\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{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"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"647",leadTitle:null,fullTitle:"Chronic Lymphocytic Leukemia",title:"Chronic Lymphocytic Leukemia",subtitle:null,reviewType:"peer-reviewed",abstract:"B-cell chronic lymphocytic leukemia (CLL) is considered a single disease with extremely variable course, and survival rates ranging from months to decades. It is clear that clinical heterogeneity reflects biologic diversity with at least two major subtypes in terms of cellular proliferation, clinical aggressiveness and prognosis. As CLL progresses, abnormal hematopoiesis results in pancitopenia and decreased immunoglobulin production, followed by nonspecific symptoms such as fatigue or malaise. A cure is usually not possible, and delayed treatment (until symptoms develop) is aimed at lengthening life and decreasing symptoms. Researchers are playing a lead role in investigating CLL's cause and the role of genetics in the pathogenesis of this disorder. Research programs are dedicated towards understanding the basic mechanisms underlying CLL with the hope of improving treatment options.",isbn:null,printIsbn:"978-953-307-881-6",pdfIsbn:"978-953-51-6746-4",doi:"10.5772/1156",price:139,priceEur:155,priceUsd:179,slug:"chronic-lymphocytic-leukemia",numberOfPages:464,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"6ed7cea1e96993e2edc66548c29bb436",bookSignature:"Pablo Oppezzo",publishedDate:"February 10th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/647.jpg",numberOfDownloads:47921,numberOfWosCitations:23,numberOfCrossrefCitations:13,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:25,numberOfDimensionsCitationsByBook:4,hasAltmetrics:0,numberOfTotalCitations:61,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 15th 2011",dateEndSecondStepPublish:"March 15th 2011",dateEndThirdStepPublish:"July 20th 2011",dateEndFourthStepPublish:"August 19th 2011",dateEndFifthStepPublish:"December 17th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"68891",title:"Dr.",name:"Pablo",middleName:null,surname:"Oppezzo",slug:"pablo-oppezzo",fullName:"Pablo Oppezzo",profilePictureURL:"https://mts.intechopen.com/storage/users/68891/images/3584_n.jpg",biography:"Dr Pablo Oppezzo received his MSc in Molecular and Cellular Biology from PEDECIBA (Uruguay) in 1999. In 2004, he received his PhD in Immunology from the University Paris VI, and did post-doctoral work at the Biochemical Structural Unit at the Pasteur Institute of Paris. In 2006 he obtained a position as Principal Investigator of Recombinant Protein Unit at Institut Pasteur de Montevideo, Uruguay. Dr Pablo Oppezzo is now the Head of the Recombinant Protein Unit and Professor in the Immunology department at the School of Medicine, Republic University (UdelaR), Uruguay. \nDr Oppezzo’s research focuses on the mechanisms involved in the origins of haematopoietic B-cell malignancies, specifically the study of the mutagenic action of the enzyme Activation-Induced cytidine deaminase. In the last years, he contributed to elucidate the mechanism of somatic hypermutation and class switch recombination process in Chronic Lymphocytic Leukemia and to identify new prognosis markers for this disease.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Institut Pasteur",institutionURL:null,country:{name:"France"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1073",title:"Bone & Musculoskeletal Oncology",slug:"bone-and-musculoskeletal-oncology"}],chapters:[{id:"27981",title:"Selected Topics in Chronic Lymphocytic Leukemia Pathogenesis",doi:"10.5772/38328",slug:"selected-topics-in-chronic-lymphocytic-leukemia-pathogenesis",totalDownloads:2127,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Sergio Bianchi, Guillermo Dighiero and Otto Pritsch",downloadPdfUrl:"/chapter/pdf-download/27981",previewPdfUrl:"/chapter/pdf-preview/27981",authors:[{id:"116671",title:"Dr.",name:"Guillermo",surname:"Dighiero",slug:"guillermo-dighiero",fullName:"Guillermo Dighiero"}],corrections:null},{id:"27982",title:"Microenvironment Interactions in Chronic Lymphocytic Leukemia: A Delicate Equilibrium Linking the Quiescent and the Proliferative Pool",doi:"10.5772/27119",slug:"microenvironment-interactions-in-chronic-lymphocytic-leukemia-a-delicate-equilibrium-linking-the-qui",totalDownloads:2532,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"F. 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There are still problems to overcome, which are linked to the following: (a) heterogeneity of cancer cells within tumors, which is mirrored in their response to a specific therapy; for example, cancer stem cells possess inherent mechanisms for self‐repair and renewal and are therefore often responsible of tumor recurrence and metastasis; (b) complex mechanisms by which tumor cells avoid the innate and adaptive immune responses (adaptability, versatility, mimicry), including by immune suppression induction [1].
\nIn addition to conventional therapeutic approaches (chemo‐ and radiotherapy), we face the shifting of the attention to the immune antitumor defense mechanisms which might offer a steady improvement to conventional therapies for tumor cells eradication. Cancer defiantly induces immune suppression and this is further deepened by anticancer therapies, which weaken the immune response, apart from killing tumor cells [2, 3].
\nIn the last decade, immunotherapy gained a leading position in cancer research and management, due to promising results recently reported in clinical studies for (a) vaccines (sipuleucel‐T) and monoclonal antibodies (ipilimumab), (b) recombinant cytokines and hematopoietic growth factors, and (c) cellular and gene therapies.
\nThe adoptive transfer of lymphocytes with high antitumor reactivity can trigger tumor regression in metastatic melanoma [4–6]. Nowadays, autologous T lymphocytes are clinically used.
Natural killer cells are a component of the innate immune response against viruses and malignant cells. Individuals having low NK cells activity are at risk to develop cancer [7]. The presence of high NK cells number within the tumor confers a good prognostic for cancer patients [8]. NK cells represent a relatively poor population, about 1–32% from the peripheral lymphocytes in healthy individuals [9]. As opposed to T cells, which hold MHC‐restricted antigen specificity, NK cells are able to directly and quickly lyse target cells without the need of an initial sensitization. It was proven that many types of tumor cells express high levels of ligands for NK cells receptors [10], which leads to their recognition and killing by NK cells [11]. The role of NK cells is regulated by (a) cytokines and chemokines which interact with inhibiting or activating receptors on NK cells [12, 13]; (b) communication with other immune cells, such as dendritic cells [14], effector TCD4+ lymphocytes [15] and regulatory T lymphocytes [16].
\nUntil now, therapies with NK cells have been successful mainly for patients with leukemia [17–22], but adoptive transfer of interleukin (IL)‐2‐activated NK cells in patients with solid tumors (melanoma or renal carcinoma) did not show clear clinical benefits [23]. Based on the fact that NK cells possess the memory of being previously activated [23–29], new strategies can be developed for enhancing
It was shown that the multiplication of NK cells can be achieved by modulation with cytokines [30–38]. The development of the methods for growing human NK cells in vitro has incited a special interest for immunotherapy [32, 36, 39–41]. With the development of methods for multiplication of human NK cells in vitro, these cells have incited a special interest for immunotherapy.
NK cells are large granular cells that play a major role in the innate immune response against viruses, bacteria, as well as malignant cells [12, 24, 42]. They were first identified in 1975 by their ability to kill tumor cells without MHC restriction or prior sensitization to tumor antigens [43–45]. The name “natural killer” refers to their natural occurrence and spontaneous ability to kill malignant cells in non‐immunized animals. NK cells are found in a variety of lymphoid and nonlymphoid tissues, including bone marrow, lymph nodes, spleen, peripheral blood, liver and lung. NK cells develop in the bone marrow from a common lymphoid progenitor cells.
\nNK cells are characterized by the expression of CD16 and CD56 surface antigens and the lack of CD3/T‐cell receptor molecules. In humans, there are two subsets of NK cells based on CD56 expression levels: CD56dim and CD56bright. Morphologically, the CD56dim NK cells are large granular lymphocytes, while CD56bright NK cells are small lymphocytes. The CD56dim subset represents the majority of NK cell population in the peripheral blood and spleen (90–95%), exhibit a high cytotoxic potential after interaction with target cells [46, 47]. They produce negligible amounts of cytokines and bear the Fc receptors (CD16) to mediate antibody‐dependent cell‐mediated cytotoxicity (ADCC). In contrast, the CD56bright subset predominates (approximately 90%) in lymph nodes and tonsils, have poor cytotoxic activity and produce very significant amounts of cytokines and chemokines [48]. The CD56bright NK cells produce chemokines and cytokines in response to cytokine stimulation, while the CD56dim population chemokines and cytokines production is stimulated by target cell recognition.
