Knowledge-Based Economy in the Competitiveness Equation. The Case of the Republic of Serbia

The study presents the new approaches of the knowledge‐based economies and competitiveness policy using two major indexes and methodologies developed by two prestigious world institutions, the World Bank and the World Economic Forum, as well as the practical consequences of their implementation at the level of individual economies in a dynamic globalised world. The main conclusion derived from the study is that without firm and steady measures for a comprehensive implementation of the mix of policies included in the two indexes, there are fewer chances of winning a better position of a country in the global concert of people and increasing the nation's wealth and standard of living. A particular attention is given to the case of the Republic of Serbia, candidate country to the European Union, pointing out both the achievements and the need for further action at the national level

Serotype distribution, antimicrobial susceptibility and molecular epidemiology of invasive Streptococcus pneumoniae in the nine-year period in Serbia

Streptococcus pneumoniae is one of the leading bacterial pathogens that can cause severe invasive diseases. The aim of the study was to characterize invasive isolates of S. pneumoniae obtained during the nine-year period in Serbia before the introduction of the pneumococcal conjugate vaccines (PCVs) into routine vaccination programs by determining: serotype distribution, the prevalence and genetic basis of antimicrobial resistance, and genetic relatedness of the circulating pneumococcal clones. A total of 490 invasive S. pneumoniae isolates were included in this study. The serotype, antimicrobial susceptibility, and ST of the strains were determined by the Quellung reaction, disk- and gradient-diffusion methods, and multilocus sequence typing (MLST), respectively. The most common serotypes in this study were 3, 19F, 14, 6B, 6A, 19A, and 23F. The serotype coverages of PCV10 and PCV13 in children less than 2 years were 71.3 and 86.1%, respectively, while PPV23 coverage in adults was in the range of 85-96%, depending on the age group. Penicillin and ceftriaxone-non-susceptible isolates account for 47.6 and 16.5% of all isolates, respectively. Macrolide non-susceptibility was detected in 40.4% of isolates, while the rate of multidrug- and extensive-drug resistance was 20.0 and 16.9%, respectively. The MLST analysis of 158 pneumococci identified 60 different STs belonging to the 16 Clonal Complexes (CCs) (consisting of 42 STs) and 18 singletons. The most common CC/ST were ST1377, CC320, CC15, CC273, CC156, CC473, CC81, and CC180. Results obtained in this study indicate that the pre-vaccine pneumococcal population in Serbia is characterized by high penicillin and macrolides non-susceptibility, worrisome rates of MDR and XDR, as well as a high degree of genetic diversity. These findings provide a basis for further investigation of the changes in serotypes and genotypes that can be expected after the routine introduction of PCVs

Estimation of the impact of electrostatic discharge on density of states in hydrogenated amorphous silicon thin-film transistors

The objective of this letter is to give an estimation of the impact of an electrostatic discharge (ESD) stress on the density of states (DOS) within the energy gap of hydrogenated amorphous silicon (a-Si:H) thin-film transistors. ESD stresses were applied by means of a transmission line model tester. The DOS in the a-Si:H was determined by Suzuki's algorithm using field-effect conductance measurements. A comparison of stressed and unstressed devices shows that there is a threshold ESD stress voltage, below which there is no damage. Above the threshold stress level, first an increase of the deep gap states is found and when stress is increased further, also in the tail states

Importance of genotyping of Thiopurine S-methyltransferase in children with acute lymphoblastic leukaemia during maintenance therapy

