imagine (Institute of molecular genetics and genetic engineering)
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Expression of autophagy markers in ovarian cancer
Get PDFBackground & objectives: Autophagy is a crucial cellular mechanism that coordinates various physiological processes. Many cancers can activate autophagy and make the tumour more aggressive. In this study, we analysed autophagy in ovarian cancers. Methods: We included 122 patients with ovarian cancers. Tissue microarray was made for immunohistochemical analysis of p62, LC3, and Beclin1 expressions. Their expressions were correlated with tumour histology type, differentiation, and stage. The percentage of positive tumour cells was estimated from the total number of tumour cells. Samples with positive cells were stratified into three ranges of positivity: 50%. Results: There was a strong positive correlation between p62 and LC3 expression, while both markers were in negative correlation with Beclin1. The expression of each analysed marker showed a statistically significant association with tumour histological type, stage, and differentiation (p<0.001). While p62 and LC3 were more prominently expressed in patients with high-grade serous ovarian cancer (HGSOC), Beclin 1 expression was lower in HGSOC and more prominent in other histology types. A higher expression of p62 and LC3 was observed in later tumour stages, while the oppo- site was observed for Beclin1 expression. Tumour differentiation positively correlated with p62 and LC3 expression, and negatively with Beclin1 expression. Conclusion: The expression of p62 and LC3 was more promi- nent in HGSOC in comparison to other histology types, while Beclin1 expression was more prominent in carcinomas other than in HGSOC. While p62 and LC3 expression was associated with higher tumour stages and tumour grades, the opposite was found for Beclin1. Prominent p62 and LC3 expression in combination with weak Beclin1 expression in HGSOC indicate the potential for application of autophagy inhibitors in patients with this tumour subtype
Pharmacogenomics hub in a strengthened IMGGE (PharmGenHUB)
Get PDFAdverse drug reactions kill hundreds of thousands of patients every year in Europe alone.
Hence the development of pharmacogenomics (PGX) to personalise therapies to improve the
outcomes of the treatments is of great importance. The EU-funded PharmGenHUB project will
support the effort of several university partners, coordinated by the Institute of Molecular
Genetics and Genetic Engineering at the University of Belgrade in Serbia to develop PGX
diagnostics, education, training, and translation of PGX knowledge into digital solutions for
medical applications in the Western Balkans (WB) region. The project will employ high-
throughput DNA sequencing to identify WB-specific drug-PGX marker pairs and to design
electronic tools for treatment individualisation in clinical practice.Principal Investigator: Dr Branka ZukicDuration period: 2022-202
Genome-Wide Association Study of COVID-19 Outcomes Reveals Novel Host Genetic Risk Loci in the Serbian Population
Get PDFHost genetics, an important contributor to the COVID-19 clinical susceptibility and severity, currently is the focus of multiple genome-wide association studies (GWAS) in populations affected by the pandemic. This is the first study from Serbia that performed a GWAS of COVID-19 outcomes to identify genetic risk markers of disease severity. A group of 128 hospitalized COVID-19 patients from the Serbian population was enrolled in the study. We conducted a GWAS comparing (1) patients with pneumonia (n = 80) against patients without pneumonia (n = 48), and (2) severe (n = 34) against mild disease (n = 48) patients, using a genotyping array followed by imputation of missing genotypes. We have detected a significant signal associated with COVID-19 related pneumonia at locus 13q21.33, with a peak residing upstream of the gene KLHL1 (p = 1.91 x 10(-8)). Our study also replicated a previously reported COVID-19 risk locus at 3p21.31, identifying lead variants in SACM1L and LZTFL1 genes suggestively associated with pneumonia (p = 7.54 x 10(-6)) and severe COVID-19 (p = 6.88 x 10(-7)), respectively. Suggestive association with COVID-19 pneumonia has also been observed at chromosomes 5p15.33 (IRX, NDUFS6, MRPL36, p = 2.81 x 10(-6)), 5q11.2 (ESM1, p = 6.59 x 10(-6)), and 9p23 (TYRP1, LURAP1L, p = 8.69 x 10(-6)). The genes located in or near the risk loci are expressed in neural or lung tissues, and have been previously associated with respiratory diseases such as asthma and COVID-19 or reported as differentially expressed in COVID-19 gene expression profiling studies. Our results revealed novel risk loci for pneumonia and severe COVID-19 disease which could contribute to a better understanding of the COVID-19 host genetics in different populations
A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors
Get PDFSdox is a hydrogen sulfide (H2S)-releasing doxorubicin effective in P-glycoprotein-overexpressing/doxorubicin-resistant tumor models and not cytotoxic, as the parental drug, in H9c2 cardiomyocytes. The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)/toxicity properties, by a multi- and transdisciplinary in silico, in vitro, and in vivo approach. Doxorubicin was used as the reference compound. The in silico profiling suggested that Sdox possesses higher lipophilicity and lower solubility compared to doxorubicin, and the off-targets prediction revealed relevant differences between Dox and Sdox towards several cancer targets, suggesting different toxicological profiles. In vitro data showed that Sdox is a substrate with lower affinity for P-glycoprotein, less hepatotoxic, and causes less oxidative damage than doxorubicin. Both anthracyclines inhibited CYP3A4, but not hERG currents. Unlike doxorubicin, the percentage of zebrafish live embryos at 72 hpf was not affected by Sdox treatment. In conclusion, these findings demonstrate that Sdox displays a more favorable drug-like ADME/toxicity profile than doxorubicin, different selectivity towards cancer targets, along with a greater preclinical efficacy in resistant tumors. Therefore, Sdox represents a prototype of innovative anthracyclines, worthy of further investigations in clinical settings
Functional prediction and comparative population analysis of variants in genes for proteases and innate immunity related to SARS-CoV-2 infection
No full textZinc(II) Complexes with Dimethyl 2,2 '-Bipyridine-4,5-dicarboxylate: Structure, Antimicrobial Activity and DNA/BSA Binding Study
Get PDFTwo zinc(II) complexes with dimethyl 2,2 '-bipyridine-4,5-dicarboxylate (py-2py) of the general formula [Zn(py-2py)X-2], X = Cl- (1) and Br- (2) were synthesized and characterized by NMR, IR and UV-Vis spectroscopy and single-crystal X-ray diffraction analysis. Complexes 1 and 2 are isostructural and adopt a slightly distorted tetrahedral geometry with values of tetrahedral indices tau(4) and tau'(4) in the range of 0.80-0.85. The complexes were evaluated for their in vitro antimicrobial activity against two bacterial (Pseudomonas aeruginosa and Staphylococcus aureus) and two fungal strains (Candida albicans and Candida parapsilosis), while their cytotoxicity was tested on the normal human lung fibroblast cell line (MRC-5) and the model organism Caenorhabditis elegans. Complex 1 showed moderate activity against both Candida strains. However, this complex was twofold more cytotoxic compared to complex 2. The complexes tested had no effect on the survival rate of C. elegans. Complex 2 showed the ability to inhibit filamentation of C. albicans, while complex 1 was more effective than complex 2 in inhibiting biofilm formation. The interactions of complexes 1 and 2 with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) were studied to evaluate their binding affinity toward these biomolecules
De novo acute myeloid leukemia harboring concomitant t(8;21)(q22;q22);RUNX1::RUNX1T1 and BCR::ABL1 (p190 minor transcript)
No full textDe novo AMLs with typical nonrandom chromosomal abnormalities are often associated with specific morphology subtypes. The t(8;21) is one of the most prominent recurrent cytogenetic aberrations (RCA) in AML, frequently associated with AML with maturation, and is characterized as a good prognostic marker. On the contrary, BCR::ABL1 rearrangement is rarely observed in AMLs, without specific morphology, carrying poor prognosis. Its distinction from blastic transformation of chronic myeloid leukemia has been a matter of long debate. The revised WHO classification (2016) recognized AML with BCR::ABL1(+) as a provisional entity. The occurrence of additional cytogenetic aberrations in AML RCA within the same leukemic clone has been detected, albeit rare cases of BCR::ABL1(+) were reported, mainly as subclones. Those additional cytogenetic and molecular findings seem to significantly affect patient prognosis. Conventional cytogenetic analysis, fluorescent in situ hybridization (FISH), and polymerase chain reaction (PCR) were applied at presentation and during the follow-up of the patient. We present a 34-year-old male patient with de novo AML harboring concomitant t(8;21) and t(9;22) in a single clone. The presence of both t(8;21) and Philadelphia chromosome (Ph+) in the same metaphases but in less than 100% of the analyzed cells, the p190 BCR::ABL transcript type, and absence of splenomegaly support that additional BCR::ABL1(+) is a part of the main leukemic clone. These findings, accompanied with an encouraging outcome of continuous cytogenetic and molecular remission after induction therapy, support BCR::ABL1 being a secondary genetic event in AML with t(8;21)
In vitro colistin susceptibility of pandrug-resistant Ac. baumannii is restored in the presence of selenium nanoparticles
No full textAims To investigate the synergistic activity of colistin and selenium nanoparticles (SeNPs) against pandrug-resistant (PDR) Ac. baumannii. Methods and Results Chequerboard and time-kill assays were employed to explore the potential synergistic interactions between colistin and SeNPs against Ac. baumannii isolates (8), previously determined as colistin-resistant (MIC range 16-256 mu g ml(-1)). Also, whole-genome sequencing (WGS) and gene expression analyses were used to elucidate the mechanisms of colistin resistance. Exceptionally strong synergistic activity (FICI range 0.004-0.035) of colistin and SeNPs against colistin-resistant isolates was revealed. Colistin (0.5 or 1 mu g ml(-1)) used in combination with SeNPs (0.5 mu g ml(-1)) was able to reduce initial inoculum during the first 4 h of incubation, in contrast to colistin (0.5, 1 or 2 mu g ml(-1)) alone. Conclusions These findings propose colistin/SeNPs combination as a new option to fight PDR Ac. baumannii, the therapeutic possibilities of which should be proved in future in vivo studies. Significance and Impact of Study Here we present the first evidence of synergy between colistin and selenium compounds against bacteria in general. Also, WGS and gene expression analyses provide some new insights into Ac. baumannii colistin resistance mechanisms.Accepted version: [https://imagine.imgge.bg.ac.rs/handle/123456789/2823