\nThese subsets also differ in the expression of interleukin (IL)‐2 receptor α chain (IL‐2Rα/CD25). CD56bright subset exclusively expresses CD25, while the CD56dim subset lacks CD25 expression. There are differences in receptor expression between the two subsets of NK cells. As opposed to the CD56bright NK cells, CD56dim NK cells express high levels of killer‐cell immunoglobulin‐like receptors (KIRs) and low levels of CD94/natural killer group 2 (NKG2) receptors. These differences have been correlated with the specific alloreactive properties of CD56dim NK cells due to their high KIR levels and their ability to kill various tumor cells [49].
\nThe murine NK cells do not express CD56 marker, but they can be divided in four subsets according to the expression of CD11b and CD27 markers: CD11blowCD27low, CD11blowCD27high, CD11bhighCD27high, CD11bhighCD27low [50]. Mouse CD27high NK cells predominate in lymph nodes and produce large amounts of cytokines, but in contrast with CD56bright NK cells, they have cytotoxic potential. In humans, expression of CD11b and CD27 markers have also revealed four subsets of NK cells with distinct maturation stages, tissue distribution patterns and functional properties [51, 52].
\nThe NK cell activating receptor NKp46 (Ncr1), in contrast to other human NK cell markers (CD56, CD16) or murine NK cell markers (NK1.1, DX5), is almost exclusively expressed by NK cells, and it can be used as an additional marker for identify NK cells [53, 54].
NK cells do not express rearranged, antigen‐specific receptors, but they express a variety of germ‐line encoded receptors that can recognize ligands on their cellular targets.
\nNK cell function, including proliferation, production of cytokines and chemokines, natural killing, lymphokine‐activated killing and ADCC, depends on an intricate balance between signals from inhibitory and activating receptors. The activating receptors interact with ligands expressed on stressed, infected, or transformed cells, or antibody‐opsonized targets (CD16/FcγRIIIa), while inhibitory receptors recognize MHC class I or class I‐like molecules [11].
\nInhibitory receptors include killer immunoglobulin‐like receptors (KIRs), the c‐type lectin, NKG2A/CD94 and leukocyte immunoglobulin‐like receptors (LILRs) [55]. The ligands for these inhibitory receptors are mostly the major histocompatibility complex class‐I (MHC‐I) molecules. Inhibitory signals prevent NK cells from becoming activated, blocking degranulation and cytokine production. Ligation of MHC‐I molecules to the inhibitory receptors acts as a form a NK cell tolerance. By this mechanism, NK cells save healthy cells from killing as long as they express normal levels of MHC class I molecules and low amounts of stress‐induced self‐molecules. During the NK cell development, signals coming from inhibitory receptors help NK cells to be “educated” to respond to MHC‐I deficient cells [56].
\nActivating receptors include the natural cytotoxicity receptors or NCRs, the c‐type lectins, NKG2D and NKG2C/CD94, the SLAM family receptors and others. NK cells express the low‐affinity Fc receptor or CD16 and the death ligands FasL and tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) that after interaction with death receptors induce apoptosis of the target cell. Although some of the ligands to activation receptors are already present on healthy cells, the expressions of many of them are induced upon cell stress [57].
\nIn case of cellular transformation or viral infection, surface MHC class I expression on the cell surface is downregulated or lost to escape from recognition by T cells. When mature NK cells encounter that cell, their inhibitory receptors are not engaged, and the unsuppressed activating signals can trigger cytokine secretion and attack of the targeted cell. In parallel, cellular stress and DNA damage upregulate “stress ligands” that can be recognized by activating NK receptors.
\nNK cells kill tumor targets through a variety of mechanisms, including release of cytoplasmic granules containing perforin and granzyme, expression of tumor necrosis factor (TNF) family members FasL or TNF‐related apoptosis‐inducing ligand (TRAIL), that induce tumor cell apoptosis by interacting with their respective receptors Fas and TRAIL receptor (TRAILR) as well as ADCC [58].
\nDuring tumor progression, tumor cells develop the ability through which they escape from NK cell response. These mechanisms include downregulation of adhesion molecules, costimulatory ligands or ligands for activating receptors, upregulation of MHC‐I molecules, soluble MIC, FasL or NO expression [59, 60], secretion of immunosuppressive factors such as IL‐10, transforming growth factor (TGF)‐β or indoleamine 2,3‐dioxygenase (IDO) and resisting Fas‐ or perforin‐mediated apoptosis [61]. In cancer patients, there are observed some NK cell defects, including decreased numbers in peripheral blood and in tumor infiltrate, reduced expression of activation receptor or intracellular signaling molecules and overexpression of inhibitory receptors, decreased cytotoxicity, defective proliferation and cytokine production.
Cytokines are the main regulators of growth, proliferation, survival and differentiation for various cell types involved in the innate and adaptive immunity. The exhibition of NK cells to cytokines induces enhanced proliferation, augmented cytokine production, higher cytotoxicity against target cells and upregulation of cytotoxic and adhesion molecules. The common γ‐chain interleukins (ILs) such as IL‐2, IL‐15, IL‐21 can activate NK cells, and the combination of IL‐12 and IL‐18 is especially potent to trigger interferon (IFN)‐γ.
\nIL‐2 and IL‐15 are the best studied cytokine activators of NK cells; they have central role for NK cell development and homeostasis, induce proliferation, costimulate cytokine production and enhance cytotoxic effector mechanisms. The both cytokine share the IL‐2/15R
IL‐21 is a cytokine structurally‐related to IL‐2, IL‐4, IL‐15. IL‐21Rα is expressed by lymphoid tissues, shows similarities with IL‐2/IL‐15R β chain and forms a complex with the common γ chain [73]. IL‐21 exerts antitumor effects through its ability to induce activation and proliferation of cytotoxic cells (T CD8+ cytotoxic lymphocytes, NK cells, NKT cells). Meanwhile, IL‐21 suppresses Foxp3 expression and the expansion of immunosuppressive Treg lymphocytes. Accordingly, IL‐21 was associated with antitumor activity in clinical practice [74]. The discovery of IL‐21 was linked to its role in NK cells proliferation and maturation. Further studies have provided however contradictory data, highlighting both the activator and the suppressor role of IL‐21. Soluble IL‐21 alone does not induce significant proliferation in mature mouse NK cells, and IL‐21R knockout mice possess normal NK cells number. Meanwhile, IL‐21 synergizes with IL‐2, IL‐15 and Flt‐3L for NK cells generation in the bone marrow and in umbilical cord blood. IL‐21 can activate the cytotoxic activity of NK cells through over expression of costimulating receptors and cytolytic molecules (perforin, granzymes). IL‐21 enhances multipotent progenitor maturation from bone marrow and activates peripheral NK cells in the absence of other stimuli.
\nIL‐12, originally identified as “NK cell stimulatory factor (NKSF)” based on its ability to enhance NK cell cytotoxicity. The primary effects of IL‐12 on NK cells are IFN‐γ and TNF‐α production. In vitro and in vivo studies have shown that IL‐12 acts on NK cells in concert with other activating cytokines, such as IL‐2 and IL‐18, or with receptor‐based interactions from pathogenic cells.
\nAlthough the IL‐18Rα is constitutively expressed on unstimulated NK cells and can induce NK cell proliferation alone, IL‐18 has been described as a costimulatory cytokine that functions synergistically with IL‐12 and IL‐15. NK cells from IL‐18 deficient mice have impaired cytotoxicity and IFN‐γ production. These findings indicate the importance of IL‐18 to NK‐mediated host defense.