Uvod. Tiopurin-S-metiltransferaza (TPMT ) je enzim koji katalizuje inaktivaciju merkaptopurina, leka koji se široko primenjuje u lečenju akutne limfoblastne leukemije (ALL) kod dece. Kada se osobe s nedostatkom TPMT leče standardnim dozama merkaptopurina, kod njih se razvija teška i po život opasna mijelotoksičnost. Cilj rada. Cilj rada je bio da se utvrdi da li kod dece s ALL koji su nosioci mutacije u genu za TPMT individualizovanjem doziranja merkaptopurina može da se smanji mijelotoksičnost terapije, te da li broj tandemskih ponovaka (engl. variable number of tandem repeats - VNTR) u promotoru gena za TPMT ima uticaja na efekte terapije merkaptopurinom. Metod rada Metodima lančane reakcije umnožavanja DNK (engl. polymerase chain reaction - PCR) ispitano je 50 nasumično odabrane dece lečene ALL IC-BFM 2002 protokolom na najčešće mutacije u genu za TPMT. Za 20 dece je PCR metodima određen VNTR genotip. Ispitanicima je tokom faze održavanja beležen broj nedelja kada su terapiju dobijali u punim ili smanjenim dozama, kao i broj nedelja bez terapije. Rezultati Među 50 dece bilo je 29 dečaka (58%) i 21 (42%) devojčica, uzrasta od 1,8 do 17,3 godine (medijana 6,2 godine). Utvrđeno je četvoro (8%) heterozigotnih nosilaca mutacija, kod kojih je otkrivena TPMT*3A varijanta. Posle 12, 14, 16 i 19 nedelja lečenja smanjenim dozama merkaptopurina bolesnici su, zbog dobrog podnošenja terapije, postepeno počeli da primaju punu dozu leka. Nije bilo odlaganja terapije. Smanjenje kumulativne doze merkaptopurina za bolesnike sa TPMT mutacijama bilo je 7,8%, 7,4%, 11,2% i 16,6%. Između dece bez TPMT mutacija i heterozigota nije za- beležena statistički značajna razlika u trajanju lečenja punim (53,6 nasuprot 55,7 nedelja) i smanjenim dozama merkaptopurina (19,9 nasuprot 15,2 nedelje). Otkrivenih VNTR bilo je između četiri i sedam. Većina bolesnika imala je različit broj VNTR na homolognim hromozomima. Najčešće uočen polimorfizam bio je VNTR*5. Nije zabeležena korelacija između nasleđivanja TPMT i VNTR genotipa. Zaključak Farmakogenetskim principima u lečenju ALL dece može se postići napredak u podnošenju lečenja merkaptopurinom.INTRODUCTION Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyses the inactivation of mercaptopurine (MP) which is widely used in the treatment of acute lymphoblastic leukaemia (ALL) of childhood. Potentially fatal myelotoxicity may develop after standard doses of MP in TPMT deficient patients. OBJECTIVES To establish if individually tailored doses of MP can reduce myelotoxicity in ALL patients carrying mutations in the TPMT gene. To establish if variable number of tandem repeats (VNTR) genotype influences the treatment effects of MP. METHOD Fifty randomly selected patients treated according to ALL IC-BFM 2002 protocol were tested for most frequent TPMT gene mutations using PCR based methods. VNTR genotype was determined in 20 children by PCR methods. During the maintenance phase, we recorded the number of weeks when therapy was applied in either full doses, reduced doses or when patients were without any therapy. RESULTS Fifty children were examined, 29 boys (58%) and 21 girls (42%); age ranged from 1.8-17.3 years (median 6.2 years). Four patients (8%) were heterozygous for TPMT mutations, all of them carrying the TPMT*3A variant. After 12, 14, 16 and 19 weeks of therapy with reduced doses of MP, the patients switched to full doses due to good tolerance. There was no therapy omission. Cumulative dose of MP was reduced for 7.8%, 7.4%, 11.2% and 16.6%, respectively, in patients with TPMT mutations. No significant difference was found between children with no mutations and TPMT heterozygotes regarding full dose therapy (53.6 vs. 55.7 weeks, respectively) and reduced dose therapy (19.9 vs. 15.2 weeks respectively). The number of detected VNTRs ranged from four to seven. The majority of patients had different number of VNTRs on homologous chromosomes. Most frequently detected polymorphism was VNTR*5. No correlation was found between TPMT and VNTR genotype inheritance. CONCLUSION Obeying pharmacogenetic principles in the treatment of childhood ALL may improve the tolerance of therapy with MP

