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In this study, the understanding of self-regulated learning as one of the key competences in contemporary education was based on Pintrich?s model of self-regulated learning. The goal was to examine the links between different motivational orientations and learning strategies among university students in Serbia and explore the relations between these variables on the one hand and academic achievement, gender, field of study, and year of study on the other. A total of 520 students enrolled in art, science, and social science studies at universities in Belgrade, Novi Sad, Nis, and Kragujevac filled out the Motivated Strategies for Learning Questionnaire (MSLQ). The obtained data were processed via a factor analysis, correlations, and non-parametric tests. We isolated six factors, including Self-Confidence and Orientation Towards Understanding, Elaboration and Metacognitive Self-Regulation Strategies, Critical Thinking and Orientation Towards Expanding Knowledge, Orientation Towards External Criteria Accompanied by Self- Discipline, Anxiety, and High Learning Motivation and Dedication to Achieving the Set Goals. The application of metacognitive self-regulation strategies could be linked to both intrinsic and extrinsic motivation. Students oriented towards external criteria exhibited higher levels of academic achievement. We identified gender differences in the application of elaboration and metacognitive self-regulation strategies in terms of learning motivation and anxiety levels. Art students were more prone to the use of the critical thinking strategy compared to science and social science students. In this paper, we highlight practical implications related to designing self-regulated learning courses for university teachers and students, along with recommendations for future research.

Understanding motivation for learning as a complex construct allows for education to be tailored to students? individual characteristics and needs. Although different combinations of motivational factors lead to different outcomes, there is still a remarkable scarcity of research on students? motivational profiles in science. To identify groups of fourth-graders characterized by different levels of intrinsic motivation and self-efficacy in science, we applied the person-centered approach. By conducting secondary analyses of data obtained via student questionnaires and science knowledge tests in TIMSS 2019 in Serbia, we examined motivational profiles? structure and relations to achievement as well as the membership of students of different genders and profile stability across two research cycles. The cluster analysis revealed four profiles characterized by different levels of intrinsic motivation, self-efficacy, and achievement. Students who reported higher levels of motivation and self-efficacy were more successful than students with lower scores on these variables. Students who reported the highest levels of self-efficacy and moderate levels of motivation demonstrated the highest achievement levels. This finding indicates that teachers need to use strategies for improving competencies and enhancing students? self-efficacy. It is necessary to examine contextual factors that might have contributed to the increase in the number of students who demonstrated low levels of intrinsic motivation and self-efficacy, and the lowest levels of achievement.

Metastases largely rely on hematogenous dissemination of tumor cells via the vascular system and significantly limit prognosis of patients with solid tumors. To colonize distant sites, circulating tumor cells must destabilize the endothelial barrier and transmigrate across the vessel wall. Here we performed a high-content screen to identify drugs that block tumor cell extravasation by testing 3,520 compounds on a transendothelial invasion coculture assay. Hits were further characterized and validated using a series of in vitro assays, a zebrafish model enabling three-dimensional (3D) visualization of tumor cell extravasation, and mouse models of lung metastasis. The initial screen advanced 38 compounds as potential hits, of which, four compounds enhanced endothelial barrier stability while concurrently suppressing tumor cell motility. Two compounds niclosamide and forskolin significantly reduced tumor cell extravasation in zebrafish, and niclosamide drastically impaired metastasis in mice. Because niclosamide had not previously been linked with effects on barrier function, single-cell RNA sequencing uncovered mechanistic effects of the drug on both tumor and endothelial cells. Importantly, niclosamide affected homotypic and heterotypic signaling critical to intercellular junctions, cell–matrix interactions, and cytoskeletal regulation. Proteomic analysis indicated that niclosamide-treated mice also showed reduced levels of kininogen, the precursor to the permeability mediator bradykinin. Our findings designate niclosamide as an effective drug that restricts tumor cell extravasation through modulation of signaling pathways, chemokines, and tumor–endothelial cell interactions.Significance:A high-content screen identified niclosamide as an effective drug that restricts tumor cell extravasation by enhancing endothelial barrier stability through modulation of molecular signaling, chemokines, and tumor–endothelial cell interactions.

Effects of positive hits on endothelial barrier, cytoskeletal organization and tumor cell motility

Effect of drug hits on cortical actin and tumor cell migration and invasion

description of the methods in the supplementary data

Phenotypes of the human pancreatic cell Ines and effects on endothelium

Methods and Reagents

Purpose:Gliomas with isocitrate dehydrogenase 1 mutations (IDH1mut) are less aggressive than IDH1 wild-type (IDH1wt) gliomas and have global genomic hypermethylation. Yet it is unclear how specific hypermethylation events contribute to the IDH1mut phenotype. Previously, we showed that the gene encoding the procoagulant tissue factor (TF), F3, is among the most hypermethylated and downregulated genes in IDH1mut gliomas, correlating with greatly reduced thrombosis in patients with IDH1mut glioma. Because TF also increases the aggressiveness of many cancers, the current study explored the contribution of TF suppression to the reduced malignancy of IDH1mut gliomas.Experimental Design: TF expression was manipulated in patient-derived IDH1mut and IDH1wt glioma cells, followed by evaluation of in vitro and in vivo behavior and analyses of cell signaling pathways.Results:A demethylating agent, decitabine, increased F3 transcription and TF-dependent coagulative activity in IDH1mut cells, but not in IDH1wt cells. TF induction enhanced the proliferation, invasion, and colony formation of IDH1mut cells, and increased the intracranial engraftment of IDH1mut GBM164 from 0% to 100% (P = 0.0001). Conversely, TF knockdown doubled the median survival of mice engrafted with IDH1wt/EGFRvIIIamp GBM6, and caused complete regression of IDH1wt/EGFRamp GBM12 (P = 0.001). In vitro and in vivo effects were linked to activation of receptor tyrosine kinases (RTK) by TF through a Src-dependent intracellular pathway, even when extracellular RTK stimulation was blocked. TF stimulated invasion predominately through upregulation of β-catenin.Conclusions:These data show that TF suppression is a component of IDH1mut glioma behavior, and that it may therefore be an attractive target against IDH1wt gliomas.

Supplementary data figures

Determination of niclosamide stability and approach for counting lung metastatic nodules

Analysis of scRNAseq findings

Work flow to assess effects of drug hits in vivo

While most cases of vascular dementia represent complex interactions between host genetics and environmental factors, mendelian forms of vascular dementia also exist. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a mendelian disease characterized by progressive vascular deterioration, cognitive deficits, and strokes. Mutations in the NOTCH3 receptor underlies the pathologies in CADASIL. NOTCH3 is primarily expressed in vascular smooth muscle cells (vSMCs) and its’ expression is critical for differentiation and functional integrity of arterial vSMCs, albeit through unclear mechanism(s). To elucidate the contribution of NOTCH3 in the maintenance of cerebral vascular architecture and function, we performed micro-computed tomography (micro-CT) on the brains of aged Notch3 -deficient animals. Micro-CT assessment of the cerebral vasculature architecture showed significant abnormalities including severe vessel dilation and tortuosity (dolicoectasia) of the middle cerebral artery and its branches in the Notch3 -/- compared to aged-match controls. To identify the molecular pathway from NOTCH3 dysregulation to the observed cerebral vascular dysfunction, we performed single-cell RNASeq on cerebral arteries isolated from young (4w) and old (104w) Notch3 -/- animals. Evaluation of the vSMC-specific transcriptomes indicated significant loss of proteins associated with muscle contraction and increased extracellular matrix production in animals that lack NOTCH3. Using a combination of immunofluorescence microscopy and in vitro functional assays, we confirmed that continued expression of Notch3 is a critical requirement for maintenance of vSMC contractile function. Impaired contractility also affected flow of cerebrospinal fluid in the parenchyma of Notch3 -/- . MRI and behavioral assessments were performed in the Notch3 -/- animals to elucidate the relationship between impaired vascular contractility to cognitive function. Taken together these findings link the molecular dysfunction of NOTCH3 through its regulation of vascular contractility and cerebral vessel architecture to altered neurological function and clarify the molecular pathways to cellular pathology of Notch3 driven dementias.