\nSuccessful adoptive cell transfer (ACT) and
Based on results from experimental animal models, adoptive transfer of autologous NK cells seems to be safe and promising for cancer therapy. Initial trials of adoptive NK cells involved infusion of CD56 bead‐selected autologous NK cells from a leukapheresis product followed by administration of systemic cytokines [75]. Upon cytokine stimulation, NK cells become lymphokine‐activated killer (LAK) cells and exhibit greater cytotoxicity against tumor cells. Although administration of cytokines improve the antitumor activity of NK cells in vitro, only limited antitumor activity of LAK cells was observed in cancer patients [23]. Similar results were also obtained when autologous NK cells and systemic IL‐2 were administrated to patients with lymphoma. Partially effective clinical outcomes were observed in metastatic renal cell carcinoma (RCC) patients that received a combination of high‐dose IL‐2 and LAK cell infusions, while treatment of non‐Hodgkin\'s lymphoma and RCC patients with
As was shown, adoptively transferring autologous NK cells was found to greatly improve clinical responses without any obvious adverse side effects in some cancers. However, these NK cells could not yet exhibit their full cytotoxic capacity in vivo, this may be due to many tumors expressing high levels of human leukocyte antigen (HLA) class I receptor and/or low levels of ligands for activating receptors that suppress autologous NK cells in vivo. For these reasons, they are focused on therapies using allogenic NK cells from related donors or other strategies to prevent such NK cell resistance.
Using the allogeneic NK cells has the advantage of the inherent alloreactivity afforded by the “missing self” concept. When donor NK cells encounter an altered MHC environment, the NK cells can be “re‐educated” by host HLA and can acquire cytotoxicity against host tumor cells without causing graft versus host disease (GVHD). Allogenic NK cells with KIR mismatch have greater tumor‐killing activity and the ability to control acute myeloid leukemia (AML) relapse [77, 78]. Adoptively transferred human‐mismatched (haploidentical) allogeneic NK cells have been shown to be a safe therapy with minimal toxicity and have been more successful for cancer immunotherapy, including against leukemia and solid cancers. In some clinical trials using adoptively transferred haploidentical allogeneic NK cells to treat AML patients, including pediatric AML patients and older AML patients no graft‐versus‐host disease (GvHD) response was observed and NK cell therapy was well tolerated. Besides hematopoietic‐derived tumors, strategies using adoptively transferred haploidentical allogeneic NK cells can also expand in patients with various malignancies, including metastatic melanoma, renal cell carcinoma, Hodgkin\'s disease and poor‐prognosis AML
NK cells are traditionally considered members or the innate branch of the immune system that responds rapidly but lack immunologic specificity in the form of a clonal antigen receptor and memory of prior activation. Recently several groups have challenged this paradigm of NK cells as pure innate lymphocytes and demonstrated memory‐like functions in NK cells.
\nThe immune system capacity to learn from previous encounters with pathogens, and respond more rapidly and effectively upon secondary infection has been termed adaptive immunity or immunological memory. After primary encounter with antigen, naïve antigen‐specific T or B cells proliferate vigorously and some of them differentiate into memory cells [79]. This stage represents the expansion phase, when the naïve cells clonally expand. Following the primary response, in the contraction phase, the majority of effector cells die and surviving cells enter the memory phase. Upon reencounter with their cognate antigen, memory cells exert their functional responses more rapidly than do naïve cells. This response to a second antigen exposure called the “recall response.”
\nAntigen‐specific responses and memory responses, both are hallmarks of adaptive immunity. Innate responses do not require pre‐sensitization and rely on germline encoded receptors and do not require clonal expansion. NK cells have long been categorized as a component of innate immunity. Although NK cells lack the ability to undergo somatic rearrangements of their receptors, these cells are developmentally and functionally more related to adaptive immune lymphocytes than innate immune cells.
\nInitially it was believed that NK cells act in the first days of infection, but now we know that NK cells function in parallel and complementary to the adaptive immune response over extended periods of time. Moreover, there are many evidences for adoptive‐like features of NK cells. Evidence for adoptive‐like features of NK cells has come from a variety of studies, and NK cell‐mediated memory can be generated in response to haptens, viruses and following combined cytokine activation.
\nNK cell memory was first described in a mouse model of hapten‐induced contact hypersensitivity (CHS), induced by chemical haptens such as 2,4‐dinitro‐1‐fluorobenzene (DNFB) and 4‐ethoxymethylene‐2‐phenyloxazol‐5‐one (oxazolone) and picryl chloride [25]. T‐ and B‐deficient mice developed vigorous specific contact hypersensitivity responses to haptens and response persisted for at least four weeks. The mice exhibited enhanced recall responses to the same chemical, but not to a different one, demonstrating antigen specificity. Furthermore, contact hypersensitivity responses could be conferred to naive mice by adoptive transfer of natural killer cells from sensitized mice.
\nThese responses possessed the hallmarks of adaptive immunity: they were sensitization dependent, persisted for at least four weeks and were only elicited by haptens to which mice had previously been sensitized. These observations indicate that natural killer cells can mediate long‐lived, antigen‐specific adaptive recall responses independent of B cells and T cells. It was shown that transfer of a subset of liver‐derived NK cells, not splenic or naïve NK cells, could confer the recall response. NK cell memory to haptens depended on expression of CXCR6, a chemokine receptor on hepatic NK cells critical for intrahepatic survival and homeostasis [80]. CXCR6 is a chemo‐attractant receptor which is expressed on roughly 50% of liver NK cells. The molecular mechanism leading to the generation of antigen‐specific memory NK cells remained elusive
Also, NK cells could mount recall responses to diverse viral antigens such as vesicular stomatitis virus (VSV), virus‐like particles (VLP) containing influenza A‐derived hemaglutinin and/or matrix protein 1, or VLP containing the HIV‐1‐derived Gag protein and/or Env protein [80]. In order to confer the recall response, liver NK cells had to express the CXCR6. Blocking CXCR6 with antibodies can impair the recall response. NK cells can respond more vigorously upon secondary stimulation against challenges with additional irritants (such as fluorescein isothiocyanate [FITC]), as well as the viruses vaccinia, and herpes simplex virus (HSV)‐2 [81–83].
\nA central issue that remains unresolved is how NK cells can recognize and differentiate between all these different antigens, since there are no known VSV, vaccinia, HSV‐2, or HIV‐specific NK receptors. The ability of NK cells to respond to such a wide diversity of distinct antigens, including pathogens that are not endemic to mice, such as HIV1, is puzzling and suggests that a hitherto unknown recombination-activating genes (RAG)-independent receptor diversification mechanism may exist in NK cells [84].
\nMost of the evidence that NK cells exhibit a memory‐like adaptive response has come from studies involving mouse cytomegalovirus (MCMV) infection. NK cells play a crucial role in the protective immune response to herpesvirus family members, especially to CMV infection. It have been shown that a subset of NK cells in the C57BL/6 strain of mice bearing the activating receptor Ly49H, specifically recognize the MCMV‐expressed ligand m157 and proliferate in response to viral infection [85–87]. Ly49H, a germ‐line encoded receptor, is expressed by a very large fraction of NK cells in naïve mice (~50% of NK cells). During viral infection, a Ly49H‐expressing subset of NK cells is extended and rapidly responds upon reinfection with MCMV, similar to classic lymphocytes memory. The germ‐line encoded MCMV‐specific receptors exist too in mouse strains, such as Bagg Albino (BALB/c), non-obese diabetic (NOD) and others, and that clonal expansions of MCMV‐specific NK cells could also be observed in those strains [88]. Similar to CD8+ T cell response, the proliferation was Ag‐specific because infection of mice with a mutant MCMV lacking m157 did not cause expansion of Ly49H+ NK cells [25]. Ly49H+ NK cells adoptively transferred in mice lacking functional Ly49H receptor proliferate 100‐1000‐fold after MCMV infection, and after a contraction phase, persist for months. When these cells are restimulated
In human, studies have focused on the memory NK cell response in infection with cytomegalovirus (CMV), Hanta virus or Chikungunya virus [90–92]. The results shown that NK cells that express the germ‐line encoded NKG2C receptor appeared in increased frequency in response to infections with these viruses. During acute HCMV infection, NKG2C+ NK cells expanded in number, and diminished partially in numbers after the resolution of the acute phase. These memory NK cells persisted for up to a year. After expansion, the NKG2C+ NK cells produced significantly more IFN‐γ in response than NKG2C- NK cells. A follow‐up study demonstrated that after adoptive transfer of NKG2C+ NK cells from CMV‐seropositive donors exhibited enhanced effector function against a secondary CMV challenge [93]. In the Hanta virus infection or Chikungunya virus infection, NKG2C+ NK cells expanded three‐ to fourfold compared to uninfected controls. In both cases, these increases were only seen in patients who were HCMV seropositive, raising the possibility that the increase in NKG2C+ NK cells reflected reactivation of latent CMV. It has been noted that in HCMV‐infected patients, after the acute infection was cleared, NKG2C+ NK cell numbers remained elevated in contrast with uninfected individuals. It is possible that these NKG2C+ NK cells present in HCMV‐seropositive individuals respond to other infections. Another study has demonstrated that the combination of CMV‐infected fibroblasts plus IL‐12‐producing monocytes induced the expansion of NKG2C+ NK cell in vitro [94].