The role of FasR/FasL system in pathogenesis of myeloprolyferative neoplasms

Mijeloproliferativne neoplazije (MPN) su hematološki maligniteti koji se karakterišu nekontrolisanom ćelijskom proliferacijom i poremećajem u procesu apoptoze. Sistem FasR/FasL je uključen u kontrolu apoptoze u različitim tipovima ćelija. U ovom radu je izučavana uloga sistema FasR/FasL u patogenezi mijeloproliferativnih neoplazija. Upoređena je ekspresija FasR i FasL između pacijenata sa MPN (24) i zdravih kontrola korišćenjem metode 'real-time' PCR. Detektovana je povećana ekspresija FasR kod pacijenata sa MPN. Nije utvrđena razlika u ekspresiji FasL. Mutacija B617F u JAK2 genu, karakteristična za MPN, je nađena kod 13 od 24 pacijenta. Pokazano je da ekspresija FasR i FasL nije povezana sa prisustvom B617F JAK2 mutacije.Myeloproliferative neoplasms (MPN) are hematological malignancies characterized by uncontrolled cell proliferation and impaired apoptosis. The FasR/FasL system is involved in the control of apoptosis in different cell types. Here we have investigated the role of FasR/FasL in the pathogenesis of MPNs. We compared FasR/FasL expression between MPN patients (24) and healthy individuals using the real-time PCR assay. We found an increase of FasR expression in MPN patients. No difference was detected in FasL expression. Mutation V617F in the JAK2 gene, a hallmark of MPN, was detected in 13/24 patients. We found that neither FasR nor FasL expression were related to the presence of JAK2 V617F mutation

Expression Of The Bcl2 Gene In Chronic Lymphocytic Leukaemia Patients

Chronic lymphocytic leukaemia (CLL) manifests as clonal expansion of mature B lymphocytes, whose accumulation is primarily attributed to the dysregulation of apoptosis. Aberrant expression, as well as genetic alterations within various Bcl2 family members and central regulators of the intrinsic, mitochondria-mediated apoptotic pathway all hasve been observed in CLL. Here, we report the expression analysis of the anti-apoptotic Bcl2 gene in a cohort of 58 CLL patients. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) analysis revealed a significant overexpression of Bcl2 mRNA in CLL samples compared to control samples (p=<0.001). Receiver operating characteristic (ROC) analysis showed that the level of Bcl2 expression exerts a high discriminatory power between patients and healthy subjects (A=0.98, 95% CI=0.95-1.009, p<0.0001)

Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia

Uvod/Cilj Sekvenciranje nove generacije (SNG) omogućilo je genomsko profilisanje svakog bolesnika. Nova saznanja u oblasti farmakogenomike omogućavaju primenu podataka dobijenih ovom metodom u cilju otkrivanja novih mogućih genetičkih markera za ciljanu terapiju mnogih, posebno malignih bolesti. Cilj ovog istraživanja je bio da se primenom SNG odre- di genetski profil akutne limfoblastne leukemije (ALL) kod dece u cilju procene mogućih molekularnih meta za ciljanu terapiju. Metode Analizirali smo DNK uzorke 17 bolesnika obolelih od ALL dečjeg doba koristeći ciljano SNG. Napredne bioinformatičke metode su korišćene da identifikuju nove mutacije u analiziranim genima i da predvide njihov uticaj i farmakogenomski potencijal. Rezultati Identifikovali smo devet genskih varijanti koje do sada nisu opisane u relevantnim bazama podataka. U navedenim varijantama identifikovane su dve 'besmislene' varijante, ABL1 p.Q252* i AKT1 p.W22*, jedna varijanta koja pomera okvir čitanja, STK11 p.G257fs*28, i šest nesinonimnih varijanti. Kreirali smo trodimenzionalni model za četiri proteina koji bi bili produkt novih nesinonimnih varijanti. Analizirali smo farmakogenomski potencijal svake varijante i otkrili da su dve, STK11 c.1023G gt T/ p.L341F i ERBB2 c.2341C gt T/ p.R781W, mogući kandidati za ciljanu terapiju. Zaključak Nove varijante otkrivene u ovoj studiji pripa- daju uglavnom genima povezanim sa Ras signalnim putem, koji je često zahvaćen mutacijama u ALL kod dece. Farmakogenomsko profilisanje svake dečje ALL biće nezamenljivo za nove terapijske pristupe. Detekcija i inicijalna analiza novih genskih varijanti, koja je predstavljena u ovoj studiji, postaće standardna procedura za dizajniranje i razvoj individualizovane terapije za decu obolelu od ALL.Introduction/Objective Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G gt T/ p.L341F and ERBB2 c.2341C gt T/ p.R781W, are suitable candidates for targeted therapy. Conclusion Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes