7837",title:"Geriatric Medicine and Gerontology",subtitle:null,isOpenForSubmission:!1,hash:"e277d005b23536bcd9f8550046101979",slug:"geriatric-medicine-and-gerontology",bookSignature:"Edward T. Zawada Jr.",coverURL:"https://cdn.intechopen.com/books/images_new/7837.jpg",editedByType:"Edited by",editors:[{id:"16344",title:"Dr.",name:"Edward T.",middleName:null,surname:"Zawada Jr.",slug:"edward-t.-zawada-jr.",fullName:"Edward T. Zawada Jr."}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"278",title:"Social Psychology",slug:"social-psychology",parent:{title:"Social Sciences",slug:"social-sciences"},numberOfBooks:2,numberOfAuthorsAndEditors:40,numberOfWosCitations:0,numberOfCrossrefCitations:5,numberOfDimensionsCitations:8,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"social-psychology",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"8262",title:"The New Forms of Social Exclusion",subtitle:null,isOpenForSubmission:!1,hash:"29bf235aa7659d3651183fe9ea49dc0d",slug:"the-new-forms-of-social-exclusion",bookSignature:"Rosalba Morese and Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/8262.jpg",editedByType:"Edited by",editors:[{id:"214435",title:"Dr.",name:"Rosalba",middleName:null,surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5761",title:"Quality of Life and Quality of Working Life",subtitle:null,isOpenForSubmission:!1,hash:"f6000bc0eeed7fcf0277a2f8d75907d9",slug:"quality-of-life-and-quality-of-working-life",bookSignature:"Ana Alice Vilas Boas",coverURL:"https://cdn.intechopen.com/books/images_new/5761.jpg",editedByType:"Edited by",editors:[{id:"175373",title:"Dr.",name:"Ana Alice",middleName:null,surname:"Vilas Boas",slug:"ana-alice-vilas-boas",fullName:"Ana Alice Vilas Boas"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:2,mostCitedChapters:[{id:"55323",doi:"10.5772/intechopen.68873",title:"Positive Psychology: The Use of the Framework of Achievement Bests to Facilitate Personal Flourishing",slug:"positive-psychology-the-use-of-the-framework-of-achievement-bests-to-facilitate-personal-flourishing",totalDownloads:743,totalCrossrefCites:2,totalDimensionsCites:3,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Huy P. Phan and Bing H. Ngu",authors:[{id:"196435",title:"Prof.",name:"Huy",middleName:"P",surname:"Phan",slug:"huy-phan",fullName:"Huy Phan"}]},{id:"55530",doi:"10.5772/intechopen.69151",title:"Quality of Life and Physical Activity: Their Relationship with Physical and Psychological Well-Being",slug:"quality-of-life-and-physical-activity-their-relationship-with-physical-and-psychological-well-being",totalDownloads:758,totalCrossrefCites:2,totalDimensionsCites:2,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Arantzazu Rodríguez-Fernández, Ana Zuazagoitia-Rey-Baltar and\nEstibaliz Ramos-Díaz",authors:[{id:"90485",title:"Dr.",name:"Arantzazu",middleName:null,surname:"Rodriguez-Fernández",slug:"arantzazu-rodriguez-fernandez",fullName:"Arantzazu Rodriguez-Fernández"},{id:"205182",title:"Dr.",name:"Ana",middleName:null,surname:"Zuazagoitia-Rey-Baltar",slug:"ana-zuazagoitia-rey-baltar",fullName:"Ana Zuazagoitia-Rey-Baltar"},{id:"205183",title:"Dr.",name:"Estibaliz",middleName:null,surname:"Ramos-Díaz",slug:"estibaliz-ramos-diaz",fullName:"Estibaliz Ramos-Díaz"}]},{id:"54577",doi:"10.5772/67821",title:"Building a Quality of Life Index",slug:"building-a-quality-of-life-index",totalDownloads:763,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Ryan M. Yonk, Josh T. Smith and Arthur R. Wardle",authors:[{id:"196259",title:"Dr.",name:"Ryan Merlin",middleName:null,surname:"Yonk",slug:"ryan-merlin-yonk",fullName:"Ryan Merlin Yonk"},{id:"197814",title:"Mr.",name:"Joshua",middleName:null,surname:"Smith",slug:"joshua-smith",fullName:"Joshua Smith"}]}],mostDownloadedChaptersLast30Days:[{id:"55349",title:"The Development of a Human Well-Being Index for the United States",slug:"the-development-of-a-human-well-being-index-for-the-united-states",totalDownloads:971,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"J. Kevin Summers, Lisa M. Smith, Linda C. Harwell and Kyle D. Buck",authors:[{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",slug:"j.