Exploiting HLA-class II disparity for anti-tumor immunity by allogeneic cellular immunotherapy

Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative treatment for various hematological malignancies. The beneficial Graft-versus-Leukemia (GvL) effect of alloSCT is mediated by donor-derived allo-reactive T cells targeting the malignant cells of the patient. Unfortunately, detrimental Graft-versus-Host-Disease (GvHD) often co-develops due to recognition of allo-antigens by donor-derived T cells on non-hematopoietic tissues. To prevent the development of GvHD, donor T cells can be depleted from the alloSCT graft. Although the risk and severity of GvHD are effectively reduced by T cell depleted (TCD) alloSCT, the absence of donor T cells in the stem cell graft also leads to an increased risk of relapses of malignancies. Early intervention with unmanipulated donor lymphocyte infusion (DLI) may effectively prevent or treat post-transplant relapses, but is frequently associated with re-introduction of GvHD. Although post-transplant relapses of chronic myeloid leukemia (CML) in chronic phase can be effectively treated with DLI, patients with relapsed acute leukemia often fail to respond to DLI and their prognosis remains poor. This disease-specific difference in efficacy of DLI may be explained by the poor capacity of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and CML in blast crisis (CML-BC) to function as professional antigen presenting cells (APC) and induce primary T cell responses. In addition, acute leukemias are generally rapidly proliferating aggressive malignancies that may outpace the donor T cell responses as induced after DLI. Therefore, novel T cell based immunotherapeutic strategies with potent efficacy, but limited treatment-related toxicity are highly relevant to improve the clinical outcome for patients with aggressive acute malignancies. In contrast to constitutive expression of HLA-class I molecules on all nucleated cells, HLAclass II molecules are only constitutively expressed on normal hematopoietic cells as well as most B-lineage and myeloid malignancies, while most non-hematopoietic cells only express HLA-class II under inflammatory conditions. Therefore, CD4+ T cells recognizing allo-antigens in the context of HLA-class II molecules under non-inflammatory circumstances are likely to mediate selective GvL reactivity without GvHD. Clinical application of HLA-identical DLI depleted of CD8+ T cells has demonstrated to induce conversion to donor hematopoiesis and disease remissions in patients with relapsed malignancies, in the absence of induction of severe GvHD. In addition, it has been demonstrated that allo-HLA-DPB1 specific CD4+ T cells can mediate profound GvL reactivity in the absence of clinically significant GvHD after DLI following HLA-DPB1 mismatched TCD alloSCT, indicating that allo-HLA-class II molecules can also serve as malignancy-specific targets. Therefore, a possible strategy to induce profound and selective GvL immunity against acute leukemia without causing GvHD may be achieved by targeting (disparate) HLA-class II molecules by CD4+ T cell based immunotherapy following TCD alloSCT. This thesis explored the benefits and threats of this approach in a preclinical mouse model and in patients.The work described in this thesis was financially supported by the Dutch Cancer Society (KWF)(grant 2008-4263).UBL - phd migration 201

Magnesium-Gold Alloy Formation by Underpotential Deposition of Magnesium onto Gold from Nitrate Melts

Magnesium underpotential deposition on gold electrodes from magnesium nitrate-ammonium nitrate melts has been investigated. Linear sweep voltammetry and potential step were used as electrochemical techniques. Scanning electron microscopy (SEM), energy dispersive spectrometry (EDS) and X-ray diffraction (XRD) were used for characterization of obtained electrode surfaces. It was observed that reduction processes of nitrate, nitrite and traces of water (when present), in the Mg underpotential range studied, proceeded simultaneously with magnesium underpotential deposition. There was no clear evidence of Mg/Au alloy formation induced by Mg UPD from the melt made from eutectic mixture [Mg(NO3)(2).6H(2)O + NH4NO3.XH2O]. However, EDS and XRD analysis showed magnesium present in the gold substrate and four different Mg/Au alloys being formed as a result of magnesium underpotential deposition and interdiffusion between Mg deposit and Au substrate from the melt made of a nonaqueous [Mg(NO3)(2) + NH4NO3] eutectic mixture at 460 K

The influence of organizational design on employee engagement in digital environment