Metastases largely rely on hematogenous dissemination of tumor cells via the vascular system and significantly limit prognosis of patients with solid tumors. To colonize distant sites, circulating tumor cells must destabilize the endothelial barrier and transmigrate across the vessel wall. Here we performed a high-content screen to identify drugs that block tumor cell extravasation by testing 3,520 compounds on a transendothelial invasion coculture assay. Hits were further characterized and validated using a series of in vitro assays, a zebrafish model enabling three-dimensional (3D) visualization of tumor cell extravasation, and mouse models of lung metastasis. The initial screen advanced 38 compounds as potential hits, of which, four compounds enhanced endothelial barrier stability while concurrently suppressing tumor cell motility. Two compounds niclosamide and forskolin significantly reduced tumor cell extravasation in zebrafish, and niclosamide drastically impaired metastasis in mice. Because niclosamide had not previously been linked with effects on barrier function, single-cell RNA sequencing uncovered mechanistic effects of the drug on both tumor and endothelial cells. Importantly, niclosamide affected homotypic and heterotypic signaling critical to intercellular junctions, cell–matrix interactions, and cytoskeletal regulation. Proteomic analysis indicated that niclosamide-treated mice also showed reduced levels of kininogen, the precursor to the permeability mediator bradykinin. Our findings designate niclosamide as an effective drug that restricts tumor cell extravasation through modulation of signaling pathways, chemokines, and tumor–endothelial cell interactions. Significance: A high-content screen identified niclosamide as an effective drug that restricts tumor cell extravasation by enhancing endothelial barrier stability through modulation of molecular signaling, chemokines, and tumor–endothelial cell interactions.

BACKGROUND: Among diffusely infiltrative gliomas in adults, 20%–30% contain a point mutation in isocitrate dehydrogenase 1 (IDH1(mut)), which increases production of D-2-hydroxyglutarate (D2HG). This is so efficient that D2HG often reaches 30 mM within IDH1(mut) gliomas. Yet, while up to 100 µM D2HG can be detected in the circulating cerebrospinal fluid of IDH1(mut) glioma patients, the exposure of nonneoplastic cells within and surrounding an IDH1(mut) glioma to D2HG is unknown and difficult to measure directly. METHODS: Conditioned medium from patient-derived wild type IDH1 (IDH1(wt)) and IDH1(mut) glioma cells was analyzed for D2HG by liquid chromatography–mass spectrometry (LC-MS). Mathematical models of D2HG release and diffusion around an IDH1(mut) glioma were independently generated based on fluid dynamics within the brain and on previously reported intratumoral and cerebrospinal D2HG concentrations. RESULTS: LC-MS analysis indicates that patient-derived IDH1(mut) glioma cells release 3.7–97.0 pg D2HG per cell per week. Extrapolating this to an average-sized tumor (30 mL glioma volume and 1 × 10(8) cells/mL tumor), the rate of D2HG release by an IDH1(mut) glioma (S(A)) is estimated at 3.2–83.0 × 10(−12) mol/mL/sec. Mathematical models estimate an S(A) of 2.9–12.9 × 10(−12) mol/mL/sec, within the range of the in vitro LC-MS data. In even the most conservative of these models, the extracellular concentration of D2HG exceeds 3 mM within a 2 cm radius from the center of an IDH1(mut) glioma. CONCLUSIONS: The microenvironment of an IDH1(mut) glioma is likely being exposed to high concentrations of D2HG, in the low millimolar range. This has implications for understanding how D2HG affects nonneoplastic cells in an IDH1(mut) glioma.

In this article we have been focused on studying the ways in which elementary school students experience art education and work of art teachers. We were interested in how students evaluate the difficulty and attraction of Art as a school subject, how much they are satisfied with the work of their art teachers and how much the work of their teachers has contributed to this subject becoming easier and more interesting to them. The sample covered 215 eighth grade students from different urban and rural elementary schools. For research purposes, a questionnaire was designed containing open­ended and close­ended questions. The research results indicate that the largest number of students evaluated art education as medium interesting and very easy, also showing that students think that the attraction and the level of difficulty of the subject itself depend a lot on the teacher. The attraction and the difficulty of the subject mostly depend on: the method of work on the curriculum, the method of work of the teacher and the diversity of tasks given to students. The results therefore suggest that the professional competences of an art teacher are the key factor in successful teaching. U radu smo bili usmereni na proučavanje načina na koje učenici osnovnih škola doživljavaju nastavu likovne kulture i rad nastavnika. Zanimalo nas je kako učenici procenjuju težinu i zanimljivost predmeta Likovna kultura, koliko su zadovoljni radom nastavnika i koliko je rad nastavnika doprineo da im predmet bude lakši i zanimljiviji za učenje. Za potrebe istraživanja konstruisan je upitnik koji je sadržao pitanja zatvorenog i otvorenog tipa. Nalazi istraživanja pokazuju da najveći broj učenika procenjuje nastavni predmet Likovna kultura kao osrednje zanimljiv i veoma lak, ali i da učenici smatraju da nastavnik u značajnoj meri doprinosi zanimljivosti i nivou težine samog predmeta. Na zanimljivost i nivo težine predmeta u najvećoj meri utiču: način obrade gradiva, način rada nastavnika i raznovrsnost zadataka koji se postavljaju učenicima. Dobijeni rezultati sugerišu da su profesionalne kompetencije nastavnika ključni faktor uspešne realizacije nastave.

Isocitrate dehydrogenase 1 mutant (IDH1(mut)) gliomas have global genomic hypermethylation, are less aggressive than IDH1 wild-type (IDH1(wt)) gliomas, and generally grow poorly in vitro and in vivo. Yet little data exist that connect specific hypermethylation targets to this unique phenotype. We previously reported that the gene encoding Tissue Factor (TF), F3, which promotes both thrombosis and malignant behavior, is among the most hypermethylated and downregulated genes in IDH1(mut) gliomas. In multiple IDH1(wt) and IDH1(mut) patient-derived glioma cell lines, F3 was hypermethylated in IDH1(mut) cells compared to IDH1(wt) cells, with reduced TF protein expression. A demethylating agent, decitabine, increased F3 transcription in IDH1(mut) glioma cells, but not in IDH1(wt) cells. TF knockdown greatly reduced proliferation, colony formation, glioma stem cell (GSC) marker expression, and xenograft growth of IDH1(wt)/EGFRvIII(amp) GBM6 cells and IDH1(wt)/EGFR(amp) GBM12 cells, but not of NF1-mutant GBM43 cells. Conversely, TF induction enhanced the proliferation and colony formation of IDH1(mut) GBM164 and TB09 cells, especially GBM164. TF also increased the in vivo “take rate” of intracranial GBM164 xenografts from 0% to 100%, but did not enable TB09 xenograft growth. TF activated receptor tyrosine kinases (RTKs) in GBM6, GBM12, and GBM164, but RTK expression was very low in GBM43 and TB09. Transcriptomic profiling showed that only two genes were downregulated after TF knockdown in GBM6 and GBM12, and also upregulated after TF induction in GBM164: PROM1, encoding CD133, and CTNND2, encoding δ-catenin. Neither gene was affected by TF manipulation in GBM43 or TB09. High F3 mRNA correlated with enrichment of GSC markers, and worse outcome, in TCGA gliomas. These data suggest that: (i) TF promotes a GSC phenotype through RTKs; (ii) CD133 and δ-catenin may be critical effectors of TF-induced GSC behavior; (iii) TF methylation reduces IDH1(mut) glioma malignancy; (iv) TF is an attractive, novel therapeutic target in IDH1(wt) gliomas.

Purpose: Gliomas with isocitrate dehydrogenase 1 mutations (IDH1mut) are less aggressive than IDH1 wild-type (IDH1wt) gliomas and have global genomic hypermethylation. Yet it is unclear how specific hypermethylation events contribute to the IDH1mut phenotype. Previously, we showed that the gene encoding the procoagulant tissue factor (TF), F3, is among the most hypermethylated and downregulated genes in IDH1mut gliomas, correlating with greatly reduced thrombosis in patients with IDH1mut glioma. Because TF also increases the aggressiveness of many cancers, the current study explored the contribution of TF suppression to the reduced malignancy of IDH1mut gliomas. Experimental Design: TF expression was manipulated in patient-derived IDH1mut and IDH1wt glioma cells, followed by evaluation of in vitro and in vivo behavior and analyses of cell signaling pathways. Results: A demethylating agent, decitabine, increased F3 transcription and TF-dependent coagulative activity in IDH1mut cells, but not in IDH1wt cells. TF induction enhanced the proliferation, invasion, and colony formation of IDH1mut cells, and increased the intracranial engraftment of IDH1mut GBM164 from 0% to 100% (P = 0.0001). Conversely, TF knockdown doubled the median survival of mice engrafted with IDH1wt/EGFRvIIIamp GBM6, and caused complete regression of IDH1wt/EGFRamp GBM12 (P = 0.001). In vitro and in vivo effects were linked to activation of receptor tyrosine kinases (RTK) by TF through a Src-dependent intracellular pathway, even when extracellular RTK stimulation was blocked. TF stimulated invasion predominately through upregulation of β-catenin. Conclusions: These data show that TF suppression is a component of IDH1mut glioma behavior, and that it may therefore be an attractive target against IDH1wt gliomas.