-kevin-summers",fullName:"J. Kevin Summers"},{id:"197486",title:"Ms.",name:"Lisa",middleName:null,surname:"Smith",slug:"lisa-smith",fullName:"Lisa Smith"},{id:"197487",title:"Ms.",name:"Linda",middleName:null,surname:"Harwell",slug:"linda-harwell",fullName:"Linda Harwell"},{id:"197488",title:"Dr.",name:"Kyle",middleName:null,surname:"Buck",slug:"kyle-buck",fullName:"Kyle Buck"}]},{id:"56529",title:"Well-being and Quality of Working Life of University Professors in Brazil",slug:"well-being-and-quality-of-working-life-of-university-professors-in-brazil",totalDownloads:814,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Alessandro Vinicius de Paula and Ana Alice Vilas Boas",authors:[{id:"175373",title:"Dr.",name:"Ana Alice",middleName:null,surname:"Vilas Boas",slug:"ana-alice-vilas-boas",fullName:"Ana Alice Vilas Boas"},{id:"196534",title:"Dr.",name:"Alessandro Vinicius",middleName:null,surname:"De Paula",slug:"alessandro-vinicius-de-paula",fullName:"Alessandro Vinicius De Paula"}]},{id:"55323",title:"Positive Psychology: The Use of the Framework of Achievement Bests to Facilitate Personal Flourishing",slug:"positive-psychology-the-use-of-the-framework-of-achievement-bests-to-facilitate-personal-flourishing",totalDownloads:743,totalCrossrefCites:2,totalDimensionsCites:3,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Huy P. Phan and Bing H. Ngu",authors:[{id:"196435",title:"Prof.",name:"Huy",middleName:"P",surname:"Phan",slug:"huy-phan",fullName:"Huy Phan"}]},{id:"55530",title:"Quality of Life and Physical Activity: Their Relationship with Physical and Psychological Well-Being",slug:"quality-of-life-and-physical-activity-their-relationship-with-physical-and-psychological-well-being",totalDownloads:758,totalCrossrefCites:2,totalDimensionsCites:2,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Arantzazu Rodríguez-Fernández, Ana Zuazagoitia-Rey-Baltar and\nEstibaliz Ramos-Díaz",authors:[{id:"90485",title:"Dr.",name:"Arantzazu",middleName:null,surname:"Rodriguez-Fernández",slug:"arantzazu-rodriguez-fernandez",fullName:"Arantzazu Rodriguez-Fernández"},{id:"205182",title:"Dr.",name:"Ana",middleName:null,surname:"Zuazagoitia-Rey-Baltar",slug:"ana-zuazagoitia-rey-baltar",fullName:"Ana Zuazagoitia-Rey-Baltar"},{id:"205183",title:"Dr.",name:"Estibaliz",middleName:null,surname:"Ramos-Díaz",slug:"estibaliz-ramos-diaz",fullName:"Estibaliz Ramos-Díaz"}]},{id:"54577",title:"Building a Quality of Life Index",slug:"building-a-quality-of-life-index",totalDownloads:763,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Ryan M. Yonk, Josh T. Smith and Arthur R. Wardle",authors:[{id:"196259",title:"Dr.",name:"Ryan Merlin",middleName:null,surname:"Yonk",slug:"ryan-merlin-yonk",fullName:"Ryan Merlin Yonk"},{id:"197814",title:"Mr.",name:"Joshua",middleName:null,surname:"Smith",slug:"joshua-smith",fullName:"Joshua Smith"}]},{id:"54386",title:"Human Work and its Discontents",slug:"human-work-and-its-discontents",totalDownloads:673,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Anderson de Souza Sant'Anna, Zélia Miranda Kilimnik and Daniela\nMartins Diniz",authors:[{id:"197768",title:"Prof.",name:"Daniela",middleName:null,surname:"Diniz",slug:"daniela-diniz",fullName:"Daniela