U eri digitalizacije, dolazi do transformacionih promena u poslovnim modelima savremenih preduzeća, što implicira promene u celom organizacionom dizajnu. Smatra se da je za uspeh preduzeća, naročito u tehnološki intenzivnim delatnostima, bitna agilnost, usklađenost elemenata dizajna, i, posebno, angažovanost radne snage. Ljudski faktor postaje ključni izvor konkurentske prednosti i zato pitanja koja se tiču međuzavisnosti organizacionog konteksta i individualnih ishoda postaju sve značajnija. Osnovni cilj doktorske disertacije jeste utvrđivanje uticaja organizacionog dizajna na angažovanost zaposlenih u digitalnom poslovnom okruženju. Analiziran je uticaj dizajna posla, i to strukturalne, kognitivne i socijalne dimenzije posla, na angažovanost zaposlenih. Zatim je ispitan indirektan uticaj strategijske agilnosti, organizacione strukture, procesa i sistema, preko dimenzija dizajna posla, na angažovanost zaposlenih. Na kraju je testirano da li organizaciona identifikacija ima moderatorsku ulogu u uticaju dizajna posla na angažovanost zaposlenih. Nakon teorijskog razmatranja osnovnih fenomena i njihovih međusobnih veza, sprovedeno je empirijsko istraživanje na uzorku od 270 ispitanika, zaposlenih u 100 preduzeća u delatnosti informisanja i komunikacija u Republici Srbiji. Za prikupljanje podataka korišćena je anketa, a rezultati su obrađeni različitim statističkim tehnikama. Sprovedena je deskriptivna analiza uzorka, analiza pouzdanosti mernih skala bazirana na Kronbahovom koeficijentu alfa, konfirmativna faktorska analiza, kao i modeliranje strukturalnih jednačina. Rezultati su pokazali da sve tri dimenzije dizajna posla delimično utiču na angažovanost zaposlenih, kao i da je uticaj najjači u slučaju autonomije zaposlenih kao karakteristike posla. Utvrđeno je da svi elementi organizacionog dizajna, osim podele rada i formalizacije, imaju indirektan uticaj na angažovanost preko neke od karakteristika posla, kao i da organizaciona identifikacija u nekim vezama karakteristika posla i angažovanosti ima značajnu ulogu moderatora. Istraživanje ima relevantne teorijske i praktične implikacije. Teorijski doprinos se, između ostalog, ogleda u osvetljavanju značaja ispitivanja organizacionog dizajna kao multidimenzionalnog fenomena i njegovih kompleksnih reperkusija na individualnom nivou. Praktično, rezultati istraživanja mogu biti korisni menadžerima svih nivoa za dizajniranje organizacije koja će omogućiti visoke nivoe angažovanosti, naročito u digitalnom okruženju. Osnovna ograničenja se tiču veličine uzorka, kao i činjenice da je istraživanje sprovedeno na teritoriji jedne države, što predstavlja osnovu za proširenje dobijenih saznanja u budućim istraživanjima.In the era of digitalization, business models of modern companies are facing transformational changes, which affect the entire organizational design. Agility, organizational alignment and the workforce engagement are considered essential for business success, especially in technologically intensive industries. The human factor is becoming a key source of competitive advantage and therefore, issues concerning the interdependence of organizational context and individual outcomes are becoming increasingly important. The main goal of the doctoral dissertation is to determine the impact of organizational design on employee engagement in the digital business environment. The influence of job design, namely the structural, cognitive and social dimensions, on employee engagement was analyzed. Then, the indirect impact of strategic agility, organizational structure, processes and systems, through the dimensions of job design, on employee engagement was examined. Finally, it was tested whether organizational identification has a moderating role in the impact of job design on employee engagement. After the theoretical consideration of the basic phenomena and their mutual connections, an empirical research was conducted on a sample of 270 respondents, employed in 100 companies in the information and communication industry in the Republic of Serbia. A survey was used to collect data, and the results were processed using various statistical techniques. A descriptive analysis of the sample, an analysis of the measurement scales’ reliability based on the Cronbach's alpha coefficient, a confirmatory factor analysis, as well as structural equation modeling were performed. The results showed that all three dimensions of job design partially affect employee engagement, while the impact of job autonomy is the strongest. It was found that all elements of organizational design, except the division of labor and formalization have an indirect impact on engagement through some of the job characteristics. Also, organizational identification has a significant moderating role in some relationships between job characteristics and engagement. The research has relevant theoretical and practical implications. The theoretical contribution is inter alia reflected in highlighting the importance of organizational design as a multilayered phenomenon which has complex repercussions at the individual level. Practically, research results can be useful to managers at all levels in order to design an organization that will enable high levels of engagement, especially in the digital environment. The main limitations concern the size of the sample, as well as the fact that the research was conducted in one country, which is the basis for expanding the knowledge in future research

