The significance of polymorphisms in the genes encoding enzymes involved in the metabolism of methotrexate in children with acute lymphoblastic leukemia

Uvod: Akutna limfoblastna leukemija (ALL) je najčešća maligna bolest u pedijatrijskom uzrastu. Primenom savremenih protokola postignuto je preživljavanje u skoro 90% obolele dece. Najnovija istraživanja su usmerena ka farmakogenetici, sa ciljem da se smanji toksičnost primenjenih lekova, koji mogu biti uzrok smrtnog ishoda ili dugoročnih komplikacija koje utiču na kvalitet života po završetku lečenja. Na osnovu farmakogenetskih ispitivanja se može vršiti modulacija terapije, odnosno odrediti dozni režim lekova koji je prilagođen svakom pacijentu. Metotreksat (engl. Methotrexate – MTX) je antagonist folata i jedan je od ključnih lekova u terapijskim protokolima za pedijatrijsku ALL. Delotvoran je u postizanju i održavanju remisije u dece sa ALL, ali su odavno poznata neželjena dejstva koja njegova primena može da izazove. Ciljevi: Sastoje se u ispitivanju uticaja gena koji kodiraju enzime uključene u metabolizam MTX i njihovih varijanti na tok i ishod lečenja dece obolele od ALL. Na prvom mestu cilj doktorske disertacije je bio da se utvrdi učestalost varijanti c.677C>T i c.1289A>C u genu za MTHFR, -680 C>A, -675 A>G, -556 T>C, -464 A>T i -317 A>G u genu za DFHR, c.80G>A u genu za SLC19A1, 28 bp tandemski ponovak i 6 bp delecija u genu za TYMS. Učestalost polimorfizama je ispitana u dece obolele od ALL i kontrolnoj grupi i učinjena je uporedna analiza incidence u bolesnih i zdravih osoba. Nezavisno od farmakogenetičkih markera, cilj je bio da se ispita farmakokinetika (engl. Pharmacokinetics – PK) MTX i da se dobijeni rezultati koreliraju sa navedenim polimorfizmima. Takođe, praćena je klinička i laboratorijska toksičnost terapije MTX i istraženo je da li postoji povezanost pojedinačnih ili udruženih varijanti u ispitanim genima sa povećanom toksičnošću MTX. Na osnovu ispitanih parametara ideja je bila da se utvrdi da li postoji modulacija terapije i u kojoj meri kod prisustva pojedinačnih i/ili udruženih genetičkih varijanti. Krajnji cilj je bio da se utvrdi uticaj navednih polimorfizama u genima za DFHR, MTHFR, SLC19A1 i TYMS na ishod dece obolele od ALL...Objective: Acute lymphoblastic leukemia (ALL) is the most common malignant disease among children and adolescents. Contemporary protocols ensure survival rate in almost 90% of affected children. The latest research is directed towards pharmacogenetics, in order to reduce the toxicity of applied drugs, which may be the cause of death or long-term complications that affect the quality of life after completion of treatment. Pharmacogenetic studies are offering basis for therapy modulation, by changing drugs dosage regimen in order to tailor the therapy according to needs of each affected patient. Methotrexate (MTX) is a folate antagonist and is one of the key drugs in therapeutic protocols for pediatric ALL. MTX is effective in achieving and maintaining remission in children with ALL, but possible adverse side effects of its use are already well known. Aims: The most important goal was to test the influence of genes encoding enzymes involved in the metabolism of MTX and their variants on the course and outcome of children with ALL. First and foremost objective of the doctoral dissertation was to determine the frequency of variants c.677C>T and c.1289A>C in MTHFR gene, - 680 C>A, -675 A>G, -556 T>C, -464 A>T and -317 A>G in DFHR gene, c.80G> A in SLC19A1 gene, 6 bp deletion and 28 bp tandem repeats in TYMS gene. The incidence of polymorphisms in children with ALL and a control group was explored and afterwards compared in order to investigate eventual different pattern between pediatric ALL patients and healthy individuals. The goal was to investigate the pharmacokinetics (PK) and clinical and laboratory toxicity during MTX treatment and then to correlate with the aforementioned polymorphisms with the idea to explore whether there is a relationship of single or associated variants in the selected genes with already established MTX toxicity. The aim was to investigate the extent of therapy modulation in presence of individual and/or associated genetic variants by summarizing all results related to MTX toxicity. The ultimate goal was to determine the effect of aforementioned polymorphisms in genes MTHFR, DFHR, SLC19A1 and TYMS to the outcome of children with ALL..