Memory‐like NK cells could be induced in vitro by cytokines activation in both mice and humans. NK cells from Rag 1‐deficent mice were pre‐activated overnight in vitro with IL‐12, IL‐18 and IL‐15, and then adoptively transferred into syngeneic Rag‐1-/- recipients. After resting in vivo, when the NK cells had reverted to a quiescent state, the cytokine pre‐activated NK cells were phenotypically similar to control NK cells. They expressed similar levels of CD69, CD11b, CD27, B220, as well as the cytokine receptors CD122, IL12Rβ1, IL‐15Rα and CD127. Also, they expressed comparable levels of granzyme B and lysed target cells similar to control NK cells in vitro [27, 95]. However, up to 3 weeks following adoptive transfer, the cytokine pre‐activated NK cells were found to respond more robustly compared to resting NK cells. These pre‐activated NK‐cells displayed enhanced IFN‐γ production upon either activating receptor ligation (Ly49H or NK1.1 receptors) or cytokines (IL‐12 and IL‐15) restimulation. This enhanced ability to produce IFN‐γ occurs in cells that have not undergone division and those that have replicated. It has been demonstrated that the enhanced functionality of memory‐like NK cells is not due to alteration in IFN‐γ transcription or mRNA stability.
\nAdoptively transferred cytokine pre‐activated NK cells proliferated rapidly in an IL‐2‐dependent manner into recipient mice bearing MHC class I‐deficient RMA‐S lymphoma or B16‐Rae1ε melanoma cell lines [96]. Exposure of NK cells to cytokines upregulated the IL‐2Rα chain, making these cells more responsive to IL‐2. It was observed a significantly reduced tumor growth and prolonged survival in recipient mice, pre‐activated NK cells exhibited enhanced functionality months following adoptive transfer, and were able to mediate more effective in vivo antitumor responses.
\nHuman NK cells also exhibit enhanced IFN‐γ production after short‐term pre‐activation with various combinations of IL‐12, IL‐15 and IL‐18 [97]. Both NK cell subsets, CD56bright and CD56dim, exhibited cytokine‐induced memory‐like NK cell. Cytokine pre‐activation led to extensive proliferation, and memory‐like NK cells maintained their capacity for enhanced recall responses. Similar to mice, IFN‐γ mRNA transcript levels did not differ between control and memory‐like NK cells. In contrast to murine memory‐like NK cells, phenotypic differences were identified between pre‐activated NK cells and controls. Human memory‐like NK cells had increased CD94, NKG2A, NKp46 and CD69 surface expression and reduced KIR and CD57 expression. Human memory‐like NK cells were also shown to be responsive to low concentrations of IL‐2.
\nA pre‐clinical study has shown that human memory‐like NK cells also have potential as anti‐leukemia cellular therapy [98]. They exhibited enhanced IFN‐γ production and increased cytotoxicity when restimulated with leukemia cell lines or acute myeloid leukemia (AML) blasts in vitro. Following adoptive transfer into immunodeficient NOD‐severe combined immunodeficiency (SCID)‐γc-/- mice, human cytokine‐induced memory‐like NK cells exhibited increased IFN‐γ production following restimulation [99].
\nTherefore, human NK cells can acquire memory‐like properties after a brief cytokine pre‐activation.
Although, the concept of NK cell memory is rather new, many studies in recent years have provided substantial evidence for adaptive features of the NK cell response. The enhanced function of memory NK cells makes them an area of interest for future use in preventing or treating inflammatory diseases, infectious diseases and cancer.
This work was supported by grand of the Romanian National Authority for Scientific Research (PN 16.22.04‐04).
Quality of higher education and training of highly qualified and employable graduates are the important prerequisites of sustainable social and economic development of society [1]. Training of graduates in line with international standards can positively impact population’s well-being in the long-term period. Nowadays, the HEIs must provide the high-quality student-centered learning and the ongoing adaptation of study programs and teaching methods to diverse expectations of labor market.
QA in higher education assumes, on the one hand, the process of creating conditions to promote the education quality, and, on the other hand, focus on an objective evaluation of the quality of learning outcomes and the professional competencies of students and graduates [2]. The education quality is one of the important components in the reproduction of the labor force, which contributes to the quality of the labor force and through it to the increase of the country’s social and economic growth. Currently, the quality of higher education is an important issue for Kazakhstan, as the country needs highly qualified personnel capable of adapting to the changing realities of the labor market and solving complex issues to ensure sustainable social and economic development of the country. Having joined the Bologna Process in 2010, Kazakhstan introduced reform of the quality assurance system aimed at further improvement of the education system, its quality, and efficiency. As a guideline, the Bologna Declaration standards [2] were chosen. In 2011, a new version of the Kazakhstan Law “On Education” was adopted [3]. It aimed at the creation of a national quality assurance system in Kazakhstan, development of an internal quality assurance system in the HEIs, increase of the capacity of national quality assurance agencies, establishment of a network of independent local quality assurance agencies, and provision for procedures of the HEIs’ accreditation. In 2012, the “Register 1″ of independent accreditation agencies was worked out.
However, at the moment, there’re no effective internal quality control systems in Kazakhstani HEIs [4]. There are no clearly defined internal standards to ensure the quality of education to evaluate the educational programs and the graduates’ training level [4]. The HEIs manage in accordance with outdated internal standards and quality assurance tools that aren’t adapted to modern conditions and national practices [4]. Normally, the quality assurance issues are limited to documentation and document workflow. The modern education system still encounters problems of centralized management [4]. The education reform came across with evident contradictions such as outdated laws and regulations governing the educational system. The new law “On Education” dated July 4, 2018, which is the so-called Law on the Autonomy of the Higher Educational Institutions provides innovations designed to resolve the contradictions between the efforts to reform education and the old management and the rules and regulations [5]. This paper analyzes the possibility and acceptability of the European best practices to be applied in Kazakhstani HEIs considering country’s local contexts and how educational reforms successful in European countries are effective in Kazakhstan. The paper provides an analysis of the QA systems of three European universities (University de Liege, Royal Institute of Technology KTH, University de Lorraine), visited in the framework of international project experts training on QA in higher education; national quality assurance system analysis of Kazakhstan, Belgium, France, and Sweden; and survey of internal QA system in three Kazakhstani universities (University of International Relations, National Agrarian University, and University of Economics, Finance and Trade). This research uses data from a survey of Kazakhstani students, faculty, and staff between March and April 2018 as one of the methods to assess the education quality. However, often the HEIs aren’t interested in an objective assessment of their effectiveness [1, 4]. In this regard, in order to get more objective assessment of the education quality, an additional survey was done to determine the more real picture of the University of International Relations graduates’ employability. Employability would be one of the indicators of the competitiveness and demand for graduates in the labor market and proof of the high quality of education in the HEI they have graduated. This research was also aimed at the identification of the nature of employment to analyze its gender aspects.
Now, there is a clear gap between the labor market, the market needs, and the education system. The labor market is managed by employers who dictate the labor force demand and specify the demand for HEI graduates on the labor market. In this regard, this research analyzes the actual situation with the employment of the University of International Relations graduates in order to assess how competitive our graduates are in the labor market and assess the quality of their training, conduct a gender analysis of the opportunities and conditions of graduates’ employment in the labor market, and analyze the role of the university-employer partnership to ensure the education quality and enhance the graduates’ employability.
