Maja Stanojevic

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (44)114.09 Total impact

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    ABSTRACT: Introduction: Among colorectal cancer (CRC) diagnoses, approximately 28% cases represent rectal cancer, which is nowadays considered as a distinct clinical entity with different molecular and genetic changes. The current management of locally advanced rectal cancer involves neoadjuvant chemoradiotherapy (CRT) prior to surgery. However, subsets of patients have no benefit from preoperative treatment. Although predictive value of KRAS mutation status was demonstrated in treatment of metastatic CRC patients with EGFR inhibitors, correlation between mutations of this gene and clinical outcome in patients with locally advanced rectal cancers is not fully established. Hence, the aim of our study was to investigate relationship of KRAS mutation status with clinicopathological features, including response to preoperative CRT and survival data, among group of 63 locally advanced rectal cancer patients from Serbia. Methods: For mutational analyses of KRAS gene, formalin-fixed, paraffin-embedded tumor tissues obtained prior to the start of chemoradiotherapy was used. After isolation of genomic DNA from deparaffined tumor specimens, exon 2 of KRAS gene (containing codons 12 and 13) was amplified. Obtained PCR products were subjected to direct sequencing. Results: KRAS mutations were detected in 35 % of patients, 91 % of which were located in codon 12 and 9 % in codon 13. Distribution of detected mutations was as follow: 41 % (9/22) of G to T transversions, 41 % (9/22) of G to A transitions and 18% (4/22) of G to C transversions. The presence of KRAS mutations was associated with tumor localization in mid rectum (p = 0.019), but not related to other clinicopathological parameters. In general, KRAS mutation status did not affect the response to neoadjuvant chemoradiotherapy (CRT). Furthermore, there was no significant difference in the overall survival between those with wild type and mutated KRAS gene (p = 0.669). However, patients harboring mutated KRAS gene, simultaneous with high VEGF expression, exibited worse response to CRT (p = 0.030) and shorter overall survival (p = 0.001), compared to those with none, or only one, KRAS status or VEGF expression changed. On the contrary, patients with G to C transversions exibited significantly better response to CRT than patients with G to A and G to T mutations (p = 0.017). In addition, the presence of G to C mutation was associated with low VEGF and Ki67 expression (p = 0.012 in both cases), parameters related to less aggressiveness of the tumor. Conclusion: Our results suggest that not only the presence but the type of KRAS mutation is important for examining its impact on patients’ outcome. Moreover, KRAS mutation status could have some predictive and prognostic importance in rectal cancer, when analyzed together with other parameters, such as VEGF and Ki67 expression.
    Belgrade International Molecular Life Science Conference for Students - BIMLS; 01/2015
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    ABSTRACT: Abstract Background: HIV-1 subtype CRF01_AE originated in Africa and then passed to Thailand where it established a major epidemic. Despite the global presence of CRF01_AE little is known about its subsequent dispersal pattern. Methods: We assembled a global dataset of 2,736 CRF01_AE sequences by pooling sequences from public databases and patient-cohort studies. We estimated viral dispersal patterns using statistical phylogeography run over bootstrap trees estimated by the maximum likelihood (ML) method. Results: We show that Thailand has been the source of viral dispersal to most areas worldwide, including 17 out of 20 sampled countries in Europe. Japan, Singapore, Vietnam and other Asian countries have played a secondary role in the viral dissemination. In contrast, China and Taiwan have mainly imported infections from neighbouring Asian countries, North America and Africa without any significant exporting transmissions. Discussion: The central role of Thailand in the global spread of CRF01_AE can be probably explained by the popularity of Thailand as a vacation destination characterized by sexual tourism and by Thai emigration to the Western world. Our study highlights the unique case of CRF01_AE, the only globally distributed non-B clade for which its global dispersal was not originated in Africa.
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    ABSTRACT: Purpose: Bats have recently been recognized as potential reservoir of emerging human pathogens, including hantaviruses and paramyxoviruses. Hantaviruses are known to be endemically present in Serbia, both in humans and in animal reservoirs comprising several rodent species, and causing hemorrhagic fever with renal syndrome. On the 4 other hand, paramyxoviruses are widely distributed worldwide and known to be associated with a range of human diseases (bronchiolitis, pneumonia, encephalitis, meningitis, parotitis, orchitis). No molecular data exist about the occurrence of human or zoonotic viruses in bats in Serbia. Aim: To examine the presence of paramyxovirus and hantavirus genetic material in bats in Serbia.
