imagine (Institute of molecular genetics and genetic engineering)
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Meta-Analysis of Circulating Cell-Free DNA's Role in the Prognosis of Pancreatic Cancer
Get PDFSimple Summary Pancreatic cancer is an aggressive disease with a poor prognosis. The analysis of cell-free DNA (cfDNA) for genetic abnormalities is a promising new approach for the diagnosis and prognosis of pancreatic cancer patients. In this study, we conducted a systematic review and meta-analysis of studies that reported cfDNA in pancreatic ductal adenocarcinoma (PDAC). In total, 48 studies were included in the qualitative synthesis, while 44 were assessed in the quantitative synthesis, including 3524 PDAC patients. An overall negative impact of cfDNA and KRAS mutations on the overall (OS) and progression free survival (PFS) (HR = 2.42, 95% CI: 1.95-2.99 and HR = 2.46, 95% CI: 2.01-3.00, respectively) were found. The performance of molecular studies to assess the presence of KRAS mutation by liquid biopsy may support global efforts to improve outcomes for PDAC patients. Introduction: The analysis of cell-free DNA (cfDNA) for genetic abnormalities is a promising new approach for the diagnosis and prognosis of pancreatic cancer patients. Insights into the molecular characteristics of pancreatic cancer may provide valuable information, leading to its earlier detection and the development of targeted therapies. Material and Methods: We conducted a systematic review and a meta-analysis of studies that reported cfDNA in pancreatic ductal adenocarcinoma (PDAC). The studies were considered eligible if they included patients with PDAC, if they had blood tests for cfDNA/ctDNA, and if they analyzed the prognostic value of cfDNA/ctDNA for patients' survival. The studies published before 22 October 2020 were identified through the PubMED, EMBASE, Web of Science and Cochrane Library databases. The assessed outcomes were the overall (OS) and progression-free survival (PFS), expressed as the log hazard ratio (HR) and standard error (SE). The summary of the HR effect size was estimated by pooling the individual trial results using the Review Manager, version 5.3, Cochrane Collaboration. The heterogeneity was assessed using the Cochran Q test and I-2 statistic. Results: In total, 48 studies were included in the qualitative review, while 44 were assessed in the quantitative synthesis, with the total number of patients included being 3524. Overall negative impacts of cfDNA and KRAS mutations on OS and PFS in PDAC (HR = 2.42, 95% CI: 1.95-2.99 and HR = 2.46, 95% CI: 2.01-3.00, respectively) were found. The subgroup analysis of the locally advanced and metastatic disease presented similar results (HR = 2.51, 95% CI: 1.90-3.31). In the studies assessing the pre-treatment presence of KRAS, there was a moderate to high degree of heterogeneity (I-2 = 87% and I-2 = 48%, for OS and PFS, respectively), which was remarkably decreased in the analysis of the studies measuring post-treatment KRAS (I-2 = 24% and I-2 = 0%, for OS and PFS, respectively). The patients who were KRAS positive before but KRAS negative after treatment had a better prognosis than the persistently KRAS-positive patients (HR = 5.30, 95% CI: 1.02-27.63). Conclusion: The assessment of KRAS mutation by liquid biopsy can be considered as an additional tool for the estimation of the disease course and outcome in PDAC patients
Supplementary data for article: Kostić, A. Ž.; Milinčić, D. D.; Stanisavljević, N. S.; Gašić, U. M.; Lević, S.; Kojić, M. O.; Lj. Tešić, Ž.; Nedović, V.; Barać, M. B.; Pešić, M. B. Polyphenol Bioaccessibility and Antioxidant Properties of in Vitro Digested Spray-Dried Thermally-Treated Skimmed Goat Milk Enriched with Pollen. Food Chemistry 2021, 351. https://doi.org/10.1016/j.foodchem.2021.129310.