Analysis of the internal QA system of Kazakhstani universities is based on a survey conducted with the staff of the Quality Assurance units and observation of three Kazakhstani universities, as well as on their self-evaluation reports provided to the accreditation commission. In all these universities, the author was engaged in the accreditation process either as an expert of the accreditation commission or as an employee who participated in the preparation of a self-evaluation report to be accredited. For the purpose of survey, the questionnaire was used to cover questions on the institutional QA, namely, whether there is a specific structure/unit in charge of the QA or major directions of the QA strategy. Is there a specific official document on a QA strategy or is it an integral part of the university’s overall strategy? Describe the QA mechanisms such as commissions, indicators, and assessment procedures. What are the internal and external stakeholders involved in the QA? Describe how they participate. Check the list to set the Standards and Guidelines for Quality Assurance in the European Higher Education Area (hereinafter ESG). Describe activities to confirm this standard implementation.
Analysis of the national and the institutional QA systems of European universities such as University de Liege (Belgium), Royal Institute of Technology KTH (Sweden), and University de Lorrain (France), which were visited under the international project training for QA experts in higher education, was done in terms of the possibilities and acceptability of application of the best European practices in Kazakhstani universities. Information provided at trainings by national QA agencies in Belgium, Agency for Quality Assurance in Higher Education (AEQES); in France, Commission des Titres d’Ingénieur (CTI) and High Council for the Evaluation of Research and Higher Education (HCERES); and in Sweden, The Swedish Higher Education Authority (UKÄ), was used in this paper.
One of the methods of internal evaluation of the University of International Relations effectiveness is monitoring and analysis of the quality of the educational services provided. In March–April 2018, the anonymous survey “Faculty Through the Eyes of Students” among the students and the questionnaire of faculty members “The social well-being of the academic staff” were conducted. Questionnaires “Faculty Through the Eyes of Students” had 10 questions regarding the faculty teaching competence in the following areas: the student-oriented approach, interaction with students including ethical behavior, the relevance of the material provided to students to the latest science achievements, the information relevance, and the use of innovative teaching methods and technologies. The students filled in 12,036 questionnaires about 404 faculty members, while the survey coverage was 90% of the entire teaching staff. According to the survey results, 96% of students were satisfied with the teaching quality. The average score was 4.8 points out of 5 possible. Thus, according to this internal assessment, the University of International Relations has a high education quality.
Under the questionnaire “The Social Wellbeing of the Faculty Members,” 413 questionnaires or 92% of the total staff were filled in by the faculty. A respondent might choose several answers from the set list of questions. A survey of respondents showed that 73% of the faculty members are satisfied with their work at the University of International Relations while 23% aren’t. 51% of them are in favor of improving the psychological climate, and 49% think that it is necessary to improve working conditions, reduce unnecessary paperwork, provide more time for scientific creative work, computerize all processes, increase the Internet speed, and improve automated processes. In general, based on the results of both surveys, the University of International Relations has a high grade of the faculty effectiveness and the entire educational process. However, just the opinions of students and faculty do not provide an objective assessment of the education quality. A more fundamental indicator of the University of International Relations effectiveness would be the graduates’ employability. “Employability is an aggregate of competencies, skills, understanding, and personal characteristics that provide graduates with career prospects that contribute to the development of the economy and society” [6]. A high indicator of the graduates’ employment proves the relevance of demand for graduates and their specialty. It would be a proof of recognition of the competences received and the education quality in this HEI.
Under this research, 1261 graduates of 2017 from 1323 of the University of International Relations were interviewed. Sixty-two graduates were foreign citizens and were not interviewed. To confirm data received under this survey, information was requested from the Interdepartmental Settlement Center for Social Payments (hereinafter Center for Social Payments) on the pension contributions made by our graduates. The 2017 database of graduates with information on respondents including passport data and the University of International Relations name was provided to the Center for Social Payments. It was done to track respondents in the tax base and to get data on their social payments. The social payments of a respondent would confirm his/her official paid employment.
Open questions with an open-ended choice of answers were used. The survey was done in the form of a telephone interview with pre-prepared questions in February to March 2018, that is, the 8th–9th months after the graduation.
In 2010, in an effort to integrate into the global educational space, Kazakhstan has signed the Bologna Process. Most Kazakhstani HEIs have signed the “Magna Carta of Universities,” which is the fundamental of the “Bologna Declaration.” The Lisbon Convention “On the recognition of qualifications on higher education in the European region” and the Sorbonne Declaration “On the harmonization of the architecture of the European higher education system” were signed, while the declaration “Zone of European higher education” was adopted. Having signed these documents, Kazakhstan demonstrated its will for democratization, improvement of the education quality, and the establishment of the autonomy of HEIs [7]. Kazakhstan has chosen to modernize the education system and comply with international standards. All the HEIs nationwide have transferred to a three-level system of education including the undergraduate, graduate, and doctoral (PhD.) The educational process was reorganized into a credit training system based on comparability with the ECTS credit transfer system. The HEIs all by themselves have started to develop and approve the procedure to transfer credits according to the ECTS type and regulate its application. “The Rules to organize the educational process under the credit technology” and “Classifier of specialties of higher and postgraduate education of the Republic Kazakhstan” with enlarged groups of specialties were approved nationwide [8].
A critical issue of modernization is the creation of a National QA system, which would not just control over the education quality but also the development of the system to ensure the quality of education. The ESG were applied as the basis for the QA system in Kazakhstan. Accreditation of the HEI and study programs is the external quality assurance mechanism. The national accreditation model is independent and voluntary. Accreditation shall be implemented by accreditation agencies included in the Register 1, which is the list of accreditation agencies in the field of education, which are the National Register of Accreditation Bodies of the Republic of Kazakhstan (hereinafter the RoK) Ministry of Education and Science. The RoK Ministry of Education and Science recognizes all European accreditation agencies listed in the European QA Register (EQAR). However, in order to be able to accredit Kazakhstani HEIs, they shall be registered in Kazakhstan and join the Register 1. Currently, 11 accreditation agencies are listed in Register 1, among them are 6 Kazakhstani organizations, Kazakhstan Agency for Quality Assurance in Education (IKAQAE), Independent Agency of Accreditation and Ratings (IAAR), Kazakhstan Association for Engineering Education (KAZSEE), Agency for Recognition and Quality Assurance in Education (ARQA), Eurasian Center for Accreditation and QA (ECAQA), and Independent Accreditation Center (IKAC), and 5 international ones—FIBAA (German), ASIIN (German), MusiQue (Belgium), ACQUIN (German), and ACBSP (USA).
Since 2017, national agencies IAAR and IKAQAE became the international ones and joined the European Association for the Quality Assurance in Higher Education (ENQA). In addition, they were listed in the European Register for Quality Assurance (EQAR) [9]. According to the report of the Center for the Bologna Process, the listing of Kazakhstani agencies into the European Register “demonstrated the recognition of procedures and processes at the European level the whole Kazakhstani education” [9]. The RoK National agencies accredit under the QA standards they have developed, in accordance with national education standards and the ESG. “Special standards analogous to the ESG in the field of the QA are not developed in Kazakhstan yet” [9]. Conceivably, the IAAR and the IKAQAE are the independent agencies and do not depend on public finance. However, the HEIs pay the agencies for accreditation and choose an accreditation agency by themselves. Eventually, these factors affect the assessment fairness, by taking into account the low level of quality culture. For example, the French High Council for Evaluation of Research and Higher Education (HCÉRES) is an independent national QA in higher education agency, which does not depend on state funding and of HEI. The HCÉRES is funded by the parliamentary vote.
Despite the fact that accreditation is voluntary for the HEIs, all of them are interested in it. First of all, the non-accredited HEIs shall not train the state-funded grantees. The status of an accredited university is critical for a HEI. Such status would confirm the compliance of a university and its educational programs with international standards. This status provides an HEI with a chance to be recognizable in Europe and to develop joint educational programs and academic mobility. However, the ambitions of Kazakhstani HEIs to be accredited shortly and the competition for being top in the ratings often resulted in an unreliable self-assessment reports and colored truth. But it is just the transparent, objective, reliable results of the internal assessment and audit of a HEI and the quality of its educational programs that are done by its staff at the institutional level could help to identify weaknesses and ways to address them. The accreditation procedure as such presupposes to pass a final verdict upon the completion of the assessment. The “F” would entail no access to many of the above benefits. It might be advisable to use the experience of the French agency HCÉRES and first provide Kazakhstani HEIs with an independent evaluation. Such an evaluation does not imply placing a HEI in the ranking, but is done in order to identify weaknesses and provide an opportunity to improve a HEI management.