    International Meeting on Emerging Diseases and Surveillance 2014, Wienna; 11/2014
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    ABSTRACT: Several studies of group A streptococci (GAS) have revealed that a small number of dominant resistant clones might be responsible for the spread of Streptococcus (S.) pyogenes resistance to macrolides. We aimed to determine the genetic diversity of macrolide resistant group A streptococci (MRGAS), isolated from patients with pharyngitis in Serbia.
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    ABSTRACT: One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program.
    BMC Infectious Diseases 07/2014; 14(1):407. DOI:10.1186/1471-2334-14-407 · 2.56 Impact Factor
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    ABSTRACT: We aimed to study epidemic trends and predictors for transmitted drug resistance (TDR) in our region, its clinical impact and its association with transmission clusters. We included 778 patients from the AIDS Reference Center in Leuven (Belgium) diagnosed from 1998 to 2012. Resistance testing was performed using population-based sequencing and TDR was estimated using the WHO-2009 surveillance list. Phylogenetic analysis was performed using maximum likelihood and Bayesian techniques. The cohort was predominantly Belgian (58.4%), men who have sex with men (MSM) (42.8%), and chronically infected (86.5%). The overall TDR prevalence was 9.6% (95% confidence interval (CI): 7.7-11.9), 6.5% (CI: 5.0-8.5) for nucleoside reverse transcriptase inhibitors (NRTI), 2.2% (CI: 1.4-3.5) for non-NRTI (NNRTI), and 2.2% (CI: 1.4-3.5) for protease inhibitors. A significant parabolic trend of NNRTI-TDR was found (p = 0.019). Factors significantly associated with TDR in univariate analysis were male gender, Belgian origin, MSM, recent infection, transmission clusters and subtype B, while multivariate and Bayesian network analysis singled out subtype B as the most predictive factor of TDR. Subtype B was related with transmission clusters with TDR that included 42.6% of the TDR patients. Thanks to resistance testing, 83% of the patients with TDR who started therapy had undetectable viral load whereas half of the patients would likely have received a suboptimal therapy without this test. In conclusion, TDR remained stable and a NNRTI up-and-down trend was observed. While the presence of clusters with TDR is worrying, we could not identify an independent, non-sequence based predictor for TDR or transmission clusters with TDR that could help with guidelines or public health measures.
    PLoS ONE 07/2014; 9(7):e101738. DOI:10.1371/journal.pone.0101738 · 3.53 Impact Factor
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    ABSTRACT: Macroautophagy (hereafter referred to as autophagy) is an evolutionary conserved catabolic process in which the cytoplasmic content is sequestered and degraded by the lysosomal machinery in order to maintain cellular homeostasis or provide energy during metabolic and hypoxic stress. It also represents an important component of the host response against infectious agents, performing surveillance and effector functions involved in detection and clearance of pathogens, including viruses. Moreover, it appears that autophagy plays a major role in determining the fate of both virally infected and uninfected cells by blocking or promoting their death in a virus- and cell-type-dependent manner. We here review the current knowledge on the complex involvement of autophagy in survival and death of the host cells during viral infection, focusing on the molecular mechanisms underlying viral modulation of autophagic response and its interference with the cell death pathways. We also discuss a possible significance of the autophagy-dependent modulation of cell death for the outcome and therapy of viral infections, emphasizing the need for a time- and cell-type-dependent fine-tuning of the autophagic response in achieving an optimal balance between beneficial and adverse effects.