Glioblastoma (GBM) is an aggressive form of brain cancer with few treatment options, characterized by over-activation of receptor tyrosine kinases (RTKs). Brain tumor-initiating cells (BTICs) is a subpopulation of cells in GBM which have the unique capacity to self-renew, facilitating recurrence. Tissue Factor (TF), normally involved in blood coagulation, is elevated in GBM and strongly correlates with more aggressive behavior. We hypothesize that TF promotes malignant behavior in glioblastoma by activating protease-activated receptor 2 (PAR2), leading to RTK stimulation and the maintenance of brain tumor-initiating cells. Therefore, our approaches are to determine: the mechanisms by which TF-PAR2 stimulates RTK signaling in GBM; the role of RTKs in mediating TF-induced BTIC maintenance in GBM, and the effect of blocking TF signaling on RTK-based therapies against GBM. Our data indicate that TF can activate multiple classes of tumor-promoting RTKs, and sustains cell proliferation through its main receptor, PAR2, even in the presence of an RTK inhibitor. We also found that TF suppression impairs the BTIC phenotype in high TF-expressing, RTK-driven GBM. This project will advance our understanding of how TF promotes malignant behavior, identify a powerful means by which cancers can resist RTK inhibitors currently in clinical use, and demonstrate the therapeutic potential of blocking TF-PAR2 signaling in cancer.

1. Aprepitant, an oral antiemetic, commonly used in the prevention of chemotherapy-induced nausea and vomiting, is primarily metabolized by CYP3A4. Aprepitant glucuronidation has yet to be evaluated in humans. The contribution of human UDP-glucuronosyltransferase (UGT) isoforms to the metabolism of aprepitant was investigated by performing kinetic studies, inhibition studies and correlation analyses. In addition, aprepitant was evaluated as an inhibitor of UGTs. 2. Glucuronidation of aprepitant was catalyzed by UGT1A4 (82%), UGT1A3 (12%) and UGT1A8 (6%) and Kms were 161.6 ± 15.6, 69.4 ± 1.9 and 197.1 ± 28.2 µM, respectively. Aprepitant glucuronidation was significantly correlated with both UGT1A4 substrates anastrazole and imipramine (rs = 0.77, p

OTS167 is a potent maternal embryonic leucine zipper kinase inhibitor undergoing clinical testing as antineoplastic agent. We aimed to identify the UDP-glucuronosyltransferases (UGTs) involved in OTS167 metabolism, study the relationship between UGT genetic polymorphisms and hepatic OTS167 glucuronidation, and investigate the inhibitory potential of OTS167 on UGTs. Formation of a single OTS167-glucuronide (OTS167-G) was observed in pooled human liver (HLM) (Km = 3.4 ± 0.2 µM), intestinal microsomes (HIM) (Km = 1.7 ± 0.1 µM), and UGTs. UGT1A1 (64 µl/min/mg) and UGT1A8 (72 µl/min/mg) exhibited the highest intrinsic clearances (CLint) for OTS167, followed by UGT1A3 (51 µl/min/mg) and UGT1A10 (47 µl/min/mg); UGT1A9 was a minor contributor. OTS167 glucuronidation in HLM was highly correlated with thyroxine glucuronidation (r = 0.91, P < 0.0001), SN-38 glucuronidation (r = 0.79, P < 0.0001), and UGT1A1 mRNA (r = 0.72, P < 0.0001). Nilotinib (UGT1A1 inhibitor) and emodin (UGT1A8 and UGT1A10 inhibitor) exhibited the highest inhibitory effects on OTS167-G formation in HLM (68%) and HIM (47%). We hypothesize that OTS167-G is an N-glucuronide according to mass spectrometry. A significant association was found between rs6706232 and reduced OTS167-G formation (P = 0.03). No or weak UGT inhibition (range: 0–21%) was observed using clinically relevant OTS167 concentrations (0.4–2 µM). We conclude that UGT1A1 and UGT1A3 are the main UGTs responsible for hepatic formation of OTS167-G. Intestinal UGT1A1, UGT1A8, and UGT1A10 may contribute to first-pass OTS167 metabolism after oral administration.

Approximately 20-30% of diffusely infiltrative gliomas in adults contain a point mutation in isocitrate dehydrogenase 1 (IDH1mut), which leads to production of D-2-hydroxyglutarate (D2HG). Production of D2HG is so efficient that D2HG concentrations often reach 30 mM within IDH1mut gliomas. Yet, while up to 100 µM D2HG can be detected in the circulating cerebrospinal fluid of IDH1mut glioma patients, the amount of D2HG to which nonneoplastic cells are exposed within and surrounding an IDH1mut glioma is unknown and difficult to measure directly in patients or animal models. Thus, to date, the majority of research on D2HG has focused on its effects inside tumor cells, with very little known about its role in the tumor microenvironment. Liquid chromatography-mass spectrometry (LC-MS) analysis indicates that patient-derived IDH1mut glioma cells release approximately 3.7-6.7 pg D2HG per cell per week in culture. Extrapolating this to an average-sized tumor (30 ml glioma volume and 1x108 cells/ml tumor, the latter based on a previously published estimate of tumor cell density), the rate of D2HG release by an IDH1mut glioma (SA) is calculated to be 3.2-5.8x10-12 moles/ml/sec. Mathematical models of D2HG production and diffusion around an IDH1mut glioma were independently generated based on intracerebral fluid dynamics and previously reported D2HG concentrations in the cerebrospinal fluid. These models estimate an SA of 2.9-17.0x10-12 moles/ml/sec, in good agreement with the LC-MS data generated from in vitro models. In even the most conservative of these diffusion models, the extracellular concentration of D2HG exceeds 3 mM within a 2 cm radius from the center of an IDH1mut glioma. This has profound implications for understanding how D2HG may alter the microenvironmental landscape in IDH1mut gliomas.

1. There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for identifying specific drug-metabolizing enzymes. We determined the cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) that metabolize MA, identified oxidative metabolites and determined pharmacologic activity at the progesterone, androgen and glucocorticoid receptors (PR, AR and GR, respectively). 2. Oxidative metabolites were produced using human liver microsomes (HLMs), and isolated for mass spectral (MS) and nuclear magnetic resonance (NMR) analyses. We screened recombinant P450s using MA at 62 μM (HLM Km for metabolite 1; M1) and 28 μM (HLM Km for metabolite 2; M2). UGT isoforms were simultaneously incubated with UDPGA, nicotinamide adenine dinucleotide phosphate (NADPH), CYP3A4 and MA. Metabolites were evaluated for pharmacologic activity on the PR, AR and GR. CYP3A4 and CYP3A5 are responsible for oxidative metabolism of 62 μM MA. 3. At 28 μM substrate concentration, CYP3A4 was the only contributing enzyme. Mass spectral and NMR data suggest metabolism of MA to two alcohols. After oxidation, MA is converted into two secondary glucuronides by UGT2B17 among other UGTs. MA, M1 and M2 had significant pharmacologic activity on the PR while only MA showed activity on the AR and GR.

The aim of this study was to discover cis- and trans-acting factors significantly affecting mRNA expression and catalytic activity of human hepatic UDP-glucuronosyltransferases (UGTs). Transcription levels of five major hepatic UGT1A (UGT1A1, UGT1A3, UGT1A4, UGT1A6 and UGT1A9) and five UGT2B (UGT2B4, UGT2B7, UGT2B10, UGT2B15 and UGT2B17) genes were quantified in human liver tissue samples (n = 125) using real-time PCR. Glucuronidation activities of 14 substrates were measured in 47 livers. We genotyped 167 tagSNPs (single-nucleotide polymorphisms) in UGT1A (n = 43) and UGT2B (n = 124), as well as the known functional UGT1A1*28 and UGT2B17 CNV (copy number variation) polymorphisms. Transcription levels of 15 transcription factors (TFs) known to regulate these UGTs were quantified. We found that UGT expression and activity were highly variable among the livers (median and range of coefficient of variations: 135%, 74–217% and 52%, 39–105%, respectively). CAR, PXR and ESR1 were found to be the most important trans-regulators of UGT transcription (median and range of correlation coefficients: 46%, 6–58%; 47%, 9–58%; and 52%, 24–75%, respectively). Hepatic UGT activities were mainly determined by UGT gene transcription levels. Twenty-one polymorphisms were significantly (FDR-adjusted P < 0.05) associated with mRNA expression and/or activities of UGT1A1, UGT1A3 and UGT2B17. We found novel SNPs in the UGT2B17 CNV region accounting for variability in UGT2B17 gene transcription and testosterone glucuronidation rate, in addition to that attributable to the UGT2B17 CNV. Our study discovered novel pharmacogenetic markers and provided detailed insight into the genetic network regulating hepatic UGTs.