Diniz"},{id:"197896",title:"Dr.",name:"Anderson",middleName:"S.",surname:"Sant\\'Anna",slug:"anderson-sant'anna",fullName:"Anderson Sant\\'Anna"},{id:"197897",title:"Prof.",name:"Zélia",middleName:null,surname:"Kilimnik",slug:"zelia-kilimnik",fullName:"Zélia Kilimnik"}]},{id:"54549",title:"Physical and Psychical Well-Being and Stress: The Perspectives of Leaders and Employees",slug:"physical-and-psychical-well-being-and-stress-the-perspectives-of-leaders-and-employees",totalDownloads:534,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Simona Šarotar Žižek and Vesna Čančer",authors:[{id:"192730",title:"Associate Prof.",name:"Simona",middleName:null,surname:"Šarotar Žižek",slug:"simona-sarotar-zizek",fullName:"Simona Šarotar Žižek"},{id:"197783",title:"Dr.",name:"Vesna",middleName:null,surname:"Čančer",slug:"vesna-cancer",fullName:"Vesna Čančer"}]},{id:"54570",title:"Exploring the Antecedents of Happiness: Reconceptualization of Human Needs with Glasser's Choice Theory",slug:"exploring-the-antecedents-of-happiness-reconceptualization-of-human-needs-with-glasser-s-choice-theo",totalDownloads:761,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Turgut Turkdogan",authors:[{id:"197018",title:"Ph.D.",name:"Turgut",middleName:null,surname:"Turkdogan",slug:"turgut-turkdogan",fullName:"Turgut Turkdogan"}]},{id:"66422",title:"Vulnerability and Social Exclusion: Risk in Adolescence and Old Age",slug:"vulnerability-and-social-exclusion-risk-in-adolescence-and-old-age",totalDownloads:241,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"the-new-forms-of-social-exclusion",title:"The New Forms of Social Exclusion",fullTitle:"The New Forms of Social Exclusion"},signatures:"Rosalba Morese, Sara Palermo, Matteo Defedele, Juri Nervo and Alberto Borraccino",authors:[{id:"214435",title:"Dr.",name:"Rosalba",middleName:null,surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"},{id:"218983",title:"BSc.",name:"Juri",middleName:null,surname:"Nervo",slug:"juri-nervo",fullName:"Juri Nervo"},{id:"218984",title:"MSc.",name:"Matteo",middleName:null,surname:"Defedele",slug:"matteo-defedele",fullName:"Matteo Defedele"},{id:"233998",title:"Dr.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"},{id:"266453",title:"Prof.",name:"Alberto",middleName:null,surname:"Borraccino",slug:"alberto-borraccino",fullName:"Alberto Borraccino"}]},{id:"54807",title:"Understanding the Concept of Life Quality within the Framework of Social Service Provision: Theoretical Analysis and a Case Study",slug:"understanding-the-concept-of-life-quality-within-the-framework-of-social-service-provision-theoretic",totalDownloads:557,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Zuzana Palovičová",authors:[{id:"196861",title:"Associate Prof.",name:"Zuzana",middleName:null,surname:"Palovicova",slug:"zuzana-palovicova",fullName:"Zuzana Palovicova"}]}],onlineFirstChaptersFilter:{topicSlug:"social-psychology",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"6837",title:"Lithium-ion Batteries - Thin Film for Energy Materials and Devices",subtitle:null,isOpenForSubmission:!0,hash:"ea7789260b319b9a4b472257f57bfeb5",slug:null,bookSignature:"Prof. Mitsunobu Sato, Dr. Li Lu and Dr. Hiroki Nagai",coverURL:"https://cdn.intechopen.com/books/images_new/6837.jpg",editedByType:null,editors:[{id:"179615",title:"Prof.",name:"Mitsunobu",middleName:null,surname:"Sato",slug:"mitsunobu-sato",fullName:"Mitsunobu Sato"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9423",title:"Applications of Artificial Intelligence in Process Industry Automation, Heat and Power Generation and Smart Manufacturing",subtitle:null,isOpenForSubmission:!0,hash:"10ac8fb0bdbf61044395963028653d21",slug:null,bookSignature:"Prof. Konstantinos