    Medicinal Research Reviews 07/2014; 34(4). DOI:10.1002/med.21303 · 8.13 Impact Factor
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    ABSTRACT: Dobrava-Belgrade virus (DOBV) is a hantavirus species that causes the most severe form of haemorrhagic fever with renal syndrome (HFRS) in Europe. DOBV has been detected in three Apodemus rodents: A. flavicollis, A. agrarius and A. ponticus. These emerging viruses appear throughout the Balkan Peninsula including Serbia as its central part. In this study, we examined the seroprevalence, molecular epidemiology and phylogenetics of DOBV from A. flavicollis captured at six Serbian localities. Furthermore, we applied microsatellite typing of host animal genome to analyse the role of host kinship in DOBV animal transmission. The overall IgG seropositivity rate over 3 years (2008-2010) was 11.9% (22/185). All seropositive samples were subjected to RT-PCR and DNA sequencing for S and L genome segments (pos. 291-1079 nt and 2999-3316 nt, respectively). DOBV was genetically detected in three samples from mountain Tara in western Serbia, a newly detected DOBV focus in the Balkans. No sequence data from human cases from Serbia are available for the studied period. However, collected DOBV isolates in this work phylogenetically clustered together with isolates from Serbian human cases dating from 2002, with 1.9% nucleotide divergence. We determined the level of kinship between seropositive and seronegative animal groups and found no significant difference, suggesting that horizontal virus transmission in the studied population was the same within and among the hatches. Our findings are the first genetic detection of DOBV in rodents in Serbia. We confirm wide and continuous hantavirus presence in the examined parts of the Balkans, underlying the necessity of continual monitoring of hantavirus circulation in A. flavicollis.
    Zoonoses and Public Health 05/2014; 62(2). DOI:10.1111/zph.12136 · 2.07 Impact Factor
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    ABSTRACT: SUMMARY Hantaviruses are endemic in the Balkans, particularly in Serbia, where sporadic cases and/or outbreaks of hantaviral human disease have been reported repeatedly, and evidenced serologically. Here, we present genetic detection of Dobrava-Belgrade virus (DOBV) hantaviral sequences in wild rodents trapped in central Serbia. All the animals were pre-screened serologically by indirect immunofluorescence (IF) test and only those with a positive finding of hantaviral antigens were further tested by polymerase chain reaction. Of the total of 104 trapped animals, 20 were found to be IF positive and of those three were positive for hantaviral RNA: one Microtus arvalis for Tula virus, and one each of Apodemus agrarius and Glis glis for DOBV. Phylogenetic analysis of the obtained sequences implies putative DOBV spillover infection of A. agrarius and G. glis from Apodemus flavicollis. However, future investigations should help to identify the most common natural host and geographical distribution of DOBV in its reservoir hosts in Serbia.
    Epidemiology and Infection 04/2014; 143(02):1-5. DOI:10.1017/S0950268814001010 · 2.49 Impact Factor
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    Dataset: fetchObject
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    Dataset: fetchObject
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    ABSTRACT: In Europe, a continuous programme (SPREAD) has been in place for ten years to study transmission of drug resistant HIV. We analysed time trends of transmitted drug resistance mutations (TDRM) in relation to the risk behaviour reported. HIV-1 patients newly diagnosed in 27 countries from 2002 through 2007 were included. Inclusion was representative for risk group and geographical distribution in the participating countries in Europe. Trends over time were calculated by logistic regression. From the 4317 patients included, the majority was men-having-sex-with-men -MSM (2084, 48%), followed by heterosexuals (1501, 35%) and injection drug users (IDU) (355, 8%). MSM were more often from Western Europe origin, infected with subtype B virus, and recently infected (<1 year) (p<0.001). The prevalence of TDRM was highest in MSM (prevalence of 11.1%), followed by heterosexuals (6.6%) and IDU (5.1%, p<0.001). TDRM was predominantly ascribed to nucleoside reverse transcriptase inhibitors (NRTI) with a prevalence of 6.6% in MSM, 3.3% in heterosexuals and 2.0% in IDU (p = 0.001). A significant increase in resistance to non- nucleoside reverse transcriptase inhibitors (NNRTIs) and a decrease in resistance to protease inhibitors was observed in MSM (p = 0.008 and p = 0.006, respectively), but not in heterosexual patients (p = 0.68 and p = 0.14, respectively). MSM showed to have significantly higher TDRM prevalence compared to heterosexuals and IDU. The increasing NNRTI resistance in MSM is likely to negatively influence the therapy response of first-line therapy, as most include NNRTI drugs.