Eco-friendly dyeing of polyamide and polyamide-elastane knits with living bacterial cultures of two Streptomyces sp. strains
No full textGiven the environmental burden of textile industry, especially of dyeing processes and the volume of synthetic dyes and surfactants, the intensive development of the greener approaches is under way. Herein, an environmentaly-friendly dyeing of polyamide (PA) and PA/Elastane (PA/EA) knits using live bacterial approach in water environment, completely eliminating usage of textile auxiliaries is described. A total of 12 pigment-producing Streptomyces strains were isolated and purified from soil and rizoshere or bark of smoke tree Cotinus coggygria samples. The antibacterial, antifungal and cytotoxic effects of crude bacterial extracts were tested. Antimicrobial effect was obtained by the majority of extracts but only two streptomycetes extracts, 11–5 and BPS51, showed moderate cytotoxicity against HaCaT human cell line. This was the reason to select 11–5 and BPS51 strains for the dyeing of the textile materials. Excellent properties of dyeing wool, silk and PA are achieved initially using live cultures, and the bioprocess is optimized on commercial PA and PA/EA knits used for stockings production. Satisfactory coloration of both knits is achieved with dynamic conditions (culture shaking at 180 rpm over 5–14 days at 30 ºC) giving the best coloration results, except in the case of the PA sample dyed with a bacterial strain 11–5. The prolongation of dyeing time leads to higher color yields independently of fabric and bacteria strain. Although the color differences between the samples before and after washing are observed, washing fastness after three washing cycles can be considered as satisfactory
Genetics of inherited peripheral neuropathies: renewed data
Get PDFNasledne periferne neuropatije čini klinički i genetički heterogena grupa bolesti uzrokovanih aksonalnom
degeneracijom motornih i senzornih neurona perifernog nervnog sistema. Odlikuju se izrazitom
alelskom i lokusnom heterogenošću, a do danas je sa ovom grupom bolesti asocirano više od 1000
mutacija u preko 100 gena. Korišćenjem klasičnih metoda genetičke dijagnostike najveći broj uzročnih
mutacija identifikovan je u 4 gena: PMP22, GJB1, MFN2 i MPZ. Najučestaliji tip, CMT1A, uzrokovan je duplikacijom
1,5 Mb u regionu hromozoma 17p11.2 i čini oko 50% svih naslednih perifernih neuropatija.
Ovom duplikacijom obuhvaćen je gen PMP22 koji kodira protein mijelinskog omotača. Recipročna delecija
ovog regiona asocirana je sa blagom naslednom neuropatijom. Geni GJB1, MFN2 i MPZ se karakterišu
širokim spektrom mutacija, a populacione specifičnosti u vidu značajnih odstupanja u
zastupljenosti pojedinih mutacija se mogu objasniti efektom osnivača.
Upotrebom masivnog paralelnog sekvenciranja omogućen je napredak u genetičkoj dijagnostici
ovih bolesti koji se pre svega ogleda u otkriću novih gena, kao i u otkriću novih mutacija u genima odranije
asociranim sa ovim, ali i sa drugim neurološkim i mišićnim bolestima. Pri tome, verovatnoća za otkrivanje
uzročne mutacije koreliše sa pozitivnom porodičnom anamnezom, prisustvom endogamije, ranim
početkom i demijelinirajućim oblikom bolesti. Takođe, kod nekih bolesnika je identifikovano i prisustvo
strukturnih varijacija koje ne obuhvataju do sada poznate uzroke naslednih perifernih neuropatija, kod
kojih je patomehanizam nastanka bolesti i dalje nepoznat.Inherited peripheral neuropathies (IPN) comprise a clinicaly and geneticaly heterogenous group of
disorders caused by axonal degeneration of motor and sensory nerves of peripheral nervous system. So
far, more than 1000 mutations in more then 100 genes has been found to be associated with IPN. Using
standard molecular-genetic diagnostics, vast number of mutations was identified in following genes:
PMP22, GJB1, MFN2 and MPZ. The most frequent, CMT1A, is caused by 1,5 Mbp duplication of 17p11.2
and represents aproximatelly 50% of all IPN. The duplication includes myelin sheet protein gene PMP22,
whereas reciprocal deletion is associated with a mild hereditary neuropathy termed HNPP. GJB1, MFN2
and MPZ genes harbour various mutations, whose frequencies vary between populations. Significant
differences of individual mutation frequencies could be mostly explained by founder effect.
Massive parallel sequencing methodologies (MPS) brought new discoveries. First of all, new genes
were found to be associated with IPN. Then, new mutations in well-known genes previously associated
with IPN, but also with other neurological and muscular disorders, were found to be disease-causing.
Also, some patients were found to carry structural variants involving regions not previously associated
with IPN, with pathomechanism of the disease yet to be resolved. Generally, a positive genetic diagnosis
was more likely to be reached in cases with positive history of neuropathy and consanguinity, early
onset and/or demyelinating neuropathy