Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"3130",leadTitle:null,fullTitle:"An Integrated View of the Molecular Recognition and Toxinology - From Analytical Procedures to Biomedical Applications",title:"An Integrated View of the Molecular Recognition and Toxinology",subtitle:"From Analytical Procedures to Biomedical Applications",reviewType:"peer-reviewed",abstract:"Molecular Toxinology has been consolidated as a scientific area focused on the intertwined description of several aspects of animal toxins. In an inquiring biotechnological world, animal toxins appear as an invaluable source for the discovery of therapeutic polypeptides. Animal toxins rely on specific chemical interactions with their partner molecule to exert their biological actions. The comprehension of how molecules interact and recognize their target is essential for the rational exploration of bioactive polypeptides as therapeutics. Investigation on the mechanism of molecular interaction and recognition offers a window of opportunity for the pharmaceutical industry and clinical medicine. Thus, this book brings examples of two interconnected themes - molecular recognition and toxinology concerning to the integration between analytical procedures and biomedical applications.",isbn:null,printIsbn:"978-953-51-1151-1",pdfIsbn:"978-953-51-5382-5",doi:"10.5772/3429",price:159,priceEur:175,priceUsd:205,slug:"an-integrated-view-of-the-molecular-recognition-and-toxinology-from-analytical-procedures-to-biomedical-applications",numberOfPages:546,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"846bd4daf35404d776a5190e12430977",bookSignature:"Gandhi Rádis Baptista",publishedDate:"July 1st 2013",coverURL:"https://cdn.intechopen.com/books/images_new/3130.jpg",numberOfDownloads:50781,numberOfWosCitations:71,numberOfCrossrefCitations:30,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:102,numberOfDimensionsCitationsByBook:3,hasAltmetrics:1,numberOfTotalCitations:203,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 15th 2012",dateEndSecondStepPublish:"April 5th 2012",dateEndThirdStepPublish:"July 2nd 2012",dateEndFourthStepPublish:"August 1st 2012",dateEndFifthStepPublish:"October 31st 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"47894",title:"Dr.",name:"Gandhi",middleName:null,surname:"Radis-Baptista",slug:"gandhi-radis-baptista",fullName:"Gandhi Radis-Baptista",profilePictureURL:"https://mts.intechopen.com/storage/users/47894/images/2530_n.jpg",biography:"BS (1993) in Pharmacy and Biochemistry from University of São Paulo. Received his master degree in Technology of Fermentation in 1996, and his PhD in Life Sciences (Biochemistry) in 2002, both from University of São Paulo. He was associate researcher (postdoctoral fellow) in the Laboratory of Molecular Toxinology at Instituto Butantan (2002-2003). Participated of several scientific missions to the National Institute of Advanced Industrial Science and Technology (AIST/MITI), Japan. Served as associate professor (2005-2008) in Department of Biochemistry at Federal University of Pernambuco. Presently, he is associate professor in Institute of Marine Sciences at Federal University of Ceara. His main scientific interests are polypeptides from marine and terrestrial organims, cell receptors, molecular interaction and recombinant DNA technology.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Universidade Federal do Ceará",institutionURL:null,country:{name:"Brazil"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"381",title:"Toxinology",slug:"biochemistry-genetics-and-molecular-biology-biochemistry-toxinology"}],chapters:[{id:"45064",title:"Peptidomic Analysis of Animal Venoms",doi:"10.5772/53773",slug:"peptidomic-analysis-of-animal-venoms",totalDownloads:2349,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:0,abstract:null,signatures:"Ricardo Bastos Cunha",downloadPdfUrl:"/chapter/pdf-download/45064",previewPdfUrl:"/chapter/pdf-preview/45064",authors:[{id:"152968",title:"Prof.",name:"Ricardo",surname:"Cunha",slug:"ricardo-cunha",fullName:"Ricardo Cunha"}],corrections:null},{id:"45052",title:"Toxins from Venomous Animals: Gene Cloning, Protein Expression and Biotechnological Applications",doi:"10.5772/52380",slug:"toxins-from-venomous-animals-gene-cloning-protein-expression-and-biotechnological-applications",totalDownloads:3959,totalCrossrefCites:2,totalDimensionsCites:14,hasAltmetrics:0,abstract:null,signatures:"Matheus F. 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Blood cells are by far the most abundant cells of which our body is comprised. Red blood cells (RBCs, or erythrocytes) and platelets (Plts, or thrombocytes) circulate in the vascular system, whereas the white blood cells that form our immune system locate both in the vascular system and in the tissues. RBCs are best known for their function as oxygen transporters and for the clearance of CO2. Plts exert a crucial function in homeostasis upon vascular damage but they also function during angiogenesis, innate immunity, inflammation, wound healing, cancer, and hemostasis [1, 2]. This chapter focuses on erythropoiesis and megakaryopoiesis. RBCs in the periphery have an average life span of 120 days, constituting approximately 45% of the blood volume. To maintain the population of RBCs, humans generate daily ~2 × 1011 reticulocytes [3]. Plts are shed by megakaryocytes (MK) and live approximately 8–9 days in humans, which require a production of ~8.5 × 1010 Plts/day [4, 5]. The generation of RBCs and Plts occurs mainly in the bone marrow (BM) in adults, although the lung has also been found to host megakaryocytic progenitors as well as Plts-shedding MKs [6]. A small population of hematopoietic stem cells (HSCs) ensures the life-long generation of blood cells, although the HSCs themselves divide rarely. Mostly, HSCs that divide give rise to one new HSC and a daughter cell that develops to an actively dividing multipotent progenitor (MPP) (Figure 1) [7]. These MPPs undergo specification through reciprocal actions of transcription factors (TF) that enhance or repress expression of lineage-specific TFs and direct the cells to a lineage-specific gene expression program [7]. Erythropoiesis and megakaryopoiesis were long thought to arise from a common progenitor, the megakaryocytic-erythroid progenitor, but recent lineage tracing indicates that MKs can also differentiate directly from HSCs [8, 9, 10]. Not only MPPs, also erythroid progenitors (erythroblasts: EBLs) and megakaryocytic progenitors (megakaryoblasts: MKBLs) have extensive potential to undergo cell divisions before they commit to the final differentiation program to generate RBCs/MKs. The final differentiation stages of both lineages have unique features. Erythroid progenitors undergo 3–4 additional cell divisions with a short G1 cell cycle phase and without regaining the cell volume (i.e., loss of cell size control) [11, 12, 13]. MKBLs, instead, undergo 4–5 cell division cycles without cytokinesis, which results in a single cell with 64–128 genome copies (N = 64–128) [14]. Erythropoiesis and megakaryopoiesis also show spatiotemporal regulation. All blood cell progenitors including erythroid progenitors and MKBLs propagate in close contact with stromal cells that produce membrane-bound factors such as stem cell factor (SCF). Upon terminal differentiation, erythroid progenitors bind to central macrophages that express receptors such as CD163, VCAM1, ICAM4, and CD163 to associate with EBLs [15, 16, 17, 18, 19]. Each macrophage binds several progenitors that undergo synchronous differentiation, which ends with phagocytosis of the extruded erythroid nucleus by the macrophage and release of reticulocytes into the circulation. The mature MKs have to interact with the endothelial cells of the vasculature and protrude proplatelets into the capillaries, where shear stress contributes to the shedding of Plts [20].
HSC commitment to the erythroid/megakaryocytic lineages with lineage-specific marker expression pattern.