    PLoS ONE 04/2014; 9(4):e94495. DOI:10.1371/journal.pone.0094495 · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: In Europe, a continuous programme (SPREAD) has been in place for ten years to study transmission of drug resistant HIV. We analysed time trends of transmitted drug resistance mutations (TDRM) in relation to the risk behaviour reported. METHODS: HIV-1 patients newly diagnosed in 27 countries from 2002 through 2007 were included. Inclusion was representative for risk group and geographical distribution in the participating countries in Europe. Trends over time were calculated by logistic regression. RESULTS: From the 4317 patients included, the majority was men-having-sex-with-men -MSM (2084, 48%), followed by heterosexuals (1501, 35%) and injection drug users (IDU) (355, 8%). MSM were more often from Western Europe origin, infected with subtype B virus, and recently infected (<1 year) (p<0.001). The prevalence of TDRM was highest in MSM (prevalence of 11.1%), followed by heterosexuals (6.6%) and IDU (5.1%, p<0.001). TDRM was predominantly ascribed to nucleoside reverse transcriptase inhibitors (NRTI) with a prevalence of 6.6% in MSM, 3.3% in heterosexuals and 2.0% in IDU (p = 0.001). A significant increase in resistance to non- nucleoside reverse transcriptase inhibitors (NNRTIs) and a decrease in resistance to protease inhibitors was observed in MSM (p = 0.008 and p = 0.006, respectively), but not in heterosexual patients (p = 0.68 and p = 0.14, respectively). CONCLUSIONS: MSM showed to have significantly higher TDRM prevalence compared to heterosexuals and IDU. The increasing NNRTI resistance in MSM is likely to negatively influence the therapy response of first-line therapy, as most include NNRTI drugs.
    PLoS ONE 04/2014; 9(4):e94495. · 3.53 Impact Factor
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    ABSTRACT: In Serbia, the first cases of HIV infection were reported in 1985, whereas antiretroviral therapy has been in use since 1987. With this study we aimed to assess the occurrence and pattern of HIV resistance mutations among newly diagnosed patients, in the period 2002-2011. The study prospectively included 181 adult patients. Genotypic HIV-1 drug resistance testing was performed and drug resistance was scored according to the 2009 WHO list for surveillance of drug-resistance mutations (SDRMs). Bioinformatic approach was used for estimation of duration of infection by calculating percentage of ambiguous basecalls per sequence, with the cut-off of 0.47% as delimitator for recent infection. The overall prevalence of TDR found in the study was 8.8% (16/181, 95% CI = 5.5-13.8). Thirty one percent of resistant samples contained multiple SDRMs. In particular, 5/16 patients with resistance carried viral strains with SDRMs to multiple ARV classes, hence one third of resistant strains were multiclass resistant, including also non-B strains. A total of 51.9% of samples (94/181) were classified as recent infection, with the significant increase in the second part of the study period. However, TDR prevalence in recent infection was 6.4% (6/94, 95% CI = 2.9-13.2), not statistically different to the one in non-recent infection. We showed a changing pattern of TDR mutations over the study period, with substantial occurrence of multiclass resistance, across different HIV subtypes. Our results highlight the need for continued surveillance of primary resistance.
    AIDS research and human retroviruses 03/2014; 30(7). DOI:10.1089/AID.2013.0270 · 2.46 Impact Factor
  • BMC Infectious Diseases 01/2014; 14(Suppl 4):O21. DOI:10.1186/1471-2334-14-S4-O21 · 2.56 Impact Factor
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    ABSTRACT: Macrolide resistance in Streptococcus pneumoniae and in group A streptococci (GAS) is a significant problem worldwide. In Serbia, data on the mechanisms of resistance and the corresponding resistance genes in streptococci are largely lacking. Therefore, we analyzed the distribution of macrolide resistance phenotypes and genotypes in 44 macrolide-resistant GAS (MRGAS) and 50 macrolide-resistant S. pneumoniae (MRSP) isolates collected in the same period. The double disk diffusion test and PCR were used to analyze resistance phenotypes and resistance genes, respectively. Among MRSP, the MLSB phenotype dominated, whereas the M phenotype was the most prevalent among MRGAS isolates. Consequently, in MRSP, the ermB gene was the most common (n=40, 80%), followed by the mefA gene (n=7,14%). In MRGAS strains, mefA dominated (n=27, 61%), followed by ermA (n=15, 33%) and ermB (n=3, 7%). In 3 MRSP isolates no resistance genes were detected, while one MRGAS strain with iMLS(B) phenotype harbored both ermA and mefA genes.