Progress in student achievement as an indicator of school effectiveness

Achievement is usually seen as a major indicator of school performance and school effectiveness. Educational effectiveness associated with the quality of education. The study of teaching, teachers' influence and effectiveness of teaching methods and procedures aimed at innovating teaching. Monitoring of progress in student achievement are monitored transformational processes in schools, and is one of the tasks of school permanent commitment to introduce innovative ways of work and monitor progress in student achievement at all levels of education. This paper was presented analysis of student achievement progress in primary education, the introduction of innovative models of teaching. The choice in this paper was going to analyze the effects of activity that had an experimental program of work on individual classes of students and impact indicators of student achievement in the interpretation of research results

Correlation analysis of craniomandibular index and gothic arch tracing in patients with craniomandibular disorders

Background/Aim. Complex etiology and symptomatology of craniomandibular dysfunction make the diagnosing and therapy of this disorder more difficult. The aim of this work was to assess the value of clinical and instrumental functional analyses in diagnosing of this type of disorders. Methods. In this study 200 subjects were examined, 15 with temporomandibular joint disorder. They were subjected to clinical functional analysis (Fricton-Shiffman) and instrumental functional analysis by using the method of gothic arch. The parameters of the gothic arch records were analyzed and subsequently compared among the subjects of the observed groups. Results. In the examined group of the population 7.5% of them were with craniomandibular dysfunction. The most frequent symptoms were sound in temporomandibular joint, painful sensitivity of the muscles on palpation and lateral turning of the lower jaw while opening the mouth. By analyzing the gothic arch records and comparing the obtained values between the observed groups it was assessed that: lateral and protrusion movements, lateral amplitude and the size of gothic arch were much bigger in the healthy subjects, and latero-lateral asymmetry was larger in the sick subjects. Latero-lateral dislocation of apex was recorded only in the sick subjects with average values of 0.22 ± 0.130 mm. The correlation between the values of Fricton-Shiffman craniomandibular index and the parameters of the gothic arch records and latero-lateral amplitude and dislocation of apex records were established by correlative statistical analysis. Conclusion. Functional analysis of orofacial system and instrumental analysis of lower jaw movements (gothic arch method) can be recommended as precise and simple methods in diagnosing craniomandibular dysfunctions

Supplementary data for the article: Raskovic, B.; Lazic, J.; Polovic, N. Characterisation of General Proteolytic, Milk Clotting and Antifungal Activity of Ficus Carica Latex during Fruit Ripening. Journal of the Science of Food and Agriculture 2016, 96 (2), 576–582. https://doi.org/10.1002/jsfa.7126

Supplementary material for: [https://doi.org/10.1002/jsfa.7126]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2017]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3397

Blood pressure in professional athletes: relationship with morphofunctional characteristics of the left ventricle and aerobic capacity

Uvod Povišen krvni pritisak (KP) je najčešće kardiovaskularno (KV) oboljenje kod sportista. Čak 80% adolescenata sportista sa povišenim KP na preventivnim pregledima će razviti hroničnu hipertenziju nakon godinu dana, a povišen KP u ranom odraslom dobu povezuje se sa višom incidencom mortaliteta i morbiditeta od KV oboljenja nekoliko decenija kasnije. Cilj Evaluacija aerobnog kapaciteta i morfofunkciolnalnih karakteristika srca zdravih sportista u grupama formiranim prema visini krvnog pritiska i ispitivanje povezanosti između visine krvnog pritiska, ehokardiografskih karakteristika leve komore srca (LK) i aerobnog kapaciteta sportista. Metode Studija preseka je obavljena u predtakmičarsko periodu. Obuhvatila je 332 profesionalnih sportista, muškog pola. Ispitanici su podeljeni u tri grupe prema vrednostima krvnog pritiska, u skladu sa aktuelnim preporukama Evropskog udruženja kardiologa (2018): (1) optimalan KP<120/80mmHg, (2) normalan KP: SKP 120-129mmHg i/ili DKP 80- 84mmHg i (3) visoko normalan: SKP 130-139mmHg i/ili DKP 85-89mmHg. Svim ispitanicima je nakon detaljne anamneze i fizikalnog pregleda, urađena biohemijska analiza krvi i izvršena antropometrijska merenja, kao i transtorakalna ehokardiografija. Aerobni kapacitet je određen primenom progresivno rastućeg, maksimalnog ergospirometrijskog testa na pokretnoj traci, direktnim merenjem maksimalne potrošnje kiseonika (VO2 max). Tokom testa su praćene i kinetika srčane frekvencije i KP. Rezultati Istraživanje je pokazalo da sportisti u grupi visoko normalan KP, u poređenju sa sportistima sa optimalnim i normalnim KP, imaju statistički značajno niži aerobni kapacitet. Utvrđene su značajno više vrednosti srčane frekvencije u miru i rezerve srčane frekvencije kod sportista sa visoko normalnim vrednostima krvnog pritiska u poređenju sa onima koji su imali optimalan KP. Sportisti sa visoko normalnim KP imali su značajno veći volumen LK i end-dijastolni dijametar LK, ali i značajno različite vrednosti varijabli dobijene tkivnim doplerom: maksimalne brzine ekskurzije mitralnog anulusa u ranoj dijastoli (e'), odnos maksimalne brzine transmitralnog protoka i ekskurzije mitralnog anulusa u ranoj dijastoli (E/e`) i odnos maksimalnih brzina transmitralnog protoka u ranoj i kasnoj dijastoli (e’/a’). Multivarijantnom analizom pokazano je da su varijable E/e i e’/a’, koje su senzitivni markeri mehanike miokarda tokom dijastole, nezavisni prediktori maksimalne potrošnje kiseonika kod svih ispitanika. Zaključak Kod profesionalnih sportisti sa visoko normalnim krvnim pritiskom utvrđen je statistički značajno niži aerobni kapacitet, nepovoljniji autonomni balans i izmenjene varijable dijastolne funkcije u poređenju sa onima čije su vrednosti krvnog pritiska bile u kategoriji optimalan i normalan KP. Ehokardiografski pregled i merenje aerobnog kapaciteta u okviru obaveznog sportskomedicinskog pregleda omogućava identifikaciju sportista sa visoko normalnim KP, stratifikaciju KV rizika i blagovremenu implementaciju preventivnih mera.Background High blood pressure (BP) is the most common cardiovascular (CV) disease in athletes. As many as 80% of adolescent athletes with elevated CP on preventive examinations will develop chronic hypertension after one year, and elevated BP in early adulthood is associated with a higher incidence of mortality and morbidity from CV disease a few decades later. Aims To evaluate the aerobic capacity and morphofunctional characteristics of the heart of healthy athletes in groups formed according to blood pressure and to examine the relationship between blood pressure, echocardiographic characteristics of the left ventricle (LV), and aerobic capacity of athletes. Methods The cross-sectional study was performed in the pre-competition period. It included 332 professional athletes. Subjects were divided into three groups according to blood pressure values, by the current recommendations of the European Society of Cardiology (2018): (1) optimal KP <120/80mmHg, (2) normal KP: SKP 120-129mmHg and/or DKP 80-84mmHg and (3) highly normal: SKP 130-139mmHg and/or DKP 85-89mmHg. After clinical examination, all subjects underwent biochemical blood analysis, anthropometric measurements, and transthoracic echocardiography. Aerobic capacity was determined using a progressive, maximal cardiopulmonary exercise test on a treadmill. Maximum oxygen consumption (VO2 max) was measured directly, and the kinetics of heart rate and BP were monitored during the test. Results Our research has shown that athletes with high normal blood pressure, when compared to counterparts with normal and optimal BP levels, have significantly lower aerobic capacity. There were significantly higher values of resting heart rate and heart rate reserves in athletes with high normal blood pressure. Echocardiography revealed significant morphological and functional differences among athletes in relation to blood pressure: athletes with high normal BP had significantly higher left ventricular volume and enddiastolic diameter of the LV, but also significantly different variables obtained by tissue Doppler: averaged peak annular early diastolic filling velocity (e'), the ratio of the maximum velocity of transmitral flow and peak annular early diastolic filling velocity (E/e`) and the ratio of peak annular early and late diastolic filling velocity (e'/a'). Multivariate analysis has shown that the variables E/e and e’/a’, sensitive markers of myocardial mechanics during diastole, are independent predictors of VO2 max in all subjects. Conclusion Professional athletes with high normal blood pressure had significantly lower aerobic capacity, less favorable autonomic balance as well as variables of diastolic function compared to those who had optimal and normal blood pressure. Echocardiographic examination and cardiopulmonary testing of professional athletes during preparticipation screening enable the identification of athletes with high normal blood pressure, stratification of cardiovascular risk, and timely implementation of preventive measures