G. Kyprianidis and Prof. Erik Dahlquist",coverURL:"https://cdn.intechopen.com/books/images_new/9423.jpg",editedByType:null,editors:[{id:"35868",title:"Prof.",name:"Konstantinos",middleName:"G.",surname:"Kyprianidis",slug:"konstantinos-kyprianidis",fullName:"Konstantinos Kyprianidis"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9428",title:"New Trends in the Use of Artificial Intelligence for the Industry 4.0",subtitle:null,isOpenForSubmission:!0,hash:"9e089eec484ce8e9eb32198c2d8b34ea",slug:null,bookSignature:"Dr. Luis Romeral Martinez, Dr. Roque A. Osornio-Rios and Dr. Miguel Delgado Prieto",coverURL:"https://cdn.intechopen.com/books/images_new/9428.jpg",editedByType:null,editors:[{id:"86501",title:"Dr.",name:"Luis",middleName:null,surname:"Romeral Martinez",slug:"luis-romeral-martinez",fullName:"Luis Romeral Martinez"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10107",title:"Artificial Intelligence in Oncology Drug Discovery & Development",subtitle:null,isOpenForSubmission:!0,hash:"043c178c3668865ab7d35dcb2ceea794",slug:null,bookSignature:"Dr. John Cassidy and Dr. Belle Taylor",coverURL:"https://cdn.intechopen.com/books/images_new/10107.jpg",editedByType:null,editors:[{id:"244455",title:"Dr.",name:"John",middleName:null,surname:"Cassidy",slug:"john-cassidy",fullName:"John Cassidy"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8903",title:"Carbon Based Material for Environmental Protection and Remediation",subtitle:null,isOpenForSubmission:!0,hash:"19da699b370f320eca63ef2ba02f745d",slug:null,bookSignature:"Dr. Mattia Bartoli and Dr. Marco Frediani",coverURL:"https://cdn.intechopen.com/books/images_new/8903.jpg",editedByType:null,editors:[{id:"188999",title:"Dr.",name:"Mattia",middleName:null,surname:"Bartoli",slug:"mattia-bartoli",fullName:"Mattia Bartoli"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10132",title:"Applied Computational Near-surface Geophysics - From Integral and Derivative Formulas to MATLAB Codes",subtitle:null,isOpenForSubmission:!0,hash:"38cdbbb671df620b36ee96af1d9a3a90",slug:null,bookSignature:"Dr. Afshin Aghayan",coverURL:"https://cdn.intechopen.com/books/images_new/10132.jpg",editedByType:null,editors:[{id:"311030",title:"Dr.",name:"Afshin",middleName:null,surname:"Aghayan",slug:"afshin-aghayan",fullName:"Afshin Aghayan"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10110",title:"Advances and Technologies in Building Construction and Structural Analysis",subtitle:null,isOpenForSubmission:!0,hash:"df2ad14bc5588577e8bf0b7ebcdafd9d",slug:null,bookSignature:"Dr. Ali Kaboli and Dr. Sara Shirowzhan",coverURL:"https://cdn.intechopen.com/books/images_new/10110.jpg",editedByType:null,editors:[{id:"309192",title:"Dr.",name:"Ali",middleName:null,surname:"Kaboli",slug:"ali-kaboli",fullName:"Ali Kaboli"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10175",title:"Ethics in Emerging Technologies",subtitle:null,isOpenForSubmission:!0,hash:"9c92da249676e35e2f7476182aa94e84",slug:null,bookSignature:"Prof. Ali Hessami",coverURL:"https://cdn.intechopen.com/books/images_new/10175.jpg",editedByType:null,editors:[{id:"108303",title:"Prof.",name:"Ali",middleName:null,surname:"Hessami",slug:"ali-hessami",fullName:"Ali Hessami"}],productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:16},humansInSpaceProgram:{},teamHumansInSpaceProgram:{},route:{name:"profile.detail",path:"/profiles/15921/jan-nikodem",hash:"",query:{},params:{id:"15921",slug:"jan-nikodem"},fullPath:"/profiles/15921/jan-nikodem",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var m;(m=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(m)}()