One of the impediments to improve the education quality would be the nontransparent and inaccurate statistics. All the HEIs of the country on an ongoing basis upload their data to the ESU-VO, Unified Management System of Higher Education. This is a multilevel information system that includes all the HEIs, the RoK Ministry of Education and Science, and other government structures and agencies involved in the education development. Quite often, the data uploaded by universities in ESU-VO differ from those provided by them in self-assessment reports and from the real situation at a HEI. HEIs are not interested in creating a transparent statistical database. For example, data on the number of students and their socioeconomic status are overestimated, since the amount of funding from the Ministry of Education and Science depends on this. The decrease in the number of students, specifically the students from low-income families, as a result has a decrease in funding from the Ministry of Education and Science. Efforts by the Ministry of Education and Science to introduce the “Platonus” electronic system have not gained traction in numerous HEIs. Specifically, at the University of Liege, a statistic list has been created on the university’s website in the public domain. All the university’s statistics is placed there. This is the automated data processing. This list is ongoingly updated. Each university unit has access to a statistical database. The use of this French experience could reduce the time spent by employees of Kazakhstani HEIs to collect and process data to be provided to accountable bodies and make university statistics transparent.
The survey of Kazakhstani universities found that all the HEIs have the developed QA system (according to their responses) with a separate unit in charge, the QA policy, mechanisms, and procedures that comply with the European QA Framework and ESG. The QA procedures include surveys of students and employers. The major standards and parameters of the Bologna Process were proclaimed in Kazakhstan at the national and institutional levels as “adopted and implemented.” However, their real implementation is yet an issue. Challenges arise since the HEIs’ employees have no skills to develop educational programs which shall comply with the qualification framework and in the regulation and evaluation of the HEIs’ activities, and they have no responsibility for learning outcomes. Universities encounter the overcentralized management and outdated internal QA tools. The institutional QA systems are limited to a quality management system that complies with the ISO 9001. The academic integrity, rating methods, the teaching quality, and the development of a “culture of quality and trust” [4] remain problematic. The development of a quality culture implies that each unit and each staffer shall be responsible and aware of their involvement in the final result, namely, in the qualitative training of specialists, and participate in the continual improvement of the education quality.
Most HEIs in France, Belgium, and Sweden are public; however, all of them have academic and financial independence. Currently, higher education in Kazakhstan transits from the centralized administration by the RoK Ministry of Education and Science to the HEIs’ autonomy. Unfortunately, very often autonomy is considered by the HEIs barely as financial self-sufficiency and independent distribution of financial and material resources. In an effort to reduce the expenditure side of the university budget, the administration often downsizes the number of faculty and staff, increasing the workload of those remaining. In the HEIs, there is still a practice to finance in-service training of faculty on a residual basis. There are contradictions between the outdated methods of education management and efforts to modernize the education system. The reforms undertaken do not yet provide full academic and financial freedom to the HEIs. Reform of the higher education system and the will to provide greater autonomy to the HEIs are restrained by outdated laws and regulations in all areas of a HEI’s development. For example, the transition to credit training technologies implies for students the independent choice of subjects for study, that is, have freedom of choice. However, the strategy of public financing of the HEIs is still based on the state education standards and compulsory model curricula, which means no alternatives to choose [10]. This contradiction limits the academic autonomy of the HEIs. Overcentralization prevents the HEIs from consideration of local needs.
The HEIs’ right to develop a corporate governance designed to fulfill not only an advisory, but also a controlling role, and to ensure interrelation and consideration of the national interests, business, and society was limited to the creation of the regents of the universities and the supervisory board at a HEI, which do not have any legal force and exist just on paper. The lack of appropriate laws and regulations restrains the expansion of the HEIs’ autonomy. Most HEIs operate as national state-owned enterprises on the basis of the right of economic management. The law “On State Property” governing these HEIs conflicts with the main strategies to develop academic and financial independence [11, 4].
To further promote the HEIs’ autonomy, a new RoK Law “On Amendments and Additions to Certain Legislative Acts of the Republic of Kazakhstan on the Expansion of the Academic and Administrative Independence of Higher Education Institutions” of July 4, 2018, was adopted, and over 70 regulatory legal acts were elaborated [5]. This law provides the state enterprises for possible transformation of the legal form into nonprofit joint-stock companies. Such transformation would be another step to autonomy, since the nonprofit form of organization makes it possible for HEIs to maintain corporate standards in management and ensure the efficient redistribution of income for its development. This law shall entitle the HEIs to legally pursue commercial activities. The reform also affected the methods to finance the HEIs and provides for the transition to credit financing without reference to the period of study [5]. The new law also provides the development of a new Classifier on the training areas. In accordance with this Classifier, the HEIs shall independently develop the new educational programs. The new Classifier will replace the old one with numerous specialties which have not been in demand in the labor market for a while [12].
The institutional autonomy is not a goal in itself. The main argument to expand the HEIs’ autonomy would be an effective QA system, which implies the HEIs’ institutional responsibility for the education quality and social responsibility for the population’s well-being in the end. “Autonomy shall be implemented under a national framework that balances institutional freedom with various social goals” [13, 14]. The HEIs’ overcommercialization, increased tuition fees, and the current methods of the RoK Ministry of Education and Science to distribute educational grants have resulted in limited access to education for the disadvantaged population. Educational grants are primarily awarded based on academic merit. School graduates from low-income families and applicants from rural areas, where poverty is 2.7 times higher than in the urban ones and the instruction level and material security of schools is lower than in the cities [15], were on a back foot. Granting autonomy to the HEIs would not mean taking away responsibility of the state to support them and the vulnerable groups. Given the low level of socioeconomic development of the country (compared to European countries), Kazakhstan needs the Government support for the HEIs at this stage of transition to academic and managerial independence.
In Europe, the transformation period in the education system to create the common education space and the labor market has more than 50 years. The national and domestic QA systems of the HEIs in France, Belgium, Romania, Sweden, and Bulgaria are guided by the ESG standards aimed at improving the education quality and developing a quality culture in higher education, bolstering the role of students and employers in the QA processes. The national QA agencies evaluate the HEIs’ activities and intend, per their recommendations provided, to promote them providing quality services and increase the graduates’ employability as the main indicator of the education quality. However, the policy to ensure the quality of each country has its own specifics, adapts to local terms, and considers the conditions for the development of the local labor market and the living standard of the population.
At the end of the last century, France and Belgium already had a developed quality assessment system. In the early 2000s, in order to ensure comparability of educational programs, create a common educational space, and promote student mobility, the European HEIs begin to transit to accreditation as the final stage of assessment to confirm that a HEI complies with the ESG standards. Currently, Belgium develops a new methodology for an external QA system. It focuses on support of HEIs and promotion of their quality approaches, the internal QA system, and strengthening autonomy and responsibility for the QA in a HEI and transfers from just a summative assessment to an effective formative assessment which involves monitoring in order to provide its results to the HEIs to improve teaching and learning.
All the analyzed European HEIs are independently responsible for the education quality while keeping their traditions and specifics that took years. The QA system of all European HEIs gives priority to their self-evaluation, assessment of learning outcomes, increased autonomy, and the level and nature of the graduates’ employment. For example, the University de Lorraine Quality Management Unit has been monitoring graduates for employment for several years. The survey key questions are set by the Ministry of Education, but the HEIs can freely add any questions of their interest. The statistics received under the survey are available on the universities’ website and used to evaluate their activities. They are also provided to the Ministry of Education to create a centralized database of all universities. At the national level, the survey results are processed, and databases are compiled at different levels, in different subjects, for each university, and at the national level.