KRIZA NA KOSOVU 1981. GODINE IZ PERSPEKTIVE DRŽAVA „VELIKE PETORKE“

Na osnovu arhivske građe prikupljene u Diplomatskom arhivu Ministarstva spoljnih poslova Republike Francuske u Parizu, u ovom radu su predstavljeni stavovi država „velike petorke“ (Francuska, Nemačka, Velika Britanija, Sjedinjene Američke Države i Italija) o kosovskoj krizi 1981. godine. Za svaku od posmatranih država analizirana su po dva dokumenta, među kojima se nalaze i poverljivi izveštaji slati u NATO u kojima je ključna tema situacija na Kosovu 1981. godine. Osim toga, predstavljene su i diplomatske note ili telegrami, a tu su i obaveštajno-bezbednosni izveštaji kao u slučaju Francuske. Kao jedan od ciljeva ovog rada ističemo i poziv istraživačima da nastave sa proučavanjem stavova država „velike petorke“ prema kosovskom pitanju i nakon 1981. kroz arhivska istraživanja i analizu nekih novih dokumenata za koje se pretpostavlja da se nalaze u arhivima u Parizu, Bonu, Berlinu, Londonu, Rimu, Briselu i Vašingtonu

RHEOLOGICAL PROPERTIES AND THE ENERGETIC VALUE OF WHEAT FLOUR SUBSTITUTED BY DIFFERENT SHARES OF WHITE AND BROWN RICE FLOUR

In order to produce dough with a lower gluten content, more enriched with rice components and satisfactory rheological properties, the rheological properties, energetic value and cake baking properties of wheat and white or brown rice flour in shares from 3 to 30% (w/w) were investigated in this paper. The water absorption in wheat-rice flour mixtures was lower and decreased to 53.5% and 54.0% along with the increase of the white and the brown rice flour share, respectively, than in wheat flour, where it was 58.8%. In the dough made from rice flour, a gluten network had thinner filaments, about 2 and 1 μm in width for white and brown rice flour, respectively, compared to those in the dough from wheat flour only, where it was about 7 μm. The dough from rice flour had almost twice higher gelatinization maximum than the gelatinization maximum of the wheat flour only. The energetic values of the dough from rice flour were smaller than the energetic value of the wheat flour, for only 1.32%. Based on Cluster analysis, the white or brown rice flour share of 20% was pointed out

Učinak razlike u procjeni osobne i supružnikove vrijednosti kao partnera na procjenu kvalitete bračnog odnosa: dijadni pristup