XK469 (NSC 697887) is a selective topoisomerase II β inhibitor eliminated mainly via aldehyde oxidase I (AOX1). We performed a candidate gene study to investigate whether AOX1 genetic variation contributes to interindividual variability in XK469 clearance. Forty-one AOX1 single nucleotide polymorphisms (SNPs) and seven liver expression quantitative trait loci were genotyped in Caucasian patients with advanced refractory solid tumors (n=59) and leukemia (n=33). We found a significant decrease in clearance (τ = −0.32, P = 0.003) in solid tumor patients with rs10931910, although it failed to replicate in the leukemia cohort (τ = 0.18, P = 0.20). Four other AOX1 SNPs were associated with clearance (P = 0.01-0.02) in only one of the two cohorts. Our study provides a starting point for future investigations on the functionality of AOX1 SNPs. However, variability in XK469 clearance cannot be attributed to polymorphisms in AOX1.

The paper presents the results of an empirical study aimed at analyzing the role of self-regulation in different approaches to learning that were established in the previous studies. We examined whether certain categories of meta cognitive strategies were present in the deep, surface and achievement-oriented approach. The sample included 560 first- to fifth-year students of the Teacher Training Faculty, the Faculty of Philosophy and the Faculty of Philology of the University of Belgrade. A shorter version of the Instrument for measuring learning goals and strategies was applied. The previous research had established that learning goals and strategies comprised by this instrument were grouped into three second-order factors: the surface, deep and achievement-oriented approach to learning. The items from the Scale of students’ meta cognitive strategies were included. Factor analysis confirmed the existence of the three approaches to learning that include learning goals and strategies. We analysed the frequency of individual approaches to learning on the total sample, the frequency of individual approaches in the respondents of different gender and the correlations of the approach to learning with the age, year of studies and academic achievement. Different meta cognitive strategies contribute to the defining of the deep and achievement-oriented approach to learning, but they do not occur in the surface approach to learning. According to the obtained findings, self-regulation can play different roles in accordance with the goals set by students and the strategies used in learning. The results of this study point to possible directions of encouraging the deep approach to learning and self-regulation at the university level, as well as in primary and secondary school. U radu su prikazani rezultati empirijskog istraživanja usmerenog na ispitivanje uloge samoregulacije u različitim pristupima učenju koji su potvrđeni u ranijim istraživanjima. Ispitivano je da li su pojedine kategorije metakognitivnih strategija zastupljene u dubinskom, površinskom i pristupu učenju usmerenom ka postignuću. Uzorak je činilo 560 studenata od prve do pete godine Učiteljskog, Filozofskog i Filološkog fakulteta Univerziteta u Beogradu. Primenjena je kraća verzija Instrumenta za merenje ciljeva i strategija učenja. U ranijim istraživanjima utvrđeno je da se ciljevi i strategije učenja, obuhvaćeni ovim instrumentom, grupišu u tri faktora drugog reda: površinski, dubinski i pristup učenju usmeren ka postignuću. Uključene su stavke iz Skale metakognitivnih strategija učenika – METAS. Faktorskom analizom potvrđena su tri pristupa učenju koji obuhvataju ciljeve i strategije učenja. Analizirani su zastupljenost pojedinih pristupa učenju na ukupnom uzorku, zastupljenost pojedinih pristupa kod ispitanika različitog pola i korelacije pristupa učenju sa uzrastom, godinom studija i akademskim uspehom. Različite metakognitivne strategije doprinose definisanju dubinskog pristupa učenju i pristupa učenju usmerenog ka postignuću, ali nisu prisutne u površinskom pristupu učenju. Prema dobijenim nalazima, samoregulacija može imati različite uloge u skladu sa ciljevima koje studenti postavljaju i strategijama koje primenjuju u učenju. Rezultati ovog istraživanja ukazuju na moguće pravce podsticanja dubinskog pristupa učenju i samoregulacije na univerzitetu, ali i u osnovnoj i srednjoj školi.

This paper provides the presentation of different operationalisations of components in different models of learning. Special emphasis is on the empirical verifications of relations between components. Starting from the research of congruence between learning motives and strategies, underlying the general model of school learning that comprises different approaches to learning, we have analyzed the empirical verifications of factor structure of instruments containing the scales of motives and learning strategies corresponding to these motives. Considering the problems in the conceptualization of the achievement approach to learning, we have discussed the ways of operational sing the goal orientations and exploring their role in using learning strategies, especially within the model of the regulation of constructive learning processes. This model has served as the basis for researching learning styles that are the combination of a large number of components. Complex relations between the components point to the need for further investigation of the constructs involved in various models. We have discussed the findings and implications of the studies of relations between the components involved in different models, especially between learning motives/goals and learning strategies. We have analyzed the role of regulation in the learning process, whose elaboration, as indicated by empirical findings, can contribute to a more precise operationalisation of certain learning components. U radu su prikazani načini operacionalizacije komponenti u različitim modelima učenja. Posebno su razmatrane empirijske provere njihovih međusobnih odnosa. Polazeći od istraživanja kongruencije između motiva i strategija učenja, na kojima je zasnovan opšti model školskog učenja koji obuhvata različite pristupe učenju, analizirane su empirijske provere faktorske strukture instrumenata koji sadrže skale motiva i strategija učenja koje odgovaraju ovim motivima. S obzirom na probleme u konceptualizaciji pristupa učenju usmerenog ka postignuću, razmatrani su načini operacionalizacije orijentacija na ciljeve i istraživanja njihove uloge u primeni strategija učenja, posebno u okviru modela konstruktivne regulacije procesa učenja. Na ovom modelu zasnovana su istraživanja stilova učenja koji predstavljaju kombinacije većeg broja komponenti. Složeni odnosi između komponenti upućuju na potrebu za daljim ispitivanjem konstrukata uključenih u različite modele. Razmatrani su nalazi i implikacije istraživanja međusobnih odnosa između komponenti uključenih u različite modele, posebno između motiva/ciljeva i strategija učenja. Analizirana je uloga regulacije u procesu učenja, čija razrada, kako ukazuju empirijski nalazi, može doprineti preciznijoj operacionalizaciji pojedinih komponenti učenja. PR Projekat Ministarstva nauke Republike Srbije, br. 47008: Unapređivanje kvaliteta i dostupnosti obrazovanja u procesima modernizacije Srbije i br. 179034: Od podsticanja inicijative, saradnje i stvaralaštva u obrazovanju do novih uloga i identiteta u društvu.

Тhis paper presents a portion of the results obtained in a more extensive study dealing with monitoring of the work methods and the effects of an experimental implementation of the Trefoil pedagogical approach, developed based on pedagogical theories by the researchers from Belgrade. The Trefoil is based on using group work, creative play, openended tasks, critical dialogue, research work and students’ involvement in projects for which teachers were trained through implementation and reflexive practice. The aim of this longitudinal study is to determine the effects of the Trefoil on encouraging initiative, cooperation and creativity in students. Research participants were all teachers and students of an urban primary school during one school year. Data on students’ creative work were collected and compared before and after the experiment, obtained by expert observation of classes and a teacher and student questionnaire. Data were processed using one-way analysis of variance for repeated measures and two-way mixed analysis of variance. The results pointed to positive effects of the Trefoil approach, which, according to qualitative data, could probably have been bigger if the experiment had lasted longer. Different assessors noticed progress in encouraging students’ creativity, but in different domains. The results have confirmed the justifiability of using the Trefoil approach, provided that its validity is tested by implementation in other educational contexts for the purposes of further research and enhancement of the initial conception. [Projekat Ministarstva nauke Republike Srbije, br. 179034: Od podsticanja inicijative, saradnje i stvaralaštva u obrazovanju do novih uloga i identiteta u društvu i br. 47008: Unapređivanje kvaliteta i dostupnosti obrazovanja u procesima modernizacije Srbije]

Circulatory metabolites are important biomarkers for many diseases, especially metabolic disorders. The biological mechanism regulating circulatory levels of metabolites remains incompletely understood. Focusing on the liver as the central organ controlling metabolic homeostasis, we investigated the potential function of nine polymorphisms associated with serum metabolomic traits in a recent GWAS.The mRNA levels of the associated genes were measured by real-time PCR and correlated with genotypes in normal liver tissue (n=42). Genotype and mRNA data were also correlated with total hepatic lipid content (HLC). Our findings were also compared with the previously published gene expression quantitative traits loci (eQTL) data in the liver.We found that seven out of nine genes were highly expressed in hepatic tissue, while expression of four genes was significantly or marginally associated with genotypes (SPTLC3 vs rs168622, P=.002; ACADS vs rs2014355, P=.016; PLEKHH1 vs rs7156144, P=.076; ACADL vs rs2286963, P=.068). The SNP rs168622 at the SPTLC3 locus was also significantly correlated with HLC (P=.02). HLC was significantly correlated with FADS1 (r=-0.45; P=.003) and ETFDH (r=0.33; P=.037) expression. When compared with published eQTL data, SNPs in SPTLC3, ACADS, ELOVL2 and FADS1 were also in strong linkage disequilibrium (R(2)≥0.41, D'≥0.96) with eQTLs significantly affecting expression of these genes (P≤1.74×10(-5)).Our study suggests that genetic variants affecting serum metabolites levels may play a functional role in the liver. This may help elucidate the mechanism by which genetic variants are involved in metabolic diseases.