Get PDFSupplementary material for: [https://doi.org/10.1016/j.foodchem.2021.129310]Related to published version: [https://imagine.imgge.bg.ac.rs/handle/123456789/1416
Biotechnologically relevant enzymes in strains of Pseudomonas genus: Identification and recombinant expression of laccases and lipases
Get PDFBakterije roda Pseudomonas imaju sposobnost produkcije i razgradnje širokog spektra jedinjenja. Cilj ove doktorske teze bio je da se u kolekciji sojeva roda Pseudomonas identifikuju i rekombinantno eksprimiraju nove lakaze i lipaze, i evaluira njihov aplikativni potencijal. Sedam sojeva obuhvaćeno je analizom oksidativne i hidrolitičke aktivnosti prema pet različitih supstrata. Kod sojeva Pseudomonas putida F6, P. putida KT2440 i P. putida CA-3, utvrđeno je prisustvo gena koji kodiraju lakaze. Proteini McoCA3, McoKT, Cbp i CopA heterologo su eksprimirani u E. coli domaćinu, prečišćeni i okarakterisani. Pokazana je njihova aktivnost u širokom pH i temperaturnom opsegu kao i visoka termostabilnost. Ispitana je i sposobnost enzima da razgrade boje koje se koriste u tekstilnoj industriji, potencijalne zagađivače voda. Ćelijski ekstrakt koji je sadržao CopA enzim iz P. putida F6 pokazao je najznačajniju aktivnost razgradivši pet od sedam testiranih boja. Kod sojeva P. aeruginosa PAO1 i P. chlororaphis B-561, detektovana je lipolitička aktivnost i utvrđen potencijal za biorazgradnju polimera kao što su polihidroksialkanoati srednjeg lanca i polikaprolakton, a degradacioni potencijal soja B-561 potvrđen je i u modelu komposta. Homologo su eksprimirana tri proteina – LipA, PlcB i LipA, ali je zaključeno da nije došlo do njihove sekrecije. U ovom radu je pokazano da su Pseudomonas sojevi dobar izvor biotehnološki značajnih enzima lakaza i lipaza. Rekombinantna ekspresija lakaza dala je funkcionalne enzime pogodne za primenu u razgradnji sintetičkih boja iz otpadnih voda. Za primenu rekombinantnih lipaza u biorazgradnji polimernih materijala neophodna je optimizacija sekrecije, ali divlji sojevi koji eksprimiraju ove enzime su dovoljno dobri biokatalizatori za njihovu razgradnju.Pseudomonas strains have the ability to produce and degrade a wide range of compounds. The main objective of this thesis was to identify, recombinantly express and characterize novel laccases and lipases from Pseudomonas spp. collection, and to evaluate their application potential. Seven strains were analyzed for oxidative and hydrolytic activity towards five different substrates. Genes encoding laccases were detected in P. putida F6, P. putida KT2440 and P. putida CA-3 strains. Proteins McoCA3, McoKT, Cbp and CopA were heterologously expressed in E. coli, purified and characterized, exhibiting broad temperature and pH range and high thermal stability. The ability of enzymes to degrade textile dyes was also examined. All enzymes proved to be very efficient in degradation of synthetic dyes, with the CopA enzyme from P. putida F6 showing the most significant activity, degrading five out of seven tested dyes. Lipolytic activity was detected in two strains: P. aeruginosa PAO1 and P. chlororaphis B-561. The potential for biodegradation of polymeric materials such as medium chain length polyhydroxyalkanoates and polycaprolactone was demonstrated, while degradation potential of B-561 was confirmed in the compost system as well. Three lipases were homologously expressed – LipA, PlcB and LipA, but they were not secreted. This study showed that Pseudomonas genus is a good source of biotechnologically relevant enzymes. Recombinant laccase expression yielded enzymes suitable for application in the degradation of persistent synthetic dyes from wastewaters. For the application of recombinant lipases in the biodegradation of polymers, optimization of the secretion is necessary, however wild type strains expressing these enzymes are good enough biocatalysts for biodegradation purpose
Phenolic compounds and biopotential of grape pomace extracts from Prokupac red grape variety
No full textPhenolic compounds and biopotential (antioxidant, cellular antioxidant and cytotoxic activity) of grape pomace (GP) skin, seed, stem and whole GP originating from indigenous red grape variety Prokupac were evaluated. The UHPLC-Orbitrap MS4 analysis showed the presence of 75 phenolic compounds (57 non-anthocyanins and 18 anthocyanins), among which considerable content of ethyl gallate was observed and malvidin-3-O-hexoside-(8,8)-methylmethyne-(epi)catechin was identified. The stem had significant content of stilbenoids. The GP seed and the whole GP showed the highest antioxidant activity estimated by ABTS(center dot)+ DPPH center dot and H2O2 scavenging assays that were strongly correlated with the presence of flavan-3-ols, phenolic acids and ethyl gallate. The GP skin exerted cellular antioxidant activity on adenocarcinoma cells (EC50 = 56.4 mg TPCs/mL) which was strongly correlated with the presence of flavonols and anthocyanins. These by-products of Prokupac red grape variety are a notable source of phenolic compounds with good antioxidant activity that can be extensively used in food and pharmaceutical industry