Analysis of isothermal sintering of zinc-titanate doped with MgO

The aim of this work was analysis of isothermal sintering of zinc titanate ceramics doped with MgO obtained by mechanical activation. Mixtures of ZnO, TiO2 and MgO (0, 1.25 and 2.5%) were mechanically activated 15 minutes in a planetary ball mill. The powders obtained were pressed under different pressures and the results were fitted with a phenomenological compacting equation. Isothermal sintering was performed in air for 120 minutes at four different temperatures. Structural characterization of ZnO-TiO2-MgO system after milling was performed at room temperature using XRPD measurements. DTA measurements showed different activation energies for pure and doped ZnO-TiO2 systems. Thus addition of MgO stabilizes the crystal structure of zinc titanate

Elektrohemijska sinteza elektroprovodnih polimera

Electroconducting polymers from the group of synthetic metals are extensively investigated due to numerous properties perspective in practical application. These materials may be synthesized by both chemical and electrochemical procedures. Chemical synthesis is suitable when bulk quantities of the polymer are necessary and up to date it presents dominant commercial method of producing electroconducting polymers. Nevertheless, the electrochemical synthesis has its advantages; it avoids usage of oxidants since conducting polymeric material is obtained at anode upon application of positive potential, leading to increased purity. On the other hand, since the polymer is deposited onto electrode, further electrochemical characterization is facilitated. Owing to actuality of the research in the field, this text aims to describe important aspects of electrochemical synthesis of electroconducting polymers, with special emphasis to polyaniline and polypyrrole.Tradicionalno shvatanje o polimerima kao odličnim izolatorima izmenjeno je sedamdesetih godina prošlog veka kada su naučnici uspeli da sintetizuju poiliacetilen čija je provodljivost bila bliska metalnoj. Ova činjenica ukazala je na novo svojstvo polimernih materijala i lansirala potpuno novo multidisciplinarno naučno polje, popularno nazvano, sintetički metali. Iako je danas pojmom elektroprovodnih polimera obuhvaćena velika grupa jedinjenja koja su klasifikovana prema prirodi prenosioca naelektrisanja, naziv elektroprovodni polimeri se najčešće koristi u literaturi upravo za polimerne materijala iz grupe sintetičkih metala koji poseduju elektronsku provodljivost kao posledicu specifičnosti molekulske strukture. Pored zahteva molekulske structure, koja podrazumeva konjugovani sistem dvostrukih veza, za provodljivost elektroprovodnih polimera neophodno je dopovanje. Termin dopovanje, iako preuzet iz terminologije klasičnih neorganskih poluprovodnika, podrazumeva u mnogome drugačiji proces. Dopovanje elektroprovodnih polimera podrazumeva oksidaciju tokom koje se, u cilju održavanja elektroneutralnosti polimernog lanca, uvodi stehiometrijska količina jona (anjona). Terminom dopovanje obuhvaćena je i protonacija polimernog lanca kiselinom, u slučaju polianilina, a nedavno je potvrđena i u slučaju polipirola. Kako je, na ovaj način, uvedena velika količina jona izmenjenja je polazna struktura elektroprovodnog polimera, tako da svojstva nastalog materijala zavise u velikoj meri od svojstava dopanta. Iako su na početku razvoja ove oblasti, elektroprovodni polimeri bili sintetizovani hemijskim postupcima, sticanjem uvida u mehanizam hemijske sinteze koja podrazumeva oksidativnu radikalnu polimerizaciju, postalo je jasno da se ovi materijali mogu dobiti i elektrohemijskim postupcima. Elektrohemijska sinteza ima prednosti, pošto se polimer dobija oksidacijom na elektrodama (anodama), čime je izbegnuta upotreba oksidacinog sredstva i omogućena veća čistoća proizvoda. Sa druge strane, elektroprovodni polimer je u većini slučajeva dobijen u obliku prevlake na elektrodi, pa je njegova dalja karakterizacija elektrohemijskim tenikama olakšana. Interesovanje za oblst sinteze elektroprovodnih polimera ne jenjava, pa je ovaj tekst posvećen osnovnim principima elektrohemijskih postupaka sinteze sa posebnim osvrtom na najpopularnije elektroprovodne polimere, polianilin i polipirol