Defensive behaviour after failure, such as denial of the responsibility for own achievement, reduces person's openness for further learning and development and, thus, is undesirable in pedagogical practice. General causality orientations success-fully predict defensive behaviours after failure. Autonomous causality orientation implies behaviours motivated by personal growth and development, while controlling orientation purports ego-involved behaviours aimed at proving one's own self-worth. The research was conducted with the aim of testing two hypotheses (additive and synergistic) about the influence of general causality orientations and their combinations on defensive attribution of failure on the exam. After their faculty exam, N=158 psychology students answered questions about the expected grade and they filled out two questionnaires: Attribution of Success on the Test and General Causality Orientation Scale. The results showed that internal attribution of success is related to greater expected grade and higher autonomous causality orientation. External attribution was characteristic for individuals with high controlling causal orientation. It was confirmed that general causality orientations can predict the way a person perceives academic success. Thus, we give recommendations on how to support and encourage autonomous and discourage controlling behaviours of students. Odbrambena ponašanja koja se javljaju nakon neuspeha, poput odricanja odgovornosti za postignuti rezultat, umanjuju otvorenost osobe za dalje učenje i razvoj i stoga su nepoželjna sa aspekta pedagoške prakse. Generalne kauzalne orijentacije omogućavaju predviđanje ovakvih odbrambenih ponašanja. Autonomna orijentacija podrazumeva ponašanje motivisano ličnim rastom i razvojem, a kontrolišuća orijentacija ukazuje na usmerenost ponašanja na potvrđivanje sopstvene vrednosti. Sprovedeno je istraživanje sa ciljem da se ispitaju dve hipoteze (aditivna i sinergistička) koje daju različita predviđanja o uticaju kauzalnih orijentacija na ispoljavanje odbrambenog ponašanja nakon ispitnog neuspeha. Nakon ispita iz fakultetskog kursa 158 studenata psihologije odgovaralo je na pitanja o očekivanoj ispitnoj oceni i popunjavalo Upitnik atribucije uspeha na testu i Skalu generalnih kauzalnih orijentacija. Rezultati pokazuju da je atribuiranje ispitnog uspeha unutrašnjim faktorima uslovljeno višom očekivanom ispitnom ocenom i autonomnom kauzalnom orijentacijom. Spoljašnja atribucija uspeha bila je izraženija kod osoba sa kontrolišućom kauzalnom orijentacijom. Potvrđeno je da kauzalne orijentacije omogućavaju predviđanje odbrambenog reagovanja na akademski neuspeh, iz čega slede preporuke koje se tiču načina podsticanja autonomnog i umanjivanja kontrolišućeg ponašanja studenata.

Gliomas with mutations in isocitrate dehydrogenase 1 (IDH1mut) have global genomic hypermethylation, are less aggressive than IDH1 wild-type (IDH1wt) gliomas, and generally grow poorly in vitro and in vivo. Yet little data exist that connect specific hypermethylation events to this unique phenotype. We previously reported that the gene encoding Tissue Factor (TF), F3, is among the most hypermethylated and downregulated genes in IDH1mut gliomas relative to IDH1wt gliomas. TF was originally described in blood coagulation, but also can enhance tumor malignancy via protease-activated receptor 2 (PAR2) signaling, though its role in gliomas is not as well understood. In this study, we further explored the significance of TF on malignancy in IDH1wt and IDH1mut gliomas, and showed that receptor tyrosine kinases (RTKs) and β-catenin are downstream effectors of TF-PAR2 signaling. Studies were performed using 6 patient derived glioma cell lines, 3 IDH1wt (GBM6, GBM12, GBM43) and 3 IDH1mut (TB09, BT142, GBM164). DNA methylation was assessed by Illumina Human 850K. TF procoagulant activity (PCA) was determined by FXa generation, using conditioned medium. Markers of malignancy included BrdU incorporation for cell proliferation, transwell invasion, and soft agar colony formation. Nude mice (N≥6/group) were transplanted with glioma cells and monitored for growth using bioluminescence imaging. The TF gene, F3, was significantly hypermethylated in IDH1mut cells compared to IDH1wt cells, with corresponding lower TF protein in IDH1mut cells. Treatment of IDH1mut glioma cells with a demethylating agent, decitabine, increased F3 transcription 5-fold and PCA 19-fold in IDH1mut cells. TF increased the in vivo "take rate" of IDH1mut GBM164 from 0% to 100% (P=0.0001, Fisher's exact test). Conversely, TF knockdown in IDH1wt cells greatly reduced cell proliferation, invasion, colony formation, and extended median survival of engrafted mice by 86% (P=0.001). In both IDH1wt and IDH1mut cells, TF-PAR2 activated β-catenin, ERK1/2, and Akt, and was associated with multiple pathways that increase high-grade behavior. Disrupting TF-PAR2 signaling had the greatest impact on tumor growth in IDH1wt gliomas driven by epidermal growth factor receptor (EGFR), a major receptor tyrosine kinase (RTK) involved in glioma malignancy. TF-PAR2 transactivated EGFR through a Src-dependent intracellular pathway, even when extracellular stimulation of EGFR was blocked, and further enhanced phosphorylation of the constitutively activated EGFRvIII. In IDH1mut cells, TF-PAR2 signaled through another RTK, PDGFR. In contrast, TF-PAR2 stimulated invasion in all glioma cell lines through an RTK-independent, β-catenin-dependent mechanism. These results demonstrate the importance of TF-PAR2 in gliomas, and show that its suppression is a critical component of the IDH1mut phenotype. Citation Format: Dusten J. Unruh, Snezana Mirkov, Seamus Caragher, Jann Sarkaria, Atique Ahmed, C. David James, Craig Horbinski. Methylation-dependent suppression of Tissue Factor is a key contributor to the less aggressive phenotype in IDH1 mutant versus IDH1 wild-type gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5443.

This paper presents findings of the research focused on determining whether learning goals and strategies influence differences in academic success. The sample consisted of 364 students of the University of Belgrade. Five categories of learning goals (knowledge orientation, extrinsic goals, self-confirmation orientation, lack of orientation and meta-learning) and four categories of learning strategies (understanding strategies, reproduction strategies, achievement-oriented strategies and lack of strategies) were included. Data were analyzed with respect to respondent's gender and field of study. According to the obtained results, there are differences in average exam grades with respect to knowledge and self-confirmation orientation, meta-learning, understanding strategies and achievement-oriented strategies. Relations of certain categories of learning goals and strategies with the length of studying are under gender influence. Students of social sciences are more oriented towards extrinsic goals compared to students of humanities and sciences. Students of social sciences and humanities apply reproduction strategies to a greater extent compared to students of sciences. The field of study does not influence differences in academic success with respect to learning goals and strategies. There is emphasis on the need for acquiring a deeper insight into perspectives of students themselves and for further research on the possibility of development of teaching, with the aim of improvement of learning process and achievement of more quality outcomes. U radu su prikazani nalazi istraživanja usmerenog na ispitivanje da li ciljevi i strategije učenja utiču na razlike u uspehu na studijama. Uzorak su činila 364 studenta Univerziteta u Beogradu. Uključeno je pet kategorija ciljeva učenja (usmerenost na znanje, ekstrinzični ciljevi, usmerenost na samopotvrđivanje, odsustvo usmerenosti i metaučenje) i četiri kategorije strategija učenja (strategije razumevanja, strategije reprodukcije, strategije usmerene na postignuće i odsustvo strategije). Podaci su analizirani u odnosu na pol ispitanika i oblast studija. Prema dobijenim rezultatima, postoje razlike u proseku ocena na ispitima u odnosu na usmerenost na znanje i na samopotvrđivanje, metaučenje, strategije razumevanja i strategije usmerene na postignuće. Odnosi pojedinih kategorija ciljeva i strategija učenja sa dužinom studiranja su pod uticajem pola. Studenti društvenih nauka u većoj meri su usmereni na ekstrinzične ciljeve, u odnosu na studente humanističkih i prirodnih nauka. Studenti društvenih i humanističkih nauka u većoj meri primenjuju strategije reprodukcije, u odnosu na studente prirodnih nauka. Oblast studija ne utiče na razlike u uspehu na studijama u odnosu na ciljeve i strategije učenja. Ističe se potreba za sticanjem dubljeg uvida u perspektive samih studenata i za daljim ispitivanjima mogućnosti razvijanja nastave, u cilju usavršavanja procesa učenja i ostvarivanja kvalitetnijih ishoda.