    Archives of Biological Sciences 01/2014; 66(1):93. DOI:10.2298/ABS1401093G · 0.61 Impact Factor
  • BMC Infectious Diseases 01/2014; 14(Suppl 4):P4. DOI:10.1186/1471-2334-14-S4-P4 · 2.56 Impact Factor
  • Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 10/2013; 19C:335-336. DOI:10.1016/j.meegid.2013.08.023 · 3.26 Impact Factor
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    ABSTRACT: Tula hantavirus (TULV) belongs to Bunyaviridae family, with negative sense RNA genome. Segmented nature of hantaviral genome allows for genetic reassortment, but the evidence of homologous recombination also exists. In this study we analyzed TULV sequences isolated in Serbia on different occasions and from different rodent hosts: 1987 strain from Microtus subterraneus and 2007 strain from Microtus arvalis. Phylogenetic analysis of both L and S segment sequences is suggestive of geographically related clustering, as previously shown for majority of hantaviruses. Reconstruction of phylogenetic tree for TULV S segment showed that both sequences from Serbia clustered together with sequences from East Slovakia, which had previously been shown to be recombinants (Kosice strain). Exploratory recombination analysis, supported by phylogenetic and amino acid pattern analysis, revealed the presence of recombination in the S segment sequences from Serbia, resulting in mosaic-like structure of TULV S segment similar to the one of Kosice strain. Although recombination is considered a rare event in molecular evolution of negative strand RNA viruses, obtained molecular data in this study support evidence of recombination in TULV, in geographically distant regions of Europe.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 09/2013; 21. DOI:10.1016/j.meegid.2013.08.020 · 3.26 Impact Factor
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    ABSTRACT: Liposarcoma represents the most frequent group of soft tissue sarcomas. The group can be divided into three different classes: (1) differentiated/undifferentiated (WDLPS/DDLPS), (2) myxoid/round cell (MLPS/RCLPS) and (3) pleomorphic liposarcoma (PLS). It has become apparent that p53-p14 and Rb-p16 pathways play important roles in the pathogenesis of various sarcoma types. Molecular studies of the genes involved in these two pathways showed wide variations between the liposarcoma subtypes or even within the same subtype. We sought to examine mutational status of p53 and methylation status of p16 (INK4a) /p14 (ARF) genes in primary and recurrent liposarcoma tumors. There were twelve myxoid (12/18, 66.7 %) and six pleomorphic liposarcoma (6/18, 33.3 %) samples. Immunohistochemical analysis revealed that p53 protein was overexpressed in 3/12 MLPS (25 %) and 6/6 PLS (100 %). Mutational analysis showed that 2/11 MLPS (18.2 %) and 2/6 PLS (33.3 %) contained mutated p53 gene. On the other hand, 3/18 samples (16.7 %) had methylated p16 promoter. However, the frequencies of the p14 (ARF) gene methylation were 83.3 % (10/12) and 50 % (3/6) in myxoid and pleomorphic group, respectively. Overall, 15 out of 18 (83.3 %) samples had either p53 gene mutation or methylated p14 (ARF) promoter. The results from the current study suggest significant impact of the p14 (ARF) gene methylation on the pathogenesis and progression of myxoid and to a lesser extent pleomorphic liposarcoma. Despite the limited number of samples, our study points to necessity of further investigation of p53-p14 and Rb-p16 pathways in liposarcoma.
    Medical Oncology 09/2013; 30(3):682. DOI:10.1007/s12032-013-0682-9 · 2.06 Impact Factor

Publication Stats

673 Citations
114.09 Total Impact Points

Institutions

  • 2014
    • Erasmus MC
      • Department of Virology
      Rotterdam, South Holland, Netherlands
    • University Children's Hospital, Belgrade, Serbia
      Beograd, Central Serbia, Serbia
  • 2000–2014
    • University of Belgrade
      • • Institute of Microbiology and Immunology
      • • School of Medicine
      • • Institute for Infectious & Tropical Diseases
      Beograd, Central Serbia, Serbia
  • 2009
    • University of Leuven
      • Rega Institute for Medical Research
      Louvain, Flanders, Belgium