The Swedish QA system under the requirements of the Bologna Process was formed with the already high-quality education in the country. The Swedish Higher Education Authority (UKÄ) is a state agency controlled by the State. The major focus of this agency is to ensure that the assessment conducted by the agency helps to improve the education quality at the university. Sweden has developed a new QA system implemented since 2017 and made up four separate assessments: an institutional assessment of the QA process, an assessment of educational programs, an assessment of degree applications, and thematic assessments. Thematic assessment would mean evaluation of the entire educational system, comparison of the achievements of the HEIs in areas important to the country, and ensuring quality in higher education by topics such as internationalization or gender equality. “Sustainable development in education” was determined for a thematic assessment in 2017. The Swedish QA system is characterized by ongoing monitoring and periodic evaluation of educational programs; a university has a close relationship with the business sector and with employers and is strongly orientated to the labor market. In Sweden, a government agency, working on labor market research, works effectively to determine the skills and competencies that will be in future demand in a country and regions.
The Swedish experience in the study of the labor market could be a good guide for Kazakhstani students when choosing subjects, for the HEIs and employers to develop educational programs, and for the Ministry of Education and Science to determine state education standards, working out strategies and programs for education development. The RoK Ministry of Labor and Social Protection of the Population in cooperation with the RoK Ministry of Education and Science forecast specialties that will be in demand on the labor market. According to the forecasts, a state educational order is formed. According to the latest forecast data, the most on-fire specialties are the industrial and the technical ones [16]. However, there is practically no more national industrial sector, and therefore there will be no demand for graduates in these subjects in the labor market. The Soviet experience of the development of vocational education which had strong relationship with the industrial sector was completely ignored since there is no industrial sector anymore. Since applicants are not interested to enroll on these specialties, it would be advisable to provide them with incentives to stimulate their choice of specialties strategically important for the country’s future.
The European HEIs are financially independent, yet the state provides them with financial support. According to the latest available data from UNESCO, in 2015 government expenditures on education in Kazakhstan amounted to 2.79% of GDP, which is way below than in European countries (Figure 1). Herewith, in Kazakhstan the share of expenditures on tertiary in total expenditures on education is lower (Figure 1). Likewise, the share of expenditures on tertiary in total expenditures for education in Kazakhstan tends to decrease and amounted to 15.26% in 2015, 11.64% in 2016, and 10.56% in 2017 [17].
Government expenditure on education as a percentage of GDP (%). Expenditure on tertiary as a percentage of government expenditure on education (%). Source: based on UNESCO data (
Currently, Kazakhstani HEIs encounter financial difficulties such as provision of a decent salary for employees, renovation of material-technical basis of HEI, promotion of academic mobility, and in-service faculty training. An unreasonable increase of tuition fees (compared to the financial capacities of local households) results in a loss of students due to the general low level of the population’s well-being. Consequently, the public finance of Kazakhstani HEIs is needed and should be a priority for the state as support to the economy and business. For the internal QA system of Kazakhstani HEIs, it would be advisable to adopt the experience of European HEIs to create mechanisms for continuous, comprehensive, and transparent assessment. On this basis further improvement of the education quality would be developed. The current practice to conduct an accelerated and chaotic assessment under the preparation for accreditation creates stress for all the HEI employees and suspends all its activities. All European countries under consideration are characterized by a high life quality and a high level of economic development, the industrial sector, the SME, the popular employment in nongovernmental organizations due to decent salaries there, and the social environment. All this creates a wide labor market and hence a greater demand for graduates. To ensure the effective modernization and reform in Kazakhstan, the government support of education also should comply with international standards; the level of the populations’ well-being and the country’s socio-economic development would allow students to choose a university that provides sound academic background and they would be able to pay for quality education and later find a decent work and fair salary.
According to the graduates’ survey results, out of a total number of respondents 1261 (100%), 929 (74%) of the University of International Relations graduates have found a job and are currently employed, of which 18 persons have started a business and are registered as individual entrepreneurs. Of a total number of respondents, 178 (14%) graduates have continued their education, while 154 (12%) persons had no job at the survey time. However, the Center for Social Payments confirmed official data for any payments only for 771 graduates out of the 929 graduates who answered they were employed. This means that only 771 graduates had a paid employment while the remaining 158 (12.5% of all respondents) were informally employed (Figure 2).
Survey of 2017 University of International Relations graduates employability. Source: based on survey results.
Seventy percent (992 persons) of all University of International Relations graduates (1323 persons) are women, while 30% (331 people) are men. Of a total number of interviewed (1261) graduates, 75% (945 persons) were women and 25% (316) men. Evidently, among those who received higher education in the University of International Relations, women are in majority. Similar situation is nationwide. In Kazakhstan, the education level of the employed population is high: 39% of the employed population have higher education, 37.5% specialized secondary education, and 17% general secondary one. At the same time, the education level among women is higher than that of men. 43.8% of employed women have higher education; this number among men is 34.5%. According to the survey, the percentage of female graduates with a high GPA (3.2–4.0 out of 4.0 possible) is 46% (out of all female graduates of 2017). Of a total number of male graduates, 42% of male graduates have a high GPA. However, whereas there’re no gender differences in the cognitive abilities of women and men, there’re gender inequalities in the labor market, namely, in hiring, in access to highly paid and prestigious jobs.
According to the graduates’ survey results, 74% of the University of International Relations female graduates surveyed have found jobs (701 persons), and out of 316 of the interviewed male graduates, 72% (228 persons) were employed. Thus, the percentage of the University of International Relations female and male graduates’ employability is almost the same. However, there is a significant difference in the employment nature. Namely, there’re gender differences in the spheres chosen by women and men and the positions offered by employers, in employment conditions and salaries. On the surface, there’s no gender discrimination as a phenomenon in Kazakhstan. Equal rights and opportunities for men and women are legislated at the state level. But in reality, there is gender discrimination in the labor market such as professional segregation, which, namely, is evident as the feminization of low-paid jobs and in the representation of women mainly at the lower levels of the economic hierarchy. A simple comparison of the average monthly wages of men and women shows the existence of gender differences when women’s labor is paid lower than men’s one, and women’s wages are 69.6% of men’s wages [18]. According to the RoK Statistic Agency, the wages of men in major groups of positions and professions are approximately 1.1–2.2 times more than the average wages of women on similar positions (Figure 3).
Average monthly nominal wage of men and women for selected occupations and functions (for all observed forms of economic activity). Source: the RoK Statistic Agency, 2018.
Women have limited access to prestigious work, since it is assumed their labor has a low return. According to the survey results, almost 70% of employed female graduates work in schools and colleges as teachers. In turn, the majority of male graduates (about 60%) work in prestigious companies, where wages are higher. The education sphere in Kazakhstan is one of the lowest paid with majority of women employed, since the men aren’t interested in such employment and do not compete with women here. Female graduates do not sustain competition with the males for well-paid jobs, where they shall work overtime and ongoingly upgrade qualifications. Even if a woman is unmarried at the time of hiring, employers prefer the man since a woman’s employment is sort of risky, namely, in terms of her future marriage and maternity leave. It is known that in future women will devote all their off-hours to the family and practically will have no opportunity to upgrade their skills and work overtime. Incompatibility of biological reproduction and economic production is “a fundamental source of dynamic allocative inefficiency and a basic cause of women’s inequality” [19].
Currently, paid work outside the home and unpaid chores and women’s time for childcare, especially in young low-income families, are almost incompatible. Low-income families cannot afford to automate their chores, hire a babysitter, and pay for preschool education. The lower the level of a household welfare, the higher the women’s workload in the household, and the less is her ability to get paid work outside the home [20]. This situation is exacerbated by inadequate social support by the Government and the lack of social infrastructure accessible to the needy families. “The lack of social policy measures and supports for unpaid family responsibilities hits poor and vulnerable families the hardest, as they have the weakest economic capacity to purchase goods (processed foods, labor saving devices) or services (private childcare, domestic help) that can free up their time for paid work. They are often forced to choose between employment and care or to combine them—choices which require painful sacrifices in terms of quality of employment and/or quality of care. These choices also have longer-term welfare and economic consequences” [21
Nationwide, in 2017, the share of the paid-employed was 77% or 6.5 million and self-employed 23% or 2 million persons [18]. At the same time, women make up 62% of all self-employed. Informally employed in the country make up 16% of the total number of employed or almost 1.4 million individuals, and almost half of them are women. Informally employed in the country do not have access to social security, are not eligible for loans, and do not have stable incomes and pension savings. According to a survey at the University of International Relations, it was revealed that 12.5% (158 individuals) of all respondents are employed in the informal sector. 57% (90 individuals) of them are women. Most of them responded that they work as interpreters/translators, but since they do not pay taxes and social contributions, they apparently work as freelancers in informal sector. This means that the work of 158 unemployed graduates is not protected by law and is normally characterized by worse working conditions. Informally employed women are more vulnerable in the labor market due to the fact that they are more dependent on social benefits, sick leave, and maternity leave.