A review of the relevant literature demonstrates disagreement regarding the number and nature of factors that affect learning goals and strategies, as well as whether the goals and strategies may be treated as separate groups of phenomena. In order to clarify this controversy, a sample of 364 Belgrade University students was given an instrument consisting of 94 indicators taken from a larger number of available instruments that measure approaches to learning, goal orientations and learning strategies. Factor analysis, applied on the obtained data, showed that six first-order factors related to learning goals and seven first-order factors related to learning strategies explain the latent structure of the phenomenon. Then, second order factor analysis was applied on the pool of obtained factor scores. The assumption that learning goals and strategies share a similar latent structure was confirmed. The results show that a large number of these factors can be predominantly reduced to three latent dimensions: deep approach, surface approach, and achievement approach. The paper suggests that precise operationalisation of the achievement approach is required in the future research.

There is a presentation of 3P model of learning (Presage-Process-Product), which comprises learning approaches placed in a wider context of the set of variables related to personality, environment, process and outcomes of learning. Three approaches to learning - surface, deep and achievement-oriented - consist of motives and the corresponding learning strategies. There is a discussion of the findings and implications of a great deal of research using the instruments based on this model. We analyzed research findings about the effect of instruction on learning approaches acquired by pupils, and especially students. It is shown how based on learning approach employed by pupils it is possible to draw conclusions about the quality of instruction. Testing the instruments on various samples indicates that the model is applicable in different cultures. Cross-cultural research opened up the problem of relation between memorising and understanding. Further research is necessary, both empirical and theoretical, that is, development of conceptualization of these constructs, and especially their role in education. Perspectives for further research also open up in the direction of studying various factors connected with personality and their relations with learning approaches. The role of learning approaches of teachers in developing the learning approaches of pupils is yet to be examined. Prikazan je 3P model učenja (Preduslov-Proces-Produkt), koji obuhvata pristupe učenju smeštene u širi kontekst skupa varijabli vezanih za ličnost, sredinu, proces i ishode učenja. Tri pristupa učenju - površinski, dubinski i pristup usmeren ka postignuću - sastoje se od motiva i njima odgovarajućih strategija učenja. Razmatrani su nalazi i implikacije većeg broja istraživanja u kojima su korišćeni instrumenti zasnovani na ovom modelu. Analizirani su istraživački nalazi o delovanju nastave na pristupe učenju koje usvajaju učenici, a naročito studenti. Pokazano je kako se na osnovu pristupa koje učenici primenjuju u učenju može zaključivati o kvalitetu nastave. Provere instrumenata na različitim uzorcima pokazuju da je model primenljiv u različitim kulturama. Kroskulturalna istraživanja otvorila su problem odnosa između memorisanja i razumevanja. Potrebna su dalja istraživanja, kako empirijska, tako i teorijska, odnosno razvijanje konceptualizacije ovih konstrukata, a naročito njihove uloge u obrazovanju. Perspektive za dalja istraživanja otvaraju se i u pravcu ispitivanja različitih činilaca vezanih za ličnost i njihovih odnosa sa pristupima učenju. Tek treba ispitati ulogu koju pristupi učenju nastavnika imaju u razvijanju pristupa učenju učenika.

Werner's syndrome (WS) is a recessive disorder of premature onset of processes associated with aging. Defective DNA repair has been reported after exposure of cells isolated from WS patients to DNA-damaging agents. The germline 4330TC (Cys1367Arg) variant in the WS gene (WRN) has been associated with protection from age-related diseases, suggesting it has a functional role. We studied whether the 4330TC variant confers altered drug sensitivity in vitro.4330TC was genotyped in 372 human lymphoblastoid cell lines (LCLs) from unrelated healthy Caucasian individuals using a TaqMan-based method. The study was powered to detect the effect of the 4330TC genotypes after exposure to camptothecin (based upon preliminary data). The effect of the 4330TC variant on the cytotoxicity of etoposide, carboplatin, cisplatin and daunorubicin was also tested. WRN expression in 57 LCLs was measured by microarray.No significant difference between the IC50 of the cells was observed among genotypes (P = 0.46) after exposure to camptothecin. No association was also observed for etoposide, carboplatin, cisplatin, and daunorubicin (ANOVA, P0.05). WRN expression also did not vary across genotypes (ANOVA, P = 0.37).These results suggest that this nonsynonymous variant has relatively normal function at the cellular level.

ObjectiveUDP-glucuronosyltransferase 2B7 (UGT2B7) plays a central role in the liver-mediated biotransformation of endogenous and exogenous compounds. The genetic basis of interindividual variability in UGT2B7 function is unknown. This study aimed to discover novel gene variants of functional signifi

The starting point of this paper are two orientations towards goals that were identified in a large number of studies: orientations towards learning and orientations towards achievement. Social goals of pupils were especially discussed. There is the analysis of the relations of these orientations with success in learning, as well as with other variables related to personality and environment. Special treatment was given to the findings of empirical research indicating the possibility of existence of multiple orientations towards goals. That means that they can be in different mutual relations and in such a way exert different influence on the achievement of success in learning. Complementary effect of different goals enables flexible behavior of pupils in different situations, and coordination of different goals can be especially important for achieving success. Regarding the conceptualization of individual orientations, it was demonstrated how it is possible to treat separately both the different strivings within orientation towards achievement and orientation towards studying, and the different social goals of pupils. The characteristics of learning situation, as well as the way in which the pupil experiences the task of learning, are significant for the effect orientations can have on goals and on achievement of success in learning. Some recommendations for encouraging the pupil in teaching process are listed, as well as the implications for further research in this field. U radu se polazi od dve orijentacije na ciljeve koje su identifikovane u većem broju istraživanja: orijentacije na učenje i orijentacije na postignuće. Posebno su razmatrani socijalni ciljevi učenika. Analiziraju se odnosi ovih orijentacija sa uspehom u učenju, ali i sa drugim varijablama vezanim za ličnost i za sredinu. Posebno su tretirani nalazi empirijskih istraživanja koji ukazuju na mogućnost postojanja multiplih orijentacija na ciljeve. To znači da one mogu biti u različitim međusobnim odnosima i tako različito uticati na ostvarivanje uspeha u učenju. Komplementarno delovanje različitih ciljeva omogućava fleksibilno ponašanje učenika u različitim situacijama, a koordinacija različitih ciljeva može biti posebno značajna za ostvarivanje uspeha. U vezi sa konceptualizacijom pojedinih orijentacija, pokazano je kako se mogu odvojeno tretirati i različite težnje u okviru orijentacije na postignuće i orijentacije na učenje, kao i različiti socijalni ciljevi učenika. Karakteristike situacije učenja, kao i način na koji učenik doživljava zadatak učenja, značajne su za delovanje orijentacija na ciljeve i na ostvarivanje uspeha u učenju. Navedene su neke preporuke za podsticanje učenika u nastavi, kao i implikacije za dalja istraživanja u ovoj oblasti.

Interindividual variability in the glucuronidation of xenobiotics metabolized by UDP-glucuronosyltransferase 1A9 (UGT1A9) suggests the presence of functional UGT1A9 variants. The aim of this study was to evaluate whether the putative functionality of the UGT1A9 variants–118T9>10 (rs3832043), I399C>T (rs2741049), –275T>A (rs6714486), and–2152C>T (rs17868320) could be confirmed in an independent study. UGT1A9 genotypes and UGT1A9 activity (i.e., flavopiridol and mycophenolic acid glucuronidation) were determined in 46 Caucasian human livers. mRNA levels were quantitated by real-time polymerase chain reaction in 35 of these livers. In addition, samples from 60 unrelated Caucasians belonging to the HapMap Project were also genotyped to confirm the allele frequencies and linkage disequilibrium (LD) pattern observed in our Caucasian livers. The allele frequencies of the–118T9>10, I399C>T, –275T>A, and–2152C>T variants were 0.39, 0.39, 0.02, and 0.02 in the livers, respectively. The I399C>T variant was in complete LD (r2 = 1) with–118T9>10 (linked alleles: C and T9, respectively). Complete LD between these two variants was also found in the HapMap samples (frequencies of–118T9>10 and I399C>T = 0.38). I399C>T and–118T9>10 correlated with neither UGT1A9 activities nor mRNA levels. Because of the low frequencies of the–275T>A and–2152C>T variants, an effect on phenotype could not be evaluated. Our data demonstrate that the common I399C>T and–118T9>10 polymorphisms do not explain interindividual variation in hepatic UGT1A9 activity and mRNA expression and are in complete LD in the donor liver samples we studied.

This paper presents different views on self-regulation in the process of learning. What is shown is the model in which self-regulation is treated as the interaction of processes connected to personality, behavioral and contextual processes. The regulation processes are organized in several phases, and within each phase self-regulatory activities are structured in different fields. Special attention is paid to the application of strategies - cognitive, meta-cognitive, motivational and strategies of resource management. As a critical component of self-regulation, the monitoring and the steps it consists of were discussed in more detail. The emphasis is on the role of feedback in monitoring, as well as on the wider significance it has for self-regulation in the process of learning. Since orientation towards the goal is considered an essential aspect of self-regulation, what was performed was the analysis of the results and implications of different researches of the relation of pupils’ orientations towards the goals with regulation of the process of learning. The possibilities for encouraging self-regulation in the tuition process were considered. By enabling pupils to make decisions, set their own goals, perform the choice and plan and organize their activities, the development of self-regulation and autonomy is encouraged. The guidelines for planning the training aimed towards the development of strategy behavior in pupils are stated. What is presented are the different methods which are applied within the model and interventions in tuition directed towards encouragement of self-regulation. U radu su predstavljena različita shvatanja o samoregulaciji u procesu učenja. Prikazan je model u kome je samoregulacija tretirana kao interakcija procesa vezanih za ličnost, bihejvioralnih i kontekstualnih procesa. Procesi regulacije organizovani su u više faza, a u okviru svake faze samoregulativne aktivnosti su struktuirane u različitim oblastima. Posebna pažnja posvećena je primeni strategija - kognitivnih, metakognitivnih, motivacionih i strategija upravljanja resursima. Kao kritična komponenta samoregulacije, detaljnije je razmatrano praćenje i koraci od kojih se sastoji. Ističe se uloga povratne informacije u praćenju, kao i širi značaj koji ona ima za samoregulaciju u procesu učenja. Pošto se usmerenost ka cilju smatra suštinskim aspektom samoregulacije, analizirani su rezultati i implikacije različitih istraživanja odnosa orijentacija učenika na ciljeve sa regulacijom procesa učenja. Razmatrane su mogućnosti podsticanja samoregulacije u nastavnom procesu. Omogućavanjem učenicima da donose odluke, postavljaju sopstvene ciljeve, vrše izbor i planiraju i organizuju aktivnosti, podstiče se razvoj samousmerenja i autonomije. Navedene su smernice za planiranje obuke usmerene na razvijanje strategijskog ponašanja kod učenika. Predstavljene su različite metode koje se primenjuju u okviru modela i intervencija u nastavi usmerenih na podsticanje samoregulacije.

We have analysed results of interviewing teachers about their attitudes towards inciting critical thinking of students and in which extent they undertake activates directed to inciting critical thinking in teaching. Studying attitudes and activities of teachers is a part of the greater research about inciting creation, initiative and cooperation in teaching. Teachers from the primary schools in Serbia (N=1441) have been interviewed by the interview of a closed type, composed for the needs of this research. The aim was to determine structure and application of attitudes, which teachers express towards inciting critical thinking applied in teaching, as well as examining relations between attitudes and activities. We have checked possibilities of predicting activities of teachers directed to inciting critical thinking based on their attitudes. According to given results, attitudes of teachers can be described by five factors, and activities directed for inciting critical thinking are grouped, according to three factors. It has been determined that there are significant connections between attitudes and activities of teachers. Some activities of teachers can be predicted based on their attitudes, and the most significant predictor of all activities directed to inciting critical thinking in teaching is readiness for inciting independent thinking, students' questions and class discussion. U radu su analizirani rezultati dobijeni ispitivanjem nastavnika o njihovim stavovima prema podsticanju kritičkog mišljenja kod učenika i o meri u kojoj preduzimaju aktivnosti usmerene na podsticanje kritičkog mišljenja u nastavi. Ispitivanje stavova i aktivnosti nastavnika deo je obimnijeg istraživanja o podsticanju stvaralaštva, inicijative i saradnje u nastavi. Nastavnici osnovnih škola u Srbiji (N=1441) ispitani su upitnikom zatvorenog tipa, sastavljenim za potrebe ovog istraživanja. Postavljen je cilj da se utvrde struktura i zastupljenost stavova koje nastavnici izražavaju prema podsticanju kritičkog mišljenja kod učenika i aktivnosti usmerenih na podsticanje kritičkog mišljenja koje preduzimaju u nastavi, kao i da se ispitaju odnosi između stavova i aktivnosti. Proveravana je mogućnost predviđanja aktivnosti nastavnika usmerenih na podsticanje kritičkog mišljenja na osnovu njihovih stavova. Prema dobijenim nalazima, nastavnički stavovi mogu se opisati pomoću pet faktora, a aktivnosti usmerene na podsticanje kritičkog mišljenja su grupisane u tri faktora. Potvrđeno je da postoje značajne veze između stavova i aktivnosti nastavnika. Pojedine aktivnosti nastavnika mogu se predvideti na osnovu njihovih stavova, a najznačajniji prediktor svih ispitivanih aktivnosti usmerenih na podsticanje kritičkog mišljenja u nastavi jeste spremnost na podsticanje nezavisnog mišljenja, učeničkih pitanja i diskusije na času.

This paper deals with different theoretical views and research regarding metacognition, its components and relations to cognition, conceptual discrepancy as well as opposing research results. Special attention was paid to the relation between metacognitive knowledge and the regulation of cognitive strategies. Reflexive awareness about personal cognitive processes is emphasized, but research discrepancies are apparent in regard to cognitive regulation. Research results focused on development of personal learning awareness and regulative skill involvement in the educational process (planning, monitoring and evaluating) are presented. A discussion was also focused on various views on relations between metacognition and the self which are of special importance for providing motivation in learning. Research data show that metacognitive awareness correlates with self. Metacognitive training affects development of the control experience and self-efficiency. The role of metacognition is emphasized as important for understanding relationship between cognition and motivation, which also affects learning self-regulation development. The paper emphasizes the significance of further study of metacognition and the possibilities for its use in the educational process. Research show that both metacognitive knowledge and regulation may be beneficial for: problem solving in learning processes, development of learning strategies and student achievement. U radu se razmatraju različita teorijska shvatanja i istraživački nalazi o metakogniciji, njenim komponentama i odnosima sa kognicijom, konceptualna neusaglašenost, kao i protivrečni istraživački nalazi. Posebna pažnja posvećena je odnosu metakognitivnog znanja i regulacije kognitivnih strategija. Većina istraživanja naglašava svesnost o sopstvenim kognitivnim procesima, dok se razlike u istraživanjima pojavljuju u vezi sa regulacijom kognicije. Prikazani su nalazi istraživanja usmerenih na razvoj svesnosti o sopstvenom učenju, kao i na uključivanje regulativnih veština (planiranja praćenja i evaluacije) u obrazovni proces. Razmatrana su različita shvatanja o odnosima metakognicije sa selfom, i njihov značaj za podsticanje motivacije u učenju. Istraživanja pokazuju da je metakognitivna svesnost u vezi sa selfom. Metakognitivna obuka utiče na razvijanje doživljaja kontrole i samoefikasnosti. Ističe se značaj metakognicije za razumevanje odnosa između kognicije i motivacije, što takodje utiče na podsticanje samoregulacije učenja. Ukazano je na značaj proučavanja metakognicije i mogućnosti primene u obrazovnom procesu. Istraživanja pokazuju da i metakognitivno znanje i regulacija mogu biti korisni za rešavanje problema u učenju, za razvijanje strategija učenja i za postignuće učenika.