Whereas steady state erythropoiesis and megakaryopoiesis of adult mammals take place in the BM and lung (MK), distinct anatomic sites of hematopoiesis are employed during development (Figure 2A). After gastrulation, in humans, mesodermal precursor cells arise in the primitive streak, migrate to the yolk sac, and develop into blood islands (hemangioblasts), which produce primitive RBCs, primitive MKs, and macrophages [21]. During this process, basic fibroblast growth factor (bFGF) influences the proliferation of the hemangioblast and thereby the production of hematopoietic cells [22]. bFGF is synergistic with vascular endothelial growth factor (VEGF) signaling in this process [23]. The primitive RBCs express embryonic type of hemoglobins (Hbs), retain the size of the early EBLs, and lose their nucleus only after prolonged circulation. Their erythropoietin (EPO)-dependence is unclear at this early stage of development [24, 25]. The primitive MKs are thrombopoietin (TPO) independent, have low ploidy compared to adult MKs, and produce fewer Plts, but contrary to primitive erythroid cells, these cells migrate to the fetal liver, where their polyploidization is TPO dependent [26, 27]. Erythroid-myeloid progenitors (EMPs) arise in the yolk sac from hemogenic endothelium (HE) through endothelial to hematopoietic transition (EHT) and give rise to the first intermediate definitive wave, producing RBCs with fetal type of Hbs, MKs, and other myeloid cells [21, 28]. The EMPs migrate and colonize the developing fetal liver where they transiently produce definitive fetal RBCs and MKs. Permanent definitive hematopoiesis in the fetal liver depends on the “birth” of HSC in the aorta main arteries, and more specifically in the aorta-gonad-mesonephros (AGM) region, where the first CD34+ HSC arises through EHT. These early HSCs are dependent on bone morphogenetic protein 4 (BMP4), VEGF, and bFGF secreted by “feeder cells,” which are located near the endothelial cells undergoing EHT, thereby promoting this transition [23, 29]. These HSCs home to the fetal liver to produce definitive fetal blood cells. From the fetal liver, the HSCs migrate to the final site of hematopoiesis; the BM, where they give rise to adult definitive blood cells. Perinatally, hematopoiesis also occurs in the spleen [30]. RBCs and Plts generated at distinct anatomic sites have distinct characteristics; for example, RBCs express different Hb molecules arising from different sites (Figure 2B). Hb consists of two α and two β subunits each bound to an iron-containing heme molecule. The α locus expresses ζ and α protein isoforms, the β locus expresses ε, γ (γ1 and 2), and β (β and δ) isoforms. Primitive RBCs express Hbe consisting of ζ and ε isoforms (Portland 1: ζ2γ2; Portland 2: ζ2β2; Gower 1: ζ2ε2; Gower 2: α2ε2); fetal RBCs are characterized by HbF consisting of α and γ isoforms; adult RBCs express HbA consisting of α and β isoforms (HbA1) plus a small amount of HbA2 consisting of α and δ isoforms. Hbs can be used to distinguish RBCs originated from different developmental stages; however, in the megakaryocytic lineages, there is a lack of such markers.
Human erythropoiesis/megakaryopoiesis during development. (A) Schematic depiction of site-specific (yolk sac/fetal liver-AGM/bone marrow) blood production during ontogeny focusing on erythroid and megakaryocytic lineages. (B) Representative HPLC tracks, showing the Hb content of
Biochemical and molecular analysis of erythroid/megakaryocytic cells requires large cell numbers. The
Application of
The aim of this chapter is twofold. First, we provide background information of the basic processes of erythropoiesis and megakaryopoiesis that underly the various cell culture models. Second, we provide details, interpret and compare results on current protocols to expand and differentiate erythroid and megakaryocytic progenitors.
The tyrosine kinase receptors directly cross-phosphorylate tyrosine residues in their own cytoplasmic tail, and they phosphorylate downstream effector molecules. They are more widely expressed compared to cytokine receptors.
Steroid hormone receptors are the best known nuclear hormone receptors. In addition to these ligand-dependent TFs that bind DNA through a Zinc-finger domain, other ligand-activated TFs exist such as the aryl hydrocarbon receptor (AhR) that binds DNA through a helix-loop-helix domain.
EPO is sufficient for steady-state erythropoiesis, when proliferative signals are mediated through the EPOR-associated RON receptor and EPO-induced differentiation is dependent on STAT5 [83, 84]. Increased erythropoiesis during development and upon blood loss requires the cooperative action of the EPOR and KIT [85]. Activation of KIT prevents differentiation and propagates the long-term proliferation of erythroid progenitors through inhibition of
Erythropoiesis is also regulated by the availability of iron, which is imported into the cell as holotransferrin via the transferrin receptor (TfR; CD71), and by selenium through selenoproteins [89, 90].
TPO is the main regulator of megakaryopoiesis, and multiple other factors can work synergistic with it. IL-6 can, in conjunction with TPO, increase hepatic TPO synthesis [94]. This effect is through the shared usage of gp130 and amplification of the same downstream JAK pathways [95]. The direct admission of IL-6, besides its effect on TPO, results in increased polyploidization and subsequently leads to an enhanced Plts production in patients [96]. IL-11 is not constitutively expressed but was shown to be induced in thrombocytopenia patients undergoing BM transplantation. Exposure of IL-11 on HSPCs directly leads to an inhibition of NF-κB signaling, which suppresses miR-204-5p, that targets and represses the expression of TPO [97]. Because of this effect on TPO, it has a dual role in MK differentiation, first, in the expansion of HSCs, second, in the terminal differentiation of MKs. In a similar way, IL-9 synergizes with IL-3 as well as with IL-4 and SCF to increase the yield of MKBL [33, 98]. Furthermore, the addition of IL-1β promotes selective megakaryocytic differentiation. IL-1β can increase the production of Plts by enhancing the effects of SDF1 and FGF4 that are produced by BM niche cells. IL-1α was shown to induce MK rupture and is considered as a stress megakaryopoiesis regulator [99].
Inhibition of AhR by SR-1 slows the differentiation program in HSCs, leading to increased expansion, and has a direct effect on MK differentiation, by slowing and/or conditioning cells to have a more synchronized maturation [74, 79, 81]. Through its effect on PU.1, it can influence RUNX1 which is one of the TF-regulating megakaryopoiesis. The introduction of SR-1 into
The most widely used immortalized mouse erythroid cell lines are MEL cells, which are EBLs transformed by Friend Leukemia virus. The viral gp55 protein activates the Epor to sustain cell growth, whereas integration of the virus upstream of
Deletion of p53 is not sufficient in human to establish immortalized erythroid cell lines. However, expression of the human papilloma virus E6/E7 proteins in EBLs differentiated from iPSC gave rise to the HiDEP cell line [101]. The E6/E7 proteins inactivate both p53 and retinoblastoma tumor suppressor proteins [102]. They are expressed from a doxycycline (dox)-inducible vector allowing for unlimited growth in the presence of EPO, SCF, and dox, and differentiation in the presence of EPO but without dox and SCF. Lack of p53 does not affect differentiation, but retinoblastoma is required for terminal erythroid differentiation [103, 104, 105]. Dox-inducible expression was also used to establish immortalized erythroid cells lines from CB (HUDEP) and from adult EBLs cultured from CD34+ HSPC (BEL-A) [106, 107]. The HiDEP, HUDEP, and BEL-A express embryonic, fetal, and adult Hbs, respectively [101, 107].