Preparation of composite material BCP/DLPLG with a different content of ceramic and polymer component

Using a new approach of synthesis, homogenisation of DLPLG polymer powder and BCP gel, BCP/DLPLG composite material has been obtained with morphological and structural characteristics making it potentially very suitable for practical application in certain fields of the reconstructive medicine. The composite material has been synthesised with different ratios of ceramics and polymer BCP/DLPLG; 65/35w/w, 10/90 w/w, 5/95 w/w and 2/98w/w. The samples were characterized by Differential Scanning Calorimetry (DSC) and Scanning Electron Microscopy (SEM).Physical chemistry 2006 : 8th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 26-29 September 200

Organic geochemistry of crude oils from the turija oil field (SE Pannonian Basin, Serbia)

The Turija oil field, being an important oil field in Serbia, is located in the Banat Depression of the southeastern part of the Pannonian Basin. Oil samples from the Turija oil field were investigated in order to estimate origin, depositional environment, thermal maturity and age of the corresponding source rocks. For that purpose, a comprehensive analysis of biomarkers and aromatic compounds was performed. n-Alkanes are predominant compounds in the total ion chromatograms of saturated fractions of all samples, showing that Turija oils are not biodegraded. The distributions of n-alkanes, which are characterised by equivalent abundances of long- and short-chain homologues and maximums at C17, C21 and C27, suggest a mixed aquatic-terrestrial origin. The uniform distributions of regular C27-C29 5α(H)14α(H)17α(H) 20(R) steranes support the previous assumption. The presence of oleanane in all samples is indicative for a contribution of angiosperm plants to the precursor organic matter (OM). Furthermore, the presence of this biomarker implies the Upper Cretaceous or younger age of the corresponding source rocks. Isoreniratane and its derivatives have been identified in all samples. Although isorenieratane can originate from β-carotene, which is widespread in algae, bacteria and terrestrial plants, the presence of other catagenetic products of isorenieratene (mass fragmentogram m/z 133 of the aromatic fraction) unambiguously confirms a contribution of green sulphur bacteria Chlorobiaceae to the precursor organic material [1]. The pristane to phytane (Pr/Ph) ratio ranges from 0.64 to 1.17, indicating reducing to dysoxic conditions during the deposition of precursor OM. The presence of the above mentioned isorenieratane derivatives implies the photic zone of anoxia. The stratification of water column is also supported by the presence of gammacerane and values of gammacerane index, GI = gammacerane x 10/(gammacerane + C30 17α(H)21β(H)-hopane) > 1 in almost all the samples. Alkylated 2-methyl-2- (4,8,12-trimethyltridecyl) chromans (MTTCs) were detected in all studied oils. A predominance of 5,7,8-trimethyl-MTTC over 5,8-dimethyl-MTTC, 7,8-dimethyl-MTTC and 8-methyl-MTTC, associated with the values of MTTC ratio (MTTC = 5,7,8-trimethyl-MTTC/ΣMTTCs) in 0.44 to 0.65 range, indicates deposition of OM in a brackish environment [2]. The maturity of Turija oils was determined using typical sterane and hopane isomerisation maturity parameters and methyldibenzothiophene ratio, MDBTR = 4-MDBT/1-MDBT [3]. The obtained results indicate that Turija oils were generated in an early stage of oil window