Within the context of effects that findings in the domain of cognitive psychology produce on the improvement of learning process in teaching, the results for examinations on student learning strategies and some of their implications were analyzed. Diverse methods for the operationalization of strategies, both cognitive and metacognitive, applied by students are featured. It is demonstrated that engagement of metacognitive processes is of crucial importance, firstly for developing efficient learning strategies and then for achieving better quality outcomes of educational process. Metacognition is treated in some studies as a process parallel to cognition and accordingly, distinction is made between cognitive and metacognitive learning strategies. But metacognitive processes are also often treated as intrinsic factors acting in the process of developing and using cognitive strategies in learning and they determine features and quality of those strategies and their effects. Some prospects for further intervening trends in the process of teaching are presented using the findings. It is emphasized that influence exerted by social environment i.e. school setting where the process of learning is going on can not be disregarded. U kontekstu uticaja istraživačkih nalaza iz domena kognitivne psihologije na usavršavanje procesa učenja u nastavi, analizirani su rezultati ispitivanja strategija koje učenici primenjuju u učenju i neke njihove implikacije. Prikazani su različiti načini operacionalizacije strategija koje učenici primenjuju, kako kognitivnih, tako i metakognitivnih. Pokazuje se da je angažovanje metakognitivnih procesa od suštinskog značaja, prvo za razvijanje efikasnih strategija učenja, a zatim i za ostvarivanje kvalitetnijih ishoda obrazovnog procesa. Pri tome se metakognicija u jednom broju studija tretira kao proces paralelan sa kognicijom i, u skladu s tim razlikuju se kognitivne i metakognitivne strategije u procesu učenja, ali se metakognitivni procesi često tretiraju i kao unutrašnji činioci koji deluju u procesu razvijanja i korišćenja kognitivnih strategija u učenju i određuju karakteristike i kvalitet tih strategija i njihovih efekata. Na osnovu datih istraživačkih nalaza, prikazane su neke perspektive koje se otvaraju u pogledu mogućnosti daljih pravaca intervencije u nastavnom procesu. Posebno je ukazano da se ne može prenebregnuti uticaj socijalnog okruženja konkretno školske sredine u kojoj se odvija proces učenja.

Investigations were conducted on learning problems using the sample of eighth-grade students of primary school (N=335). The respondents opted for one or more than seven offered statements related to: insufficient previous knowledge, insufficient studying, teaching contents (extensive, difficult unintelligible), textbook and teacher’s method of presenting the contents. On the basis of the results obtained, one-third of students have problems in mastering teaching contents of foreign language, physics and chemistry, and about one-fourth in mastering those of history and mathematics. All the mentioned causes of problems are present in varying degrees in some school subjects. The causes of learning problems are markedly present in a larger number of school subjects and they are related to some characteristics of teaching contents. Respondents point out, to a large extent, that teaching contents of technical education are uninteresting. In addition, students’ responses indicate that it is necessary to improve the method for mastering the teaching contents in various school subjects i.e. methods applied in the teaching process. Subjective causes, as pointed out by students, are connected with some of the subjects they have characterized as the most difficult. Unintelligible textbook is stressed to the lowest extent as a cause of learning problems compared to other causes stated for the majority of school subjects. Ispitivani su uzroci problema u učenju na uzorku učenika osmog razreda osnovne škole (N=335). Ispitanici su se opredeljivali za jednu ili više od sedam ponuđenih tvrdnji koje se odnose na: nedovoljno prethodno znanje nedovoljan rad, gradivo (obimno, teško, nezanimljivo), udžbenik i način predavanja nastavnika. Prema dobijenim podacima, oko trećine ispitanog uzorka učenika ima probleme u savladavanju nastavnog gradiva stranog jezika fizike i hemije, a oko četvrtine uzorka u savladavanju gradiva istorije i matematike. Svi navedeni uzroci problema u učenju zastupljeni su u različitoj meri u odnosu na pojedine nastavne predmete. Primetno su zastupljeni uzroci problema u učenju većeg broja predmeta koji se odnose na pojedine karakteristike nastavnog gradiva. U velikoj meri, ističe se nezanimljivost gradiva tehničkog obrazovanja. Pored toga, učenički odgovori ukazuju na potrebu za usavršavanjem načina savladavanja gradiva različitih predmeta, odnosno metoda koje se primenjuju u nastavnom procesu. Subjektivne uzroke učenici ističu upravo u vezi sa nekim od predmeta koje su okarakterisali kao najteže. Nerazumljiv udžbenik u najmanjoj meri se ističe kao uzrok problema u učenju, u odnosu na druge navedene uzroke, kod većine predmeta.

Background: IDH1 mutations (IDH1mut) occur in 20-30% of gliomas, induce DNA hypermethylation, and are associated with a better prognosis than IDH1 wild-type (IDH1wt) gliomas, yet the basis for this remains unclear. Furthermore, venous thromboemboli (VTE) are a serious complication in glioma patients, and the mechanism for this is also unclear. We recently discovered that IDH1mut gliomas are much less likely to develop VTE compared to IDH1wt gliomas. Our data suggests that suppression of Tissue Factor (TF), the primary initiator of coagulation, is a key reason for this. TF also directly enhances tumor malignancy via protease-activated receptor 2 (PAR2). In this study, we further explored the significance of TF on malignancy and thrombosis in IDH1wt and IDH1mut gliomas. Methods: Assays were performed using 6 patient derived glioma cells, 3 IDH1wt (GBM6, GBM12, GBM43) and 3 IDH1mut (TB09, BT142, GBM164). DNA methylation was analyzed by Illumina Human 850K. TF procoagulant activity (PCA) was determined by FXa generation, using preoperative glioma patient arterial plasma, conditioned medium, or cells. In vivo models of cancer induced thrombosis were created via surgical stenosis of the inferior vena cava of mice engrafted with IDH1wt or IDH1mut gliomas. In vitro markers of malignancy were measured by BrdU incorporation for cell proliferation, serum gradient Matrigel-coated transwell inserts for invasion, soft agar colony formation for clonogenicity. Nude mice (N≥6/group) were orthotopically transplanted with IDH1wt glioma cells and monitored for growth using bioluminescence imaging. Results: The TF gene, F3, was significantly hypermethylated in IDH1mut cells compared to IDH1wt cells, and IDH1mut glioma cells had lower levels of TF protein and TF PCA compared to IDH1wt cells. Exogenous treatment with the product of IDH1mut enzyme, D-2-hydroxyglutarate, directly suppressed TF PCA by 38% in IDH1wt cells (P=0.03), as did transgene IDH1mut expression. Mice with IDH1mut glioma xenografts produced fewer and smaller IVC thrombi than mice with IDH1wt xenografts (0.9±0.9 vs 10.3±3.6 mg, P=0.02). Patients whose gliomas contained IDH1mut had lower TF PCA compared to IDH1wt (0.5±0.2 vs 1.2±0.2 pg/mL, P=0.04), and there was a strong link between levels of TF PCA and subsequent development of VTE (P=0.03). TF knockdown greatly reduced cell proliferation, invasion, and colony formation of IDH1wt cells. Likewise, the PAR2 antagonist, GB83, inhibited IDH1wt cell proliferation by 54% (P Conclusions: IDH1mut mediated suppression of TF expression and PCA may be a critical component of the less thrombogenic, and less malignant, IDH1mut phenotype. Targeting TF-PAR2 signaling may therefore represent a novel therapeutic strategy to reduce IDH1wt glioma malignancy. Citation Format: Dusten Unruh, Snezana Mirkov, Charles D. James, Craig Horbinski. Mutant IDH1 and tissue factor in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1345. doi:10.1158/1538-7445.AM2017-1345

The degree of macrovesicular steatosis is typically evaluated in liver biopsies by visual estimation, which is subject to intraobserver and interobserver variations. Computer morphometry and biochemical measurement may provide more accurate results. Our aim was to develop a morphometry method and compare its results with visual and biochemical measurements. Twenty-six fresh frozen liver specimens were each divided into 4 aliquots. Three aliquots were processed biochemically to extract fat, and the fat content was defined as the weight percentage of fat. One aliquot was fixed in formalin, from which hematoxylin and eosin slides were made and reviewed by 3 pathologists to estimate fat content. Digital images of slides were analyzed by computer morphometry, which defined fat content as the percentage of area occupied by fat droplets. The results showed that individually, each method produced highly precise and reproducible measurements. Compared with each other, they showed very strong correlations (correlation coefficient r = 0.81-0.95). The range of fat content in all 26 specimens was 2.2% to 15% by biochemical, 0.8% to 82.5% by visual, and 0.3% to 19.6% by morphometry method. Visual estimation appeared to have a systematic bias, giving results nearly 4-fold higher than other methods. This may be because visual estimation denotes the fraction of hepatocytes containing fat droplets, instead of the true fraction of fat. Strong correlations between different methods suggest that all 3 are valid methods for measuring steatosis. Computer morphometry is easy to implement and not affected by the bias seen in visual estimation. It may serve as a potential supplemental or alternative method.

High interindividual pharmacokinetic variability was observed in phase 1 studies of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor. Thus, we hypothesized that the variability can be explained by genetic variants of the uridine 5′-diphosphate-glucuronosyltransferases (UGTs) involved in vorinostat metabolism. Baculosomes expressing human UGTs and 52 human liver microsomes were screened for vorinostat glucuronidation activity to identify the potential enzymes and functional variants. UGT2B17 had the largest activity. Human liver microsomes with at least one copy of UGT2B17 showed significantly greater enzymatic activity than those with UGT2B17 null genotype (P