Multiple cell lines have been generated to study megakaryopoiesis with among them; MEG-01 (suspension cells) and DAMI (adherent/suspension cells) both megakaryoblastic leukemia cell lines [108, 109]. These cell lines are mostly positive for MK-specific markers (see in Section 2.3.3) but are not a homogenous population. Although they proliferate in a MKBL-like state with some spontaneous differentiation and limited terminal differentiation, they can be induced to differentiate by the addition of phorbol myristate acetate. Under these conditions, the cells can become polyploid, increase their expression of MK-associated proteins, like von Willebrand factor, and are able to produce proplatelets although with low efficiency. Mechanistic insights were uncovered with these lines; for example, the formation of long, beaded cytoplasmic extensions of MKs that yield platelets upon shear stress. This process was also observed in normal healthy MKs
RBCs and MKs can be cultured for research and clinical applications from multiple primary tissue sources including HFL, CB, BM, mobilized peripheral blood (MPB), and peripheral blood mononuclear cells (PBMC). HFL is obtained from abortions on medical indication. HFL-derived erythroid cells express HbF and can be expanded to large numbers and differentiated to hemoglobinized enucleated RBCs. For MK culture, this source is less ideal, mainly because of the harshness of the isolation method. Ethical concerns rule out HFL as a general source for transfusion, but with proper consent allows research into fetal hematopoiesis development. A widely available and ethically accepted source is CB which is commonly used for production of both erythroid cells and MKs. CB is obtained at birth when Hb-switch occurs from HbF to HbA1 (γ to β switch) and both Hb types are expressed in CB-derived cultures. The presence of HSPCs with a fetal hematopoietic program in CB has notable effects in the MK cultures. MKBL expansion is high; MK polyploidization and proplatelet formation are decreased compared to cultures of adult cells. As adult hematopoietic source, either BM or PBMC can be applied. BM is a limited source that can be more difficult to obtain, but does yield large quantities of HSPCs that can differentiate to erythroid and MK lineages. HSPCs can also be isolated from PBMCs, which is less invasive therefore a less limited source. This makes PBMC an ideal source to scale-up RBC production. The HSPC percentage in PBMC is significantly lower compared to BM, which can be enhanced by leukophoresis and by mobilizing BM HSPCs using G-CSF (10 μg/kg) alone or in combination with CXCR4/CXCL12 inhibition [19, 111]. G-CSF alone leads to 5–30% mobilization [15]. HSPC mobilization is caused by the downregulation of adhesion and chemokine processes and by the loss of BM macrophages [15, 112, 113, 114, 115]. The mobilization can cause side effects for the donor, including headaches, fatigue, vomiting, muscle pain, bone pain, thrombocytopenia, citrate toxicity, etc., in which females experience the most adverse events [116]. These MPBs are ideal for RBC/Plt production because of their HSPC richness.
The MKs can be cultured in Cellgro (Corning), and both cell types can be cultured in StemSpan (Stem Cell Technologies) or other Iscove’s modified Dulbecco’s medium (IMDM)-based media. We generated a completely defined GMP-grade medium called Cell-Quin (Migliaccio et al. with minor modifications) that is highly efficient in expanding and differentiating EBLs/RBCs and MKs/Plts, with the ability to culture other hematopoietic progenitors and blood cell types [117].
Several parameters characterize the differentiation stage of erythroid cells. Expansion of EBL cultures is only possible when they maintain cell size control during their cell cycle, which is achieved by the cooperative action of SCF and glucocorticoids [12, 13, 118]. Terminal differentiation in the presence of EPO involves 3–4 cell divisions during which cells’ surface marker expression changes and gets smaller due to loss of cell size control until cell cycle arrest and extrusion of their nuclei, concurrently, accumulating Hb [119]. Thus, surface marker expression pattern, cell size and morphology (enucleation), Hb content, and cumulative cell numbers are a measure of differentiation (Figure 4A–C). Morphological features of the cells (nuclei-cytoplasm ratio, hemoglobinization, nuclei condensation, and polarization) are commonly assessed by cytospins coupled with Giemsa/benzidine stainings (Figure 4A). The purity of the erythroid population and its distribution over different maturation stages can be assessed by monitoring the progression of various cell surface markers. Commonly used markers are CD36, CD71 (transferrin receptor), CD117, and the erythroid-specific markers band 3 (SLC4A1) and CD235 (glycophorin A). The generally accepted dynamics of these markers during erythroid differentiation: pro-EBLs (immature EBL stage) are characterized by CD34−/CD36+/CD117+/CD71high/CD235low/−, while during expansion phase, EBLs gain CD235 expression and become CD117+/CD71+/CD235+. In terminal differentiation phase, EBLs remain positive for CD235 and lose their expression of CD117 followed by the gradual loss of CD71, which is associated with reticulocyte formation [120].
Characteristics of erythroid and megakaryocytic cultures. (A) Erythroid-specific morphology by cytospin with Giemsa/benzidine staining. Left: pro-EBL, right reticulocytes. (B) Erythroid expansion growth curve from PBMCs (n = 4). (C) Flow cytometry of terminal erythroid differentiation, DNA staining by DRAQ5 resulting in three distinct populations: DRAQ5+ big cells: nucleated EBLs (red); DRAQ5+ small cells: nuclei (blue); DRAQ5− cells: enucleated reticulocytes (purple). (D) MK-specific morphology by cytospin with MGG-staining. Left: MKBL; right: polyploid MK (arrows). (E) Proplatelet-forming MK (arrows (beads on a string)).
The first human erythroid culture systems utilized the knowledge obtained from genetics, e.g., discoveries in the field of cytokines, growth factors, and their receptors. In these first protocols, HSPCs were expanded in the presence of IL-3, SCF plus or minus IL-6. It is followed by a step in which the resulting erythroid progenitors were further expanded and differentiated in the presence of EPO [121]. This protocol was modified, using low EPO concentrations in step 1 (0.5 U/ml) and high concentrations (>3 U/ml) in step 2 [122]. Others used high concentrations of EPO throughout step 1 and step 2 [123, 124]. These two-step protocols are based on the original protocol of Fibach and coworkers who employ IMDM supplemented with serum or plasma [121]. Serum and plasma contain factors that support erythropoiesis in these cultures. The major factor in the serum is transforming growth factor β (TGFβ), which is a potent differentiation factor for erythropoiesis [57, 125]. These cultures show a high degree of spontaneous differentiation, which is often used to study expansion and differentiation of EBLs carrying a genetic defect. The quality differences between serum batches and the use of different cytokines make these culture protocols difficult to compare. Two major changes increase the yield of these erythroid cultures and enable synchronous differentiation. First, glucocorticoids cooperate with SCF to retain pro-EBLs and early basophilic EBLs in their undifferentiated state [57, 126]. Second, serum-free medium avoids the differentiation promoting effect of TGFβ. However, the available serum-free media are suboptimal and require complementation with lipids [73]. Even better expansion is achieved with a serum-free medium optimized for expansion of EBLs [117]. The differentiation arrest in the presence of glucocorticoids and the absence of serum enables the expansion of a homogeneous early EBLs culture that can undergo up to 20 cell divisions to achieve a million-fold expansion [73, 119]. Using Cell-Quin, we can obtain 2 × 1010 EBLs within 16 days, starting from 5 × 107 PBMCs (Figure 4B). Expansion of EBLs in the presence of serum and in the absence of glucocorticoids irrevocably results in differentiation and transfer of the cells to differentiation conditions. Of note, addition of glucocorticoid agonists in a serum-based culture will still induce spontaneous differentiation due to the presence of TGFβ [57]. At any moment during expansion phase, cells can be transferred to differentiation conditions in which the medium is supplemented with EPO, Ins, and low level of plasma/serum [119, 120]. Although expansion of EBL cultures is achieved in serum-free medium, terminal differentiation to enucleated cells requires at least 2% serum or plasma [119, 120]. Using Cell-Quin medium, we currently obtain >90% enucleation, a deformability that corresponds to values between freshly isolated reticulocytes and erythrocytes, and normal oxygen association and dissociation values (van den Akker and von Lindern, manuscript in preparation). We use DRAQ5 staining coupled with flow cytometry analyses to quantify reticulocyte/nuclei/nucleated cell ratio (Figure 4C). Flexibility is measured on a ARCA, and oxygen binding by the Hemox analyzer [127, 128].