The first insight into the genetic structure of the population of modern Serbia
Get PDFThe complete understanding of the genomic contribution to complex traits, diseases, and response to treatments, as well as genomic medicine application to the well-being of all humans will be achieved through the global variome that encompasses fine-scale genetic diversity. Despite significant efforts in recent years, uneven representation still characterizes genomic resources and among the underrepresented European populations are the Western Balkans including the Serbian population. Our research addresses this gap and presents the first ever targeted sequencing dataset of variants in clinically relevant genes. By measuring population differentiation and applying the Principal Component and Admixture analysis we demonstrated that the Serbian population differs little from other European populations, yet we identified several novel and more frequent variants that appear as its unique genetic determinants. We explored thoroughly the functional impact of frequent variants and its correlation with the health burden of the population of Serbia based on a sample of 144 individuals. Our variants catalogue improves the understanding of genetics of modern Serbia, contributes to research on ancestry, and aids in improvements of well-being and health equity. In addition, this resource may also be applicable in neighboring regions and valuable in worldwide functional analyses of genetic variants in individuals of European descent
Natural bacterial isolates as an inexhaustible source of new bacteriocins
No full textMicroorganisms isolated from various traditionally fermented food products prepared in households without commercial starter cultures are designated as natural isolates. In addition, this term is also used for microorganisms collected from various natural habitats or products (silage, soil, manure, plant and animal material, etc.) that do not contain any commercial starters or bacterial formulations. They are characterized by unique traits that are the result of the selective pressure of environmental conditions, as well as interactions with other organisms. The synthesis of antimicrobial molecules, including bacteriocins, is an evolutionary advantage and an adaptive feature that sets them apart from other microorganisms from a common environment. This review aims to underline the knowledge of bacteriocins produced by natural isolates, with a particular emphasis on the most common location of their genes and operons, plasmids, and the importance of the relationship between the plasmidome and the adaptive potential of the isolate. Applications of bacteriocins, ranging from natural food preservatives to supplements and drugs in pharmacology and medicine, will also be addressed. The latest challenges faced by researchers in isolating new natural isolates with desired characteristics will be discussed, as well as the production of new antimicrobials, nearly one century since the first discovery of colicins in 1925
Tailoring conservation to suit Serbian spruce
Get PDFMediterranean forest tree species are particularly sensitive to the global climate
warming, and two Mediterranean conifers, Sicilian fir and Serbian spruce, stand out
as currently the most threatened ones due to their extremely narrow distribution
range. Both species are IUCN-red listed and protected by the law. Conservation of
Serbian spruce (Picea omorica) was initiated in 1955, when a rigid conservation
strategy was applied, without any intervention allowed in c. 30 remnant populations
scattered within an area of c. 200 km2 in the Western Balkans. Such a strategy,
implemented without any genetic knowledge on the species, remained to the present
days, and the only advancement regarding Serbian spruce conservation over the
past 15 years refers to the inclusion of seven populations (four natural populations
and three planted stands) into the pan-European network of genetic conservation
units (GCUs) for the dynamic conservation of forest genetic resources. In the
meanwhile, a drought-induced physiological weakening of Serbian spruce trees
followed by infestation of Armillaria ostoyae and, in turn, a rapid dieback of trees has
been observed, suggesting that Serbian spruce is losing the race against climate
warming. However, at the same time, genetic knowledge on the species improved
significantly. Whole-population genetic characterizations provided in-depth
understanding of within-population genetic patterns and genetic changes in natural
regeneration following disturbances. Therefore, the conditions for geneticallyinformed