The main aim of this study was to investigate the effects of mate value assessment and mate value discrepancy on perceived marital quality, using an assessment of personal and partner mate value obtained by both partners. The sample included 442 heterosexual couples that have lived together for at least a year. The Actor-Partner Interdependence Model (APIM) was used to investigate the effects of personal and partner mate value assessment on the evaluation of marital quality. In addition, two interaction effects were added to the model to examine the effect of mate value discrepancy on perceived marital quality. The APIM model showed significant actor and partner effects of the partner\u27s mate value assessment on the evaluation of both husbands\u27 and wives\u27 marital quality. The model also showed a significant effect of personal mate value assessed by wives on husbands\u27 marital quality assessment. However, the current evidence does not confirm the assumption of a possible combination of partners\u27 mate value promoting marital quality above and beyond the contribution of both partners\u27 mate value.Glavni cilj ovog istraživanja bio je istražiti učinke procjene osobne i supružnikove vrijednosti kao partnera i razlike u spomenutim vrijednostima na procjenu kvalitete bračnog odnosa, koristeći se procjenom osobne i supružnikove vrijednosti dobivene od oba partnera. Uzorak istraživanja obuhvaćao je 442 heteroseksualna para, koji su zajedno živjeli najmanje godinu dana. Model međuovisnosti aktora i partnera (APIM) iskorišten je za istraživanje učinaka procjene osobne i supružnikove vrijednosti kao partnera na procjenu kvalitete braka. Osim navedenoga, modelu su dodana dva interakcijska učinka, kako bi se istražio učinak razlike u procjeni osobne i supružnikove vrijednosti kao partnera na procijenjenu kvalitetu braka. APIM model pokazao je značajne aktorske i partnerske učinke procjene supružnikove vrijednosti kao partnera na procijenjenu kvalitetu braka obaju supružnika. Model je pokazao i znatan učinak procjene osobne vrijednosti supruge kao partnerice na suprugovu procjenu kvalitete bračnog odnosa. Međutim, model ne potvrđuje pretpostavku o interakcijskom učinku procjene osobne i supružnikove vrijednosti kao partnera na procjenu kvalitete braka

Making a new consensual elite in Serbia

The text firstly addresses the thesis that systemic transformation – from a socialist to a capitalist order – changes both the preconditions on the basis of which political elite is constituted, and its main characteristics. Considering the specific course of transformation in Serbia, this indicates the difficulties for the transformation of its divided political elite – characterizing the aftermath of the breakdown of socialism – into a consensual elite that represents a type prevailing in liberal-democratic systems. The political elite in Serbia may thus be defined as primarily fragmented, with initial elements of consensuality. The main thesis is examined through an analysis of the changes in the character of political elites at two different levels: subjective, regarding their attitudes towards the EU based on 2007 and 2009 IntUne data; and objective (patterns of recruitment of their members based on 1989, 2003 and 2015 data on intra – and intergenerational mobility). The main findings reveal the gradual (although not yet completed) consolidation of political elites regarding their attitudes towards the EU, but also changing patterns of elite members’ recruitment based on political competition and the increasing self-reproduction of the ruling elites, indicating the formation of biased pluralism

Expression Analysis of SOX14 during Retinoic Acid Induced Neural Differentiation of Embryonal Carcinoma Cells and Assessment of the Effect of Its Ectopic Expression on SOXB Members in HeLa Cells

SOX14 is a member of the SOXB2 subgroup of transcription factors implicated in neural development. Although the first SOX14 gene in vertebrates was cloned and characterized more than a decade ago and its expression profile during development was revealed in various animal model systems, the role of this gene during neural development is largely unknown. In the present study we analyzed the expression of SOX14 in human NT2/D1 and mouse P19 pluripotent embryonal carcinoma cells. We demonstrated that it is expressed in both cell lines and upregulated during retinoic acid induced neural differentiation. We showed that SOX14 was expressed in both neuronal and non-neuronal differentiated derivatives, as revealed by immunocytochemistry. Since it was previously proposed that increased SOXB2 proteins level interfere with the activity of SOXB1 counteracting partners, we compared expression patterns of SOXB members during retinoic acid induction of embryonal carcinoma cells. We revealed that upregulation of SOX14 expression is accompanied by alterations in the expression patterns of SOXB1 members. In order to analyze the potential cross-talk between them, we generated SOX14 expression construct. The ectopic expression of SOX14 was demonstrated at the mRNA level in NT2/D1, P19 and HeLa cells, while an increased level of SOX14 protein was detected in HeLa cells only. By transient transfection experiments in HeLa cells we showed for the first time that ectopic expression of SOX14 repressed SOX1 expression, whereas no significant effect on SOX2, SOX3 and SOX21 was observed. Data presented here provide an insight into SOX14 expression during in vitro neural differentiation of embryonal carcinoma cells and demonstrate the effect of its ectopic expression on protein levels of SOXB members in HeLa cells. Obtained results contribute to better understanding the role of one of the most conserved SOX proteins