Commitment of MKBL and differentiation of MKs can be monitored by the expression of cell surface markers and by the morphological features of the cells (Figure 4D and E). MKBLs are characterized by CD34+/CD41a+ expression and blast-like morphology. In terminal differentiation, MKs gradually lose their expression of CD34+, leading to a subdivision of stages: early MKs are CD34+/CD41a+/CD42+ and late MKs are CD34−/CD41a+/CD42+.
To obtain large numbers of MKBLs, SCF/FL and TPO are used during the first 4–7 days of cultures started from CD34+-HSPCs. TPO without SCF and FL allows terminal differentiation to proplatelet-forming cells. To increase the expansion potential, IL-3 can be included only in the initial phase as its prolonged exposure directs the HSPC toward the monocyte/granulocyte lineage. With the addition of IL-6, the MK specification and TPO signaling can be enhanced. With the addition of either IL-1β, IL-9, or IL-11 during the first phase of CD34+ differentiation, MK commitment is enhanced instead of progenitor proliferation. It is important to determine the main goal of an experiment before starting the culture: does the experiment require large numbers of MKBLs, or should MK enrichment be maximal, because a good expansion of MKBL tends to compromise terminal differentiation and vice versa (Hansen and van den Akker, unpublished results). Factors such as IL-1β and IL-9 increase polyploidization, formation of proplatelets, and Plts shedding. There is some concern about using IL-1β, because of its proinflammatory nature. Particularly, as it is closely related to IL-1α, and the increased Plt shedding may cause rupture of MKs [33, 99]. To introduce proplatelet formation, IL-6 can be used in high concentrations (>100 ng/ml), by itself or in combination with TPO. SR-1 influences megakaryopoiesis on an early and late stage of the culture, as described above, having a positive effect on the expansion of HSC and terminal differentiation of MK [80, 81]. During the terminal stages of MK cultures (during proplatelet formation), it becomes increasingly essential to prevent the activation of the MKs and produced proplatelets. The addition of heparin prevents the coagulation of plasma added to the media but cells are still able to clump together, thereby having a negative impact on the differentiation and proplatelet production. To prevent activation, signaling via the GPIIb/IIIa (ITGA2B) receptor can be blocked with tirofiban hydrochloride monohydrate. Whereas an MK sheds thousands of Plts
Pluripotent stem cells offer a novel approach for developmental studies, drug screening/discovery, disease modeling, and regenerative medicine. ESCs originate from the inner cell mass of a blastocyst stage embryo, while iPSCs are somatic cells that are reprogrammed back to this embryonic stage [129, 130, 131, 132]. Hematopoietic differentiation of ESC/iPSC cells follows the various stages of blood development from early embryonic stages (Figure 2A). This offers a valuable tool to study early human hematopoiesis which is difficult because of ethical issues and tissue availability. Besides, differentiation of iPSCs opens opportunities for large-scale manufacture of blood products with the expectancy of clinical application [133]. Several groups showed the potential of ESCs in blood cell production, the source which was later replaced by iPSCs with similar outcome including our group (Figure 5) [134, 135, 136, 137, 138, 139, 140]. The published protocols generally include four culture phases: (1) mesoderm induction, (2) hematopoietic/erythroid/megakaryocytic commitment, (3) expansion of the specific cell pool, and (4) terminal maturation. The hematopoietic differentiation phases
Erythroid/MK differentiation of iPSC according to Hansen et al. showing the different phases of differentiation, with their corresponding growth factor combination and morphological changes [
Optimization of iPSC-erythroid differentiation cultures. (A) iPSC-derived erythroid cells arose (D12+0) and expanded in Cell-Quin or StemSpan media. (B) Representative FACS-plots of iPSC-derived erythroid cell (D12 harvest), with or without EPO and SCF from day 6 onward.
As pointed out before, early erythropoiesis/megakaryopoiesis (yolk sac) in humans is not well studied, resulting in a lack of knowledge on the regulatory program at these developmental stages. Therefore, the generally applied cytokines might not ideally mimick the
Introduction of erythroid/MK-specific TFs into iPSC-derived hematopoietic cells, often named “forward reprogramming”, is being pursued as an approach to improve differentiation outcome. HOXA9, ERG, RORA, SOX4, and MYB have been introduced into human pluripotent stem cells. Engraftment into NSG mice resulted in erythroid cells, which were more skewed to definitive erythropoiesis (lack of embryonic Hbs, mainly HbF and some HbA, some enucleation) compared to TF-free counterparts [160, 161]. These results suggest the possibility of more mature erythroid cell production from iPSCs if certain TFs are included; however, the
The technical differences between published differentiation methods are leading to slight discrepancies in marker expression pattern, purity, yield, and stage of development. However, currently all published methods are limited by technical pitfalls, including the production of developmentally immature (nonadult) cell types which may be the cause of low yield and difficulty to terminally differentiate toward functional end stage blood cell types (e.g., low enucleation potential of iPSC-erythroid cells and low efficiency of iPSC-Plt formation).
The purity of the iPSC-derived erythroid population, and its distribution over different maturation stages can be assessed by the erythroid-specific markers used for definitive erythroid culture systems (Section 2.3.2); however, their progression differs in some aspects. Based on our differentiation scheme (Figure 5), we recognize three maturation stages: (i) an early erythroid population (harvest at day 10–14) is CD71high/CD235high/CD36med/high, which is not yet hemoglobinized and displays big nuclei [136]. Furthermore, the cells are negative for CD18 (myeloid lineage marker) confirming specification toward the erythroid lineage; (ii) a 100% pure erythroid population (day 7–9 expansion) is CD71/CD235/CD36med with some spontaneous differentiation, which is recognized by hemoglobinization and condensation of the nuclei; (iii) a mature erythroid population (D7-14 terminal differentiation) gives rise to CD235high/CD71high/med/CD36low cells. However, there is a slight CD71 decrease associated with reticulocyte formation, and iPSC-derived erythroid cells do not become CD71 negative. Morphologically, these cells were somewhat different from their definitive counterparts. Despite hemoglobinization, nuclear condensation, and polarization, we do not observe a decrease of cytoplasm size and the enucleation potential is poor. Technical variations in the published methods (timing, added growth factors) cause notable differences in the erythroid marker expression pattern; therefore, it is hard to compare and/or draw general conclusions. The emergence of CD71+/CD235+ population is generally reported with purity discrepancies. For example, Yang et al. [163] reported 80% CD71/CD235 purity (with CD34+/CD43+ preselection and OP9 coculture), Salvagiotto et al. [148] by a feeder-free monolayer system reached 40% pure population, while Kobari et al. [135] with EB-based induction reached 98–99% comparable to our findings. The pattern of CD36 expression is not entirely clear. Mao et al., for example, used a four-step differentiation scheme, including an AGM coculture induction step, and defined the following gene expression profile: early definitive EBLs derived from CD235+/CD34low/CD36−, and they develop to CD235+/CD34−/CD36−, CD235+/CD34−/CD36−/low, CD235+/CD34−/CD36− cells in sequence [164]. Others including us found high CD36 expression during the early erythroid stage [136].