conservation and, eventually, species genetic rescue have been met, and a
ten-year program, worth 10 million EUR and comprising ten work packages, has
been formulated and will be presented.Genomics and Adaptation in Forest Ecosystems. Book of Abstracts. EvolTree Conference 2021, 14 – 17 September 2021, Birmensdorf, Switzerlan
Personalized medicine and COVID-19: the importance of genomic host profiling and bioinformatics
Get PDFNovi koronavirus SARS-CoV-2, uzročnik upale pluća, sposoban je da zarazi ljude i izazove novu bolest COVID- 19 koja je preopteretila zdravstvene sisteme širom planete i izazvala globalnu ekonomsku krizu. Klinička slika i tok bolesti kod pacijenata obolelih od COVID-19 varira od asimptomatske do letalnog ishoda. Kako se radi o istom uzročniku bolesti, individualni genomski profil pacijenta krije odgovor na pitanje medicinske nauke o uzroku ovog fenomena. U radu su sumirana dosadašnja znanja o genetičkim markerima koji su odgovorni za široki spektar kliničkih slika, kao i da li se već može primeniti individualizovan pristup lečenju. Prikazane su dosada istraživane varijante u genima (sa osvrtom na populacione specifičnosti) odgovorne za predispoziciju i odgovor na SARS-CoV-2 virusnu infekciju, farmakogenetičke varijante od značaja za lekove koji se koriste u lečenju pacijenata obolelih od COVID-19, kao i nutrigenetički markeri u genima važnim za metabolizam mikronutrijenata, vitamina D, selena i cinka, koji se takođe koriste u terapiji pacijenata sa COVID-19. Udruženi napor istraživača, multidisciplinarni pristup, dostupnost modernih tehnologija koje imaju kapacitet analize celokupnih genoma, buduće sveobuhvatnije studije sa dobro okarakterisanim grupama pacijenata, kao i razvoj robusnijih bioinformatičkih alata koji koriste mašinsko učenje i napredne statističke metode, omogućiće identifikaciju novih genetičkih markera čoveka povezanih sa COVID-19, bolje razumevanje same patofiziologije bolesti, razvoj prave ciljane terapije kao i istaći značaj nutrigenomike i farmakogenomike za primenu personalizovane medicine u lečenju COVID-19.The new cause of pneumonia, coronavirus SARS-CoV-2, capable of infecting people and causing the new disease
COVID-19, overloaded health systems around the planet and caused a global economic crisis. The clinical
presentation and the course of the disease in COVID-19 patients vary from asymptomatic to lethal. As it
is the same cause of the disease, the individual genomic profile of the patient reveals the answer to the
question of medical science about the cause of this phenomenon. The paper summarizes the current knowledge
about genetic markers responsible for a wide range of clinical pictures, as well as whether an individualized
approach to treatment can already be applied. The variants identified so far in genes (with reference
to population specifics) responsible for predisposition and response to SARS-CoV-2 viral infection, pharmacogenetic
variants of importance for drugs used in the treatment of patients with COVID-19, as well as nutrigenetic
markers in genes important for the metabolism of the micronutrients, vitamin D, selenium and
zinc, also used in the therapy of patients with COVID-19, are presented. The combined effort of researchers,
a multidisciplinary approach, the availability of modern technologies that have the capacity to analyze entire
genomes, future more comprehensive studies with well-characterized patient groups, and the development
of more robust bioinformatics tools using machine learning and advanced statistical methods will
enable the identification of novel human genetic markers associated with COVID -19, better understanding
of the pathophysiology of the disease, development of the proper targeted therapy as well as point out the
importance of nutrigenomics and pharmacogenomics for the application of personalized medicine in the
treatment of COVID-19
Iron status among blood donors deferred due to low haemoglobin level
Get PDFUvod/Cilj. Određivanje nivoa hemoglobin (Hb) je rutinski deo selekcije dobrovoljnih davalaca krvi. Prethodno publikovane studije pokazale su da se nedostatak gvožđa javlja kod redovnih davalaca krvi. Cilj ove prospektivne studije je bio da se utvrdi status gvožđa kod davalaca kod kojih je pre davanja utvrđen nizak nivo Hb i da se proceni stepen korelacije kapilarnih metoda, sa referentnom metodom određivanja Hb iz venske krvi, kao i sa i nivoom feritina. Metode. U periodu od februara 2017. do decembra 2018. godine, bilo je uključeno 200 dobrovoljnih davalaca sa niskim nivoima Hb, starosne dobi 19-64 godine (medijana 39 godina). Hb je određivan primenom metode bakar sulfat, kapilarnom metodom "HemoCue", i iz venske krvi u sklopu određivanja kompletne krvne slike (KKS). Nivo feritina određivan je primenom turbodimetrijske metode. Rezultati. Nizak nivo feritina utvrđen