All respondents noted that it is very difficult to find jobs in national and private companies, where wages are higher than in public sector, without any support and patronage. Employers require work experience in a certain field, which is mostly unacceptable for the HEIs’ graduates. All respondents said the majority of job ads require 1–3 years of work experience in the relevant field. Also, respondents noted that if any work experience wasn’t required, such job did not require higher education and had low wages (50,000KZT/month ($135)). Employers aren’t interested in additional on-the-job training for newcomers. One of the respondents said he lost his first job because the employer would need employees who already know everything and would not waste time for training. “Nobody was eager to share information I didn’t know,” the respondent complained. The HEIs’ graduates are the least competitive in the labor market due to a lack of work experience and relevant skills. The situation with female graduates is exacerbated due to gender stereotypes about hiring. State-support programs for the HEIs’ graduates to encourage employers to hire graduates could assist newcomers to avoid stress, depression, and disappointment.
According to official statistics, the unemployment rate in the RoK among youngsters is 38% of the total number of unemployed nationwide, and most of them are the HEIs’ graduates [18, 15]. In this case, it is more difficult for female graduates to find job than for males. The level of woman’s unemployment nationwide among the youth is about 8%, while the man’s unemployment rate is 6% [18]. Women are the majority among the unemployed. Female graduates face great difficulties in the labor market while getting more prestigious job. Employers secretly prefer to hire men, because they assume that women would marry sooner and go on maternity leave and could not work overtime due to their family obligations. Several female respondents noted that employers asked them on job interviews whether they intend to marry or have children sooner. Such questions shall violate women’s rights.
One hundred fifty-four persons out of all the respondents did not get a job. 61% of all unemployed respondents are women while 39% are men. Some unemployed respondents have valid reasons, among them are the army service for men and the maternity leave for women who have to perform only unpaid chores and childcare. Unemployed female graduates with children at the survey time responded they cannot get paid work since they devote all their time to childcare and chores, due to the fact that they cannot afford the babysitting services. Women’s unpaid work in the reproductive sector including childcare and education of future generation is important to reproduce the labor force and the future national economic growth [22]. The state support of young families and the improvement of social infrastructure would be cost-effective both for the families and for society as a whole.
Women are in minority among those who start business in the country. At the same time, most women entrepreneurs have small businesses. Only 15% of large companies in the country are headed by women [18]. Women choose small businesses since it does not require high costs and resources, as well as special knowledge and skills to manage financial documents and reports [23]. The University of International Relations graduates both females and males are in equally difficult positions when in open business, due to lack of financial resources and entrepreneurial skills. According to the survey results, only 1.9% of employed graduates were able to start business. Herewith, among the respondents who started business only 16% are women, while 84% are men. Obviously, the HEIs’ graduates need the state support to start and run the business, in the form of preferential taxation, access to loans, etc. In addition, the HEIs could pre-train students for business through the integration in the curricula of courses on the basics of entrepreneurial skills, business management, and project management.
The most important aspect to ensure the education quality is the development of partnerships with real sector of economy. All the universities surveyed have entered into partnerships with business and public sectors where students had internships. For students, it is a good opportunity to test their knowledge and skills in real conditions, and for employers it is possible to assess the competencies of potential employees. According to the survey at the University of International Relations, 37% of employed graduates found jobs through the university in entities which are the university’s strong partners and mainly in the organizations where they’d internships. The university-employer cooperation is also implemented through business and public sector representatives teaching at the university, development of educational programs, assessment of students, and job fairs. Employers’ survey on their satisfaction with the quality of training of the HEIs’ graduates is one of the methods to assess the conformity of knowledge, skills, and competencies gained with the needs of the labor market. The question remains. How to ensure the objectivity of the assessment? How to process the comparability of the assessment results on the training quality in different universities? How to consider the different specializations of the HEIs, differences by region, between urban and rural areas and cultural and national aspects?
The further strengthening of the University-Business network and the more systematic involvement of employers in the development of educational programs would facilitate the adaptation of program content to the needs of the labor market and the elimination of the gap between the labor market and education.
To be competitive, the HEIs’ graduates currently should be able to solve issues in different fields of expertise. In this regard, interdisciplinary education is relevant for the HEIs. Educational programs including interdisciplinary courses in the field of entrepreneurship or project management can develop business and projects’ development skills. Interdisciplinary courses in the gender economics can increase awareness of socioeconomic processes in society, instill a culture of equality, and develop critical thinking.
The primary standards and parameters of the Bologna Process adopted at the national and the institutional levels in Kazakhstan encounter a problem of their real implementation. First of all, the reformation should consider the level of socioeconomic development of the country, the conditions to develop the local labor market, and the living standard of the population. It may take some time to change the mindset, develop skills, and teach the universities’ staff to be responsible in developing educational programs that comply with international standards and in regulating and evaluating the HEIs’ activities.
The internal QA system of Kazakhstani HEIs should focus on the adoption of the experience of European HEIs to create mechanisms for continuous, comprehensive, and transparent assessment. The current practice to conduct an accelerated and chaotic assessment under the preparation for accreditation creates stress for all the HEI employees and suspends all its activities. An analysis of the QA systems of European universities has revealed that using the best practices of the European national and institutional QA systems can be a solution to the education quality in Kazakhstan. In the meantime, it should be borne in mind that Kazakhstan has completely different starting conditions for modernization than European countries. This paper argues that educational reforms successful in European countries are still ineffective in Kazakhstan due to the lower level of socioeconomic development of the country, a quality culture and quality of life, and insufficient budget expenditures to finance education.
Currently, Kazakhstani HEIs need the support of the state and the QA agencies to create a mechanism of an ongoing, comprehensive, and transparent self-evaluation that helps to improve the university and educational programs and does not imply a race for a place in ratings, in creation incentives for an effective and objective internal evaluation.
For the successful implementation of the best European practices in Kazakhstan, it is necessary that government expenditures on education, the welfare level of the population, and the life quality and socioeconomic development of the country also comply with international standards, so that Kazakhstanis can choose a HEI that provides quality education, be able to pay for quality education, and get a decent work.
Based on the survey results, the University of International Relations has a high percentage of graduates’ employability and trains competitive graduates. Despite the fact that there’re no gender differences in the cognitive abilities of male and female graduates and the employability percentage is almost the same for both women and men, women are more vulnerable, cannot compete in the labor market, and are employed in less paid sectors. Women are fewer among those who start and run their business. The low competitiveness of the female labor force in the labor market is primarily associated with their childcare and chore obligations, which require more women’s time the lower the well-being is in the household. Woman’s labor in the reproductive sector is not paid for but is important in shaping human capital and the labor force quality. Thus, the gender aspect is an essential factor that can impact future wages, employment opportunities, and skills development and retraining. State social support for young families and incentives for employers to hire female and male graduates will ultimately bring economic benefits to society as a whole. Employability is a common issue that should be solved jointly by a student himself and with the support of the HEIs, business, and the state.
The employers’ survey on the assessment of the graduates’ competences could provide a more realistic picture of the demand for graduates in the labor market, as well as their professions, and most importantly, on the quality of their training in the HEIs. It would also be rational to have an additional survey of the same 2017 graduates a few years later, to track/analyze considering the gender aspects—whether they were able to retain their jobs or find opportunities to retrain in order to get new skills that meet the modern demands of the labor market, who of them was able to be promoted, and whether women after maternity leave could brush up and compete in the labor market.
I would like to express my special thanks to adjunct professor of University of Eastern Finland Heimo Mikkola for the scientific guidance, technical assistance, and moral support. I am very grateful to Erasmus+ program and European team of the project “Implementation of Education Quality Assurance System via Cooperation of University-Business-Government in Higher Education Institutions” for the great opportunity to go through experts training on QA in higher education.
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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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