The kinetics during differentiation/maturation of MK from iPSC follow the same steps as from definitive CD34+ cells, namely MKBL (CD34+/CD41a+), early MK (CD34+/CD41a+/CD42+), and late MK (CD34−/CD41a+/CD42+). The MKs can undergo some polyploidization albeit not in similar level as
Human ESC/iPSC-derived erythropoiesis/megakaryopoiesis, with the current knowledge, do not reach the adult definitive stage, but give rise to a mixture of primitive and definitive fetal/adult cells. Very little is known about human erythropoiesis/megakaryopoiesis in the early stages, between days 17 and 23 of embryogenesis (yolk-sac, AGM region) due to the fact that abortions are primarily performed at later fetal stages and in addition have serious ethical concerns. Hbs are commonly used to distinguish between developmental waves; however, HbF expressing RBCs both arises from yolk sac and later from fetal liver, and momentarily, there is a lack of markers, which can clearly distinguish these two waves (Figure 2A and B). The iPSC-derived erythroid cells predominantly express HbF, in addition to embryonic types of Hb. We and others also showed the presence of a small portion of adult Hb [135, 136, 153, 154, 155]. From the embryonic type of globins, both the presence of Gower 1 and Gower 2 Hb has been reported, but the ratio greatly differs between methods [135]. The presence of Gower 2 Hb indicates that the cells are capable of the first globin switch (ζ to α) to provide more mature primitive-state RBCs. Interestingly, the presence of adult types of Hb also differs between protocols as some group were able to show HbA1 or the presence of β chain, whereas others, including us, observed mainly HbA2 [135, 155]. It is unknown whether primitive erythropoiesis
Unlike in the erythroid lineages where the expression of stage-specific Hbs can be used to determine the ontogeny phase, this type of readout is not available in the MK lineage. There are, however, intrinsic differences between megakaryocytic cells derived at different sites during ontogeny. For instance, polyploidy is a measure of ontogeny
The final yield of our method is relatively high; however, the comparison with other methods is difficult due to technical discrepancies. There are different ways to calculate the final yield, which also depends on the iPSC maintenance system (single cell vs. clumps) and on the induction system (2D or 3D), resulting various ways to report the final yield. Single cell-seeded iPSC cultures can be normalized both to the initial number of seeded cells or to colony number. Furthermore, the comparison of absolute cell number produced (harvested) between 2D and 3D systems is not entirely realistic because of the different nature of the two cultures. We use single cell-seeding, which allows to calculate the yield/iPSC and yield/colony number to represent differentiation efficiency. In our hands, one iPSC colony can give rise on average 5.6 × 106 erythroid cells after 9 days of expansion. While a single iPSC gives rise to ~8 × 103 erythroid cells (harvest) and subsequent 9 days expansion results in ~2 × 105 erythroid cells/iPSC on average [136]. The expansion potential (from harvest day) compared to definitive cell types remains relatively low, in line with other methods irrespective of culture condition (Figure 4B). The terminal maturation of iPSC-erythroid cells toward enucleating reticulocytes is inefficient with the existing methods and is currently one of the major hurdles to overcome. In our hands, matured iPSC-erythroid cultures had 30–40% enucleation rate based on their nuclei count; however, the resulting reticulocytes appeared to be instable. Altogether, iPSC-derived erythroid cells are able to expand but for limited time and length, with suboptimal enucleation capacity. Probably, this is also coming from the fact that iPSC-derived erythroid cells, based on their globin expression, do not entirely correspond to a fetal/adult definitive wave.
MK yield from iPSCs is higher than CD34+ differentiation (6.9 × 103 cells/iPSC). Unlike the erythroid system in which differentiation can be inhibited for several days by the addition of glucocorticoid analogues, the megakaryocytic system currently lacks such a specific expansion advantage. As a result, iPSC-MK yield and purity is currently low compared to the iPSC-erythroid yield. Even though the yield of MK is low, a small number of MK still could produce significantly large amount of Plts. The
The production of cultured red blood cells for transfusion purposes has been the holy grail for transfusion medicine. However, a main challenge is the well-described limitation in cell density during the expansion phase [171]. A single transfusion unit contains 2 × 1012 RBCs. Conventional cultivation systems using dishes or flasks can reach up to 10 × 106 cells/mL, meaning that more than 1000 L of culture would be required for the manufacture of a single transfusion unit [172]. Handling of such large volumes is impractical if static culture conditions are maintained. Thus, multiple bioreactor designs have been proposed to improve the volumetric productivity of the process (produced cells/volume of medium). A static culturing system mimicking BM tissue has been proposed, in which cells are grown in a porous scaffold and nutrients are continuously fed through hollow fibers, while used media containing waste from metabolism are removed [173]. This system allows to have continuous replenishment of spent components in the media, while it is possible to re-use some of the most expensive components such as growth factors and transferrin. Also, it separates cells from large shear stress sources. Although an optimal design of this system could lead to the production of transfusion units at competitive costs compared to the price of rare blood units, it would require significant improvements in transfer of nutrients and matured RBCs between the scaffold and the inflow/outflow streams [174]. Mass transfer limitations in diffusion-governed systems can be tackled with agitation. It is relevant to note that conflicting reports have been made on the effect of shear due to agitation in
The high sensitivity of MK to shear stress renders culturing and flow cytometry assays challenging. However, it can also be exploited to generate
The ability to produce large numbers of enucleated, hemoglobinized RBCs opens the perspective of producing cultured red blood cells (cRBC) for transfusion purposes. The feasibility to do so has been demonstrated by the team of Luc Douay who cultured 1 mL of packed cRBC from CD34+ HSCs and transfused it to a healthy volunteer, with a cRBCs half-life of 26 days after injection [133, 179]. Donor-derived RBC transfusion is a cornerstone of modern medicine in the treatment of trauma, chronic anemia, and in surgery. The existence of 30 blood group systems, such as the ABO and Rhesus system, generates at least 300 distinct blood group antigens [180]. Recurrent transfusions carry an inherent risk on alloimmunization to nonidentical blood group antigens, which complicate further transfusions. Besides, this cellular therapy is dependent on donor availability with a potential risk of blood-borne diseases.
In a recent publication, Ito et al. [178] were able to generate Plts in transfusion quantities, where the functionality of these Plts was shown in
day 0 expansion: purify PBMCs by Ficoll and seed in StemSpan or Cell-Quin supplemented with 1 ng/ml human IL-3, 2 U/ml EPO, 10 ng/ml hSCF, 10−6 M DEX at 10 × 106 cells/ml, 37°C, and 5% CO2.
Optional: to remove remaining RBCs after Ficoll purification, the use of RBC lysis buffer is suggested.
day 2 and 4: replace half of the medium; add all factors to the medium except for IL-3.
day 5: EBLs appear as large (nongranulated) blasts.
Optional: to remove remaining lymphocytes, purify the culture by density centrifugation on a 1.075 g/ml Percoll gradient.
day 6–20: put the cells daily or every second day to 0.5–0.7 × 106/ml medium supplemented with EPO, SCF, and DEX (concentration is same as day 0).
day 0 terminal differentiation: wash the cells twice with PBS and re-seed in medium supplemented with 10 U/ml EPO, 1 mg/ml holotransferrin, 2–5% plasma, 5 U/ml heparin at 2 × 106/ml.
day 9–14: let the cells differentiate with half media change every 2–3 days.
day 0: collect CD34+ cells by MACS isolation from CB, BM, PBMC, or MPB and seed in Cellgro or Cell-Quin with 100 ng/ml FL, 50 ng/ml hSCF, 50 ng/ml TPO, 20 ng/ml IL-6 at 1 × 106 cells/ml, 37°C, and 5% CO2.