je kod 42,7% muškaraca i 57,3% žena (p = 0,008). U odnosu na nivo feritina lt 12 mg/L, odnosno gt 50 mg/L, zabeležena je značajna razlika između polova (p = 0,023, odnosno p = 0,022). Poređenje vrednosti Hb dobijenih kapilarnim metodama u odnosu na referentne vrednosti Hb, određene iz KKS, pokazalo je da metoda s bakar sulfatom daje lažno niske vrednosti Hb kod 10,5% slučajeva (p lt 0,001). Vrednosti Hb dobijene metodom "HemoCue-a" značajno su korelirale sa vrednostima Hb iz KKS, dok korelacija između nivoa feritina i Hb, određenog pomoću obe kapilarne metode, nije uočena. Zaključak. Kod 51,5% naših davalaca krvi koji su vraćeni zbog niskih vrednosti Hb utvrđen je snižen nivo feritina. Na osnovu ovih rezultata neophodno je odrediti algoritam za detekciju nedostatka gvožđa, dok je kapilarna metoda (HemoCue) pogodnija metoda za testiranje Hb pre davanja krvi.Background/Aim. Haemoglobin (Hb) determination is a routine part of the blood donor selection process. Previously reported studies have revealed that iron deficiency is common in frequent donors. This prospective investigation was aimed at examining iron status among blood donors with low circulating Hb and evaluating correlation between Hb values determined by capillary methods and those obtained by reference method from venous blood count (BC), as well as ferritin level. Methods. Between February 2017 and December 2018, 200 consecutively recruited regular blood donors with low Hb, aged 19 to 64 years (median 39), were included. Hb level was determined using the copper sulphate method, the HemoCue capillary method, and also from venous blood within the complete blood count (CBC) test. Plasma ferritin was determined turbidimetrically. Results. In 42.7% of men and 57.3% of women, ferritin concentration was low (p = 0.008). The relative numbers of males and females, with levels lt 12 mg/L (p = 0.023) or gt 50 mg/L (p = 0.022), differed. Comparison of the values obtained with the capillary methods with reference Hb levels obtained from the CBC test showed that the copper sulphate procedure gave false fails in 10.5% of cases (p lt 0.001). Hb values from HemoCue were significantly correlated with Hb values from the CBC test, but no correlation was observed between ferritin levels and Hb levels determined by both capillary method. Conclusion. Low ferritin was observed in 51.5% of Serbian blood donors deferred due to low Hb. Based on our results, the determination of the algorithm in the iron deficiency detection is necessary, while the capillary method (HemoCue) represents a more convenient method for Hb testing prior to blood donation
Synthesis and characterization of polyethylene terephthalate (PET) precursors and potential degradation products: Toxicity study and application in discovery of novel PETases
No full textPolyethylene terephthalate (PET) is widely used material and as such became highly enriched in nature. It is generally considered inert and safe plastic, but due to the recent increased efforts to break-down PET using biotechnological approaches, we realized the scarcity of information about structural analysis of possible degradation products and their ecotoxicological assessment. Therefore, in this study, 11 compounds belonging to the group of PET precursors and possible degradation products have been comprehensively characterized. Seven of these compounds including 1-(2-hydroxyethyl)-4methylterephthalate, ethylene glycol bis(methyl terephthalate), methyl bis(2-hydroxyethyl terephtahalate), 1,4-benzenedicarboxylic acid, 1,4-bis[2-[[4-(methoxycarbonyl)benzoyl]oxy]ethyl] ester and methyl tris(2-hydroxyethyl terephthalate) corresponding to mono-, 1.5-, di-, 2,5- and trimer of PET were synthetized and structurally characterized for the first time. In-silico druglikeness and physico-chemical properties of these compounds were predicted using variety of platforms. No antimicrobial properties were detected even at 1000 mg/mL. Ecotoxicological impact of the compounds against marine bacteria Allivibrio fischeri proved that the 6 out of 11 tested PET-associated compounds may be classified as harmful to aquatic microorganisms, with PET trimer being one of the most toxic. In comparison, most of the compounds were not toxic on human lung fibroblasts (MRC-5) at 200 mg/mL with inhibiting concentration (IC50) values of 30 mg/mL and 50 mg/mL determined for PET dimer and trimer. Only three of these compounds including PET monomer were toxic to nematode Caenorhabditis elegans at high concentration of 500 mg/mL. In terms of the applicative potential, PET dimer can be used as suitable substrate for the screening, identification and characterization of novel PET-depolymerizing enzymes.Related to Supplementary material: [https://imagine.imgge.bg.ac.rs/handle/123456789/1733]Related to accepted version: [https://imagine.imgge.bg.ac.rs/handle/123456789/1732