Re-seed cells when concentration exceeds 2.5 × 106 cells/ml, otherwise keep cells as undisturbed as possible at stable CO2 levels.
day 4: cells start to commit to the MK lineage (~10–20%), cells are collected and spun down at 200 g to start terminal differentiation.
day 0 terminal differentiation: re-seed cells in media (Cellgro or Cell-Quin) supplemented with: 50 ng/ml TPO and 10 ng/ml IL-1β at 0.5 × 106 cells/ml.
During terminal differentiation, the addition of tirofiban hydrochloride monohydrate and heparin is recommended.
Pipetting should be kept to minimal.
1 μM of SR-1 can be used to increase polyploidization and Plt production.
day 11: cells will be committed to the MK lineage (80–100%) and consist of MKBLs and early MKs.
Cell collection from these days onward should be performed using 2 mL or larger pipettes and avoid the usage of hand pipettes to circumvent cell lysis and shear stress [157, 166].
Centrifugation steps are on 150 g, low ramp, and brake.
Flow cytometry techniques on unfixed MKs at this stage will induce granule release and proplatelet formation.
day 12–16: MK cells will mature to late MKs and start producing proplatelets.
Centrifugation steps are 100 g, low ramp, and brake.
CB starts proplatelet production earlier than adult sources.
Proplatelets can be harvested using Plts isolation protocols.
Proplatelets are easily activated, treat them as regular Plts.
As described in this chapter, there are multiple protocols to culture RBCs and MKs from a variety of hematopoietic tissues. Depending on the goal (fundamental research, drug screening, or clinical applications), one should consider beforehand which source can be used. For clinical applications, the use of a fully defined unlimited source would be preferred. For this, iPSC (generated with nonintegrating method) hold great potential but differentiation toward RBCs and Plts has to be improved.
We would like to thank Esther Heideveld, Joan Gallego Murillo, Department of Hematopoiesis and Laboratory for Cell Therapy (Sanquin, Amsterdam) for their experimental and scientific input.
We are grateful for the support by the Ministry of Health (PPOC: 11-035, 15-2089), the Landsteiner Foundation for Blood Transfusion Research (LSBR1141), the European Union (FA H2020-MSCA ITN-2015, RELEVANCE), and the Netherlands Organization for Scientific Research (NWO/ZonMw 40-41400-98-1327; 40-00812-98-12128).
None.
AGM | aorta-gonad-mesonephros |
AhR | aryl hydrocarbon receptor |
bFGF | basic fibroblast growth factor |
BM | bone marrow |
BMP4 | bone morphogenetic protein 4 |
CB | cord blood |
cRBC | cultured red blood cell |
DEX | dexamethasone |
dox | doxycycline |
EBL | erythroblast |
EHT | endothelial to hematopoietic transition |
EMP | erythroid-myeloid progenitor |
EPO | erythropoietin |
EPOR | EPO receptor |
ESC | embryonic stem cell |
FL | FLT-3 ligand |
FLI-1 | friend leukemia integration 1 |
FLT-3 | Fms-like tyrosine kinase 3 |
GR | glucocorticoid receptor |
Hb | hemoglobin |
HE | hemogenic endothelium |
HFL | human fetal liver |
HSC | hematopoietic stem cell |
HSPC | hematopoietic stem/progenitor cell |
IL | interleukin |
Ins | insulin |
InsR | insulin receptor |
iPSC | induced pluripotent stem cell |
MK | megakaryocyte |
MKBL | megakaryoblast |
MPB | mobilized peripheral blood |
MPP | multipotent progenitor |
PBMC | peripheral blood mononuclear cell |
Plt | platelet |
RBC | red blood cell |
SCF | stem cell factor |
SR-1 | StemRegenin 1 |
TF | transcription factor |
TPO | thrombopoietin |
T3 | 3,5,3′-triiodothyronine |
VEGF | vascular endothelial growth factor |
Chronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Source | Type of trial | Interferon | Diagnosis | No. | Prior treatment status | Response rate |
---|---|---|---|---|---|---|
Yacoubet al. [15] | Phase II, multicenter | Pegylated IFN alfa-2a | PV | 50 | Resistance to HU or HU intolerance | CR:22% PR:38% |
ET | 65 | CR:43% PR:26% | ||||
Masarova et al. [16] | Phase II, single-center | Pegylated IFN alfa-2a | PV | 43 | Untreated or previously treated with cytoreductive therapy | CR:77% PR:7% |
ET | 40 | CR:73% PR:3% | ||||
Samuelsson et al. [18] | Phase II | Pegylated IFN alfa-2b | PV | 21 | Untreated or previously treated with cytoreductive therapy | CR: 69% for the entire group |
ET | 21 | |||||
Huang BT et al. [19] | Open label, multicenter | IFN alfa-2b | PV | 136 | Untreated or previously treated with cytoreductive therapy | OHR:70% Molecular response:54.7% |
ET | 123 | OHR (JAK2+ patients):83% CHR:23 cases OHR (JAK2-patients): 61.4% CHR:12 cases | ||||
Gisslinger et al. [23] | phase III, multicenter | Ropeginterferon | PV | 257 | Previously treated | OHR:53% |
Quintás-Cardama et al. [26] | phase II | Pegylated IFN alfa-2a | PV | 40 | Untreated or previously treated with cytoreductive therapy | OHR:80% CR:70% Molecular remission:54% |
ET | 39 | OHR:81% CR:76% Molecular remission:38% | ||||
Sørensen et al. [36] | Phase III, multicenter, COMBI | Pegylated IFN alfa-2a with ruxolitinib or Pegylated IFN alfa-2b with ruxolitinib | PV | 32 | Untreated or previously treated with cytoreductive therapy | OHR:44% CR:28% |
MF | 18 | OHR:31% CR:9% | ||||
Casassus et al. [40] | Open label, multicenter | IFN alpha-2b | Mastocytosis | 20 | Untreated and previously treated | PR:35% Minor remission: 30% |
Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; HU: hydroxycarbamide/hydroxyurea; CR: complete remission; PR: partial remission; and OHR: overall hematological response.
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
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Convective motion driven by water temperature gradient was important for Bukit Merah and Bera Lake.",book:{id:"6184",slug:"applications-in-water-systems-management-and-modeling",title:"Applications in Water Systems Management and Modeling",fullTitle:"Applications in Water Systems Management and Modeling"},signatures:"Zati Sharip, Shahirwan Aman Shah, Aminuddin Jamin and Juhaimi\nJusoh",authors:[{id:"186369",title:"Dr.",name:"Zati",middleName:null,surname:"Sharip",slug:"zati-sharip",fullName:"Zati Sharip"},{id:"220302",title:"Mr.",name:"Shahirwan",middleName:null,surname:"Aman Shah",slug:"shahirwan-aman-shah",fullName:"Shahirwan Aman Shah"},{id:"220303",title:"Mr.",name:"Aminuddin",middleName:null,surname:"Jamin",slug:"aminuddin-jamin",fullName:"Aminuddin Jamin"},{id:"220304",title:"Mr.",name:"Juhaimi",middleName:null,surname:"Jusoh",slug:"juhaimi-jusoh",fullName:"Juhaimi Jusoh"}]},{id:"71359",doi:"10.5772/intechopen.90652",title:"Effects of Climate Change on Water Resources, Indices, and Related Activities in Colombia",slug:"effects-of-climate-change-on-water-resources-indices-and-related-activities-in-colombia",totalDownloads:726,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"In Colombia, a country with great climatic diversity, the water balance is affected in one way or another by climate change depending on the region. Thus, there may be increases and decreases in precipitation and, in all cases, a huge increase in temperature. This document presents some studies carried out in different areas of the country regarding the effects of climate change on water resources, including its influence on hydroelectric power generation, some changes in the water balance in arid areas, and the opportunity to ensemble climate change scenarios. Likewise, it outlines a possible future water supply-demand relationship, where supply is associated with a change in the water balance and demand with some crops, activities, and sectors that need water to survive. This allows to estimate some future status indices to see the overall picture of climate change in connection with the country’s water resources.",book:{id:"8098",slug:"resources-of-water",title:"Resources of Water",fullTitle:"Resources of Water"},signatures:"Nathaly Güiza-Villa, Carlos Gay-García and Jesús Efren Ospina-Noreña",authors:[{id:"311362",title:"Ph.D.",name:"Jesús Efren",middleName:null,surname:"Ospina-Noreña",slug:"jesus-efren-ospina-norena",fullName:"Jesús Efren Ospina-Noreña"},{id:"311363",title:"Dr.",name:"Carlos",middleName:null,surname:"Gay-García",slug:"carlos-gay-garcia",fullName:"Carlos Gay-García"},{id:"311364",title:"M.Sc.",name:"Nathaly",middleName:null,surname:"Güiza-Villa",slug:"nathaly-guiza-villa",fullName:"Nathaly Güiza-Villa"}]},{id:"62709",doi:"10.5772/intechopen.79732",title:"Sustainability of Irrigation in Uzbekistan: Implications for Women Farmers",slug:"sustainability-of-irrigation-in-uzbekistan-implications-for-women-farmers",totalDownloads:1056,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"This chapter focuses on a discussion of how global efforts to align local irrigation management with the good governance principles affect the lives of the rural poor, specifically women. Drawing in empirical data collected in post-soviet Uzbekistan, I illuminate unexpected effects of an apparently well-intended irrigation project on those categories of farmers whose connections to state apparatus of agricultural commerce of cotton were weak. Using fieldwork data from a village largely affected by desiccation of Aral Sea, I describe the everyday struggles by these people, who are mostly women, engage to make their living and provide subsistence to their families in situation of economic trauma, environmental disaster, and massive outmigration of male population. This analysis puts forward the local voices of real people whose lives are being restructured by sustainability oriented actions. Such perspective is often missed in scholarly and professional literature. These findings are hoped to assist policy developers in formulating irrigation programs in ways that would embrace sustainability both in terms of environmental and social justice.",book:{id:"6886",slug:"water-and-sustainability",title:"Water and Sustainability",fullTitle:"Water and Sustainability"},signatures:"Elena Kim",authors:null}],mostDownloadedChaptersLast30Days:[{id:"58856",title:"The Effects of Climate Change on Rural-Urban Migration in Sub-Saharan Africa (SSA)—The Cases of Democratic Republic of Congo, Kenya and Niger",slug:"the-effects-of-climate-change-on-rural-urban-migration-in-sub-saharan-africa-ssa-the-cases-of-democr",totalDownloads:1890,totalCrossrefCites:5,totalDimensionsCites:7,abstract:"Water is essential for the existence of living organisms including humans. Water is needed in farms to grow crops, firms and manufacturing industry to produce products and services. This chapter examines water resources availability and management in Sub-Saharan Africa (SSA) in climate change perspective using vector auto-regression (VAR) time series analysis. Water is known to be unevenly distributed among countries and continents around the world, particularly in Sub-Sahara Africa; the water availability varies between member countries and regions in the individual country, water supply systems experience enormous pressure to make water accessible to people in both rural and urban communities. Water security remains to be an integral part of the SSA’s effort to achieve food security and supply, halve poverty and eradicate hunger. This chapter more importantly aims to investigate impact of rainfall and temperature issues––that are climate change proxy variables––on water security and people movement in three Sub-Saharan African countries that are Democratic Republic of Congo, Kenya and Niger. This article assesses some possible causes of migration from rural to urban area using VAR and granger causality tests; this process involves four variables namely Rural Migration ‘MR’, Urban Migration ‘MU’, Rainfall ‘Rain’ and Temperature ‘Temp’. The model predicts rainfall and temperature across 10 years and examines how these changes impact water availability and people movement in relevant countries. This study finds that some countries are experiencing water security challenges upon which large numbers migrate to urban areas. The study reveals that variations in rainfall and temperature have compounded people movements from rural areas. It is noted that the agricultural production in SSA have not improved over time and in fact, it has further decreased due to the move away from rural areas by many farmers.",book:{id:"6184",slug:"applications-in-water-systems-management-and-modeling",title:"Applications in Water Systems Management and Modeling",fullTitle:"Applications in Water Systems Management and Modeling"},signatures:"Omar Moalin Hassan and Gurudeo Anand Tularam",authors:[{id:"148090",title:"Dr.",name:"Gurudeo",middleName:null,surname:"Tularam",slug:"gurudeo-tularam",fullName:"Gurudeo Tularam"},{id:"208956",title:"Mr.",name:"Omar",middleName:null,surname:"Moalin Hassan",slug:"omar-moalin-hassan",fullName:"Omar Moalin Hassan"}]},{id:"73528",title:"Characteristics and Assessment of Groundwater",slug:"characteristics-and-assessment-of-groundwater",totalDownloads:813,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"Groundwater system is very vital to humanity and the ecosystem. Aquifers are determined based on the absence or presence of water table positioning, that is, confined, unconfined, leaky aquifers and fractured aquifers. The objective of this chapter is to discuss the characteristic and assessment of groundwater within the scope of vertical distribution of GW, types of the aquifer system, types of SW-GW interface, and SW-GW interaction at both local and regional scales. The properties of the aquifer depend on the physical characteristics of the materials (porosity, permeability, specific yield, specific storage, and hydraulic conductivities) which are determined by techniques like resistivity surveys and pumping tests followed by remote sensing and geographic information system for better information on the groundwater system. Furthermore, understanding the SW-GW interactions through available methods (seepage meter, heat tracer, and environmental tracer) is useful in watershed management, that is, risk management and assessment of the aquifer system.",book:{id:"9981",slug:"groundwater-management-and-resources",title:"Groundwater Management and Resources",fullTitle:"Groundwater Management and Resources"},signatures:"Naseem Akhtar, Muhammad Izzuddin Syakir, Mohd Talha Anees, Abdul Qadir and Mohamad Shaiful Yusuff",authors:[{id:"201647",title:"Mr.",name:"Mohd Talha",middleName:null,surname:"Anees",slug:"mohd-talha-anees",fullName:"Mohd Talha Anees"},{id:"203218",title:"Dr.",name:"Muhammad Izzuddin",middleName:null,surname:"Syakir Ishak",slug:"muhammad-izzuddin-syakir-ishak",fullName:"Muhammad Izzuddin Syakir Ishak"},{id:"324417",title:"Ph.D. Student",name:"Naseem",middleName:null,surname:"Akhtar",slug:"naseem-akhtar",fullName:"Naseem Akhtar"},{id:"328134",title:"Mr.",name:"Mohammad Shaiful",middleName:null,surname:"Yusuff",slug:"mohammad-shaiful-yusuff",fullName:"Mohammad Shaiful Yusuff"},{id:"328135",title:"Mr.",name:"Abdul",middleName:null,surname:"Qadir",slug:"abdul-qadir",fullName:"Abdul Qadir"}]},{id:"73757",title:"Groundwater Recharges Technology for Water Resource Management: A Case Study",slug:"groundwater-recharges-technology-for-water-resource-management-a-case-study",totalDownloads:598,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The irregularity in monsoon has severely affected the water availability at surface and sub-surface systems. Diminishing surface and sub-surface availability has not only decreased the water availability, but it additionally affected the ecosystem and increased disastrous situations like floods and droughts, resulting problems of stress on groundwater recharge. Groundwater recharge is a technique by which infiltrated water passes through the unsaturated region of groundwater and joins the water table. It is based upon soil type, land use land cover, geomorphology, geophysical and climate (viz. rainfall, temperature, humidity etc.) characteristics of a region. Over the years, due to variations in weather pattern and overexploitation of aquifers groundwater recharge has decreased and groundwater level has reduced in the most parts of the country. This has led to severe water deficit problems in several parts of the country. This can be solved by different direct and indirect methods of groundwater recharge technology. This technology can reduce the wastage of water and enhance groundwater availability for uses in different sector like irrigation, domestic and industrial uses.",book:{id:"9981",slug:"groundwater-management-and-resources",title:"Groundwater Management and Resources",fullTitle:"Groundwater Management and Resources"},signatures:"Jatoth Veeranna and Pawan Jeet",authors:[{id:"325776",title:"Dr.",name:"Pawan",middleName:null,surname:"Jeet",slug:"pawan-jeet",fullName:"Pawan Jeet"},{id:"328200",title:"Mr.",name:"Jatoth",middleName:null,surname:"Veeranna",slug:"jatoth-veeranna",fullName:"Jatoth Veeranna"}]},{id:"62709",title:"Sustainability of Irrigation in Uzbekistan: Implications for Women Farmers",slug:"sustainability-of-irrigation-in-uzbekistan-implications-for-women-farmers",totalDownloads:1055,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"This chapter focuses on a discussion of how global efforts to align local irrigation management with the good governance principles affect the lives of the rural poor, specifically women. Drawing in empirical data collected in post-soviet Uzbekistan, I illuminate unexpected effects of an apparently well-intended irrigation project on those categories of farmers whose connections to state apparatus of agricultural commerce of cotton were weak. Using fieldwork data from a village largely affected by desiccation of Aral Sea, I describe the everyday struggles by these people, who are mostly women, engage to make their living and provide subsistence to their families in situation of economic trauma, environmental disaster, and massive outmigration of male population. This analysis puts forward the local voices of real people whose lives are being restructured by sustainability oriented actions. Such perspective is often missed in scholarly and professional literature. These findings are hoped to assist policy developers in formulating irrigation programs in ways that would embrace sustainability both in terms of environmental and social justice.",book:{id:"6886",slug:"water-and-sustainability",title:"Water and Sustainability",fullTitle:"Water and Sustainability"},signatures:"Elena Kim",authors:null},{id:"71359",title:"Effects of Climate Change on Water Resources, Indices, and Related Activities in Colombia",slug:"effects-of-climate-change-on-water-resources-indices-and-related-activities-in-colombia",totalDownloads:725,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"In Colombia, a country with great climatic diversity, the water balance is affected in one way or another by climate change depending on the region. Thus, there may be increases and decreases in precipitation and, in all cases, a huge increase in temperature. This document presents some studies carried out in different areas of the country regarding the effects of climate change on water resources, including its influence on hydroelectric power generation, some changes in the water balance in arid areas, and the opportunity to ensemble climate change scenarios. Likewise, it outlines a possible future water supply-demand relationship, where supply is associated with a change in the water balance and demand with some crops, activities, and sectors that need water to survive. This allows to estimate some future status indices to see the overall picture of climate change in connection with the country’s water resources.",book:{id:"8098",slug:"resources-of-water",title:"Resources of Water",fullTitle:"Resources of Water"},signatures:"Nathaly Güiza-Villa, Carlos Gay-García and Jesús Efren Ospina-Noreña",authors:[{id:"311362",title:"Ph.D.",name:"Jesús Efren",middleName:null,surname:"Ospina-Noreña",slug:"jesus-efren-ospina-norena",fullName:"Jesús Efren Ospina-Noreña"},{id:"311363",title:"Dr.",name:"Carlos",middleName:null,surname:"Gay-García",slug:"carlos-gay-garcia",fullName:"Carlos Gay-García"},{id:"311364",title:"M.Sc.",name:"Nathaly",middleName:null,surname:"Güiza-Villa",slug:"nathaly-guiza-villa",fullName:"Nathaly Güiza-Villa"}]}],onlineFirstChaptersFilter:{topicId:"872",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517",scope:"Paralleling similar advances in the medical field, astounding advances occurred in Veterinary Medicine and Science in recent decades. 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After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. 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A dynamic career research platform which is based on the thematic areas of comparative vertebrate physiology, stress endocrinology, reproductive endocrinology, animal health and welfare, and conservation biology. \nEdward has supervised 40 research students and published over 60 peer reviewed research.",institutionString:null,institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},{id:"20",title:"Animal Nutrition",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",isOpenForSubmission:!0,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. He teaches various degree courses in zootechnics, sheep production, and agricultural sciences and natural resources.\n\nDr. Ronquillo’s research focuses on the evaluation of sustainable animal diets (StAnD), using native resources of the region, decreasing carbon footprint, and applying meta-analysis and mathematical models for a better understanding of animal production.",institutionString:null,institution:{name:"Universidad Autónoma del Estado de México",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null},{id:"28",title:"Animal Reproductive Biology and Technology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/28.jpg",isOpenForSubmission:!0,editor:{id:"177225",title:"Prof.",name:"Rosa Maria Lino Neto",middleName:null,surname:"Pereira",slug:"rosa-maria-lino-neto-pereira",fullName:"Rosa Maria Lino Neto Pereira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9wkQAC/Profile_Picture_1624519982291",biography:"Rosa Maria Lino Neto Pereira (DVM, MsC, PhD and) is currently a researcher at the Genetic Resources and Biotechnology Unit of the National Institute of Agrarian and Veterinarian Research (INIAV, Portugal). 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Singh",profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"8018",title:"Extracellular Matrix",subtitle:"Developments and Therapeutics",coverURL:"https://cdn.intechopen.com/books/images_new/8018.jpg",slug:"extracellular-matrix-developments-and-therapeutics",publishedDate:"October 27th 2021",editedByType:"Edited by",bookSignature:"Rama Sashank Madhurapantula, Joseph Orgel P.R.O. and Zvi Loewy",hash:"c85e82851e80b40282ff9be99ddf2046",volumeInSeries:23,fullTitle:"Extracellular Matrix - Developments and Therapeutics",editors:[{id:"212416",title:"Dr.",name:"Rama Sashank",middleName:null,surname:"Madhurapantula",slug:"rama-sashank-madhurapantula",fullName:"Rama Sashank Madhurapantula",profilePictureURL:"https://mts.intechopen.com/storage/users/212416/images/system/212416.jpg",institutionString:"Illinois Institute of Technology",institution:{name:"Illinois Institute of Technology",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Proteomics",value:18,count:4},{group:"subseries",caption:"Metabolism",value:17,count:6},{group:"subseries",caption:"Cell and Molecular Biology",value:14,count:9},{group:"subseries",caption:"Chemical Biology",value:15,count:14}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:9},{group:"publicationYear",caption:"2021",value:2021,count:7},{group:"publicationYear",caption:"2020",value:2020,count:12},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:2}],authors:{paginationCount:148,paginationItems:[{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/165328/images/system/165328.jpg",biography:"Vahid Asadpour, MS, Ph.D., is currently with the Department of Research and Evaluation, Kaiser Permanente Southern California. He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. 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